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The patient was a 75-year-old man who had undergone potentially curative surgery for Stage Ⅲb rectal cancer followed by resection of liver metastases. Two years after the resection of liver metastases, lung and remnant liver metastases were found. He received chemotherapy for unresectable metastatic tumors. Based on the findings of molecular and pathological examinations(RAS: wild type; BRAF: wild type; MSI: negative; HER2: negative), the following chemotherapy regimens were administered: first-line, FOLFIRI plus panitumumab(PANI); second-line, mFOLFOX6; third-line, trifluridine/tipiracil; fourth- line, regorafenib. After fourth-line treatment, he was judged to have disease progression due to the increase in his lung and liver metastases and the elevation of tumor markers. All standard regimens were refractory, but the Eastern Cooperative Oncology Group performance status was zero and a liquid biopsy for RAS still showed wild type. Therefore, rechallenge therapy with anti-epidermal growth factor receptor(EGFR)drugs, cetuximab(CET)and irinotecan(IRI), was administered 13 months after the final course of FOLFIRI plus PANI treatment. After 4 courses of CET plus IRI, the size of the 2 metastatic tumors markedly decreased and his tumor marker levels normalized.

This study reports a case of a 61-year-old man with a chief complaint of anemia. The patient was diagnosed with esophageal cancer(Stage Ⅰ). Preoperative examination revealed alcoholic liver cirrhosis(Child-Pugh A, liver damage B). After a period of abstinence to improve liver function, minimally invasive esophagectomy, retrosternal reconstruction with a gastric tube, and two-field lymph node dissection were performed. The thoracic duct was preserved during the operation. Post- surgery, the bill pleural effusion was increased. Drainage was initiated using thoracentesis with frosemide, spironolactone, and tolvaptan. On post-operating day(POD)35, the patient was discharged; however, right pleural effusion continued to increase. Therefore, cell-free and concentrated reinfusion therapy for right pleural effusion was performed on POD 56. After the treatment, the pleural effusion was well-controlled with 20 mg of frosemide. This case suggested that cell-free and concentrated pleural effusion reinfusion therapy contributed to the management of refractory pleural effusion in patients with esophageal cancer accompanied by cirrhosis.

Case 1: The patient was a 74-year-old man with a performance status(PS)of 0. He was referred to our department for pyloric gastric cancer with multiple liver, lung, and lymph node metastases. We started chemotherapy after making the diagnosis of an unresectable gastric cancer. During chemotherapy, the hemoglobin level dropped due to bleeding from the tumor. We attempted endoscopic hemostasis, which was not successful; therefore, we attempted a palliative radiotherapy. The total dose was 30 Gy in 10 Fr and hemostasis was achieved on the 10th day from the start of the radiotherapy. There were no adverse events due to the radiation, and the chemotherapy could be restarted 5 days after the end of the radiotherapy. Case 2: The patient was a 78-year-old man with a PS of 2. He was referred to our department because of vomiting and anemia. As a result of a close inspection, we made the diagnosis of an unresectable gastric body cancer with para-aortic lymph node metastasis and peritoneal dissemination, for which chemotherapy was initiated. Anemia was observed at the first visit, and we started radiotherapy to stop the tumor bleeding. The total dose was 30 Gy in 10 Fr, and hemostasis was achieved on the 12th day. There were no adverse events during the radiotherapy, and chemotherapy could be continued. Palliative radiotherapy is an available method of hemostasis that is less invasive than surgery or transcatheter arterial embolization and can be expected to have a certain effect for gastric cancer bleeding, although it takes several days to obtain a therapeutic effect.

A 60-year-old man underwent thoracoscopic subtotal esophagectomy and posterior mediastinal gastric tube reconstruction after neoadjuvant chemotherapy. One year and 8 months postoperatively, recurrence was observed in the abdominal lymph nodes around the celiac artery and abdominal aorta. Chemoradiotherapy was initiated, followed by chemotherapy. Two months after the completion of chemoradiotherapy, the patient developed epigastric pain and anorexia because of the necrotic lymph node penetrating the gastric tube with cavity formation. Upper gastrointestinal endoscopy revealed a 25- mm-sized ulcer with central necrotic slough on the posterior wall of the stomach. Abdominal symptoms alleviated after conservative treatment with fasting and administration of antibiotics, and the inflammatory reaction improved. Oral nutritional supplements were started on hospitalization day 7, and abdominal symptoms or inflammatory reactions did not recur after resuming diet. The patient was discharged on hospitalization day 39 when the general condition stabilized. Subsequently, chemotherapy was restarted, and no regrowth of metastatic lesions was observed on endoscopy or CT examination 4 months later. Three years and 8 months after the recurrence, the recurrent disease has been controlled.

Comprehensive genomic and transcriptome analyses using next-generation sequencing(NGS)analysis has lead a discovery of a variety of novel driver gene mutations and new therapeutic targets for cancer patients, and has remarkably improved outcome of the patients through the development novel molecular targeting drugs. Even so, in so-called intractable or refractory cancers, those "druggable"alterations common to the diseases are rarely found due to the high diversity of the tumor. Furthermore, most of molecular target therapy is known to acquire the resistance to the drug by means of multiple factors such as up-regulation of the partially inhibited pathway, mutation of the target, activation of alternative pathways, histological translocation, and oncogene de-addiction. Understanding of intra-tumoral heterogeneity and tumor-stromal crosstalk in tumor microenvironment with consequence of biological network re-construction are also of key importance to overcome the resistance. These suggest the limitation of mono-layer OMIC approach focusing on genome and/or cancer cell alone to identify truly effective therapeutic target and biomarker. Under these circumstances,"Trans-OMICS" concept has emerged as a novel approach to clarify a global biochemical network across multiple omics layers(eg genome, transcriptome, proteome, and metabolome)directly correct with a variable phenotype by use of both multi-omic measurements and computational data integration. This approach has great potential for drug discovery and clinical implementation of omics-based cancer medicine. We introduce here the outline of technologies and analysis for Trans-OMICS approach, and review for the recent studies in oncology research with showing our recent attempt.

