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The aim of this study was to evaluate the clinical effectiveness of intra-arterial chemotherapy combined with degradable starch microspheres (DSM) for liver metastases and the possibility of predicting the effectiveness of the chemotherapy by pretreatment diagnostic imaging. The subjects were 67 patients with metastatic liver cancer, treated with Seldinger method via the left brachial artery, and tumor selective hepatic injection using a micro-catheter. The early response rate was 38.7% for colorectal cancer, 42.8% for gastric cancer, 16.7% for bile tract cancer and 80% for uterine cancer. The relationship between effectiveness and the tumor occupation rate in the liver estimated from pretreatment CT images was not significant, but the degree of tumor stain in the early phase of contrast enhancement CT correlated well with early responsiveness of the liver metastases for this treatment. This suggests the possibility of pretreatment prediction of the effectiveness of intra-arterial chemotherapy combined with DSM for metastatic liver tumors.

A 61-year-old man was admitted to our hospital in December 1994 for a suspected retroperitoneal tumor. Systemic imaging investigations demonstrated retroperitoneal solid tumor, which was diagnosed as malignant fibrous histiocytoma (MFH) by immunohistochemistry for alpha 1-antitrypsin. In March 1995, he was treated with 3 courses of systemic chemotherapy with cisplatin, ifosfamide and doxorubicin followed by the same therapy in March 1996, without serious side effects. MFH is known to be resistant to ordinary chemotherapy. However, the CT showed a marked decrease in the size of the tumor, and the tumor disappeared within 2 months after the first treatment. The patient also recovered rapidly from abdominal pain, for which complete remission has been achieved for more than 5 years. The present chemotherapy may be an effective treatment for retroperitoneal MFH.

To facilitate the proper and quick evaluation of cancer chemotherapy, the issues of surrogate and true endpoints in clinical trials were reviewed. Surrogate endpoints are defined as response variables that can substitute for a true endpoint due to their close correlation with the true endpoint, and their occurrence earlier than true endpoint. The response rate in cancer chemotherapy has been used as a surrogate or true endpoint for the evaluation of treatments. However, recent studies revealed that response rates do not always correlate with survival time (time to failure), and better surrogate endpoints such as time to progression, median survival time, or various surrogate biomarkers are now under investigation.

The issue of medical practice guidelines has attracted the attention of doctors and health care professionals in Western countries since the middle 1980s. Such guidelines aim to assist in clinical decision-making in order to reduce variations in care and unnecessary costs for delivered health care service, and to improve the outcomes of medical care. Strangely, however, there is no interest or attention given to this topic in the medical and health care fields in Japan. As the president of the 71st Japanese Gastric Cancer Association, the author hopes to generate interest in this topic by opening a symposium at the annual meeting of the JGCA this year. As an introduction to this session, the present paper provides a short review of medical practice guidelines, their development cycle, and their advantages and disadvantages.

A case of lung cancer with superior vena cava syndrome treated with internal thoracic arterial infusion of anti-cancer drugs by the implantable port system was reported with our technique. In this case, blood supply was mainly from internal thoracic artery. A trans-catheterial contrast enhanced helical CT was very helpful to identify the routes of blood supply to the lung cancer.

Pyrimidine nucleoside phosphorylase (PyNPase), among which thymidine phosphorylase (dThdPase) exists mainly in human tumor tissues, is an enzyme to convert 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-fluorouracil. Recently, it was reported that dThdPase was identical to platelet-derived endothelial cell growth factor, angiogenetic factor. Therefore, we expect that there is possibility of dThdPase being a prognostic factor.We investigated for a possible correlation between PyNPase activities in tumor tissues and prognostic factors of histological findings, examined the influences of preoperative oral 5'-DFUR administration to PyNPase levels and investigated for a correlation between HPLC methods and ELISA methods in patients with gastric cancer.Higher levels of PyNPase were observed in patients with advanced t,n,v, and ly factors. PyNPase levels decreased by 5'-DFUR in patients with differentiated cases. A high correlation was found between HPLC and ELISA methods.This study suggests that we must investigate possibility of PyNPase being a prognostic factor in more detail.

The Japanese Ministry of Health and Welfare issued a revised version of Good Clinical Practice (GCP) in 1997 which regulates the method and procedure of new drug development. The largest issue is the discrepancy between the present status of drug development system and requirements by new GCP. Characteristics of phase III study in the surgical field requires a large number of accrued patients, takes long observation time, and much money to achieve. The study needs well-trained doctors, nurses, study coordinators, a data manager, and statisticians. However, conventional study has largely depended on doctors who might not be able to respond to all requirements without the cooperation of other paramedical staff. Pharmaceutical companies could afford in a few months to organize a new drug development system to meet the requirements of the new GCP. However, physician-directed clinical study has insufficient financial support to realize data assurance of high quality. Because the development of actual treatment depends on the results of physician-directed clinical study, a high-level research organization such as in the western countries should be urgently established, and the fruits of the study should be reflected in government policy in the health assurance system.

