Gan To Kagaku Ryoho

[Quality of life assessment in radiation therapy]

Hirokawa Y. Akagi Y. Ito K.
Dept. of Radiology, Hiroshima University School of Medicine, Japan.
Cancer treatment outcome should be evaluated not only with conventional parameters of survival, local control, and response rate, but with quality-of-life (QOL) based parameters. As radiation therapy is a treatment to eradicate cancer without resection of tissues or organs, a better functional or cosmetic result could be obtained compared with surgical treatment. If basically functional or cosmetic results are better, QOL of the patient could be expected to be even more superior. Patient QOL should be assessed from the physical, psychological, and social standpoints. So, adequate instruments or scoring systems are essential to obtain data. In this paper, we introduce an outline of QOL-related research activities in cancer treatment, especially in radiation therapy. We also attempt to assess the functional outcome and late complications, which would affect patient QOL. Finally, the concept of quality adjusted survival time or utility analysis is also mentioned.

Abdominal stop flow infusion breaks drug resistance in systemically pretreated progressive FIGO IIIc and IV ovarian cancer.

Aigner KR. Gailhofer S. Brammer C.
Dept. of Surgical Oncology, Asklepios Paulinen Klinik, Wiesbaden, Germany.
Fourty-five patients with progressive FIGO IIIc (36/45 pts.) and IV (9/45 pts.) ovarian cancer, who were in progression under prior cisplatin-based chemotherapy, were submitted to aortic infusion and stop flow infusion with the same drugs. 36/45 patients (80%) had four-quadrant and 9/45 patients (20%) had two-quadrant peritoneal carcinosis, 33/45 with severe ascites. Overall clinical response was 93%: 5/45 CR (11%), 21/45 PR (47%), 16/45 MR (35%). Complete resolution of ascites occurred in 9/33 patients (27%), a substantial reduction of ascites of more than 50% in 14/33 patients (43%). Median survival time was 12.5 months, median time to progression 8.6 months. Toxicity was minimal and in most patients performance and quality of life improved shortly after therapy.

[Aortic stop flow and hypoxic perfusion chemotherapy for unresectable gallbladder cancer]

Aoki T. Tsuchida A. Aoki T. Asami K. Uda O. Inoue K. Masuhara S. Kasuya K. Ozawa T. Koyanagi Y.
Dept. of Surgery, Tokyo Medical College.
We performed the aortic stop flow and hypoxic perfusion chemotherapy for unresectable gallbladder cancer under general anesthesia and made the perfusion only in the abdominal cavity by clamping the abdominal aorta and inferior vena cava near the site of diaphragma. Although temporary hypertension occurred just after clamping the aorta, no severe problem could be seen during operation. After surgery the patient had no abnormalities such as liver or kidney dysfunction, and tumor markers gradually came to decrease. Furthermore, the effectiveness of this therapy is greatly anticipated for the unresectable abdominal cancer, evaluating the selection of anti-cancer drugs and their administration dosage etc.

[A case of advanced gastric cancer with multiple bone metastasis successfully treated by both methotrexate and 5-fluorouracil sequential therapy, and endoscopic intratumoral injection of 5-fluorouracil]

Sasahara K. Uchida Y. Kamei M. Matsuda K. Kawabata H. Nishioka M.
Third Dept. of Internal Medicine, Kagawa Medical University.
We reported a case of advanced gastric cancer with multiple bone metastasis successfully treated by both methotrexate (MTX) and 5-fluorouracil (5-FU) sequential therapy, and endoscopic intratumoral injection of 5-fluorouracil. A 38-year-old man was admitted to our hospital complaining of appetite loss and bone pain. He could not walk by himself for the bone pain. Upper gastrointestinal endoscopy revealed a lesion like II c + III in the greater curvature of the angulus. By both MTX /5-FU sequential therapy and endoscopic intratumoral injection of 5-FU, partial response (PR) was obtained against gastric primary lesion, and his performance status was improved. PR was maintained for 5 months. Severe side effects of the chemotherapy were not observed.

[A case of unresectable advanced gastric cancer with severe obstructive jaundice responding to combined chemotherapy with 5-fluorouracil and low-dose cisplatin]

Yasumoto K. Iwamoto M. Hoshiko M. Kawabata S. Takeda J. Shirouzu K.
First Dept. of Surgery, Kurume University School of Medicine.
A 69-year-old male patient with gastric cancer complaining severe jaundice was readmitted for the purpose of chemotherapy. The primary tumor was unresectable, and his jaundice was gradually increasing because of the growth of tumor, so the patient was treated by combined chemotherapy with 5-fluorouracil and low-dose cisplatin for 2 courses (1 course = 4 weeks), which resulted in remarkable reduction of jaundice without any severe side effects. So, the patient could be discharged and spend a useful life for about 10 months with good quality of life. This therapy might be a useful palliative chemotherapy for cases of this kind.

[Successful treatment of hepatic metastasis of gastric cancer with 5-DFUR and Lentinan]

Takita M. Onda M. Tokunaga A. Shirakawa T. Ikeda K. Hiramoto Y. Teramoto T. Oguri T. Fujita I. Okuda T. Mizutani T. Kiyama T. Yoshiyuki T. Matsukura N.
First Dept. of Surgery, Nippon Medical School.
Satisfactory therapeutic effects are rarely obtained with oral chemotherapy for gastric cancer. We have experienced successful treatment for synchronous hepatic metastasis of gastric cancer with 5'-DFUR and Lentinan. The patient was a 78-year-old female, diagnosed as having gastric cancer with multiple hepatic metastases, who underwent gastrectomy. Immunohistochemistry of the resected specimens with anti-thymidine phosphorylase (dThdPase) antibody yielded positive results for dThdPase in the primary tumor as well as the hepatic metastases. Two months after surgery, administration of 400 mg of 5'-DFUR per day and 2 mg i.v. of Lentinan every other week was started. Four months after discharge, carcinoembryonic antigen (CEA) in plasma showed an abrupt logarithmic decline. Furthermore, a 99% reduction in hepatic metastases was demonstrated by abdominal CT. At present, 22 months after surgery, the patient is managed on an outpatient basis with no complaints of any side effects. Immunochemotherapy using 5'-DFUR and Lentinan may be effective against gastric malignancies expressing dThdPase activity.

[Studies on TNM classification of carcinoma of the exocrine pancreas]

Yamamoto M. Ohashi O. Saitoh Y.
First Dept. of Surgery, Kobe University School of Medicine, Japan.
A total 17,121 patients with pancreatic cancer have been collected by the Pancreatic Cancer Registration Committee of the Japan Pancreas Society. Significant differences in the postoperative prognosis were observed between patients with tumor limited to the pancreas and with tumor extending to surrounding tissues or adjacent organs. The lymph node metastases and distant metastases were definitive factors on the prognosis after resection. It might was possible for the subdivision of regional lymph nodes as Japanese classification to provide the Stage classification. Further development of the TNM system is necessary for assessing the outcome of most advanced cancers.

[Molecular diagnosis of gastrointestinal cancers]

Yasui W. Tahara E.
First Dept. of Pathology, Hiroshima University School of Medicine.
Common and distinct genetic alterations are involved in the multistep mechanism of gastrointestinal carcinogenesis. Inactivation of the p53 and APC genes, activation of teleomerase and anomalous CD44 expression are common events that serve as a genetic marker for differential diagnosis of cancer. Amplification of cyclin D1 gene is preferentially found in esophageal cancer, whereas cyclin E gene amplification is frequently associated with both gastric and colorectal cancers. Multiple genetic alterations differ depending on the two histological types of gastric cancer. These genetic alterations can be applied in the multistep mechanism of the development and progression of gastrointestinal cancers. By application of these observations in clinical practice, we can facilitate and improve the differential diagnosis on cancer, obtain information on the grade of malignancy, determine patient prognosis, and identify patients at high risk for developing multiple cancers.