A 51-year-old woman was seen in our hospital because an ascending colon tumor with extensive abdominal wall abscess was detected on computed tomography(CT). On the same day, we performed open drainage and laparoscopic assisted ileocolostomy. Postoperative day 35, we performed right hemicolectomy with abdominal wall resection and closure of the colostomy as a radical surgery. After surgery, we started(negative pressure wound therapy: NPWT)to the surgical wound site; hence, the abdominal wall defect could be healed without a musculocutaneous flap. Laparoscopic assisted open drainage, a two-stage operation, and NPWT are useful in a case of colon cancer with abdominal wall abscess.

We report a case of heterochronic cervical esophageal cancer with a subcutaneous abscess successfully treated using chemoradiation. A 68-year-old man underwent esophagectomy for middle thoracic esophageal cancer 13 years ago. In April 2015, upper gastrointestinal endoscopy revealed advanced residual cervical esophageal cancer. Enhanced CT showed a massive tumor with a subcutaneous abscess, and the tumor had invaded the left internal jugular vein and the 8th cervical spine. We firstly performed abscess drainage and administered antibiotics. After the inflammation decreased, we started chemora- diation. Chemotherapy consisted of 70mg/m / 2 cisplatin(day 1)and 700 mg/m2 5-FU(days 1-5)combined with almost 60 Gy radiotherapy(1.8 Gy/day, 5 days/week, days 1-49). We administered cisplatin and 5-FU only once because renal dys- function occurred. Consequently, we changed the regimen to weekly 100mg/m2 paclitaxel administration(day 1). After 2 months, a clinical complete response(CR)was obtained and we stopped chemotherapy. Eight months after chemotherapy cessation, the patient shows no sign of recurrence. These results suggest that chemoradiation is an effective treatment for cervical esophageal cancer with a subcutaneous abscess.

An asymptomatic 35-year-old man visited our hospital because of an esophageal abnormality identified on a medical check-up. Gastrointestinal endoscopic examination revealed a 4 cm diameter submucosal tumor(SMT)in the upper esophagus. endoscopic ultrasound fine-needle aspiration biopsy(EUS-FNAB)was performed. Histopathological examination showed that it was strongly positive for a-SMA and partially positive for c-kit. An esophageal leiomyoma was suspected but esophageal gastrointestinal stromal tumor(GIST)could not be completely ruled out. After considering the patient's age and the location of the tumor, we performed thoracic enucleation of the esophageal SMT. Immunostaining findings showed that it was a-SMA positive and S-100 negative. Mast cells, but not tumor cells were partially stained with c-kit. The final pathological diagnosis was leiomyoma. The postoperative course was uneventful. We report this case together with a review of the literature.

Cancer mortality in Japan is forecasted to become high; thus, learning about cancer, cancer prevention, and cancer treatment will be indispensable for the Japanese. Recognition of the increasing rates of cancer has initiated a discussion regarding the introduction of cancer education into the regular educational curriculum for the younger generation. The importance of cancer education is noww idely recognized, and the 2nd Basic Plan to Promote Cancer Control Programs is directed at early initiation of education. The Ministry of Education, Culture, Sports, Science and Technology is nowreview ing the detailed plan, with an intention to draw a conclusion by the end of the 2016 business year. However, ongoing debates have revealed that there are many obstacles in the way of this practice. Much effort should be directed at solving these issues in the most realistic way. This paper reviews potential actions by oncology specialists, and attempts to clarify the possible role of an academic society for oncology specialists in the development of cancer education systems at school.

Background: Japan Society of Clinical Oncology published a guideline for anti-emetic therapy two years ago. This guideline was a first evidence based guideline of anti-emetic treatment for the patients who received chemotherapy in Japan. To investigate a current situation of anti-emetic treatment in Japan, we analyzed the data from nationwide questionnaire., Material: Questionnaire analysis; From June 2012 to August 2012, we gave 24 questionnaires on the Japan Society of Clinical Oncology Website and collected the response from the member of 5 major academic oncology societies. The questionnaires included degree of recognition, penetration, usefulness, problems and user type of medial stuff for the anti-emetic guideline published by (JSCO)., Results: Questionnaire; 1,529 medical stuff responded to our questionnaire. 1,308 (85.5%) stuffs recognized JSCO guidelines, 586 (51%) had regard for guideline and 489 (42.6%) referred to the guideline. 899 (78.3%) changed their practice in clinic to recommended practice by the guideline. But 385 (33.5%) complained high medical cost of recommended anti-emetic therapy., Conclusions: Degree of recognition and penetration of our guideline for anti-emetic therapy were very high in Japan.

