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Growth fractions detected by a monoclonal antibody, Ki-67, were examined in 40 human breast cancer tissues and the results compared with the immunocytochemical reactivities of epidermal growth factor receptor (EGFR) and estrogen receptor (ER). The proportion of proliferating cells displaying Ki-67 positive staining was significantly higher in the EGFR positive tumors than in the EGFR negative tumors (p less than 0.01). The average percentage of Ki-67 positive cells in the EGFR positive tumors was 19.9 per cent, whereas that in the EGFR negative tumors was 8.0 per cent. By contrast, an inverse relationship between the proportion of proliferating cells and ER positive cells detected by anti-ER monoclonal antibody was observed. This data indicated the difference in growth fractions with relation to the EGFR and ER status of breast cancer.

The efficacy of Bestatin as adjuvant immunochemotherapy for patients with resectable gastric cancer was investigated. Ninety-six patients with similar background factors were randomized into two groups; a control group and an experimental group, the patients in the experimental group receiving a daily oral dose of 60 mg Bestatin over a long period. All 96 patients were treated with a bolus intravenous injection of mitomycin C (MMC) plus oral administration of tegafur (FT-207, FT). The survival rate of the patients in the MMC + FT + Bestatin group was more favorable than that of the patients in the MMC + FT group, but the difference was not statistically significant. The survival rates of the MMC + FT + Bestatin group patients in the stratification of stage III + IV and positive histological serosal invasion, ps(+), were significantly superior to those of the MMC + FT group patients (Logrank test: p less than 0.05). Moreover, in patients with positive histological serosal invasion, the recurrence of peritoneal dissemination was significantly suppressed in the MMC + FT + Bestatin group.

In order to predict natural resistance to Adriamycin (ADM), the amplification of multidrug resistance gene 1 (MDR1) was investigated in 50 human cancer specimens using Southern blot analysis. Genomic DNA was extracted from both human solid tumors and adjacent normal tissues for the analysis. MDR1 gene amplification was not observed in any of the patients tested, including 5 patients in whom ADM was not clinically effective. On the other hand, chemosensitivity tests performed on the tumor cells of these 5 patients indicated resistance to ADM. Our results therefore indicate that MDR1 gene amplification is rarely seen among clinical samples and that conventional chemosensitivity tests might be more useful for the prediction of ADM resistance in cancer patients than the analysis of MDR1 gene amplification.

In order to evaluate the efficacy of combined immunochemotherapy with mitomycin-C, tegafur, PSK and/or OK-432 as an adjunct for curatively resected gastric cancer, a prospective randomized controlled study using the envelope method was performed, in which 266 institutions from around Japan participated. The 3 year survival rates for all cases, and for ps(+).n(+) cases, were insignificantly higher in the immunochemotherapy groups receiving PSK and/or OK-432 than in the control group. However, because 28.2 per cent of the cases were excluded from the final statistical analyses, the results of this study may have questionable statistical credibility. Changes in the stimulation index (SI) suggest that the administration of PSK may result in an inhibition of the immunosuppressive activity of cancer patients. The high SI group showed a significantly higher 4 year survival rate than the low SI group.

The population of peripheral blood lymphocytes expressing surface receptors for a lectin, wheat germ agglutinin (WGA), which has been shown to recognize the same receptors as the soluble immune suppressor factor (SISF) elaborated from suppressor cells on the lymphocyte surface, was analyzed by using fluorescein isothiocyanate-conjugated WGA on flow cytometry in cancer patients. It was found that the populations of WGA+ lymphocytes in cancer patients were significantly higher than those in either normal volunteers or patients with benign disease and increased with progress of the tumor. The populations decreased after treatment in patients who underwent curative resection of the tumor and in responders of immunochemotherapy but not in those who received non-curative surgery or in non-responders. It was suggested that the increase of receptors for SISF on the lymphocyte surface might play an important role in the negative regulation of immune responses in cancer patients and that WGA might be a useful parameter for immunosuppression.

Nuclear DNA ploidy pattern was examined in 22 breast carcinomas with a tumor mass of up to 2.2 cm and compared with the clinical and histological parameters of the malignant potentiality of breast carcinomas. The 22 carcinomas were divided into 11 aneuploid and 11 near-diploid carcinomas. It was found that the histological type, histological grade, nuclear grade, mitotic index and lymphatic invasion were either only slightly, or not correlated at all with the DNA ploidy pattern. Nevertheless, lymph node metastasis and negative estrogen receptor status was more frequently seen in the patients with aneuploid carcinoma than in those with near-diploid carcinoma.

A combination of MFC (Mitomycin-C, 5-FU and Cytosine arabinoside) was administered to 32 gastric cancer patients and study was made of the therapeutic efficacy in relation to the histological pattern. In evaluation based on the degree of cancer cell infiltration (INF), chemotherapy was more effective in cases with INF alpha and beta than those with INF gamma. As for the grade of follicular hyperplasia in regional lymph nodes of gastric cancer, the higher was the grade, the more effective was the chemotherapy. However, a significant relationship could not be observed between histological pattern of stromal reaction of the gastric cancer and clinical effects of chemotherapy. The grade of lymphocyte infiltration or connective tissue reaction in the stroma was not related with the therapeutic effects. No relationship was also obtained between the grade of sinus histiocytosis of lymphoid reaction in the lymph nodes and therapeutic effects.