[Surgery and multidisciplinary treatment for colorectal cancer]

Sakamoto J. Kato J. Yasue M.
Dept. of Surgery, Aichi Prefectural Hospital.
Evaluation of surgery and multidisciplinary treatment for colorectal cancer was performed based on the review of the results of clinical trials. Although most improvement in prognosis for colorectal cancer patients was obtained by the development of surgical techniques until the mid-70's, further extended surgery could not have demonstrated the obvious improvement in survival after the 80's. In this regard, various multidisciplinary treatments were evaluated by a meta-analysis of clinical trials. Among those modalities, preoperative irradiation for rectal cancer, postoperative adjuvant chemotherapy for resected colorectal cancer and biochemical modulation of 5-fluorouracil by methotrexate or leucovorin for advanced colorectal cancers proved to be significantly effective for improvement of prognosis. Clinical trials of immunochemotherapy using either levamisole or PSK for resected colorectal cancers, a trial of hepatic artery infusion for liver metastasis, and a trial of an adjuvant monoclonal antibody treatment, were also reported to demonstrate significant effects. For further progress in multidisciplinary treatment for colorectal cancers, standardization of the appropriate surgical technique for each stage of the disease is much anticipated.

[Current status of combined modality therapy for esophageal cancer: from the standpoint of medical oncology]

Ohtsu A.
No information.
Surgery is considered to be a standard therapy for stage III or the earlier stage of esophageal cancer. However, the standard therapy is changing because of the recent advances in the non-surgical approach, especially chemoradiotherapy. Various obstacles remain to estimate the outcomes of combined modality therapy, while the consensus of the treatment for such stage excluding T4 diseases are as follows: 1) Concurrent chemoradiotherapy has a superior outcome to radiation alone in patients with squamous cell carcinoma. 2) Recent chemoradiotherapy without surgery achieves results comparable to surgery alone. 3) Preoperative chemoradiotherapy can achieve better results than surgery alone in patients with adenocarcinoma. 4) Preoperative chemotherapy is still experimental. Our preliminary results of chemoradiotherapy for esophageal cancer also showed comparable data to extended surgery in terms of survival. Some significant points to be elucidated regarding combined modalities in stage III or earlier are: 1) the comparison of definitive chemoradiotherapy with Japanese extended surgery, and 2) evaluation of efficacy of surgery after chemoradiotherapy. However, these studies require randomized trials comparing surgery with non-surgical treatment, which appears to present significant obstacles. Critical estimation for each study should be recommended based on accurate clinical staging, biological behavior, and intention-to-treat.

[Gastric lymphoma--a case report]

Ohtsu T. Boku N.
No information.
A 24-year-old male patient with a history of gastric ulcer was referred to our hospital in September 1995. His chief complaints were epigastralgia and weight loss of 3 kg during a short period. The upper G.I endoscopy performed on 9/22/1995 revealed multiple ulcers with a histological diagnosis of atypical lymphoid cell proliferation. Follow-up endoscopy, one month later, showed an appearance of superficial gastric lymphoma, and histology of the biopsy specimen revealed MALT lymphoma associated with H. pylori. Despite an eradication therapy for H. pylori, which consisted of lansoprazole, teprenone and amoxicillin, the progression of the ulcerative lesions was observed on the endoscopy two weeks after initiation of the treatment. However, the subsequent endoscopy, one month later, disclosed a regression both macroscopically and histologically. The lymphoma disappeared completely on the follow-up endoscopy in April 1996 with no lymphoma cells in histology. No recurrences of the lymphoma have been observed up to now.

[Treatment of patients with recurrent esophageal carcinoma]

Year 1998
Sato N. Ishida K. Ikeda K. Koeda K. Ohtsuka K. Kimura Y. Aoki K. Ogasawara S. Iwaya T. Saito K.
Dept. of Surgery 1, Iwate Medical University, School of Medicine.
From 1987 to 1997, 211 patients with thoracic esophageal carcinoma underwent radical surgery. The 5 year survival rate was 87% in pTNM stage I, 64% in stage II A, 57% in stage II B, and 31% in stage III. The survival curve was improved by postoperative chemotherapy including CDDP/5-FU as compared with surgery alone. Relapse occurred in 59 of these patients (28%). Lymphatic recurrence was recognized in 32 patients, hematogenic recurrence in 19, mixed type in 4, and intramural or local recurrence in 4 patients. In spite of through lymph node dissection, postoperative lymphatic recurrence was most frequent at the upper mediastinum and neck. Among hematogenic metastases, pulmonary and hepatic metastases were observed at equal incidences. The 1 year survival rate and median survival period of the patients with recurrent carcinoma were 36% and 191 days (26-1,122), respectively. There was no significant difference in prognosis between lymphatic and hematogenic recurrence. The prognosis for patients who underwent active therapy for recurrence (42 cases) was significantly better than for those who underwent only palliative therapy (17 cases). Resection of the site of recurrence was performed in 4 cases. The combination therapy of resection or irradiation and combined chemotherapy with CDDP and 5-FU resulted in a better prognosis (median survival period was 504 days) than irradiation alone or chemotherapy alone. In conclusion, early diagnosis and active multimodality therapy were important to improve the prognosis of recurrent esophageal carcinoma.

[Treatment of recurrent gastric cancer]

Year 1998
Tsushima K. Sakata Y.
First Dept. of Internal Medicine, Hirosaki University, School of Medicine, Japan.
The recurrence rate of resected gastric cancer with curative intent was around 20%. When early gastric cancer was excluded, the rate was around 30%. Peritoneal dissemination accounted for half the recurrences, and was followed by hematogeneous metastasis, including hepatic metastasis. Chemotherapy was the main treatment modality because the possibility of curative resection was very low. Systemic chemotherapies based on biochemical modulation, particularly CDDP/5-FU therapy, have been routinely performed. For localized diseases, loco-regional therapies like drug administration via hepatic artery and intraperitoneal administration have been also applied.

[Diagnosis and treatment for recurrent hepatocellular carcinoma]

Year 1998
Yoshikawa M. Ebara M. Fukuda H. Sugiura N. Saisho H.
First Dept. of Medicine, Chiba University, School of Medicine.
In order to investigate the mechanism of recurrence of hepatocellular carcinoma (HCC), 322 patients with HCCs (size: < or = 3 cm) treated by percutaneous ethanol injection (PEI), transcatheter arterial embolization (TAE) or radiation therapy were evaluated. Cumulative recurrent rates of new lesions after the initial therapy were 25% (1-year), 57% (2-year) and 71% (3-year). In 116 patients whose tumors were multiple at the time of initial therapy, the recurrent rates were higher compared with 206 patients with a single tumor. In 228 of all patients, new lesions were observed in the noncancerous liver after initial therapy. We observed a single new lesion in 67% of the 134 patients, whose HCC was single at the time of initial therapy. In the remaining 33% of these patients, multiple new lesions were observed. As for the recurrence site, we found new lesions at a different segment of the liver from the initial HCC in 52% of these 134 patients. In the patients with multiple recurrent HCCs, the survival rates were lower in comparison with the patients whose recurrent HCC was single. In the patients whose new lesions were found within 1 year after the initial therapy, the survival rates were also lower compared with the patients whose new lesions were not detected during 1 year. In conclusion, the mechanism of multicentric occurrence may be closely correlated with the intrahepatic recurrence of HCC in consideration of the high incidence of recurrent rates of HCCs and their recurrent pattern.