The use of hepatectomy for the treatment of liver metastasis from gastric cancer has been controversial. We report a case of metachronous liver metastasis from gastric cancer, which we successfully treated with hepatectomy. A 59-year-old man underwent laparoscopy-assisted total gastrectomy with D1 plus lymphadenectomy for gastric cancer. The histopathological findings revealed that the tumor was a well-differentiated tubular adenocarcinoma, T2(MP), N1(#1 2/3), M0, fStage II, according to the 14th edition of the Japanese Classification of Gastric Carcinoma. TS-1 was administered as adjuvant chemo- therapy for 1 year after the operation. About 5 years after the gastrectomy, a recurrent tumor was detected in S5/8-7 of the liver. Although chemotherapy with TS-1 plus Lentinan was administered, the liver tumor increased in size. Percutaneous transhepatic portal embolization was performed to improve liver function followed by resection of the right lobe of the liver. Paclitaxel plus doxifluridine (5'-DFUR) was administered for 6 months as adjuvant chemotherapy. No recurrence was observed for 17 months after hepatectomy.

A 35-year-old woman underwent hemicolectomy and RFA for ascending colon cancer with multiple liver metastases in February, 2005. She received postoperative hepaticarterial infusion chemotherapy with 5-FU, and systemic hemotherapy with UFT for 10 months after the operation. A local recurrence of the anastomosis was detected in March, 2006, and she underwent a resection for it. This was followed by 6 courses of adjuvant chemotherapy with modified FOLFOX6. Because multiple liver metastases and lymph node metastases were detected in March, 2007, she received RFA and 6 courses of adjuvant chemotherapy with modified FOLFOX6 again. Liver metastases disappeared but lymph node metastases still remained. Therefore, she received 4 courses of bevacizumab plus modified FOLFOX6. The metastatic lesions disappeared and were judged to be CR. Therefore, she was followed-up with the oral administration of UFT. Metastases of liver and lymph nodes of the mediastinum were detected in May, 2008, for which she received 4 courses of bevacizumab plus FOLFIRI2. Because the effects of the chemotherapy were judged to be CR, she continued with 4 courses of the same regimen. The regimen was discontinued due to diarrhea, and she therefore began to receive 4 courses of bevacizumab plus LV/5-FU regimens. CR has been maintained at present, over 7 years after the initial surgery.

A 61-year-old complaining of anorexia and general fatigue was admitted to our hospital for further examination. She was diagnosed as advanced sigmoid colon cancer with multiple metastases of lung, liver, and left hydronephrosis. Since curative surgery was not deemed possible, we started chemotherapy with bevacizumab/FOLFOX6 (bi-weekly drip infusion). After the 6th course, colonoscopy revealed a significant tumor reduction and changes to the scar tissues. CT did not reveal a complete disappearance, but found some reductions in metastases of lung and liver. Sigmoidectomy and lymph node resection (D1) were performed. We did not disappeared any dissemination and the histological diagnosis revealed a complete disappearance of cancer cells in the main tumor. She was discharged 13 days after surgery, following chemotherapy which included bevacizumab and XELOX. The chemotherapy using bevacizumab/FOLFOX6 is a candidate for the standard treatment strategy for inoperable advanced colon cancer. Herein we report this rare case with a review of the literature.

A 46-year-old woman with lower abdominal distension was diagnosed as gastric cancer in our hospital. She had multiple metastases of lungs, lymph nodes, bilateral ovaries, and uterus. After she underwent sub-total gastrectomy, bilateral oophorectomy, and total hysterectomy, she received adjuvant chemotherapy followed by docetaxel and S-1. After 6 courses of chemotherapy, PET/CT revealed no recurrences (complete response), and she was therefore administered S-1 for only 6 months. She has remained without recurrence 15 months after the operation.

Major advances in cancer research, remarkable progress in cancer management and the rapid increase of cancer incidence force public attention upon the unsetted education system of oncology specialists, in Japan. Despite the well-recognized importance of education, very few formal training programs have been established due to little collaboration among many specialties. Cancer patients and their families require the best care and support through the entire process, and optimal treatment for patients cannot be provided without an oncology health care team that includes various specialists such as medical-, radiation-, and surgical oncologists, among other professionals. The increasing demands of oncology experts promote the establishment of a nationwide education system of various oncology subspecialties, and the urgent requirement for rapid improvement has brought about a unique primary certification system for oncology, Gann-chiryou Ninnteii: This system provides education for candidates in basic principles common to management and treatment of malignant diseases, which can enhance the quality of oncology care. Educational programs for various oncology subspecialties such as drug and radiation, and palliative medicine, are also rapidly developing in Japan, but many obstacles remain. A wide variation is still found among the different oncology subspecialties regarding the requirements of such training programs including admission requirements to the programs and the training duration. For clinical oncology disciplines in Japan, the final destination and the most effective way to the goal were discussed by introducing the special circumstances and latest status.

The development of new active agents, along with rapid progress in biomedical technology in recent decades, has resulted in major progress in cancer treatment, but at the same time it has made cancer management much more complex: Medical treatment must now be supplemented by various other types of care. Cancer patients and their families require the best care and support through the entire process, and optimal treatment for patients cannot be provided without an oncology health care team that includes various specialists such as medical-, radiation-, and surgical oncologists, and other professionals. The oncology education system in Japan, however, is unable to comply with this demand at present, although educational programs for highly trained and dedicated oncology experts are rapidly developing. Oncologists, whether subspecialized in medical, pediatric, radiation, or surgical oncology, must comprehend a formidable knowledge base and then effectively interact with medical colleagues in a wide range of disciplines in cancer care. Since the rapid improvement of this poor oncology environment is urgently required, the Japanese Board of Cancer Therapy has made a proposal to develop a primary certification system for oncology, Gannchiryou Ninnteii: This system provides education for candidates in basic principles common to management and treatment of malignant diseases, which can enhance the quality of oncology care and also maintain the standards for certification of various oncology specialists who are now developing in Japan. Candidates are required to pass the certifying examination after satisfactory completion of graduate education in a specialty and the following training programs as a fundamental oncologist. The first certifying examination is scheduled in January, 2008. The details for certification were reviewed.