In order to examine the efficacy of adjuvant chemotherapy employing Mitomycin C (MMC) and carmofur (HCFU) for patients with noncuratively resected colorectal carcinoma, a cooperative study was performed by 54 institutions in the Kyushu and Chugoku areas in Japan. The prospective randomized controlled study consisted of two groups, one receiving only MMC and the other receiving MMC as well as HCFU. Out of an original total of 200, 170 cases were evaluable. Concerning the 30-month survival rate, a better result was observed in the MMC + HCFU group than in the MMC only group (Z-test: p less than 0.05). Significantly better survival rates were obtained in those cases with disseminating peritoneal metastasis, hepatic metastasis and Stage V cancer in the MMC + HCFU group as when compared with the MMC only group (generalized Wilcoxon test: p less than 0.05). No significant side effects due to the combined administration of HCFU were recognized. The combined administration of MMC and HCFU were recognized. The combined administration of MMC and HCFU was suggested to be a safe and effective adjuvant chemotherapy in noncuratively resected cases of colorectal carcinoma.

The effectiveness of Levamisole combined with Mitomycin-C, FT-207 and PS-K for treating gastric cancer was investigated in a prospective randomized controlled study. All patients had undergone gastrectomy during the years from August 1977 to November 1980. Five year survival rates revealed no difference between groups given or not given Levamisole. In those with positive lymph node metastases plus obvious serosal invasion, there was a significant elevation in the survival rate at four years after gastrectomy. The effectiveness of Levamisole was confirmed by postoperative changes in the PPD skin test, lymphocyte blastogenesis to PHA and serum inhibition index.

The clinical efficacy of intratumoral (IT) OK-432 immunotherapy in advanced cancer patients was investigated. Furthermore, the infiltration of lymphocyte subsets into the tumor tissues after the IT administration of OK-432 was also immunohistologically examined in order to analyze the mechanism of action of OK-432 immunotherapy. Forty-four patients with advanced cancer were treated with IT OK-432 immunotherapy. Ten KE (1 mg) of OK-432 was given either daily or on every second day and repeated as often as possible, the mean frequency of OK-432 injections being 18.1 +/- 14.5 times, ranging between 5 and 25 administrations. Thirty-one of the 44 patients were evaluable, 3 of whom (9.7 per cent) developed a partial response and 5 (16.1 per cent) a minor response. Intratumoral OK-432 immunotherapy, however, did not necessarily prolong the survival time. Leu 1, 3 and 7 reactive cells infiltrated into the tumor tissues treated by OK-432 injection, more frequently, when compared with cells which had been treated by recombinant TNF injection. Thus, it was suggested that IT OK-432 immunotherapy might be effective for the local control of tumor growth through the host mediated action, and that, in combination with systemic therapy, may enhance the clinical effects and prolong the survival time in advanced cancer patients.

Using the human tumor clonogenic assay technique, the effects of Mitomycin C plus either alpha-interferon or gamma-interferon were studied against five human tumor xenografts serially transplanted into nude mice (three gastric and two colon cancers). When the survival fraction found with the drug combination was smaller than the multiplication of survival fractions with either drug alone, the combined effect was defined as synergism. Similarly, antagonistic effect was defined when the survival fraction of drug combination was larger than the larger one observed in either interferon or Mitomycin C alone. Four out of five human tumor xenografts (three gastric and one colon cancers) showed synergistic effects in combination of alpha-interferon with Mitomycin C. Though two gastric cancer xenografts exhibited synergistic effects in combination of gamma-interferon with Mitomycin C, antagonistic effects, which was not found in combination of alpha-interferon with Mitomycin C, were observed in one gastric cancer and one colon cancer xenografts.

To evaluate the effect of operative stress on a tumor growth, thoracotomy and/or laparotomy were performed 48 hours after the intraperitoneal inoculation of Sato lung cancer cells in Donryu rats. The survival time and the spread of the tumor were examined. Thoracotomy and laparothoracotomy reduced significantly the survival time of the inoculated rats as compared with the control but no significant difference was observed between the two test groups subjected to operative stress. No difference was observed in the spread of the tumor between the test groups and the control. These results indicated that the operative stress increased only the number of metastatic foci and did not change the characteristics of the tumor cells.

To clarify the effects of oxygen tension on colony formation of fresh human tumor cells, we examined 25 fresh human tumor samples (sixteen gastric cancers, three colon cancers, three breast cancers, one esophageal cancer, one leiomyosarcoma and one malignant lymphoma), using the human tumor clonogenic assay (HTCA) technique. Three different oxygen tensions (2 per cent, 5 per cent, 20 per cent) were tested. At 5 per cent O2, which is considered to be physiological oxygen tension, 19 out of 26 tumors (13/16 in gastric cancer, 2/3 in colon cancer, 1/3 in breast cancer, 1/1 in esophageal cancer, and 1/1 in leiomyosarcoma) showed significant increases of plating efficiencies as compared to those at 20 per cent O2. On the other hand, decreases in plating efficiencies were observed at 2 per cent O2 in seven out of 12 tumors as compared to 20 per cent O2 and eight out of 12 tumors, as compared to 5 per cent O2.