[Diagnoses and treatments for recurrent colon cancer]

Year 1998
Arai Y.
Dept. of Diagnostic Radiology, Aichi Cancer Center, Nagoya, Japan.
The incidence of recurrence after curative resection in colon cancer is approximately 20%, and liver metastasis is the most common. Diagnostic modalities including recent techniques for recurrent colon cancer for example also in the liver, are not complete to point out minimal lesions. Thus, it is very hard to evaluate that recurrent lesions are localized or not. On the other hand, only regional treatments such as surgical resection and hepatic infusion chemotherapy are effective for this cancer, and the effect of systemic chemotherapy including 5-FU-LV and new agents are still now limited. From these points of view, for better management of patients with recurrent colon cancer, deeply understandings of incompleteness of imaging diagnoses and well application of local treatments are required.

[Rectal cancer]

Year 1998
Koyanagi Y. Katoh K. Majima T. Satoh S. Fujimitsu Y.
Dept. of Surgery, Tokyo Medical College, Japan.
We examined the diagnosis and treatment of recurrent rectal cancer with particular regard to localized recurrence. Early diagnosis of localized recurrence is extremely important for the selection of therapeutic strategy. Among strategy options available are surgical treatment, including resection of all pelvic organs, but this should be performed with no decrease in the QOL of the patient.

[Immunohistochemical staining of thymidine phosphorylase in primary colorectal carcinoma and metastases]

Year 1998
Tokunaga N. Sadahiro S. Yasuda S. Mukai M. Ishida H. Kimura T. Suzuki T. Ishikawa K. Iwase H. Kameya T. Tajima T. Makuuchi H.
Dept. of Surgery, Tokai University School of Medicine.
Thymidine phosphorylase (TdRPase) is an enzyme involved in the pyrimidine metabolism. It was reported that many cancers contained higher levels of TdRPase than normal tissues. And TdRPase has been reported to be identical with the platelet-derived endothelial cell growth factor. To clarify the distribution of TdRPase in primary and metastatic colorectal cancer, we carried out immunohistochemical staining of formalin-fixed specimens. We investigated 35 primary colorectal cancers resected surgically, 27 hepatic metastases and 8 lung metastases from colorectal carcinoma. TdRPase was highly expressed in primary colorectal cancer with lung metastases (100.0%) and surgically resected lung metastases cancer (87.5%). The staining correspondence between primary colorectal cancer and metastases was 19 cases (70.4%) in the liver metastases and 7 cases (87.5%) in the surgically resected lung metastases. The above results suggested that immunohistochemical staining for primary colorectal cancer may provide information about the sensitivity of metastases to the chemotherapy.

[Correlation between pyrimidine nucleoside phosphorylase (PyNPase)/thymidine phosphorylase/platelet-derived endothelial cell growth factor and histological prognostic factor, and influence of 5-deoxy-5-fluorouridine (5-DFUR) administration on PyNPase

Year 1998
Satoh B. Ohtoshi M. Ishida Y. Hen-mi K. Kaneko I. Soda M. Sugihara J. Shibagaki F. Iwai N. Nakamura T. Yamasaki T. Matsumoto S.
Dept. of Surgery, National Himeji Hospital.
PURPOSE: Among the pyrimidine nucleoside phosphorylases (PyNPase), thymidine phosphorylase (dThdPase) exists mainly in human tumor tissues, and is an enzyme which converts 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-fluorouracil. Recently, it was reported that dThdPase was identical to platelet-derived endothelial cell growth factor which was an antiogenetic factor, therefore. We think dThdPase may be a prognostic factor. METHODS: We investigated the possible correlation between PyNPase activities in tumor tissues and prognostic factors of histological findings, and examined influences of preoperative oral 5'-DFUR administration at a dose of 1,200 mg/body for 7 days on PyNPase activities and serum immunosuppressive acidic protein levels in patients with gastric cancer. RESULTS: Higher levels of PyNPase activities were especially observed in patients with v+ (p = 0.0161). PyNPase activities (p = 0.1668) and IAP (p = 0.0830) levels showed a decrease by 5'-DFUR administration. CONCLUSION: This study suggests that we must investigate in detail the possibility of PyNPase being prognostic factor, and 5'-DFUR administration may improve the prognosis of patients with gastric cancer.

[Effect of diazepam on delayed nausea and vomiting caused by anticancer agents]

Year 1998
Tong FZ. Zhang JQ. Qiao XM. Mao YC. Meng FY. Liu HJ. Hui S. Zhu FX. Shu W. Hong J.
Dept. of Oncologic Chemotherapy, People's Hospital, Beijing Medical University.
We conducted an evaluation of the usefulness of antiemetics (5-Hydroxy-tryptamine 3 receptor antagonism, 5HT3RA) combined with diazepam for delayed nausea and vomiting due to anticancer agents in 17 patients with various malignancies (such as lung Ca, breast Ca, esophagus Ca, gastric Ca, colon Ca, and non Hodgkin's disease) for whom chemotherapy was performed with different regimens in the Dept. of Oncologic Chemotherapy, People's Hospital, Beijing Medical University. Antiemetics (5HT3RA) combined with diazepam were given only to cases that had symptoms of nausea and vomiting induced by anticancer agents in the 1st course and invalidity with antiemetics (5HT3RA) alone in this study. Antiemetic (5HT3RA) agents + Dexamethasone were dosed before chemotherapy and also diazepam 5 mg orally after 24 hours (namely, when nausea was observed). Nausea was reduced and vomiting decreased after the antiemetic treatment with 5HT3RA + Dexamethasone and diazepam. These results indicated that 5HT3RA and diazepam combination therapies were more effective than 5HT3 RA + Dexamethasone alone for delayed nausea and vomiting. Further, the antiemetics had characters that a short adminiter time, few times and a take not over dose. The only side effect related to this antiemetic therapy was light somnolence. Antiemetics combined with diazepam might be a useful therapy against delayed nausea and vomiting induced by anticancer agents.

[Efficacy of combination of ondansetron injection and tablet in CAF-induced emesis in breast cancer patients]

Year 1998
Shinohara H. Yonekawa H. Machimura T. Furukawa T. Nishihori H. Kurihara N. Urakami H. Nemoto Y.
Dept. of Surgery, National Ohkura Hospital.
Efficacy of combination of ondansetron injection and tablet on CAF (cyclophosphamide, adriamycin, 5-fluorouracil) induced emesis were investigated in 10 breast cancer patients (33 courses). Complete suppression rate of nausea or vomiting were approximately 75%, approximately 90% respectively for every treatment day. According to judgement criteria, antiemetic rate of approximately 100% was achieved during the study period. As to food intake of each treatment day, in approximately 70% of treatment courses was assessed as '(patient was) able to eat most of the meal'. Trend in emetic episodes and food intake in each patient receiving several courses of CAF therapy were evaluated. As a result, those patients experiencing nausea or vomiting or had effect on their food intake, were found to be in the similar condition in the following course (s) of CAF. No adverse drug reaction nor clinical laboratory test abnormalities due to ondansetron was observed. In this investigation, combination of ondansetron injection and tablet was shown to sufficiently suppress CAF-induced nausea and vomiting, and their efficacy was confirmed. Still, the study suggested that number of emetic episodes or degree of anorexia differs according to each individual. Therefore we regard additional administration of ondansetron or concomitant use of steroids should be considered when necessary.

[Psychiatric studies of chemotherapy and chemotherapy-induced nausea and vomiting of patients with lung or thymic cancer]

Year 1998
Takatsuki K. Kado T. Satouchi M. Nakajima T. Nagai K. Ohsugi F. Yanagida E. Minegaki A.
Dept. of Thoracic Disease.
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.