Worldwide research on the human genome exerts a major impact on medical science. The growing evidence that genetic polymorphisms in the metabolism, the disposition, and the targets of drugs can have an even greater influence on the efficacy and the toxicity led to the creation of a novel chemotherapeutic strategy, personalized medicine. Much effort has been directed toward identifying the indicators of individual response to drugs, and these studies have provided a variety of potent predictive markers of individual drug response, which include some significant markers in clinical practice with sufficient evidence. Personalized medicine based on the response prediction using genomic marker is increasingly being recognized as a practical treatment approach in cancer chemotherapy, and to be indispensable when molecular targeted drugs are involved in the therapy. Even so, the ingenious and intricate mechanism of individual drug response creates obstacles in predicting chemotherapeutic response: Multiple factors are involved in the mechanisms, and key factors for drug response vary significantly among individuals. DNA chip technology enables us to overview a huge number of gene expressions simultaneously, but gene expression profiles of drug sensitivity vary considerably even for the same drug, which shows the limited value of a static microarray-expression profile as a marker aimed at individualizing patient therapy. Selection of a set of truly significant genomic markers and understanding of their interplay are of key importance in prediction of individual response to drug therapies. Challenges to such biological complexity are now started to identify a better genomic marker. The contribution of genomic marker research to anticancer chemotherapy and problems of the day were reviewed.

Pharmacogenomics is a large-scale systematic approach using a variety of genomic technologies to discover drug response determinants and promote a better understanding of the genetic and molecular basis underlying variable drug response among patients. However, few critical prediction markers of drug response have been validated to date. Drug sensitivity is determined by multiple genes:drugs are often involved in complex metabolic pathways before they produce anti-cancer activity, and the related genes do not act in isolation. Although the worldwide research on the human genome exerts a major impact on medical science and advanced medicine, the detailed function and interaction of most genes remain unclear. There is clear evidence that a variety of genes are closely associated with cellular drug sensitivity, but most of the regulatory mechanisms of their expressions are poorly understood. To understand the drug sensitivity mechanism and identify the key biomarkers, recent attention has focused on the transcriptional mechanisms of drug sensitivity genes and their network. These approaches in genome research and the functional analysis may revolutionize the anticancer chemotherapy world. The possible contribution of new challenges and problems of the day were reviewed while showing recent findings on the analyses of 5-FU metabolic pathway and the key gene DPYD as an example.

In the present study, we demonstrate the treatment results of TS-1 on 22 gastric carcinoma patients (15 far advanced and 7 recurrent patients) from June 1999 to December 2000. TS-1 was administered at 75 mg/m2/day, twice daily per body for 28 days followed by a 14-day interval (1 cycle). Successful treatment was obtained in from 1 to 11 cycles, and we obtained 9 (47.4%) partial responses (PR), 7 stable disease (NC) and progressive disease (PD) among 19 evaluable patients. PR was obtained in 7 (58.3%) out of 12 primary lesions of the stomach. We also obtained 1 CR of liver metastasis and 4 PR of 9 distant lymph node metastases (44.4%). Moreover, malignant ascites disappeared in 4 (57.1%) out of 7 cases and PR was obtained in 3 (50%) out of 6 measurable cases of peritoneal disease. In addition, two patients had hydronephrosis which improved after 1 cycle of TS-1 treatment. The adverse effects observed were grade 3 bone marrow suppression in three cases, severe diarrhea in one case, one case of liver dysfunction and a few cases of nausea and vomiting. These results indicate that the oral tegafur compound, TS-1, is a new therapeutic tools for advanced and recurrent gastric carcinomas, especially peritoneal disease.

Worldwide research on the human genome is having a major impact on medical science and advanced medicine, although the detailed function and interaction of most genes remain unclear. The elucidation of human genome data makes it possible to take global views of biological processes and characteristics of cancer and individual drug response. This brings a number of new challenges such as genome based drug development and tailored cancer chemotherapy based on the individual genomic make-up. When a disease gene is identified, truly effective drugs targeting the genes can be developed. When biological characteristics such as polymorphism and gene expression profiles are closely related to drug response, an individually optimized drug therapy can be realized. cDNA microarray technology and new high-throughput single nucleotide polymorphism (SNP) screening offer great hope for such a global view by providing a systematic way to survey DNA and RNA variation. Evolutionary engineering techniques continue to be developed, which significantly promotes studies to understand molecular mechanisms causing diseases, novel disease genes, and genes related to drug response. Such progress in genome research and the functional analysis may revolutionize the anticancer chemotherapy world. The possible contribution of genome research to anticancer chemotherapy and problems of the day are reviewed herein.