Psychiatric studies were made on 26 inoperable patients with lung cancer or thymic cancer to exam the possible correlation of chemotherapy and chemotherapy-induced nausea and vomiting. All patients were informed of their disease and how to undergo the therapy. Psychiatric tests of CMI (Cornell Medical, Index), MAS (Manifest Anxiety Scale), SDS (Self-Rating Depression Scale) and QOL questionnaire were performed just before the chemotherapy. SDS and QOL questionnaire were also done after chemotherapy. The patients were given chemotherapy including CDDP (80 mg/m2) and anti-emetic agents of 30 mg of azasetron, 750 mg of methylprednisolone and 1,800 mg of domperidone. The patients showing neurosis, anxiety or depression had significantly high nausea scores, so we concluded that psychiatric support was needed to improve these patients' QOL in chemotherapy.

A multi-center collaborative study was conducted in curatively resected gastric cancer patients at Stages II and III to compare oral 5-FU (Group A), oral Tegafur (Group B) and i.v. MMC + oral 5-FU (Group C). From May 1982 to April 1985, 1,012 cases were enrolled at 55 institutions. Some 138 (13.8%) were excluded, and 874 were analyzable. In the analysis of background factors, Group B had more cases with tumor of large diameter and advanced Stage. Adverse effects were relatively mild in all groups, and there was no problem in drug tolerance. Five-year survival rate was 67.6%, 62.4% and 68.6% in Groups A, B and C, respectively, reflecting no significant difference among them. It was 85.0%, 83.0% and 81.1% in Stage II and 52.5%, 51.0% and 59.0% in Stage III of Groups A, B and C, respectively. No significant difference was found, but Stage III of Group C showed a slightly higher survival rate. Supportive clinical study will be required to assess the usefulness of MMC as an introduction therapy. We found no difference in efficacy between 5-FU and Tegafur as maintenance therapy. The life-prolongation effect of fluoropyrimidines in comparison with surgery alone should be studied separately.

In a prospective randomized controlled trial (PRCT) of adjuvant chemotherapy for gastric cancer patients participated by 6 cancer center hospitals, inter-institutional and inter-individual differences about several factors related to the surgery and remote survivals were analyzed. From 1988 to 1992, 1,049 evaluable patients were enrolled and stratified to 6 groups according to the grade of the serosal invasion and curability, and analyzed statistically.1) There were no inter-institutional differences about postoperative survival rate, but there were slight differences about patient's background factors and entry policy of each institution. 2) There were no inter-institutional differences about several factors related to the surgery such as operative time, bleeding volume during operation, and the length of the administration periods. 3) There were no inter-individual differences about the length of the administration periods, but there were a little differences about operative time and the volume of hemorrhage. When the PRCT of adjuvant chemotherapy of which the end point is survival would be designed, no inter-institutional differences about remote survival and surgical operation in each institution should be confirmed before starting the trial.

We completed a reservoir system for injection to bronchial artery. A slender catheter was indwelled in bronchial artery through left subclavian artery or right femoral artery in five cases with lung cancer. Reservoir was embedded subcutaneously, and injection to bronchial artery was performed repeatedly on an outpatient basis. Used drugs were CDDP, bleomycin and adriamycin. RI angiography confirmed the accumulation of 99mTc-MAA in primary lung tumor. Satisfactory therapeutic effect can be expected by the use of reservoir system for bronchial arterial injection, and seemed to become one of the established therapies, improving quality of life with advanced lung cancer.

As mentioned in the first of the present series of reports, lung cancers were fed by various arteries such as bronchial arteries, internal mammary arteries, inter-costal arteries and branches of subclavian arteries such as thyro-cervical truncus or thoraco-dorsal arteries, according to the size and stages of tumors and the processes of therapy. On the basis of these anatomical findings of the feeders of lung cancers, we tried several effective and reasonable ways of cannulation of catheters, which were connected with an implantable port system.

Arterial injection therapy for lung cancers is concentrated on the bronchial arteries, because they are reported by the main feeders of lung cancers. In the present study, we attempted intermittent arterial injection therapy with implantable port system. In the cases of lung cancers, in the present study, tumors were mainly fed by bronchial arteries originating from intercostal-bronchial arteries in right lungs, and those directly originating from aorta in the left lungs. However, in the processes of BAI (Bronchial Arterial Injection Therapy), main feeders often were obstructed and the new feeders originated from branches of subclavian arteries, such as thyro-cervical truncks, internal mammary arteries, thoraco-acromial arteries and intercostal arteries. They formed networks surrounding the lungs. Adequate study of the feeding arteries should be performed in the course of arterial injection therapy of lung cancers.

From 1946 to 1990, 10,485 patients with gastric cancer were been surgically treated in the Cancer Institute Hospital, Tokyo. Retrospectively, we analyzed prognostic factors, especially in those without distant metastasis. Prognosis of the patients with tumors which invaded the proper muscle layer improved dramatically (from 70% to 90%). However, patients who had advanced tumors with serosal invasion did not show good survived (from 20% to 40%). To improve the prognosis of patients with serosal positive gastric cancer, a new and effective prophylactic therapy for peritoneal recurrence is needed.