[Cure by THP-COP therapy in patients with perforated T-cell type malignant lymphoma of the jejunum]

Year 1998
Kajiura Y. Ogoshi K. Nakamura K. Miyaji M. Kondo Y. Makuuchi H. Tajima T. Oobayashi Y. Masumoto A. Horiki T. Suzuki T.
Dept. of Surgery II, School of Medicine, Tokai University.
A 52-year-old man had suffered abdominal pain from Dec. 15, 1992. On Jan. 1993, he was admitted to our hospital for a diagnosis of T-cell malignant lymphoma of stomach of diffuse large cell type by gastroendoscopical biopsy. On the following day, he underwent emergency an operation with a diagnosis of panperitonitis. A perforation site had been found at the jejunum 60 cm distant from the Treitz ligament. It was resected and sutured concomitant with omental patch. The pathological diagnosis was the same. After the operation, we started THP-COP therapy on Jan. 25, 1993. During the admission, he was given THP-COP therapy 6 times, and had a complete remission. He was discharged Feb. 26, 1994, and shows no evidence of disease at this writing.

[A case of hepatic metastasis of rectal cancer with familial adenomatous polyposis treated by transarterial administration of low-dose leucovorin and 5-FU]

Year 1998
Ishii Y. Wakayama H. Nakayama K. Ami K. Iida M. Hotta M. Oota K. Yamazaki S. Takahashi M.
Dept. of Surgery, Oota Nishinouchi Hospital.
A 37-year-old man was diagnosed as having a rectal cancer with familial adenomatous polyposis, with the mutation of APC gene, and gastric polyposis, hypertrophy of the retinal pigment epithelium and a lipoma of the left arm. The patient underwent a total colectomy for the rectal cancer and a partial resection of the liver for metastasis (S3) which was detected on laparotomy, followed by cannulation in the hepatic artery. After the operation, 5-FU alone and low doses of CDDP and 5-FU were administered, but the level of serum CEA elevated and CT scanning showed multiple liver metastases. Then, low doses of leucovorin (30 mg/body bolus) and 5-FU (500 mg/body/h) were injected through an injection port every week. After 6 months, the level of serum CEA reduced and CT scanning showed minor response (about 30% on the decrease rate), without side effects, including diarrhea, stomatitis and bone marrow suppression.

[TNM classification--pediatric tumors]

Year 1998
Hayashi Y. Ohi R. Okabe I. Todo S. Iwafuchi M. Tsuchida Y. Takahashi H. Ohnuma N. Hashizume K. Miyano T. Saeki M. Honna T. Yokoyama J. Nishi T. Toyosaka A. Suita S. Yamasaki S.
Dept. of Pediatric Surgery, Tohoku University School of Medicine.
The clinical and postsurgical TNM classifications (cTNM and pTNM) for neuroblastoma (NB), nephroblastoma (WT) and soft tissue sarcomas were presented in 1982 by the TNM Committee in UICC in collaboration with SIOP. The Japanese TNM Committee proposed new pTNM systems (J-pTNM) for NB and WT, and new cTNM and pTNM system for primary liver carcinoma in infants and children (HT). These pTNMs were based on the staging systems developed by the Malignant Tumor Committee of the Japanese Society of Pediatric Surgeons. The proposal of subdivision of M category in NB was presented for testing the new telescopic ramifications of TNM. The TNM for HT was added as a new classification recommended for testing. The effectiveness of these TNM systems was assessed using NB, WT and hepatoblastoma (HB) cases which were registered in collaborating institutes. The analyses suggested that pTNM, especially the J-pTNM system in NB, WT and HT were effective for the assessment of prognoses, although cTNM systems were not enough to assess the extent of the disease.

[Recent advances in research on SMANCS]

Year 1998
Maeda H.
Dept. of Microbiology, Kumamoto University School of Medicine.
During the past five years we observed many advances in the study of the polymer drug, "SMANCS". This first polymeric drug was approved by the Japanese Ministry of Health and Welfare in 1994 as a drug for primary liver cancer, in which the arterial injection of oily formulation in Lipiodol (a lipid contrast medium) is the standard procedure. The advantage of this tactic is the most extraordinary cancer targeting efficiency with the least systemic side effect and very prolonged slow release of SMANCS. The mechanism of tumor selective accumulation of SMANCS and polymeric drugs in general is discussed in view of the so called-EPR (enhanced permeability and retention) effect of solid tumor. The mode of action of SMANCS at the cellular level seems to accompany the generation of superoxide radical which damages DNA; strand break and modification of guaninine by 8-hydroxylguanine. Immunological potentiation involves either the cellular (M phi, T-cell, NK-cell) or molecular level (induction of cytokines, including interferon gamma). The in vivo effect of SMANCS is most pronounced in the tumor vessels where more concentrated SMANCS is accessible due to the EPR effect, and perhaps the generation of O2.-. Nitric oxide generated by both inducible form of NO synthase (iNOS) by the infiltrated macrophages and NOS of endothelial cells, and superoxide from SMANCS will readily react to form peroxynitrite (O2- + NO-->ONOO-), which is a very potent cytotoxic molecule and will damage (nitrate and oxidize) DNA and proteins. Thus, tissue damage and vascular injury or collapse will be the principle tumor toxic mechanism of SMANCS at tissue level. The dose of SMANCS (or grade I-IV tumor filling) and tumor regression parallel each other, and a profile of AFP-value and technical issues of SMANCS/Lipiodol administration intraarterially are also discussed.

[Targeted chemotherapy of hepatocellular carcinoma with SMANCS/Lipiodol--how to use SMANCS/Lipiodol]

Year 1998
Konno T. Tabaru K. Isogai M. Nagamitsu A. Oda T.
First Dept. of Surgery, Kumamoto University School of Medicine.
The first drug only for arterial injection, SMANCS/Lipiodol, which offers targeted chemotherapy for hepatocellular carcinoma (HCC), now commercially available. Based on our experience using SMANCS/Lipiodol for 424 patients with HCC, the golden standard of how to use SMANCS/Lipiodol for complete necrosis of tumor was described. The initial dose of SMANCS/Lipiodol was varied 2 to 6 mg per body, mainly depending on the size of the tumor. All feeding arteries of HCC have to be verified on angiogram, and the drug must be injected via an adequate artery. Sometimes, a tumor changes its feeding arteries. Additional administrations with an interval of one month were done till the entire tumor was filled with SMANCS/Lipiodol (grade 4). One or two months after achievement of grade 4, we must examine how much drug was removed from tumor on CT. If the entire tumor is not filled with the drug, further injections are recommended to maintain grade 4. Almost all tumors shrank in 3 to 4 months while maintaining grade 4. Frequent administration of low doses (1-3 mg per body) is recommended. Discontinvation of administration was done on the following findings; tumor size reduction of over 90% or complete disappearance of tumor stain. With arterial injection therapy of SMANCS/Lipiodol, survival of patients with unresectable HCC was prolonged, especially in 272 patients who were good candidates for therapy. (Those with Child C liver cirrhosis, with a tumor occupying all four segments of the liver, and/or with extrahepatic spread at initial arterial injection of the drug were excluded.) The 1, 2, 5, and 10 year survival rates were 83%, 58%, 34%, and 25%, respectively.