A transabdominal resection for esophagocardial cancer and cervical esophagojejunal anastomosis was devised by our group. Since 1973, seventy-six such operations have been done and the long-term follow up study showed a good survival rate. These findings justify our efforts to perform the operative procedure without opening the chest. To obviate cervical esophagocutaneostomy which is indispensable to this method and may contribute to complications, we altered the operative procedure to blunt dissection of the esophagus and retrosternal esophagojejunostomy, using the EEA stapler. Details of the operative procedures used for nine patients are reported herein.

Long-term adjuvant immunochemotherapy carried out on the gastrectomized patients with stomach cancer was reported. The protocol comprises the administration of large-dose of Mitomycin-C (20+10) mg just after gastrectomy and the long-term administration of PSK, FT-207 or (PSK+FT-207). Almost no side effects were observed. According to the studies on the immunological parameters, the increased reactions in PPD skin test and lymphocyte blastogenesis induced by PHA and PWM were observed remarkably in group (P+F) 3 or 6 months after gastrectomy. As for the survival rate, group (P+F) showed the most preferable results at one year in stage IV, at two years in stage III and at three years in all the stages, respectively after gastrectomy.

The effects of intraperitoneal administration of OK-432 on tumor cells in ascites, in relation to the infiltration of effector cells and on the immune responses of the host, particularly, with regard to immune suppressive mechanisms, were investigated in 25 patients with cancerous ascites. The effects of OK-432 depended on frequency of the repeated and continuous administrations through a tube placed in the peritoneum during laparotomy. Infiltrations of neutrophils and lymphocytes were observed in the ascites within a short period after the administration and monocyte infiltration followed. Disappearance of tumor cells correlated well with the infiltration of these cells. No marked changes in the proliferative responses of peripheral blood lymphocytes were noted and decreases in serum inhibitory factor levels in sera were observed in patients given larger doses of OK-432. A marked reduction in Concanavalin-A-induced suppressor cell activities was observed after OK-432 administration. OK-432 administration probably leads to a disappearance of tumor cells by enhancing peritoneal effector cell activities and by inhibiting the induction of suppressor cell activities, in a dose dependent manner.

Comparative studies between the in vitro human tumor clonogenic assay (HTCA) and nude mouse-isotope assay (NM-IA), in which the final evaluation was made with 3H-thymidine incorporations of tumor cells transplanted into nude mice, were performed simultaneously on 60 fresh human tumors. Tissues used included 27 gastric cancers, 10 breast cancers, 7 colorectal cancers, 4 gallbladder cancers, 4 sarcomas, 3 lymphomas, and 5 other tumors. Mitomycin C (MMC), 5-fluorouracil (5-FU), cyclophosphamide (CPM) and adriamycin (ADM) were tested. The overall evaluable rate was 66.7 per cent in HTCA and 83.3 per cent in NM-IA, respectively. When the per cent survival in HTCA and the per cent inhibition in NM-IA less than 50 per cent was defined as drug sensitive, the drug sensitive rates of MMC, 5-FU, CPM, and ADM were 23.1, 16.7, 11.8, and 27.8 per cent in HTCA and 17.6, 18.4, 22.4, and 25.5 per cent in NM-IA, respectively. Although statistically significant correlations between the results of HTCA and those of NM-IA were obtained for MMC and ADM, no correlation was observed for 5-FU and CPM. The overall predictive accuracy rate of clinical response was 83.3 per cent (true positive rate 50 per cent and true negative rate 92.9 per cent) in HTCA and 76.0 per cent (true positive rate 37.5 per cent and true negative rate 93.8 per cent) in NM-IA, respectively.

In order to estimate the combined effects of UFT with other anticancer agents, a nude mouse experimental system (NMES), and a subrenal capsule assay (SRCA) were investigated. Three human tumor xenografts were serially transplanted into nude mice and examined. These were; EH-1 established from esophageal cancer, SH-6 from gastric cancer and CH-3 from colon cancer. The antiproliferative effects were estimated in accordance with the NCI therapeutic protocol. Significant antiproliferative effects were obtained only in NMES and a positive relationship was observed between the two assays (p less than 0.05). In the groups which were treated with a single agent, positive tumor responses were observed against mitomycin C in SH-6, against cis-DD platinum in SH-6 and EH-1, and against adriamycin in EH-1, respectively. On this study the synergistic, additive and subadditive effects were defined as the positive combined effects. The combination of MMC and UFT produced positive combined effects for all xenografts in both assays.

In a retrospective cohort study, a total of 235 (2.32 per cent) second malignancies were clinically observed in 10,138 patients during the average 8.8-year follow-up period. The patients had undergone gastrectomy for gastric cancer during 1960-1975, in seven different institutions. This observed number was smaller than the expected one of 340.9 (p less than 0.01). Among the 235, cancers of the gastrointestinal tract (111) were the most frequent and followed by respiratory (54) and urogenital (25) cancers. Twelve cases of malignant lymphoma and five of leukemia were also noted. With regard to adjuvant chemotherapeutic agents such as mitomycin-C (MMC), 5-fluorouracil (5FU) or its derivative Tegafur, and cyclophosphamide (EDX), no significant differences in the rate of second malignancies were obtained between the chemotherapy and non-chemotherapy groups. The occurrence rate of second malignancies tended to be higher in the Billroth II group than in the Billroth I, the significance of which is yet to be determined.