We discussed the advances and clinical issue including complications in the treatment of gastric cancer infiltrating the adjacent organs. Recent years, the proportion of the patients with gastric cancer infiltrating the adjacent organs are decreasing, but there isn't remarkable advances in the treatment result of them. That is due to the fact that about one half of them has distant metastasis, such as peritoneal dissemination or liver metastasis. Whatever the survival rate of the patients who was performed combined resection is better than unresected cases. The postoperative complications of the combined resection cases is two times as much as the uncombined resected cases. Therefore we should perform combined radical resection for the patients without distant metastasis, and for the patients with distant metastasis, we should perform palliative surgery for the purpose of improving QOL.

A total of 8,993 cases of gastric cancer which were undergone gastrectomy at Cancer Institute Hospital, Tokyo were subjected to the multi-variate analysis of prognostic factors in gastric cancer. Relative ratio of hazard risk indicated the rank of importance in prognostic factors as the following order: Hepatic metastasis, radicality of surgery, macroscopic tumor type, serosal involvement, number of involved lymph node, and grade of lymph node metastasis. Difference in the results of analysis was observed between mono- and multi-variate analysis in the following categories: site of primary lesion, type of resection, and chemotherapy. These results suggested the importance of multimodality therapy to achieve the absolute curative surgery for advanced cancer, and also the importance of multi-variate analysis for the proper evaluation of prognostic factors.

We discussed the accuracy and clinical issue of preoperative diagnosis for 764 patients with gastric cancer from 1987 to 1990. The accuracy of diagnosis, location, tumor size, wall invasion, involved lymph node were 81.8, 80.5, 62.2, 82.5% respectively. The clinicopathological characteristics of the regions which we missed preoperative diagnosis are infiltrating type and scirrhous type in diagnosis of tumor size, and large tumor in diagnosis of wall invasion. Especially in the case of early gastric cancer, we missed diagnosis of wall invasion of the regions with clinicopathological characteristics as follows: depressed type, undifferentiated type and ulceration in lesions. Now it is difficult to diagnosis wall invasion before surgery, so we have to be careful to determine the indication of endoscopic resection or limited operation for early gastric cancer, especially with clinicopathologic characteristics stated as above.

Now we use the nodal grade (N, n) as a prognostic indicator in patients with gastric cancer according to the general rules for the gastric cancer study. But there are both of patients with good and poor prognosis in the same nodal grade. Then we analyzed the survival of patients with gastric cancer based on the nodal grade and the number involved lymph nodes, and discussed the new prognostic indicator with both of them. We classified the three groups based on the number of involved nodes as follows: 0.1-4.5-. There is the differences in survival between each pair of groups statistically. The relationship between the nodal grade (N, n) and the number of lymph node metastasis is that the survival of patients with involved nodes more than five is equal to the survival of the patients with high nodal grade and involved nodes 1-4. Therefore it suggest that the new grading consisting of them will be more better prognostic indicator.

A total of 8,230 cases of gastric cancer treated at CIH were subjected to the analysis of the pattern of lymphatic spread with an aim of getting indication for the lymph node dissection of Small gastric cancer. Modified dissection (D1-alpha) is indicated for the patients with following conditions: 1) every elevated or flat type mucosal cancer, 2) excavated (IIc) type mucosal cancer less than 10mm in diameter, 3) elevated or flat type submucosal cancer less than 10mm in diameter, 4) excavated submucosal cancer less than 5mm in diameter. Extended dissection (D2 + alpha) is indicated for small cancer which exposed to serosa. Cancer in the upper thirds needs total gastrectomy or cardiectomy according to the state of #5 and 6 nodes, with complete dissection of #1 to 11 nodes associated with sampling of #16 nodes. Total gastrectomy with complete dissection of #1 to 11 nodes and sampling of #16 nodes is indicated for the advanced small cancer in the middle thirds, and total gastrectomy with complete dissection of #1 to 13 nodes and sampling of #14, 16 nodes is indicated for cancer in the lower thirds.

The recurrence rate of resected gastric cancer was 31.9%. The rate was in creasingly higher in proportion to the lack of radicality. The most common type of recurrence was peritoneal dissemination, followed by hematogeneous metastasis, local recurrence, and distant lymph node metastasis. The treatments for recurrence were surgery (9.3%) and chemotherapy (16.1%). Systemic chemotherapy (intravenous iv) was common, and local chemotherapy (intraarterial ia, intraperitoneal ip) was rate. The efficacy of systemic chemotherapy (iv) for recurrent gastric cancer without local recurrence was suggested. The efficacy of local chemotherapy (ia) was suggested for peritoneal dissemination and local recurrence.

We have been trying to perform endoscopic mucosal resection (ER) since 1987, and limited operation since 1985 (nerve preserving operation since 1991) for early gastric cancer. 205 patients were performed ER from 1978 to 1990, 78 patients were performed limited operation from 1985 to 1993. We perform ER according to the indication as follows: 1) differentiated IIa type, size approximately 2 cm, 2) differentiated IIc type, size approximately 1cm, Ul(-), 3) undifferentiated IIc type, size approximately 5mm, Ul(-). And the indication of limited operation is the patients with intramucosal cancer and tumor size approximately 2cm. Up to date, we have never experienced recurrence of these patients undergone ER or limited operation. As to QOL, these therapy will be expected to improve QOL of early gastric cancer patients, especially per os and body weight loss after surgery.