Low-dose FP therapy was carried out in 30 patients with far advanced gastric cancer and assessed according to anti-tumor effect and quality of life (QOL). This therapy consisted of CDDP (3.5-7 mg/m2/day infused on Days 1-5 every week) and continuous infusion of 5-FU (250 mg/m2/day for 28 days). A partial response was observed in 15 cases, so the overall response rate was 50%. The response rates with stomach and lymph node cancers were higher than those of other organs (64.3% and 55.6%). Patients without peritoneal dissemination, with good performance status (PS) (0, 1) and differentiated histologic type showed a significantly higher response rate than patients with peritoneal dissemination, poor PS (2, 3, 4) and undifferentiated histologic type (p = 0.0034, 0.0253, 0.0080). No side effects (> or = WHO grade 3) were observed. The QOL of patients was assessed according to the percentage of patients with an observed improvement of diet, who could be discharged from hospital, and the duration in hospitals in relation to survival time (hospital stay). The QOL of patients with low-dose FP therapy was better than that of patients with usual combination chemotherapy. Low-dose FP therapy is a promising regimen for patients with far advanced gastric cancer.

A nationwide questionnaire survey was carried out on low-dose cisplatin-5-FU therapy for solid malignant tumors (mostly stomach and colon cancer) regarding its antitumor as well as adverse effects. The regimen was defined as 4 weeks administration of cisplatin 2-5 mg/body, 5 days a week, which was used in 47% of 82 institutions studied. Cases were classified into an Ab regimen (86 cases) with cisplatin 3-5 mg/body, and a Bb regimen (122 cases) with cisplatin 6-30 mg (mostly 10 mg)/body, both of which were given 5-FU 300-500 mg/body daily. The antitumor effect (CR + PR) was shown to be slightly higher in the Bb regimen than in the Ab regimen, and was 35% overall. Very few adverse effects appeared with either regimen for mostly major digestive, hepatic and renal functions, except for myelodepressions (leucopenia and thrombocytopenia), which were more than grade 3 in only a few percent with the Ab regimen, and a little more than 10% with the Bb regimen. The advantages and disadvantages of the A/Bb regimens appeared to be counter-balanced in terms of their antitumor and adverse effects. Most institutions using the Ab regimen favored repeating the regimen cycle as much as possible. Those using more than 6 cycles accounted for about 20% of hospitals.

We devised an X-ray examination to detect early gastric cancer, especially small gastric cancer, during the period between 1996 and 1997. As a result, the rate of gastric cancer detection by mass screening was 0.50%; and the rate of early gastric cancer detection was 79%. 1. Characteristics of gastric cancer detected by mass screening: Characteristics of gastric cancer were depressive-type undifferentiated cancer less than 4.0 cm diameter in work-place screening and depressive-type differentiated cancer less than 4.0 cm in area screening; 2. gastric cancer less than 2.0 cm in diameter was 75 (68%) of the 110 cases (total detected gastric cancer). 2) We have to consider that gastric cancer differs by sex and age. 3) EMR accounted for 39 (35%) of the 110 cases in treatment. This method resulted in a higher gastric cancer detection rate and served to maintain QOL.

Precise prediction of recurrence risks is of importance in the selection of adjuvant chemotherapy. A proportional hazards regression analysis was performed to seek objective criteria for 234 gastric cancer patients. The analysis showed that a high level of carcinoembryonic antigen (CEA) in peritoneal washing (100 ng/g protein) was an independent risk factor for peritoneal recurrence, and a high MMP9 (92 KD type IV collagenase) level in serum was a powerful indicator of hematogenous recurrence. In addition, the PHREG analysis in 1453 gastric cancer patients showed that MF therapy (mitomycin C i.v. + fluoropyrimidine derivatives) and PF therapy (Cisplatin i.p. + fluoropyrimidine derivatives) might be effective in the prevention of hematogenous and peritoneal recurrence after a curative operation, respectively. Based on these findings, a recurrence type-oriented adjuvant chemotherapy, i.e., PF therapy for high CEA group and MF therapy for high MMP9 group, was designed. The retrospective analysis showed significant survival benefit in stage III gastric cancer patients who underwent a curative operation. The 5-year survival rate was 67%, while that of the historical control was 46%. Prediction of recurrence type using CEA levels in peritoneal washings and MMP9 levels in sera may be of value in the selection of a proper population of patients for PE or MF therapy after gastrectomy. The selection system of adjuvant chemotherapy using such objective criteria may improve the prognosis of gastric cancer patients and keep their good quality of life through the selection of proper candidates and by eliminating patients in no need of therapy.

Using 4 human cancer cell lines, the relevance of NAD(P)H: quinone oxidoreductase (DT-diaphorase) activity to mitomycin C (MMC)-induced cytotoxicity was investigated. KB cells (oral epidermoid carcinoma) had more than 4 times higher DT-diaphorase activity than PH101 (pancreatic cancer), SH 101 (gastric cancer), or K562 (myelogenous leukemia) cells. The sensitivity to MMC was greatest in KB cells. Concentrations causing 50% inhibition of cell growth (IC50 value: microgram/ml) by 30 min treatment with MMC were 0.4 in KB, 1.1 in PH101, 1.6 in SH 101, and 1.9 in K 562. Treatment with 1.5 micrograms/ml of MMC induced DNA total cross links, and the indices were 0.18 in KB, 0.10 in SH101, 0.09 in SH101, and 0.06 in K 562. When DT-diaphorase activity was inhibited by non-toxic dicoumarol (50 microM), DNA damage and cytotoxic activity induced by MMC were decreased in all cells examined. Especially in KB cells, it was remarkable. Since it was shown that the level of cellular DT-diaphorase activities were correlated with the responses to MMC, we suggest that bioreduction by DT-diaphorase may activate MMC.