[Effect of arterial administration of a high molecular weight anti-tumor agent styrene maleic acid neocarzinostatin for multiple small liver cancer]

Year 1998
Ikeda K. Saitoh S. Kumada H.
Dept. of Gastroenterology, Toranomon Hospital.
To assess the characteristics of a zinostatin derivative, 29 patients with multiple hepatocellular carcinoma of 3 cm or less in diameter were treated with intra-arterial injection of the high molecular weight anti-tumor agent, styrene-maleic acid neocarzinostatin, mixed with Lipiodol. Computerized tomography 3 months after the first therapy showed complete accumulation of Lipiodol in 8 patients (27.6%), 50% to 99% accumulation in 4 (13.8%), 10 to 49% in 10 (34.5%), and less than 10% in 7 (24.1%). After repeated injections, Lipiodol accumulation of the entire area of the original tumor was found in 11 patients (37.9%). The degree of Lipiodol accumulation depended on the angiographic vascularity of the tumor and on the images of computerized tomogram during arterial portography. Although complete accumulation of Lipiodol was found in all tumors in 10 (58.8%) of the 17 patients with well-demarcated round-shaped hypervascularity, only one (8.3%) of 12 patients with ill-demarcated tumors could achieve complete accumulation of the Lipiodol in the tumors. Taking into account the fact that hypervascularity on angiograms is closely correlated with the degree of Lipiodol accumulation on computerized tomograms obtained later, well-demarcated round-shaped liver cancer is the best candidate for styrene-maleic acid neocarzinostatin therapy among various stages of liver cancer.

[Arterial infusion chemotherapy with SMANCS-Lipiodol for multiple hepatocellular carcinoma]

Year 1998
Takizawa K. Honda M. Obuchi M. Matsuoka S. Shima H. Uchiyama K. Hasebe S. Doai K. Satoh S. Kuniyasu Y.
Dept. of Radiology, Showa University Fujigaoka Hospital.
Fifty-five patients with hepatocellular carcinoma were treated with oily anticancer agent SMANCS dissolved in Lipiodol (SMANCS-LPD). The local response rate after the first arterial infusion in all patients was 39%, against 63% in 27 patients with Lipiodol accumulation occupying more than two thirds of tumor areas. The infusion therapy with SMANCS-LPD is adapted for a vascular-rich hepatocellular carcinoma. An infusion of 4 mg of SMANCS was ineffective for patients with tumors distributing in bilateral lobes of liver. Thus, an increase of infusion dosage or repeated infusions were recommended for such cases.

[Repeated arterial infusion of zinostatin stimalamer using port for advanced hepatocellular carcinoma]

Year 1998
Yoshikawa M. Ebara M. Fukuda H. Sugiura N. Saisho H.
First Dept. of Medicine, Chiba University, School of Medicine.
Four patients with advanced hepatocellular carcinoma were treated by repeated arterial infusion of zinostatin stimalamer (SMANCS). Every 4 weeks, 4 mg of SMANCS and 4 ml of Lipiodol were administered via the proper hepatic artery using an implantable arterial port. Three patients with advanced liver cirrhosis (Child B or C) could no longer be treated after 2 or 3 courses of SMANCS infusion because of hepatic failure. In the remaining patient also with compensated liver cirrhosis (Child A), a partial response was observed after 5 courses of chemo-infusion, but we discontinued infusion of SMANCS because of hepatic failure. To assess the usefulness of SMANCS for repeated arterial chemo-infusion by the port, we evaluated 103 patients with advanced HCC treated by Lipiodol emulsion mixed with 70 mg of epirubicin (EPI) using a port. An average course was 11 arterial infusions, and the overall response rate was 40%. One-year survival rates were 62% in Child A, 59% in Child B, and 53% in Child C. Compared with Child A and B patients, both elevation of serum total bilirubin levels and decrease of serum albumin levels were observed after 9 months in Child C patients. In conclusion, SMANCS may have more severe hepatic toxicity in comparison with Lipiodol emulsion mixed with EPI.

[Arterial infusion of SMANCS for multiple recurrent tumors after hepatic resection]

Year 1998
Takano S. Kono S. Iwai S.
3rd Dept. of Surgery, Nihon University.
We investigated the possible side effects and efficacy of arterial infusion of SMANCS as compared to Lipiodol + epirubicin TAE for multiple recurrent tumors after hepatic resection. As a result, no significant difference in GOT, GPT, and total bilirubin was observed between the two groups. No significant difference was found in white blood cell count and platelet count, and there was no significant difference in clinical side effects between the two groups. Grade III response rates after arterial infusion of SMANCS were found in 4 patients (66.6%), and these results showed no significant difference as compared to Lipiodol + epirubicin TAE. Proper hepatic arterial infusion of SMANCS appeared to be useful in multiple recurrent tumors from the standpoints of safety and the rate of Lipiodol deposition.

[Advantages and disadvantages of SMANCS-Lipiodol intrahepatic arterial infusion chemotherapy for unresectable hepatocellular carcinoma]

Year 1998
Suzuki M. Fukuhara K. Unno M. Endoh K. Takeuchi H. Kodama H. Oikawa M. Matsuno S.
1st Dept. of Surgery, Tohoku University School of Medicine.
Though SMANCS-Lipiodol suspension has advantages over tumor regression, its disadvantages should also be considered: (1) Anaphylactic reaction due to its high molecular weight. (2) Since it readily destroys the tissue, a smaller dose and repeated administration are required. (3) Due to its low viscosity, it easily enters the arterioles and causes damage even to the extrahepatic organs. When this drug is infused into the left hepatic artery in subsegmental fashion, it enters the neighboring gastric tissues through the communication of the left hepatic and left gastric arteries, and this ultimately causes intractable gastric ulcers. Considering the above facts, this drug should be used carefully.

[Results of SMANCS/Lipiodol injection therapy for multiple intrahepatic recurrence of hepatocellular carcinoma]

Year 1998
Nakaba H. Hashimoto T. Sunada S. Akamatsu D. Ito A. Teramoto S. Ohara S. Katayama S.
Dept. of Surgery, Kure National Hospital.
Hepatocellular carcinoma (HCC) often recurs in the remnant liver after hepatectomy. Treatment is often ineffective in cases of multiple recurrence. We treated 18 cases of multiple recurrence with SMANCS/Lipiodol injection (SML). Four patients were treated with SML once, 11 patients were treated twice, and each patient was treated with three or four times with SML. The Effective rate of the 1st SML was 30%, but the effective rate of the 2nd SML was 60% in the plasma tumor marker levels. The effective rate between unilobular recurrence and bilateral recurrence was the same. A complete response was obtained in 2 cases, and partial response in 2 cases. The effective rate of SML was 4/18 (22.2%). These effective cases suffered a recurrence within a year. The cumulative survival rate at the end of the 24th month was 42.4%. Overall survival was significantly higher in the group with SML than in the group with TAE or TAI with the multiple recurrence. SML may be effective in early recurrence because these recurrent nodules are vascular-rich and there is much lipiodol accumulation. SMANCS/lipiodol injection therapy is expected to be an effective treatment in cases of early multiple recurrence after hepatectomy.

[Arterial infusion of SMANCS-Lipiodol for advanced hepatocellular carcinoma]

Year 1998
Miura K. Nakao N. Yoshimoto A. Yamano T. Inoue J. Takayasu Y.
Dept. of Radiology, Hyogo College of Medicine.
Twenty-four patients were treated with arterial infusion of SMANCS dissolved in Lipiodol. Twenty of these patients had HCC with the main trunks of portal vein occluded by tumor, and four patients had severe cirrhosis and multiple HCC. The actual dose of SMANCS administered each patient ranged from 4 to 6 mg. Side effects occurred in 50%. Severe side effects such as shock and shivering-chilliness were observed in 18%. The differences between the values of hepatic functional serum indexes obtained before and after treatment with SMANCS were small and transient. With regard to the therapeutic response of the arterial infusion of SMANCS, the mean survival time was approximately 2.8 months. It was suggested that the more effective administration of SMANCS was combination of the arterial infusion of SMANCS-Lipiodol with TAE at the level of the right hepatic artery of left hepatic artery for multiple HCC.