To evaluate the clinical significance of the surgical procedure of left upper abdominal evisceration (LUAE), we analysed the prognosis of patients who received LUAE in the Cancer Institute Hospital from 1980 to 1990 using pair matching analysis. Survival benefits were observed in the patients with the tumor located in the upper or middle part of the stomach, and especially in those with Borrmann type 4 gastric cancer. Even in cases of peritoneal dissemination, patients who received LUAE survived longer than those with conventional total gastrectomy. These results indicated that LUAE should be a standard surgical approach for Bormann type 4 gastric cancer.

Six adjuvant chemotherapy protocols with 10 chemotherapy regimens were subjected to meta-analysis with an aim to clarify the survival benefits of adjuvant chemotherapy in gastric cancer. All adjuvant chemotherapies were compared with surgery alone, in cases from 1959 to 1982 in the Cancer Institute Hospital, Tokyo in the setting of controlled randomized study; and 1,177 gastric cancer patients with curative surgery were entered the studies. Pooled odds ratio and its 95% confidence interval was 0.63(0.51-0.78). The results suggested the survival benefits of adjuvant chemotherapy with mitomycin C and/or 5-fluorouracil in gastric cancer.

A 16-year-old female patient with gastric cancer was recently treated at our institute. She had macroscopically curative surgery, but relapsed to die 7 months after surgery due to peritoneal dissemination. We experienced three teen-agers over past 45 years, who were 0.019% of all cases treated in our institute. Histological type of these cases was undifferentiated adenocarcinoma, exposing to serosa. Though they had suffered abdominal discomfort for long time, proper diagnosis was not done due to their young age. Even the teen-ager who has abdominal complaints should be subjected to a thorough examination of gastrointestinal tract. Oncogene analysis should be done for the familial strain of gastric cancer.

From 1946 to 1990, a total of 10,485 cases of gastric cancer patients were treated at the Cancer Institute Hospital (CIH), Tokyo. During the past 46 years, CIH contributed to various aspects of surgical treatment of gastric cancer; extensive radical surgery for advanced cancer, safe reconstruction methods after total gastrectomy, modified surgery for early stage cancer, and multimodality therapy for moderately advanced cancer. Five-year survival rate was 20% for all cases in 1940s, and 66.5% for 1980s. Improvement in the treatment results could be attributed to the relative increase in the number of early stage cancers, the increase in the rate of curative surgery (R0), and incorporation of multi-modality therapy before or after curative surgery. Stage-oriented therapy is mandatory for further improvement in the treatment results and the patient's quality of life after surgery.

Data management in the clinical trial is not always processed adequately in Japan. Data management largely depends on the doctor who is in charge of the study. For the effective data processing to the computer, careful attentions should be paid to the proper selection of data-items and quantity, design of data format, coding of data to the format, and the procedure of data input into the computer. These procedures are mainly owed to data managers and computer engineers in the large clinical trials of western countries. Establishing local and central data center and identify of the data manager in our country are urgent for effective implementation of multiinstitutional clinical trial.

Though many previous reports suggest the clinical significance of adjuvant chemotherapy in gastric cancer, they are not always confirmed by the statistics. Treatment failures could be attributed to the minor benefit of chemotherapy for advanced cases, too much tumor burdens after surgery relative to the antitumor effect of chemotherapy, and statistically inadequate operation of clinical study. Improvement would be expected in the near future by carrying out a well designed control study with incorporation of new drugs such as CDDP or etoposide, or powerful regimen with MTX and 5 FU, or 5 FU and Leucovorin.

Combined effect of N-[4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenyl]-N'-(2-nitrobenzoyl ) urea, HO-221, with various antitumor agents was studied using L 1210 leukemia in vivo and in vitro. Ten anticancer drugs were chosen from alkylating agents, antitumor antibiotics, antimetabolites and plant alkaloids each. The combined effect was assessed by comparing ILS (increase of life span) in the combined group with the sum of ILS of each single agent. Synergistic effect was considered to exist if ILS of the combination-treatment group exceeds the sum of those in 2 single-treatment groups. The two-drug combination of HO-221 with cyclophosphamide (CPA), adriamycin (ADM), mitomycin C (MMC), vindesine (VDS), vincristine (VCR) or etoposide showed remarkable synergistic effects with 60-days survivors. However, the combination chemotherapy with antimetabolites, 5-fluorouracil (5-FU) and methotrexate (MTX) showed competitive effects. Moreover, the synergistic cytocidal effect in vitro by the clonogenic assay was observed in combination of HO-221 with the same drug using in vivo test. The present results indicate that HO-221 seems to be a useful antitumor agent in combination chemotherapy.