A biscoclaurine alkaloid, cepharanthine (CE) potentiated antitumor activity of doxorubicin (ADM) against human carcinoma cell lines, K 562 (myelogenous leukemia), PH 101 (pancreas cancer) and SH 101 (gastric cancer). The effect of CE was irreversible and ADM activity was potentiated only in the presence of CE. While, CE could not augment anticancer activities of mitomycin C (MMC) or 5-fluorouracil (5-FU). We also found an increase of cellular plasma membrane potential in the presence of CE. In physiological condition, ADM was charged positively, while MMC or 5-FU was neutrally charged compound. Thus, we suggest that CE can potentiate the activity of positively charged anticancer drugs by increasing plasma membrane potential. Since electronegative plasma membrane potential exerts a net driving force which attracts and retains positively charged compound, it may be accompanied with an increase of drug accumulation.

In order to determine the most effective anticancer agent for individual human tumor, we have performed several chemosensitivity tests, such as human tumor clonogenic assay (HTCA), succinic dehydrogenase inhibition test (SDI-T), nude mouse isotope assay (NM-IA) and subrenal capsule assay (SRCA). In this study, an novel in vitro chemosensitivity test (ATP-assay) measuring ATP amounts of cancer cells was carried out in 69 fresh gastro-intestinal tumors obtained at surgery. As the results, the evaluable rate of ATP assay was 87.0%. The positive rate of ATP assay against all tumors were 13.3% in mitomycin-C (MMC), 11.7% in adriamycin (ADM), 13.3% in 5-fluorouracil (5-FU) and 18.3% in cis-diamminedichloroplatinum (CDDP), respectively. Overall predictive accuracy rate was 82.8%. The comparative study of the survival rates of the patients with stage IV gastric cancer, receiving sensitive anticancer agents assayed by ATP assay, and those receiving negative anticancer agents revealed that the survival rate of the patients treated with sensitive drugs was longer with Kaplan-Meier analysis. From these results, it seems reasonable to conclude that ATP assay is of value in determining the chemosensitivity of gastrointestinal cancer in each patient.

The effectiveness of bestatin combined with mitomycin C and tegafur as an adjuvant to surgery for gastric cancer was investigated in a prospective randomized controlled study. All patients underwent curative gastrectomy during the period from November 1980 to April 1984. Five-year survival rate revealed no significant difference between groups with or without bestatin. The effectiveness of bestatin was suggested in postoperative peritoneal recurrence in cases with positive histological invasion into the veins of the stomach wall.

In order to determine the most effective anticancer agents for individual human tumor, succinic dehydrogenase inhibition test (SDI-T) and adenosine triphosphate inhibition assay (ATP-A) as in vitro chemosensitivity tests were performed. Fifty tumors and 57 tumors derived from cancer patients surgically methods were examined by SDI-T and ATP-A respectively. As the results, the evaluable rate was 70% by SDI-T and 94.7% by ATP-A, respectively. With SDI-T, the positive rate against all tumors was 51.4% in mitomycin-C (MMC), 42.9% in adriamycin (ADM), 20.0% in 5-fluorouracil (5-FU), 54.3% in cis-diamminedichloroplatinum (CDDP). On the other hand, with ATP-A, that was 20.4% in MMC, 29.5% in ADM, 20.6% in 5-FU, 20.4% in CDDP, respectively. Retrospective and prospective clinical trials were also carried out to determine the usefulness of both assays. With SDI-T, overall predictive accuracy rate was 57.1% while with ATP-A that was 88.9%. Furthermore, the rates of sensitivity for the same tumors using SDI-T and ATP-A were compared. The rate of the same sensitive cases in both assays were 30% with MMC, 70% with 5-FU, 42.1% with ADM, 36.8% with CDDP, respectively. In conclusion, it is suggested that ATP-A was more useful than SDI-T as in vitro chemosensitivity test to determine the most adequate drug for cancer patients.

The present study was designed to predict the clinical effect of UFT and FT-207 in short-term administration using a nude mouse-xenograft system. Five human tumor xenografts transplanted into nude mice were used. UFT and FT-207 were administered with the LD10 doses orally for seven consecutive days. Tumor size was measured on day 7, 14 and 21 after the administrations. No significant differences in antiproliferative effects were observed between the measurements of tumor size made on day 7 and day 21. UFT inhibited significantly the tumor growth of CH-I established from colon cancer in which the prolongation of life span has been obtained by clinical long-term administration of UFT. These results suggest that this chemosensitivity test system using nude mice is useful for prediction of clinical response at 7 days after final administration of UFT and FT-207.

From January 1984 to December 1987, 63 unresectable liver cancers (22 hepatocellular carcinoma and 41 metastatic liver cancer) were treated with multidisciplinary therapy: partial resection of liver, hepatic arterial infusion, coagulation therapy using microwave tissue coagulator and intratumoral injection of the liver. The median survival period was 5-7 months, and the clinical response rate was 21.6% in these therapies, but there was no statistically significant difference between the treatments. Recently, we usually use degradable starch microspheres (DSM) with anticancer agents in hepatic arterial infusion. Adriamycin + DSM was administered for hepatocellular carcinoma, and Mitomycin C + DSM was used for metastatic liver cancer. The regimens were used for 12 cases, 6 of hepatocellular carcinoma and 6 of metastatic liver cancer, with a response rate of 50%, respectively. We also undertook chemosensitivity tests for liver cancer. The coincidence of clinical response with results of chemosensitivity tests was above 50%. In future, we shall use the most effective anticancer agents for individual tumors with DSM in arterial infusion.