The variation in estrogen receptors (ER) between primary and regional nodal metastatic lesions was examined by an estrogen receptor immunocytochemical assay (ER-ICA) in 25 mammary carcinoma patients. The ER status was evaluated in terms of the percentage of ER positive stained cells, staining intensity and distribution of those stained cells. The overall ER status was consistent in both sites, however, the percentage of ER positive cells and the staining intensity were not always consistent. A decrease in the percentage of ER positive cells and staining intensity was demonstrated in the nodal metastatic lesions of 4 and 3 cases out of a total 14 ER positive cases, respectively. The mean percentage of ER positive cells in the nodal metastatic lesions was 57 per cent compared with 73 per cent in primary lesions. Thus, a tendency of both the percentage of ER positive cells and the staining intensity to decrease in nodal metastases as when compared with primary lesions in breast cancer was demonstrated.

An unusual case of primary esophageal melanoma is reported herein. A 68 year old man who had experienced occasional dysphagia for about one month without suffering any weight loss was admitted to our department. An esophagogram revealed two lobulated masses and esophagoscopy showed a pigmented tumor in one of the masses. Curative surgery was thus performed through a right thoracotomy. The macroscopic appearance of the resected specimen was very unusual and it was subsequently proven to be primary malignant melanoma of the esophagus by histological examination. Postoperatively, cyclophosphamide and interleukin-2 were administered intravenously, followed by lymphokine-activated killer therapy. However, multiple liver metastases were found on a CT scan, 3 months after the operation and he died about 1 month later. The operative indications for primary malignant melanoma of the esophagus are discussed in this report.

In the chemotherapy for gastric cancer, the most sensitive anticancer agent against individual tumors should be prescribed. The establishment of a sensitivity test using nude mice as an in vivo model is urgently awaited by clinicians and researchers alike. Seventy-three tumors derived from human gastric cancer were transplanted subcutaneously into nude mice and these mice were then treated intraperitoneally with anticancer agents. Mitomycin C (MMC), 5-fluorouracil (5-FU) and cyclophosphamide (CPM) were used. The doses given were 3 mg/kg of MMC, 75 mg/kg of 5-FU and 200 mg/kg of CPM. IN 52 of the 73 cancers, chemosensitivity was evaluated by the microscopic changes in the tumors. The rate of positive sensitivity against gastric cancer was 42.2% in MMC, 34.6% in 5-FU and 30.8% in CPM, respectively. The sensitivity of each agent tested by this method indicated a good correlation with the clinical therapeutic effects. Our results suggest the feasibility of evaluation of the sensitivity of various agents from the microscopic changes on tumors transplanted into nude mice.

Estrogen receptor (ER) expression was investigated by ER-immunocytochemical assay (ICA) and the dextran coated charcoal (DCC) method in 10 recurrent or primary-advanced breast cancer patients treated with endocrine or chemo-endocrine therapy. In 6 of these 10 patients, ER was examined both before and after treatments by the 2 methods. ER contents measured by the DCC method were found to be decreased after treatments, however, no change in the immunoreactivities of ER-ICA was observed. In the remaining 4 patients, the ER of new lesions refractory to endocrine or chemo-endocrine therapy was examined. ER status was determined as negative in 3 of the 4 patients by the DCC method, whereas by ER-ICA, the proportion of ER stained cells was about 70 per cent, those cells being diffusely distributed in the section. A discrepancy between ER-ICA and the DCC method was thus demonstrated in breast cancer patients treated by endocrine therapy.

In a retrospective cohort study, a total of 22 (0.22 per cent) carcinomas of the gastric remnant were clinically observed, as second malignancies, in 7,672 patients during the average of a 9.4-year follow-up period. All had undergone distal subtotal gastrectomy for gastric cancer from 1960-1975 in seven different institutions. Of 22 carcinomas of the gastric remnant, 5 were at the anastomotic site, 14 distant from the anastomosis; the location was unknown in three. All five carcinomas of the anastomotic site occurred after Billroth II operation. Time intervals between the first operation and the occurrence of second cancer varied from two to 21 years. With regard to the administration of adjuvant chemotherapeutic agents such as mitomycin-C (MMC), 5-fluorouracil (5FU) or its derivative Tegafur, no significant differences in the rate of second malignancies were obtained between the chemotherapy and non-chemotherapy groups. The occurrence rate of cancer of the gastric remnant between Billroth I and Billroth II groups showed no statistically significant difference, although it did tend to be slightly higher in the latter.

A study on surgical biopsy for treatment of breast cancer was done by sending out questionnaires to membership institutions of the Japan Mammary Cancer Society. The problems related to diagnostic biopsy of the breast mainly concern the following two points; the first is the methodology, incisional or excisional, the second, whether delay between biopsy and radical mastectomy influences survival. The prognostic features in patients with excisional biopsy were significantly superior. The prognostic features in patients with excisional biopsy were significantly superior. As for the lapse of time between biopsy and radical mastectomy, 14 days were considered safe, and under conditions such as T2 or n0, this maximum was 7 days.