HO-221, N-[4-(5-bromo-2-pyrimidinyloxy)-3-chlorophenyl]-N'-(2- nitrobenzoyl) urea is a new benzoylphenylurea derivative. The compound exhibits significant antitumor effects against various animal tumors, and was especially effective against the solid tumors implanted subcutaneously. HO-221 inhibits DNA polymerase alpha activity strongly in vitro. In this study, we examined the cross-resistance of HO-221 to various antitumor agents using sublines of mouse leukemia. HO-221 showed antitumor effects in mice bearing L 1210 or P 388 leukemia resistant to 10 antitumor agents, DM (daunomycin), MMC (mitomycin C), CDDP (cisplatin), 5-FU (5-fluorouracil), Ara-C (cytosine arabinoside), MTX (methotrexate), CPA (cyclophosphamide), CQ (carboquone), ADM (adriamycin) and VCR (vincristine), respectively. These antitumor agents were also effective in P 388 leukemia resistant to HO-221 (P 388/HO-221). Furthermore, CDDP- and MMC-resistant sublines showed a collateral sensitivity to HO-221 in vivo. The grow the inhibitory effects were also noted in vitro in ADM-, CDDP- and MMC-resistant cells by HO-221. However, the in vitro experiments didn't show such collateral sensitivity on the resistant sublines. These results suggest that there is no cross-resistance between HO-221 and other known antitumor agents, and that HO-221 seemed to be worth for evaluating clinical usefulness.

HO-221, N-[4-(5-Bromo-2-pyrimidinyloxy)-3-chlorophenyl]-N'-(2-nitrobenzoyl ) urea is a novel benzoylphenylurea derivative. We had interested in various pharmacological actions of benzoylphenylurea compounds. Therefore, many compounds were synthetized and tested in various screening systems. In the process with these tests, we found HO-221 which showed an excellent antitumor activity. The antitumor activity of HO-221 was judged from the survival time and the tumor weight of experimented tumor-bearing animals. HO-221 preparation was orally administered. The compound exhibited significant effects against various animal tumors (P388, L1210, M5076, LLC, C38, S180, W256), and especially effective against the solid tumors. HO-221 was also markedly effective to MX-1 and LX-1 implanted into nude mice. However, the effect against mouse B16 melanoma was moderate. In addition, HO-221 showed a schedule dependency and once every 4 or 7 days treatments were most effective. The antitumor activities of the compound against advanced L1210 and Lewis lung tumors were examined. Tegafur and ara-C were used as reference drug for the study. Three agents showed the antitumor activities against L1210. Against Lewis lung carcinoma, HO-221 showed both the increase of life span and the tumor growth inhibition. On the other hand, tegafur and ara-C were ineffective for the increase of life span.

HO-221, N-[4-(5-Bromo-2-pyrimidinyloxy)-3-chlorophenyl]-N'-(2-nitrobenzoyl ) urea is a novel benzoylphenylurea derivative. We previously reported HO-221 showed significant antitumor activities against various experimental tumor models, and was especially effective against the solid tumor. In this report we studied the mechanism of action of the compound. The inhibitory activity of HO-221 and 6 kinds of antitumor agents on DNA polymerase alpha was examined in vitro. HO-221 inhibited DNA polymerase alpha activity strongly. From the comparison with IC50 values of individual agents, the inhibitory activity of HO-221 was almost equivalent to aphidicolin and ara-CTP. By double reciprocal plot analysis, the inhibition of HO-221 was found to be non-competitive with the dCTP unlike that of aphidicolin and ara-CTP. Furthermore, HO-221 showed almost no effect on RNA polymerase activity and the protein synthesis. The effect of HO-221 on cell cycle progression of HL-60 cells was examined by flow cytometry analysis. The compound accumulated cells at S phase at a low concentration. The compound showed accumulation of cells in G1, G1-S and G2 + M phases. At higher concentrations, HO-221 increased the G1 phase of tumor cells, stopping the cell cycle progression. Therefore, G1 and S phase accumulation by HO-221 was considered to be correlated with the inhibition of DNA polymerase alpha dependent DNA synthesis. These results suggest that HO-221 is a novel antitumor agent with different mechanism of action from the known antitumor agents.

Early phase II study in patients with advanced and recurrent gastrointestinal cancer was conducted from August 1986 through December 1987 to evaluate synergic effect of the combined use of AO-90 amino acid solution (free from Methionine) and anticancer agents (5-FU and MMC). Thirty five patients were subjected to the clinical evaluation according to the two criteria, i.e., the solid cancer chemotherapy direct efficacy criteria and the criteria of improvement of gastrointestinal passage disorder. Among 21 patients appropriately eligible for the direct efficacy criteria, the rate of more than partial response was 23.8% (5/21), while the rate of 27.8% (5/18) was observed in the patients who completely met the evaluation requirements. Among 14 patients with gastrointestinal passage disorder due to cancer, 57.1% (8/14) of the patients effectively responded to the therapy.