[Evaluation of transcatheter hepatic segmental or subsegmental infusion of SMANCS for treatment of hepatocellular carcinoma]

Year 1998
Inoue Y. Tomoda K. Oi H. Nakamura H.
Dept. of Radiology, Minoo City Hospital.
A total of seventeen patients with hepatocellular carcinoma (HCC), nineteen HCCs, who underwent as an initial treatment transcatheter hepatic segmental or subsegmental arterial administration of SMANCS alone for hepatocellular carcinoma (HCC), were studied to evaluate the efficacy and complication of that treatment. The initial treatments provided CR in eight patients (47%), and repeat administrations of SMANCS achieved CR in an additional four patients (24%). The initial treatment provided a dense deposit of Lipiodol in the twelve tumors (63%), in five of which Lipiodol was thereafter washed out in some portions of the tumor. Complete necrosis was obtained in nine (75%) of fourteen hypervascular tumors, and in two (40%) of five intermediately vascular or hypovascular tumors. Segmental or subsegmental administration of SMANCS was well tolerated with self-controlled abdominal pain or fever well responding to medication. Ascites was seen in three cases, and atrophy of the segment infused occurred in five patients. Cholinesterase significantly reduced at one week and one month, then recovered to baseline two to three months after initial treatment. The cumulative survival rates were 77% at 1 year, 66% at 2 years, and 53% at 5 years in the whole patients. The survival rate was 100% at 5 years in the Child A group. In the patients who obtained CR using SMANCS alone, the survival rates were 89% at 1 year, 74% at 2 years and 56% at 5 years. Although this method may transiently deteriorate hepatic function, segmental or subsegmental administration of SMANCS may be an excellent therapeutic method for treatment of HCC and promising for use in properly selected patients.

[Intra-arterial infusion of SMANCS for treatment of patients with hepatocellular carcinoma--adverse reactions and complications]

Year 1998
Sakaguchi T. Yoshimatsu S. Sagara K. Yamashita Y. Takahashi M.
Division of Radiology, Kumamoto Regional Medical Center.
Although intra-arterial infusion of SMANCS has been demonstrated to be highly effective for treatment of patients with hepatocellular carcinoma, it is reported to cause critical adverse reactions and complications. We examined the adverse reactions of SMANCS on the hepatic artery in 78 patients with hepatocellular carcinoma, who were infused with SMANCS from right, left or proper hepatic artery at our hospital. SMANCS caused right hepatic artery occlusion in 15 patients (19%) and the average amount of infused SMANCS was 6.8 mg. The tumor volume in the artery occluded patients was smaller than that in the artery non-occluded patients. Then, the mechanism by which SMANCS caused arterial occlusion was its induction of arterial injuries by excess infusion. When SMANCS was infused to whole liver, it induced decreased hepatic functional reserve and liver atrophy, followed by delayed liver failure. Other adverse reactions were no different from those in patients infused with epirubicin-lipiodol emulsion.

[Comparative studies on the antitumor activities and side effects of segmental SMANCS/Lip-TAE with segmental SMANCS/Lip-TAI for hepatocellular carcinoma]

Year 1998
Matoba M. Okimura T. Yamamoto I.
Dept. of Radiology, Kanazawa Medical University.
We compared the effectiveness of treatments and the influence of side effects on liver function and clinical symptoms between segmental SMANCS/ Lip TAI and segmental SMANCS/Lip-TAE. The early tumor response rate of the group treated by TAI was 23.6%, and that of the group treated by TAE was 80.0%. In the group treated by TAE, the therapeutic effects were better in the nodular type than in the diffuse type of HCC, and we were also able to obtain a good tumor response rate on the multiple HCC and large HCC. However, there was no difference in the response period between the groups treated by TAI and TAE. In both groups, there were no significant differences in the appearance rate and degree of side effects. In conclusion, segmental SMANCS/Lip-TAE seemed to be an effective treatment for HCC without any serious complications.

[SMANCS/TAE for hepatocellular carcinoma: comparison with SMANCS/TAI]

Year 1998
Shimizu T. Endou H.
Dept. of Radiology, Hokkaido University School of Medicine.
To evaluate the effects of SMANCS/TAE for hepatocellular carcinoma, AFP reduction rates, tumor reduction rates of SMANCS/TAE were compared with those of SMANCS/TAI. SMANCS is a stylene-maleic acid neocarzinostatin. TAE means transcatheter arterial embolization with gelatin sponge after SMANCS infusion and TAI means transcatheter arterial infusion of only SMANCS-iodized oil suspension. For evaluation of the AFP reduction rate, 13 SMANCS/TAEs were compared with 32 SMANCS/TAIs. In these cases, pretreatment serum AFP levels were higher or equal to 100 ng/ ml. The average dose of SMANCS/TAE was 4.2 +/- 1.8 (S. D) mg and that of SMANCS/TAI was 3.9 +/- 1.8 (S. D) mg (N. S: t-test, p = 0.59). Student's t-test revealed that the AFP reduction rate of SMANCS/TAE was not significantly superior to that of SMANCS/TAI (p = 0.78), and both AFP reduction rate of SMANCS/TAE and SMANCS/ TAI were not correlated with the dose of SMANCS. Tumor reduction rates of 12 SMANCS/TAEs and 14 SMANCS/TAIs on CT examination were calculated. The average dose of SMANCS/TAE was 4.5 +/- 1.9 (S. D) mg and that of SMANCS/TAI was 3.8 +/- 2.1 (S. D) mg (N. S: t-test, p = 0.29). The average tumor reduction rate of SMANCS/TAE was 25.3 +/- 30.1 (S. D)% and of SMANCS/TAI was 13.8 +/- 29.1%. Student's t-test revealed the tumor reduction rate of SMANCS/TAE was not significantly larger than that of SMANCS/TAI (p = 0.33). AFP reduction rate and tumor reduction rate of SMANCS/TAE were not significantly different from those of SMANCS/TAI. Although the number of cases was not enough, these results suggest SMANCS/TAI should be applied for treatment of hepatocellular carcinoma rather than SMANCS/ TAE.

[Outcome of TAE for hepatocellular carcinoma: comparative study of SMANCS-TAE and non-SMANCS/LpTAE]

Year 1998
Itsubo M. Koike K. Toda G.
Department of Internal Medicine 1, Jikei University School of Medicine.
The therapeutic effectiveness of transcatheter arterial embolization (TAE) with intraarterial infusion of SMANCS/lipiodol mixture was retrospectively compared to TAE with intraarterial infusion of epirubicin/lipiodol mixture in initial treatment of 54 patients with unresected hepatocellular carcinoma. The therapeutic effects were evaluated by the rate of tumor necrosis after the initial procedure and the cumulative survival rate. Eighteen patients were treated with SMANCS, and 36 patients were treated with epirubicin. There was no significant difference in patient background between the two groups; the hepatic functional reserve was not seriously disturbed in most of the patients, and multiple hepatic lesions were seen in half the patients. Complete tumor necrosis assessed by the imaging of dynamic CT one month after TAE was seen in approximately 40% of the cases in each group. Local recurrence was seen in half the patients after assessment of complete tumor necrosis within one year in both groups. There was no significant difference in survival period. There was also no significant difference of the frequency and degree of the side effects. In conclusion, no distinct difference of outcome was found in the two groups in this comparative study. Further studies in many cases over a longer period will be needed to elucidate the effects of SMANCS in TAE.