Transabdominal resection of esophagocardial cancer and reestablishment of alimentary continuity using a by-pass method with gastric tube or colonic segment have been performed in 40 patients including 5 with squamous cell carcinoma. Of 40, 4 cases were at stage II, 8 cases at stage III and 28 cases at stage IV. Major factors which determined the stage were peritoneal dissemination and serosal invasion in the stage IV patients. The removal of the lesion was performed curatively in 13 (33%). Major complications in the post-operative course were the leakage of anastomosis and respiratory failure. Nine of 40 cases (23%) were combined with minor leakage at the cervical anastomosis, but such did not interfere with the resumption of oral ingestion of food. The 3 year survival rate was 46% in the cases of stages (II + III) and 16% in the cases of stage IV, indicating moderately high rates as compared with that in cases of cancer located in the upper third of the stomach with the limited proximal extension within the esophagocardial junction.

The resected stomach from a 58-year old male patient showed a 4.3 X 3.2 cm, depressed (II c) lesion in the body, histology of which revealed moderately differentiated tubular adenocarcinoma with invasion reaching the submucosa. Widespread metastases of lymph nodes including superior mesenteric and para-aortic ones were noted. The patient once worked in a mustard gas (Yperite) factory, and had chronic bronchitis. The exposure to this toxic substance was discussed in relation to the diffuse metastases of cancer.

Fifty-three tumor specimens, including thirty-one stomach and seven esophageal cancers, were examined to determine the individual tumor sensitivity to chemotherapeutic agents. Using the subrenal capsule assay (SRC assay), tumor specimens were implanted under the renal capsule of male, 8 week old ddY mice, after cutting the tissues into 1.5 mm cubed fragments. Following the implantations, chemotherapeutic agents were injected daily for 3 days and the relative variations of tumor weights were calculated. An 84.9 per cent of the total evaluability rate was obtained and implanted tumor specimens responded to chemotherapeutic agents in 26.7 per cent. The correlation rate between tumor sensitivity in SRC assay and clinical responses was obtained in 72.9 per cent. The predictive accuracy rate of the clinical responses was 50.0 per cent, while 100 per cent of the prediction rate of clinical resistance was obtained. With regard to upper gastro-intestinal cancers, 83.9 per cent of the evaluability rate and 18.2 per cent of response rate in SRC assay were obtained. These results indicate that this assay is equivalent to other procedures for predicting individual tumor sensitivity.

The antiproliferative effects of the fluoropyrimidine derivatives, 5-fluorouracil (5-FU), 1-(2-tetrahydrofuryl)-5-fluorouracil (Tegafur), UFT, 1-hexylcarbamoyl-5-fluorouracil (HCFU), and 5'-deoxy-5-fluorouracil (5'DFUR), were investigated in a 4 day subrenal capsule assay. The antiproliferative effects against two human tumor xenografts established in athymic mice were examined after treatment with three different doses of each anticancer agent, and the adequate dose of each anticancer agent in this experimental system was estimated as: 473 mg/kg for Tegafur, 433 mg/kg for UFT, 50 mg/kg for HCFU and 185 mg/kg for 5'DFUR, respectively. A comparative study of the antiproliferative effects of fluoropyrimidine derivatives was carried out against 7 xenografts. According to our criteria of positive tumor response, the effective rates were: 1 of 7 (14.3 per cent) by 5-FU, 2 of 7 (28.6 per cent) by Tegafur, 2 of 7 (28.6 per cent) by UFT, 1 of 6 (16.7 per cent) by HCFU, and 1 of 4 (25.0 per cent) by 5'DFUR, respectively. Although no statistical differences were demonstrated between the agents, the utility of a chemosensitivity test before clinical use was suggested.

To elucidate the role of the spleen on immunosuppression of gastric and esophageal cancer, suppressor cell activities of spleen cells (SCs), splenic vein lymphocytes (SVLs) and peripheral blood lymphocytes (PBLs) were investigated. Concanavalin-A induced suppressor cell (Con-AS) activity of SCs was significantly higher in patients with gastric cancer than in those with benign diseases. Higher Con-AS activity of SCs was observed in esophageal cancer patients with tumors located in the lower portion of the esophagus. In comparison with suppressor activities of SCs and SVLs, the decrease of the predominance of suppressor precursors in SCs and the increase of the spontaneously activated suppressor cells in SVLs were noted with the advance of the tumors. Culture supernatants from splenic adherent cells significantly induced suppressor cell activities as well as did sera from splenic venous blood. From these results, it is concluded that the generation of suppressor precursors in the spleen is dependent on the location of tumors and that the maturation of suppressor cells occurs in the spleen by factors released from splenic adherent cells, then migrates into the peripheral blood.

A new operative technique for esophagocardial cancer was reported with resection and re-establishment of alimentary continuity at cervical esophagus which obviates thoracotomy but still retains adequate removal of the lesion. Ten cases of esophagocardial cancer thus treated were presented and the clinical data were analyed. The distance between esophageal stump and esophagocardial junction measured on the resected specimen ranged from 3.0 to 6.7 cm with an average of 5.1 cm. No remaining tumor cells were detected microscopically on the oral cut margin of the specimen in all cases. To compensate for the inadequated lymph node dissection intensive postoperative adjuvant irradiation and/or chemotherapy was advocated.