A 78-year-old man had a tumor of Borrmann type II affecting about one third the circumference of sigmoid colon, which was diagnosed as well-differentiated adenocarcinoma from biopsy. Although surgical intervention was recommended and the radical operation seemed possible from preoperative examination, the patient first refused it. Of necessity, systemic administration (s.c) and single endoscopic topical infusion of OK-432 and oral treatment of UFT were performed for 1 month. Since the patient agreed to receive an operation later, sigmoidectomy and lymph node dissection (R 2) were performed, resulting in the disappearance of tumor cells histologically. One week before endoscopic infusion, oral UFT and subcutaneous OK-432 were initiated. Although no macroscopic change was found during the topical infusion as compared with the time of first examination, the bulging disappeared, showing a polypoid change and IIc-like findings after 3 weeks. The operation was performed after an additional week, after which a benign tumor was found macroscopically and the disappearance of tumor cells histologically. Although many reports have dealt with the effect of endoscopic treatment for gastric carcinoma, there have been fewer reports describing the endoscopic treatment performed in patients with colon carcinoma, making it difficult to evaluate its therapeutic effect. However, this endoscopic therapy was suggested to be capable of becoming a useful treatment for inoperable colon carcinoma from the present case, whereas chemotherapy was found to have almost no effect on colon carcinoma in general.

The Cooperative Study Group of Surgical Adjuvant Chemotherapy for Gastric Cancer in Japan with the participation of 334 institutes nation-wide had conducted the secondary study in order to investigate the usefulness of futraful in long term treatment, based on the results obtained by the primary study. The following method was taken for the study and patients were randomly divided into three groups: A group-given a high dose of MMC immediately after operation; B group-given futraful for one year after MMC administration; C group-given futraful alone for long-term. The number of eligible cases for data analysis was 3,o30. Side effects observed during the long term treatment with futraful were considered to be minor. Although the occurrence of hematocytopenia was slightly frequent because of possible increase of influence by the concomitant use of MMC, no tendency of hepatic disorders and any subjective side effects to be strengthened by MMC combination was observed at all. As for 2-year survival, an elevated survival was found in the group of concomitant use of MMC and futraful; Especially, a significantly high survival was found in the cases of stage III and n (+) . ps (+). Furthermore, the survival was elevated in proportion to the increase of total dosage of futraful. This suggested the usefulness of futraful for long term treatment.

JFMTC conducted the third adjuvant chemotherapy study for gastric cancer patients after curative surgery from 1982 to 1983. Patients were randomly allocated to one of the three arms by telephone method controlled at the headquarters of the foundation. This method resulted in the marked reduction of ineligible cases (253 cases, 6.0% of 4,236 cases), compared with those in the first study (18.3%). Main reasons of ineligibility were the violation of entry criteria due to the misjudgment of noncancer, duplicate cancers and operative curability. Telephone method for random allocation seems to contribute to the improvement in the data quality of a clinical trial.

Patients who had undergone gastrectomy for stomach cancer were placed on adjuvant chemotherapy two weeks after surgery. They were divided into three groups according to the following regimen in order to compare the 3-year survival rate : in the first group, administration of futraful was carried out for 3 consecutive months and followed by administration of PSK for 2 consecutive months. This course was repeated for more than 2 courses. Administration of futraful in the second group was repeated for 3 consecutive months with 2 months of withdrawal and repeated for more than 2 courses. The third group received surgery alone. When all the patients of each group were compared, there was no difference in 3-year survival rate, but the group receiving alternating therapy with futraful and PSK showed a significantly high survival rate for the first year only. Further, among patients having stage III carcinoma, those with n2 + n3 or poorly differentiated adenocarcinoma had a remarkably high survival rate.

In view of the usefulness of long-term adjuvant chemotherapy, the Cooperative Study Group of Surgical Adjuvant Chemotherapy for Gastric Cancer adopted as a second cooperative study a randomized controlled trial including three groups; MMC alone, Futraful alone and a combination of MMC and Futraful. In the groups given Futraful alone and the combination therapy, the survival and disease-free rate were improved at five years, in patients with stage III. Moreover, the survival and disease-free rate for the group given combination therapy were higher than those for the group given Futraful alone. Also, in the groups given Futraful alone and the combination therapy, toxicities probably due to the long-term Futraful therapy were minor, without serious side effects. Therefore, a long-term combined adjuvant chemotherapy with MMC and Futraful seems to be an effective chemotherapy regimen for resectable gastric cancer. A more potent regimen and cyclic therapy may be needed to improve the result of treatment.

The Cooperative Study Group of Surgical Adjuvant Chemotherapy for Gastric Cancer adopted, as a second cooperative study, a prospective randomized trial on three groups: MMC alone, Ftorafur alone, and a combination of MMC and Ftorafur. The number of patients subjected to this analysis was 3033. The usefulness of long-term adjuvant chemotherapy was studied, based on a follow-up period of 4 years after surgery. No definite differences were observed in general. However, classified by prognostic factors, both the survival and disease free rates were improved in patients with stage III, n (+) ps (+) advanced cancer, to whom Ftorafur alone was administered for a long-term period. In patients who underwent of curative resection, the long-term administration of Ftorafur alone tended to prevent recurrence postoperatively, especially within the first two postoperative years. However the survival and disease free rates in the group receiving Ftorafur combined with MMC were higher than those of the group receiving Ftorafur alone. Moreover the combination of MMC and Ftorafur prolonged survival even in patients who did not undergo curative resection, and was found to be particularly useful in such patients, as designated by more than two prognostic factors.