[Significance of arterial infusion of SMANCS-dissolved Lipiodol in therapeutic strategies for hepatocellular carcinoma]

Year 1998
Jin-no K.
Dept. of Clinical Research, National Shikoku Cancer Center Hospital.
The arterial infusion of lipiodol (LPD) containing SMANCS (SMANCS/LPD) has been considered to be a tumor-targeting therapy for hepatocellular carcinoma (HCC). It is important to establish a role of this new therapy in systematic strategies for HCC. LPD has no embolic effect, and the lipophilic anti-cancer agent, SMANCS, suspended in LPD and delivered selectively in tumors, shows therapeutic effect. Accordingly, it is essential for therapeutic efficacy that HCC cells have a chemosensitivity to SMANCS. The maximum dose of SMANCS/LPD is 6 ml at one time, which is not sufficient for voluminous tumors. These are the disadvantages of SMANCS/LPD therapy. Furthermore, HCC tissues, in which lipiodol is retained, is limited to moderately differentiated, with large blood spaces. SMANCS/LPD is not effective for well- and poorly -differentiated HCCs, because blood spaces in these histological types are too small for SMANCS/LPD to be deposited. On the other hand, transcatheter arterial embolization therapy (TAE) is effective by occluding feeding artery with small pieces of gelatin sponge, and a much tumor necrosis is obtained by TAE at one time. However, HCC cells beneath and within the capsule, and invading outside the capsule, are viable, possibly due to backflow of blood via drainage vein. Tumor thrombi and tiny intrahepatic metastases also escape the TAE effect. Previously we reported the new therapy at the first time: the combination of arterial infusion of SMANCS/LPD and TAE (LpTAE). LpTAE has some therapeutic benefits of both therapies; SMANCS/LPD fills up a whole tumor, and part of the LPD flows out from the tumor, is trapped in the capsular invasion and microscopic metastatic foci with the necrotic change. LPD prevents regurgitation of blood flow in drainage vein, and promotes necrotic change. After LpTAE, Lipiodol CT shows 4 kinds of LPD-deposition pattern in HCC; the therapeutic effects of LpTAE are exactly evaluated by these patterns. For total necrosis, HCC nodule shows a complete type, in which the whole tumor shows a metallic density by lipiodol deposition. In other patterns, the LPD-deposited area in tumors generally shows necrosis, and non-LPD-deposited areas are viable. The second line of the therapies. PEIT or resection, can be selected by the LPD-deposition pattern. We consider that the intraarterial infusion of SMANCS/LPD reinforces TAE, and LpTAE is one of the most effective therapies.

[Comparison of therapeutic effects of SMANCS (+TAE) and Non-SMANCS/LpTAE]

Year 1998
Nabeshima M. Ochi J. Hikita H. Nishikawa H. Ohara T. Torii A. Fujita S. Takeda J. Miura K.
Division of Gastroenterology, Kyoto Katsura Hospital.
Therapeutic effects of SMANCS and LpTAE were evaluated for hepatocellular carcinoma (HCC). Since June 1995, SMANCS has been used in 59 patients for their first treatment. LpTAE had been performed for HCC before introduction of SMANCS in our hospital, and 71 patients treated after 1992 were chosen for comparison with the therapeutic effect of SMANCS. Among the patients treated with SMANCS, complete and partial responses (CR and PR) were obtained in 24 cases (41%) and 17 cases (33%), respectively. SMANCS accompanied by TAE was more effective than SMANCS alone. The effects did not depend on the level of the hepatic arterial branch at which SMANCS was administered. In patients treated with LpTAE, CR and PR were obtained in 12 cases (17%) and 18 cases (25%), respectively. SMANCS was significantly more effective than LpTAE. Because of our short experience with SMANCS, we could only show a two year survival rate. The one- and two-year survival rates for SMANCS were 71% and 57%, respectively. They were not significantly different from those for LpTAE, at 80% and 60%. Despite good results of treatment for HCC, a better prognosis could not be expected by SMANCS in this study. These results may be explained as follows. The evaluating the cause of death within two years after first treatment, hepatic failure was more common in patients treated with SMANCS. After treatment by SMANCS, 11 patients (55%) died from hepatic failure. On the other hand, 4 patients (15%) died from hepatic failure after LpTAE. Although there is no significant difference of Child Pugh score, this may indicate that SMANCS has been used for patients with lesser hepatic reserve and this leads to early deaths in patients treated with SMANCS. However, because of the short experience in this study, further observation is necessary for precise evaluation of clinical efficacy of SMANCS.

[Our initial experience with SMANCS in TAE for liver cancer]

Year 1998
Fujita M. Inoue E. Kuroda C. Kasugai H. Sasaki Y. Nakano H. Imaoka S.
Dept. of Diagnostic Radiology, Osaka Medical Center for Cancer and Cardiovascular Diseases.
To evaluate the efficacy and adverse reaction of SMANCS, we reviewed 10 cases treated by TAE with SMANCS among 896 cases treated by TAE for liver cancer during the past three years at our institute. Our criteria for using SMANCS were as follows: a) reduced effectiveness of past TAE with Lipiodol, hydrophilic drugs and gelatin sponge; b) sufficient caliber and blood flow in the hepatic artery; and c) good hepatic function. The 1- and 2-year survival rates after treatment with SMANCS were 50% and 25%, respectively. The 3- and 5-year survival rates after initial treatment (first TAE, etc.) were 40% and 20%, respectively. There were no significant complications in clinical course, however, subsequent hepatic arteriogram often showed arterial change that may interfere with further regional therapy for the liver.

[Transcatheter arterial embolization with SMANCS and epiADM for hepatocellular carcinoma]

Year 1998
Ihaya T. Ametani M. Matsusue E.
Dept. of Radiology, Tottori Red Cross Hospital.
We have attempted transcatheter arterial embolization (TAE) with SMANCS and epiADM for 40 patients with hepatocellular carcinoma and evaluated its therapeutic effects and side effects. There were 7 cases of stage I disease, 10 cases of stage II disease, 10 cases of stage III disease and 13 cases of stage IV disease. Patients underwent TAE superselectively following infusion of w/o emulsion of epiADM and SMANCS-lipiodol. No severe side effect was observed compared with conventional Lp-TAE except in one case with hepatic biloma after treatment. The overall response rate was 70%, and 54.5% in the patients with recurrent tumor after Lp-TAE. The serum AFP value decreased in 16 patients out of 20 patients. Hepatic resection was performed in 2 patients after treatment, and no viable tumor cell was recognized in the specimen. Our result suggested that TAE with SMANCS and epiADM will contribute to improved therapeutic efficacy for hepatocellular carcinoma.

[Treatment of hepatocellular carcinoma by segmental SMANCS Lipiodol-TAE]

Year 1998
Hayashi T. Uchida H. Matsuo N. Sakaguchi H. Anai H. Tanaka T. Yamamoto T. Ooue S. Yoshioka T. Makutani S. Oishi H.
Dept. of Radiology, Nara Medical University.
Segmental SMANCS Lipiodol TAE (Seg. SMANCS Lp-TAE) using SMANCS was used to treat HCC in 58 patients and was evaluated in comparison with Seg. Lp-TAE using Epirubicin performed in 50 patients with respect to the course of atrophy of the embolized area, recurrence rate and side effects. On serial CT (Lp-CT) performed after TAE, in cases with P type in which the tumor is present in the periphery of the embolized area and showing Type I homogeneous accumulation of Lp within the tumor, the incidence of atrophy in the embolized area including the tumor was high and the recurrence rate was low. Although no significant difference in the recurrence rate was noted between the groups in which SMANCS and EPI were used, there were more cases with marked atrophy and a lower recurrence rate in the former. No difference was found in post-procedural side effects such as fever between the two groups, while hypotension was rarely observed during the procedure in the group in which SMANCS was used and was easily managed with intravenous steroids. The present results suggest that Seg. SMANCS Lp-TAE is an effective local treatment for HCC limited to a subsegment or segment.