In order to evaluate the combination of immunochemotherapy with mitomycin C (MMC), futraful (FT) and PSK, as an adjuvant to surgery for curatively resected gastric cancer, a randomized controlled study by the sealed envelope method was performed with the participation of 97 hospitals in the Kyushu and Chugoku districts of Japan. The MMC + FT + PSK group showed a significant increase in 5 year survival from the other groups (p less than 0.05). Moreover the survival rate was significantly higher in the MMC + FT + PSK group than in the MMC + FT group (p less than 0.01). According to the analysis on stratification, the MMC + FT + PSK group showed the best survival rate in cases with positive lymph node metastases, positive serosal invasion and positive lymph node metastases plus serosal invasion, and in cases of undifferentiated carcinoma by histological type and in those with a preoperative positive PPD reaction (p less than 0.01 or p less than 0.05). Thus, the combination of MMC, FT and PSK was indicated to be useful as an adjuvant immunochemotherapy for those patients with gastric cancer submitted to curative resection.

Spleen cells (SC), splenic venous blood lymphocytes (SVL) and peripheral blood lymphocytes (PBL) from gastric and esophageal cancer patients were simultaneously tested for natural killer (NK) and nonspecific suppressor (Ts) cell activities. Furthermore, the influence of Ts activity on the augmentation of NK activity by a biological response modifier (BRM) was also investigated. Positive Ts activities were frequently detected in the SC, SVL and PBL of advanced cancer patients. The NK activities of SC and SVL were maintained even in advanced cancer patients, though significantly depressed NK activities were observed in the PBL of advanced cases. Cancer patient SC, SVL and PBL with positive Ts activity showed low NK activities. Moreover, the NK activities of SVL and PBL were low in the patients with positive Ts activity in SC. The NK activity of normal control PBL was strongly augmented by interleukin 2, interferon and OK-432. These BRMs exhibited comparable capacities to augment the NK activities of SC, SVL and PBL with negative Ts activity in cancer patients, however, the effects of these agents seemed to be low in cells with a positive Ts activity. These results suggested that NK activity might be regulated by nonspecific suppressor cells and the presence of suppressor cells might affect the augmentation of NK activity through BRM in circulating blood lymphocytes and also in spleen cells.

In 501 Japanese patients with gastric cancer, the relationships between preoperative lymphocyte proliferative (LP) responses to mitogens and prognosis of patients were evaluated. Peripheral blood lymphocytes were cultured in the presence of either autologous or allogeneic serum and their LP responses to phytohemagglutinin (PHA) and pokeweed mitogen were investigated. An apparent inverse relationship between LP responses and stage of the disease was found in LP responses to PHA in the presence of autologous serum. The survival rate of patients with higher responses was significantly greater than those with lower responses, when LP responses to PHA in the presence of autologous serum served as the criterion. Probabilities of staging which were computed on the basis of LP response to PHA affirmed the reciprocal relationship between LP responses and stage of the disease. From these results, it is concluded that evaluation of LP responses may be a valuable tool in the assessment of the clinical stage and in the prediction of prognosis.

The in vitro lymphocyte response to PHA was determined in patients with gastric cancer in various stages prior to the surgical treatment. The lymphocyte responsiveness in the presence of homologous pooled AB serum in patients of stages II, III and IV were markedly reduced as compared with that in healthy controls (stages II, III; p less than 0.05, stage IV; p less than 0.01). Inhibition of normal lymphocyte responsiveness to PHA by serum from patients in stages III and IV were statistically significant only in the advanced stage. It was concluded that the suppression of the immune response in the early stage of gastric cancer was mainly due to the impairment of lymphocyte itself, which advanced with the progress of the stage and was modified by the serum inhibitory effect in advanced stages. In patients with advanced cancer, the higher was the lymphocyte responsiveness to PHA and PWM prior to the initial treatment, the more effective was the immunotherapy. This shows that the indication of the immunotherapy in patients with advanced cancer could be initiated. Furthermore, the correlation between the lymphocyte responsiveness to PHA and the clinical results of immunotherapy was discussed.

Two patients with intestinal metaplasia of the stomach, whose distribution was exclusively confined to the fundic gland area, are presented herein. The first, a 51-year-old male, had been treated for pernicious anemia for 14 years when he was found to have gastric cancer. His serum gastrin level was quite high, whereas his gastric acid output was markedly low. The polypoid cancer in the fornix of the stomach, which had been removed endoscopically, revealed tubular adenocarcinoma with its invasion limited to the mucosa. The resected stomach showed no residual carcinoma but had numerous minute foci of intestinal metaplasia, diffusely distributed but exclusively confined to the fundic gland area, by macroscopic observation using the leucine aminopeptidase-alkaline phosphatase double staining method. The intestinal metaplasias were all of the complete type, and the parietal and chief cells were almost completely lost. The second patient, a 76-year-old male without pernicious anemia, underwent total gastrectomy for two polypoid cancers in the body of the stomach. The resected specimens, in addition to two hyperplastic polyps in the transitional area, showed the same distribution of intestinal metaplasia as seen in the first patient.

Macroscopic disseminating peritoneal metastasis of gastric cancer (P) was investigated in relation to its compatibility with microscopic findings (p) in 52 (P1 19, P2 21, P3 12) cases among 240 gastrectomized cases by cytological, histological, clinical and postmortem findings. In total, numbers of the evaluations for yes (P is p), probable (P is probably p), possible (P is possibly p), probably not (P is probably not p) and no (P is not p) were 28 (53.8%), 8 (15.4%), 14 (26.9%), 2 (3.8%) and 0, respectively, These results indicate that macroscopic disseminating peritoneal metastasis is compatible with microscopic findings, in most cases. Although histology is the most contributory factor for the evaluation of peritoneal dissemination, cytology of lavaged saline from the Douglas pouch also is important.