After curative surgery for gastric cancers judged macroscopically to be at stage 2 or 3, patients were divided into 4 groups by randomization. As the basic treatment, patients were given one-shot Mitomycin and Tegafur as maintenance therapy for 8 months (group A). PSK (group B), OK-432 (group C) or both PSK and OK-432 (group D) were added to the treatment of group A for 8 months. Sera were obtained from these groups of patients at 4 weeks and 3, 6, 9 and 12 months after surgery. In all of these groups, values of IAP increased slightly at 4 weeks but decreased at 3 months and were maintained at such a level by 12 months. On the other hand, suppressive effects of such sera on the blastogenesis of murine spleen cells in response to PHA varied among these group. In groups A and C, the suppressive effect of sera increased after surgery and was detected continuously by 12 months. In groups B and D, in contrast, the suppressive effect disappeared from 3 to 12 months. The rise and fall of such a suppressive effect of sera may reflect the mode of action of PSK.

To clarify the clinical efficacy of SPG, a beta-1, 3 glucan extracted from cultured Schizophyllum commune Fries, a randomized comparative study was performed in combination with mitomycin C+5-fluorouracil (MF protocol) or tegafur (F protocol). A total of 514 cases with inoperable or recurrent gastric cancer were randomly allocated to either the SPG group or the control group, 367 of which were finally assessed for clinical efficacy. SPG was intramuscularly given at a dose of 20 mg twice a week or 40 mg once a week. Significant prolongation of life span was confirmed in the SPG group (MF protocol: p less than 0.01, F protocol: p less than 0.05), although the combination of SPG did not demonstrate a remarkable antitumor effect in both MF and F protocols. Among immune response parameters tested, the positive reactions in the PHA skin test were maintained in the SPG group and decreases in lymphocyte counts were inhibited by SPG in the MF protocol. Side effects associated with SPG therapy were noted in 6 of 258 cases treated with SPG. From these results, it is indicated that the combination of SPG and the chemotherapeutic agents may be useful in treating patients with inoperable or recurrent gastric cancer.

Recent advances in radiation chemistry and radiation biology have led to the combined use of radiosensitizing agents with radiation in the treatment of radioresistant tumors. Various chemicals, including cancerocidal drugs, are used, although radiation sensitizers are defined as drugs which can increase cellular radiosensitivity but have no direct cancerocidal effect. At least four classes of agents, pyrimidine analogues, hypoxic cell sensitizers, PLDR inhibitors and thiol-depleting agents, can modify radiosensitivity and have potential for differential sensitization. Pyrimidine analogues are incorporated into DNA in replicating tumor cells, and can sensitize these cells to radiation up to a factor of 3. Results of clinical trials of intra-arterial infusion of BUdR have not proved satisfactory, especially with regard to long-term survival, possibly because of the existence of non-replicating cells in the tumor. The latter two are still in the experimental stage of study. The radioresistance of hypoxic cells in tumor has been regarded as one of the limiting factors in the local control of cancer by radiation. Attempts to improve the situation involve high-LET radiation and combined use of chemicals, such as oxygen, prefluorochemicals and electron-affinic compounds, with low-LET radiation. Although some clinical trials in head and neck cancer and in cervical cancer have yielded positive results in patients treated using hyperbaric oxygen, attempts have been made to devise other methods, such as those using perfluorochemicals with normobaric oxygen, because of the technical difficulty involved with the former method. A more promising and easier method is the combined use of electron-affinic chemicals, which like oxygen can sensitize the hypoxic cells. Misonidazole (alpha 2-nitroimidazole derivative) was found to be an excellent sensitizer of this kind in cultured mammalian cells and in some rodent tumors. Several randomized clinical trials to determine its efficacy have been carried out on a word-wide scale, but most of them failed to demonstrate any beneficial effect, mainly because of the drug's neurotoxicity which limits its dose. After misonidazole, many researchers have made every effort to develop more efficient hypoxic cell sensitizers. The present state and future prospects of study were reviewed with special reference to studies currently being undertaken in Japan.

No means have yet been devised for detecting cancer of the esophago-gastric junction at an early stage, and no effective chemotherapy or irradiation regimen for this area is yet available. Recently, a very important lymphatic pathway and extension route for E. G-junction cancer has been discovered. A new operative procedure involving a thoraco-abdominal approach, wide dissection of the lymphatic system and safe reconstruction is discussed in this paper.

A multi-institutional cooperative study of postoperative immunochemotherapy for gastric cancer was studied using PSK and/or OK-432 combined with Tegafur (FT) and/or MMC. A total of 3,630 gastrectomized patients from 412 institutions were entered into the study using 6 randomly assigned protocols. Unbiased background cases were analyzed by 4-year or 5-year survival rates (SVR) for each protocol. The efficacy of combined PSK with FT was noticed in all cases of curative operation macroscopically and in n(-) X ps(+) cases (4-y SVR). The combination of MMC, FT and PSK produced better survival than MMC with FT or PSK administration in all cases of macroscopic curative operation (5-y SVR) and in non-curative operation (4-y SVR). The combination of MMC, FT, PSK and OK-432 was effective for poorly differentiated cancer (4-y SVR). Immunochemotherapy with MMC, FT, PSK and OK-432 was more effective in patients with preoperative positive PPD skin test than in those with negative PPD skin test. These results suggested that adjuvant immunochemotherapy using PSK and/or OK-432 combined with MMC and FT is effective for the improved survival of gastrectomized patients with gastric cancer.