The anticancer activity of KW2149, a new derivative of mitomycin C (MMC), was investigated against 5 human tumor xenografts derived from digestive organs using 4-day subrenal capsule assay (SRCA). Normal immunocompetent mice were used in this assay. For the comparative study, KW 2149 and MMC were administered intraperitoneally for 3 days after implantation, and the anticancer activity and the weight loss of mice were evaluated. The total doses were determined as 1/2, 1/3 and 1/4 of LD50 value of each anticancer agent. The anticancer activities of the two drugs were almost the same with no significant difference in 3 xenografts. Thus, it may be suggested the difference of the anticancer spectrum between the two drugs. The anticancer activity of KW2149 indicated higher correlation with the administered doses as compared with MMC. The toxicity of KW2149 was almost the same as MMC according to the weight loss of mice.

A chemosensitivity test for UFT and FT-207, which are used in long-term administration clinically, was investigated for prediction of clinical response. Five transplantation-established human tumor xenograft systems were examined using subrenal capsule assay. Both anticancer agents showed antiproliferative effects according to the total administered dose. Two of 5 tumors were determined to be sensitive to UFT using microscopic measurements following intragastric administration of 1/2 of the LD50 value, while they were shown to be resistant to 5-FU. In these two cases, prolongation of life span by long-term administration of UFT was shown clinically. All these experiments could be performed on condition that the loss of body weight in mice was less than 20%. These results suggest that in the 4-day subrenal capsule assay, clinical responses to long-term administration of UFT or FT-207 are predictable using intragastric high-dose administration which does not induce more than 20% body weight loss in experimental mice.

Using the human tumor clonogenic assay technique, the combined effects of mitomycin C (MMC) with alpha-interferon (HLBI) were surveyed in comparison with 33 fresh human tumor specimens. Tumors in this study were 16 gastric cancers, five breast cancers, four liposarcomas, three colon cancers, two gall bladder cancers, two esophageal cancers, and one hepatoma. When the survival fraction observed in drug combination was smaller than the multiplication of each survival fraction observed in each drug alone, the combined effects were considered to be synergistic. Twenty-two of 33 tumors (gastric cancer 11/16, breast cancer 5/5, liposarcoma 2/4, colon cancer 1/3, gall bladder cancer 2/2, esophageal cancer 1/2, and hepatoma 0/1) formed adequate colony numbers for the evaluation of combined drug effects. Synergistic effects were observed in seven tumors (three gastric cancers, one breast cancer, one gall bladder cancer, one liposarcoma and one esophageal cancer), although three tumors (one gastric cancer, one gall bladder cancer, and one colon cancer) exhibited antagonistic effects.

A rapid method using nude mice has been established as an in vivo model for assessing the chemosensitivity of individual human tumors, in which the final evaluation is made with 3H-thymidine (3H-TdR) incorporation into the treated tumor. In 234 of 289 cancers, the chemosensitivity of anticancer agents was evaluated by this method. This assay proved to be feasible in a sufficiently high percentage of human primary tumors (81.0%). The rate of positive sensitivity against all tumors was 23.8% for MMC, 12.3% for 5-FU, 29.1% for CPM and 23.5% for ADM, respectively. The sensitivity of anticancer agents varied according to the type of cancer. Correlation between the sensitivity test and the end results after chemotherapy in cases of inoperable gastrointestinal cancers was investigated, prospectively. Out of 19 cases, the 50% survival time of 11 patients treated with sensitive agents was longer than that of 8 patients treated with insensitive agents. From a prospective-correlative study carried out on 25 patients, this assay appeared to be correlated with clinical response (overall agreement, 76.0%) with specific agreements of sensitivity and resistance of 37.5% and 94.1%, respectively. From these results, it seems reasonable to conclude that this sensitivity test using a human/nude mouse system is a useful screening assay for revealing appropriate agents for the treatment of patients with cancer.

Comparative studies between the in vitro human tumor clonogenic assay (HTCA) and our original in vivo method (NM-IA) in which the final evaluation was made with 3H-TdR incorporation of tumor cells transplanted into nude mice were simultaneously performed on 44 fresh human solid tumors (22 gastric cancers, 6 breast cancers, 4 gall bladder cancers, 4 liposarcomas and 8 other tumors). Mitomycin C (MMC), 5-fluorouracil (5-FU), adriamycin (ADM) and cyclophosphamide (CPM) were tested. The evaluable rate was 73% (32/44) in HTCA and 89% (38/44) in NM-IA. Although correlation between the results of HTCA and those of MN-IA was obtained for MMC and ADM, no correlation was observed for 5-FU and CPM.