Based on the experimental results that operative stress of thoracotomy or laparothoracotomy has enhanced tumor growth remarkably in rats compared with laparotomy, a new combined treatment with by-pass operation, irradiation and immunochemotherapy was investigated in 39 advanced thoracic esophageal cancer patients. At by-pass operation, abdominal esophagus was divided and its proximal stump was closed immediately. Cervical esophagus was then divided and its distal stump was pulled out to the right supraclavicular region to make outer fistula. Thus, anticancer drug was poured into the esophagus through outer fistula very easily just before irradiation and then irradiation was performed under the condition that the lesion was immersed in the drugs. As anticancer agent, Mitomycin-C, 5-Fluorouracil or Bleomycin was given alternately. Lately, the combination of 5-Fluorouracil and Vitamin A was preferably used. The changes of immunological parameters and the survival after the onset of treatment was reported.

The incidence of esophageal cancer is much higher in men than in women and the prognosis is generally worse in men than in women. This seems to depend on the difference in the hormonal environments of the patient. In this paper, androgen receptors (AR) were measured in 21 cases of human esophageal cancer. Of these, two cases of esophageal cancer xenografts implanted into nude mice were AR positive. In EH-1, an established cell line from human esophageal cancer, the number of binding sites was increased and tumor growth was enhanced by testosterone administration. On the other hand, the number of binding sites was decreased and tumor growth was suppressed by castration. The administration of estrogen, however, did not inhibit tumor growth.

Streptococcal preparation (OK-432), a new type of anti-cancer agent, was given to the patients with advanced cancer in combination with Mitomycin-C, 5-FU and Cytosine arabinoside. OK-432 was administered intramuscularly with a daily dose of 2.0 KE consecutively or locally into the tumor with a large-dose of 100 KE. Most cases tolerated the long term administration of OK-432 without any severe side effects and the highest dose reached was 314 KE during 161 days of treatment. Of the 53 patients evaluated, 31 were given the initial large dose intratumoral OK-432. Thirteen were judged 0-C and Category 1 according to the Karnofsky criteria for a response rate of 44.8 per cent as compared with 12.5 per cent in the group without the initial large-dose administration.

The effects on the prognosis of breast cancer, of the delay between biopsy and radical mastectomy were studied in 394 patients. No delay had been experienced by 148 cases (no delay group), no biopsy had been performed in 166 cases (no biopsy group) and 80 cases had experienced a delay of 1 day or longer after having had a biopsy taken at a different institution (delay group). The recurrence rate of the no delay group was 10.8 per cent (16/148), whereas that of the delay group was 18.8 per cent (15/80). The relapse free survival rate of the no delay group was superior to that of the delay group (Kaplan Meier's method: p less than 0.05). The delay group was further divided into two groups according to the duration of delay, namely: a group whose delay was less than 7 days and another whose delay was longer than 8 days. There was no significant difference between the relapse free survival rates of the no delay group and the less than 7 days group, however, a significant difference was observed between the no delay group and the longer than 8 days delay group (p less than 0.05). The acceptable delay between biopsy and radical mastectomy may therefore be concluded as less than 7 days.

The antitumor activities of KW-2152, a new isoquinon derivative, were examined in thirteen human tumor xenografts, transplanted into nude mice. KW-2152 was administered intravenously at a schedule of q4d X 3, in daily doses of 7.3 mg/kg and 3.6 mg/kg, and q2d X 6 with a daily doses of 7.3 mg/kg, respectively. KW-2152 displayed significant antitumor activities against the human tumor xenografts in 3 out of 13 strains (23.1 per cent) at the schedule of q4d X 3, with a daily dose of 7.3 mg/kg. Depending on the schedule of administration, tumor activity was observed in 8 out of 13 strains (61.5 per cent) at a schedule of q2d X 6, with a daily dose of 7.3 mg/kg. SH-2 and SH-9 gastric tumors were sensitive to KW-2152 and growth was completely inhibited with the schedule of q4d X 3, and a daily dose of 7.3 mg/kg. Thus, KW-2152 seems to have a wide antitumor spectrum, and the possible antitumor effects for clinical use, warrant attention.

From 1973 to 1987, 235 patients with esophageal squamous cell carcinoma were treated at Hiroshima University. Of these patients, 121 (51.5 per cent) were submitted to esophagectomy, 93 (39.6 per cent) to bypass surgery and 21 (8.9 per cent) to either exploratory or no surgery. In this report, the 93 cases who underwent bypass surgery were analysed. Ten patients died within thirty days after their operation (10.8 per cent) and there were 33 cases of hospital death (35.5 per cent). Following the bypass surgery, 49 (59.0 per cent) cases were able to tolerate over 50 per cent of their normal oral intake and 22 cases (26.5 per cent) were able to tolerate between 25 per cent and 50 per cent. For twelve cases (14.6 per cent), however, oral ingestion proved impossible up until the time of death due to such complications as leakage. The overall survival rates were 44.3 per cent at 6 months, 12.7 per cent at 1 year and 2.8 per cent at 5 years, respectively. Two cases survived for over 5 years. Hyperthermia was applied in combination with chemotherapy from 1981, however, no case survived for over one year without radiation therapy. Recently, radiation plus hyperthermia is being performed in combination with immunochemotherapy.