Seventy-six (30.6%) out of 248 cases of diffuse infiltrating cancer of the stomach according to Kajitani's classification of gross appearance were surgically treated by LUAE. The survival rate of LUAE cases was better among both relative non-curative cases and Stage IV cases than that among cases treated by other forms of surgery. The survival rate of for LUAE cases was slightly better for cancer located mainly in the upper and mid-portion of the stomach than for cases of diffuse infiltrating cancer not treated by LUAE used as historical controls.

A 12-year-old girl with acute non-lymphocytic leukemia was treated with a protocol involving high-dose cytosine arabinoside (Ara-C) for intensification of early therapy. The patient, who had been revealed to have CNS infiltration on admission, achieved complete remission after receiving ACMA/BHAC combination and intrathecal MTX. As an early intensification treatment, ID/HD Ara-C was safely and effectively administered; this consisted of ADR (45 mg/m2 iv) Day 1, intermediate-dose Ara-C (0.5 g/m2, 1-h drip, q. 12 h) Days 2-4, and high-dose Ara-C (3 g/m2, 3-h drip, q. 12 h) Days 10-11, followed by L-asp (6,000 U/m2, im) on Day 12. Ten months later, the patient has been in continuous complete remission. High-dose Ara-C should be included with caution as an early intensification of treatment to improve the therapeutic results of childhood ANLL.

Effect of tumor burden on the electrophoresis of lymphocytes and macrophages was analyzed with a fully automated cell electrophoretic instrument (Parmoquant). The histogram patterns of peripheral lymphocytes of mice shifted to the lower mobility zone, and that of thymocytes shifted reversely, in the course of development of tumor. In cancer patients, emergence of low mobility T cell (LMT) was observed, and LMT correlated with immunosuppressive factors significantly. The ratio of LMT to high mobility T cells (HMT) tended to increase with tumor growth, and showed extremely high value in the case of recurrent cancers. In the follow-up studies, the LMT/HMT value varied in parallel with tumor growth. The unimodal patterns of macrophages changed to multiple peaks with tumor burden, in experimental animals and in clinical study. At terminal stage, it showed unimodal peak of lower mobility and phagocytic activity decreased. The result indicates that LMT associated with depressed immune state of cancer patients, and electrophoresis of immuno-competent cells may be usefull for cancer diagnosis and early detection of recurrence, because this method is very easy to assay and highly reproducible.

Twenty-one patients were treated with sequential doses of MTX and 5-FU so as to be classified by MTX dosage into an intermediate MTX-dose group and a high MTX-dose group. In the intermediate-dose MTX group, the drug was given at a dosage of 100 mg/m2 intravenously (i.v.) and followed 1 hour later by 5-FU at 800 mg/m2 i.v. (dripping for 1 hour); the drugs were recycled every 1 week. In the high-dose MTX group, the drug was administered at a dose of 1.5 g/m2 i.v. (dripping for 2 hours) and followed 1 hour later by 5-FU at 1.5 g/m2 i.v. (dripping for 2 hours); the drugs were recycled every 2-3 weeks. Average MTX concentrations in serum at the start of 5-FU administration were 1.69 X 10(-5) and 1.33 X 10(-4) mol/l/h in the intermediate and high-dose MTX groups, respectively. Six (50%) of 12 patients adequately treated with intermediate-dose MTX had a partial response (PR), and one (14.3%) of 7 evaluable patients treated with high-dose MTX had a PR. Major toxicity included diarrhea (33.3%) in the intermediate-dose MTX group and hair loss (71.4%) in the high-dose MTX group. Hematological toxicity was mild in MTX group: six (50%) of 12 patients had a granulocyte count nadir less than 1,000/microliters and one (8.3%) of 12 patients had a platelet count nadir less than 10(5)/microliters in the intermediate-dose MTX group. Five (71.4%) of 7 patients had a granulocyte nadir less than 1,000/microliters and two (28.6%) of 7 patients had a platelet count nadir less than 10(5)/microliters in the high-dose MTX group.

A total of 5,480 cases of gastric cancer was subjected to the analysis of main prognostic factors in gastric cancer. The uppermost factor which affected the prognosis of gastric cancer patients was the curability of surgery. Five year survival rates were 72.7% for the absolute curative cases, 33.6% for relative curative cases, and 13.8% for relative non-curative cases. None of the patients, who had absolute non-curative surgery, survived more than five years. Curability of surgery depended on the extent of cancer spread such as liver metastasis, peritoneal dissemination, remote lymphatic spread and continuous infiltration of adjacent organs. Gross and histological tumor types were important for the destination of cancer spread: localized, and well differentiated types tended to hematogenous metastasis. Infiltrating, and undifferentiated typestended to peritoneal dissemination.