Clinical trials of 4-day subrenal capsule assay (SRC assay) were carried out. One hundred and forty-one cases were investigated in order to evaluate the clinical utility of the assay. A total evaluability rate of 81.0% and a response rate of 36.5% were obtained in the SRC assay. The overall predictive accuracy between the tumor sensitivity of the assay and the clinical response was 82.1%. The percentage inhibition of %DNA/protein content of the implanted tumor, as a new predictor of the tumor growth inhibition, also indicated a good prediction rate for the assay. Correlation between the sensitivity test and the end results after chemotherapy in cases of inoperable gastric cancer classified as stage IV was investigated, retrospectively. Comparison of the survival curves between the patients treated with sensitive agents and those with insensitive agents exhibited a significant advantage for the former (p less than 0.01). These results suggest the utility of the SRC assay for clinical use, but histological studies exhibited certain limitations of this assay due to the existence of early host rejection of the implanted tumor. The utility of the SRC assay should be finally evaluated using more histological assessments and clinical trials.

The combined effects of Mitomycin C (MMC) with alpha-interferon (HLBI) or gamma-interferon (TRP-2), which have become attractive drugs for use as Biological Response Modifiers, were investigated using the human tumor clonogenic assay technique. Tumors in this study were five human tumor xenografts serially transplanted into nude mice (three gastric cancer, two colon cancer). When the survival fraction occurring with the combination was smaller than that obtained by multiplication of the survival fractions occurring with either drug alone, the combined effect was considered to be synergism. Four out of five xenografts (three gastric cancer, one colon cancer) showed synergistic effects for the combination of MMC with alpha-interferon. Although two gastric cancer xenografts showed synergism for the combination of MMC with gamma-interferon, antagonistic effects were observed in one gastric cancer and one colon cancer xenograft.

Subrenal capsule assay(SRC assay) has been reported to be an effective and rapid method for predicting the tumor sensitivity of individual patients to anti-cancer agents. In order to establish a more objective method of determining sensitivity in SRC assay the DNA content was measured by the schmidt-Thannhauser-Schneider method and the protein content was estimated using Bio-Rad protein assay, after removal of a tumor implanted in the subrenal capsular space of ddY mice. Percentage inhibition of DNA/protein had a high correlation with that of relative increase of tumor weight, although three groups treated with mitomycin-C, 5-fluorouracil and cyclophosphamide indicated different values of tumor sensitivity. From these results, the percentage inhibition of DNA/protein seems to be more objective than microscopic measurement for predicting tumor sensitivity.

In order to estimate tumor chemosensitivity of fluoropyrimidine derivative, inhibition of thymidylate synthetase (TS) was investigated using a nude mouse experimental system. Four human tumors xenografted in nude mice; H-111, SH-8 and SH-10, each established from gastric cancer, and EH-1 from esophageal cancer, were used. When the transplanted tumor volumes reached to approximately 200 mm3, 1-hexylcarbamoyl-5-fluorouracil (HCFU) was given for 5 days. Tumors was removed for the measurement of total and free TS at 0 hr, 6 hrs and 24 hrs after the last administrations. Simultaneously, the anti-proliferative effects were investigated according to the therapeutic protocol of NCI. No positive correlation between the inhibition rate of TS and the anti-proliferative effects was observed, although the absolute values of free TS were similar to the tumor inhibition rates. The measurement of total TS provided a highest concentration in SH-8, while extremely low in EH-1. On the analysis of free TS, a significant increase of the concentration was observed at 24 hrs after the last administration compared with at 6 hrs in SH-8. These results indicate that free TS had a potentiality as a new parameter for predicting tumor chemosensitivity of fluoropyrimidine derivative and the analysis of TS should be affected strongly by the characteristics of enzymic activity of examined tumor.

Anticancer activity of KW 2149, a new derivative of mitomycin C (MMC), was investigated using 4 human tumors xenografted into nude mice. The basic methodology was essentially the same with NCI's therapeutic protocol. For the comparative study, KW 2149 or MMC was administered intraperitoneally at a schedule of q4d X 3. Daily doses were determined as a 1/3, 1/4 and 1/5 of LD50 value of each anticancer agent (7.5 mg/kg, 5.6 mg/kg and 4.5 mg/kg for KW 2149, and 2.7 mg/kg, 2.1 mg/kg and 1.7 mg/kg for MMC). Anticancer activity of KW 2149 seemed to be dependent on the doses. Comparing with MMC, KW 2149 produced higher response rates at the doses of 1/3 and 1/4 of LD50 and was less toxic judging from the decrease of the body weight. This study may indicate an utility of KW 2149, as a new anticancer agents, or suggest the difference of anticancer activities between these two agents.

The combined effects of interferon alpha-A/D (IFN alpha-A/D) with 5-fluorouracil and fluoropyrimidine derivatives such as 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur), UFT, 1-hexylcarbamoyl-5-fluorouracil (HCFU) and 5'-deoxy-5-fluorouracil (5'-DFUR), were examined by 4-day subrenal capsule assay. Four human tumor xenografts serially transplanted in athymic mice, H-111, SH-10 established from gastric cancers, CH-4 and CH-5 from colon cancers, were used. In this experiment, the adequate dose of each agent was estimated as 50 mg/kg for 5-FU, 473 mg/kg for tegafur, 433 mg/kg for UFT, 50 mg/kg for HCFU, 185 mg/kg for 5'-DFUR and 1 x 10(5) IU for IFN alpha-A/D, respectively. When synergistic, additive and subadditive effects were defined as positive combined effects, all combinations produced positive combined effects against H-111 and CH-5, while negative ones were observed for all combinations against CH-4. The combinations of 5-FU, HCFU and 5'-DFUR with IFN alpha-A/D produced synergistic effects against SH-10. These results indicate that the combination therapy of 5-FU and fluoropyrimidine derivatives with IFN alpha-A/D would be useful.