The combined effects of moderate local hyperthermia, bleomycin and ethanol were investigated with Lewis lung carcinoma tumors in female C57BL/6 mice. Different combinations of treatments were performed on days 4 and 7 after tumor implantation. Combined treatment of 41 degrees C hyperthermia and bleomycin resulted in mild reductions of tumor growth. Hyperthermia plus bleomycin led to marked reduction in tumor growth under the condition of a 43 degrees C temperature. The antitumor effects of 41 degrees C hyperthermia combined with bleomycin were enhanced by the additional use of ethanol, and these effects were more remarkable than those of 43 degrees C hyperthermia and bleomycin. A possible application of these findings to clinical therapy for advanced esophageal cancer was discussed.

Transabdominal resection of esophagocardial cancer and reestablishment of alimentary continuity using a bypass method have been performed in 64 patients. Twelve underwent a bypass with a gastric tube and in 30, a colonic segment was prepared. In the remaining 22, a jejunal segment was used as the bypass organ. Leakage of cervical anastomosis occurred in 4 (18 per cent) but all were limited to minor leakage and oral ingestion was resumed within 10 days after operation. In one, necrosis of the jejunal segment occurred. The history of jejunoesophagoplasty was reviewed and the usefulness of jejunal segment as a substitute of an esophagus was emphasized.

In order to determine the indications of chemosensitivity tests against various anticancer agents, clinical trials of 4 different assays, namely; nude mouse isotope assay (NMIA), subrenal capsule assay (SRCA), human tumor clonogenic assay (HTCA) and adenosine triphosphate inhibition assay (ATPA), were performed on 391 patients. Analysis of the correlation between assay results and clinical effects presented the possibility of determining the indications as follows; (1) The positive clinical response of mitomycin C (MMC) should be predicted by ATPA; (2) The clinical tumor resistance against MMC should be predicted by SRCA; (3) Concerning 5-fluorouracil (5-FU) the chemosensitivity test (ATPA) should only be used for the detection of tumor resistance in the assay; (4) The poor results of this study indicated the difficulty of correctly estimating the effects of cyclophosphamide (CPM); (5) The perfect prediction of clinical effects in this trial indicated that cis-DDPlatinum (CDDP) should be estimated by SRCA; (6) The positive clinical tumor response against adriamycin (ADM) should be predicted by SRCA, while the negative one should be predicted by HTCA; and (7) ATPA showed good potential for estimating not only time dependent drugs such as 5-FU, but also cytotoxic drugs.

The antitumor activities, resulting from the combined treatment of leukocyte interferon (IFN-alpha), with recombinant human immune interferon (IFN-gamma), against human tumor xenografts in nude mice, were studied. Nine human tumor xenografts, (7 from gastric carcinoma, 1 from gallbladder carcinoma and 1 from breast carcinoma), were serially transplanted into nude mice for the purpose of this experiment. Each human tumor xenograft was inoculated subcutaneously into BALB/c nu/nu nude mice and treatment was started after the estimated tumor had reached 100-300 mg. IFN was administered intramuscularly at a schedule of qd X 14. Treatment with either IFN-alpha or IFN-gamma alone, did not produce any antitumor effect against the various human tumor xenografts, however the combination of IFN-alpha with IFN-gamma resulted in achieving significant antitumor effects against the various human tumors. Inhibition of tumor growth was observed in 7 of the 9 tumors (77.8 per cent), and regression of the tumor was noted in 5 of the 9 tumors (55.6 per cent).

The effects of oxygen tensions on the antitumor activity of mitomycin-C (MMC) were surveyed using the human tumor clonogenic assay technique. Six human tumor xenografts (4 gastric cancers, and 2 colon cancers) were used in this study. Tumor cells were continuously exposed to MMC during the experimental period at various oxygen tensions, such as 2 per cent, which is considered to be hypoxic oxygen tension, 5 per cent which is considered as the physiological oxygen tension, and 20 per cent which is the conventional in vitro culture condition. The antitumor activities of MMC on the 6 human tumor xenografts increased when the oxygen tension was lowered from 20 per cent to 5 per cent. However, no further increases of the antitumor activities of MMC were observed by lowering the oxygen tension from 5 to 2 per cent. Additionally, the in vitro antitumor activities of MMC at various oxygen tensions were compared with the in vivo chemosensitivities evaluated in nude mice. In five of the 6 human tumor xenografts, in vitro chemosensitivities assayed at 2 or 5 per cent oxygen tension were concordant with in vivo chemosensitivities, although in vitro chemosensitivities assayed at 20 per cent were concordant with in vivo chemosensitivities in 3 of the 6 tested tumors.

Transabdominal resection for esophagocardial cancer and reestablishment of alimentary continuity using bypass methods were performed in 76 patients. Thirteen underwent a bypass with a gastric tube and in 30, a colonic segment was prepared. In the remaining 33, a jejunal segment was used as a bypass organ, with considerable success. The 5 year survival rates were 68.8 per cent in those with stages (I + II), 16.5 per cent in those with stage III, 12.6 per cent in those with stage IV and 22.5 per cent in all cases, indicating similar results compared to those with cancer located in the upper third of the stomach with the limited proximal extension within the esophagocardial junction and operated on during the same period.