[Combination of transcatheter arterial infusion of SMANCS and embolization (SMANCS-TAE) for hepatocellular carcinoma]

Year 1998
Hirashima N.
Dept. of Gastroenterology, Chukyo Hospital.
Patients with unresectable hepatocellular carcinoma (hepatoma) with hypervascularity were treated by SMANCS-TAE, which was performed by a superselective catheterization technique to inject gelatin sponge particles after administration of SMANCS. In 24 of 30 (80%) patients of first hepatoma treated by SMANCS-TAE, Grade 4 was obtained after about 1.5 (1-3) courses. The 2-year survival rate was 33%. SMANCS-TAE appears to have the same potential and safety as Lipiodol-TAE, treated selectively. Moreover, we can reduce the course of treatment and obtain good QOL of hepatoma patients except in advanced cases (vp 3 or T 4).

[Subsegmental transcatheter hepatic arterial embolization under balloon occlusion of the corresponding hepatic vein with SMANCS]

Year 1998
Shibata H. Sogabe M. Tsutsui A. Yokoi T. Morimoto M. Fukuda T. Hayashi S. Muguruma N. Ohkita Y. Okahisa T. Okamura S. Ito S.
Second Dept. of Internal Medicine, School of Medicine, University of Tokushima.
Recently, subsegmental transcatheter hepatic arterial embolization under balloon occlusion of the corresponding hepatic vein has been performed to treat hepatic infarction in subregion hepatocellular carcinoma (HCC). Here, we report subsegmental transcatheter hepatic arterial embolization under balloon occlusion of the corresponding hepatic vein with styrene maleic acid neocarzinostatin lipiodol (SMANCS) (SMANCS-TAE under balloon occlusion of the corresponding hepatic vein). This study included 9 patients with HCC who underwent SMANCS-TAE under balloon occlusion of the corresponding hepatic vein. In all patients, the therapeutic effects (TE) were evaluated according to the criteria of direct response to liver cancer treatment on abdominal computed tomography (CT) 3 weeks after surgery. In 7 patients who could be followed for more than one year, there was no postoperative relapse at the site of treatment. Furthermore, this procedure facilitated the detection of accumulation of SMANCS not only in the tumor but also in the subregion of the tumor in patients with HCC involving immature arterial tumor neoplastic vessels. In patients with large HCC complicated by severe heart failure showing a poor general condition, this procedure allowed treatment to be completed without complication. SMANCS-TAE under balloon occlusion of the corresponding hepatic vein, which can also embolize the portal vein by applying targeting chemotherapy with SMANCS, may cause necrosis not only in the tumor but also in noncancerous liver tissues. This procedure may be an indication for a larger number of cases than standard TAE, facilitating more complete local treatment.

[SMANCS-TAE combined with PEI in the treatment for hepatocellular carcinoma]

Year 1998
Numata K. Tanaka K. Kiba T. Saito S. Morita K. Kitamura T. Kondo M. Morimoto M. Shirato K. Hori A. Shimamura T. Isozaki T. Arata S. Okazaki H. Fujii T. Sekihara H.
Dept. of Third Internal Medicine, Yokohama City University School of Medicine.
From January 1996 to August 1997, 24 patients with advanced hepatocellular carcinoma (HCC) equal to or more than 2 cm (mean +/- SD; 4.1 +/- 3.0 cm) in main tumor diameter were treated by SMANCS-TAE (20 cases) or SMANCS-TAI (4 cases) combined with PEI. Six cases had solitary lesion, 16 cases had multiple lesions, and 2 cases had massive lesions. After this combination therapy, 21 of 24 cases had complete tumor necrosis. During 3 to 19 months follow up period, 12 cases had cancer-free survival (SMANCS-TAI; 3 cases), and 9 cases had tumor recurrences (3 cases were local recurrences and 6 cases involved new lesions). Two cases died of hepatic infarction and cancer death, however, the remaining 22 cases were surviving. SMANCS-TAE combined with PEI is useful treatment for advanced large or multiple HCC lesions in patients who are poor surgical risks.

[Progress in diagnosis of gastric cancer and improvement of treatment results]

Year 1998
Maruyama M. Takemoto N. Takekoshi T.
Dept. of Internal Medicine, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
The diagnosis of gastric cancer has made remarkable progress in the last 20 years, thanks to the establishment of diagnostic methodology including double contrast radiography, endoscopy (gastrocamera and fiberscope), and endoscopic biopsy. The treated number of early gastric cancers began to account for more than 50% around 1985 in the majority of Japanese institutions which specialized in gastroenterology. It is considered that the improvement of the treatment result is mostly due to the increasing number of early gastric cancers, although the progress in surgery for advanced cancer may also be a contributing factor. Now endoscopic mucosal resection has become a common treatment method for small early cancer, and the use of laparoscopic surgery has been increasing. We are now in an era seeking for rationalization of treatment options in view of reductive and function preserving surgery.

[Recent advances in endoscopic mucosal resection for early gastric cancer]

Year 1998
Hosokawa K. Yoshida S.
Division of Endoscopy, National Cancer Center Hospital East, Kashiwa, Japan.
Our indications of endoscopic mucosal resection (EMR) for early gastric cancer (EGC) as a radical treatment are as follows: 1) histology: intestinal type; 2) macroscopic type: IIa and IIc; 3) without ulcerative change. We do not put restrictions on the size of the lesion. EMR is performed on lesions which are suspected to have submucosal invasion for a diagnostic purpose. The ratio of EMR cases to the total EGC cases is increasing in recent years and amounted to about 40% of EGCs treated at the National Cancer Center Hospital in '96. From '87-'96, we had 440 cases of EGCs (intestinal type, histologically) at the National Cancer Center Hospital and National Cancer Center Hospital East. Eighty-five cases (19.3%) turned out to have submucosal invasion and judged non-curative resection. The overall rate of cut-end-free cases was 72.3%, while the overall rate of curative resection (excluding cases with submucosal invasion) was 63.0%. Though we had 37 cases of recurrence after EMR, there were no cases of death from the original disease with additional treatment or observation (due to complication or age). The cut-end-free rates of each period ('87-'90, '91-'93, '94-'96) were 53.1%, 61.3% and 81.6%, respectively. The mean diameter of the lesion of each period became larger, at 11.9 mm, 12.0 mm and 14.0 mm, respectively. To resect a larger lesion in one piece, we began EMR with cutting the mucosa around the lesion using a newly improved endoscopic device called an insulation-tipped diathermic knife (IT knife) from '95. With this IT knife, we could resect 75% of the lesions sized 11-20 mm in one piece, while we could resect 29% with the conventional method (strip biopsy). Though the results of EMR are improving in recent years, new endoscopic technics of EMR to resect easily and surely are expected.

[Laparoscopic surgery for early gastric cancer--its advantages and pitfalls]

Year 1998
Ohgami M. Otani Y. Kumai K. Kubota T. Fujita K. Igarashi N. Ishikawa H. Kim YI. Kitajima M.
Dept. of Surgery, Keio University, Tokyo, Japan.
We have successfully established two different laparoscopic procedures for early gastric cancer since March 1992, which are laparoscopic wedge resection of the stomach using a lesion-lifting method and laparoscopic intragastric mucosal resection. The indication is as follows; (A) mucosal cancer, (B) < 25 mm, if the lesion is elevated type, (C) < 15 mm and Ul (-), if the lesion is depressive type. The advantages of these methods are; 1) minimally invasiveness, 2) sufficient surgical margin, 3) feasibility of detailed histology, 4) feasivility of perigastric lymph node dissection. In contrast, there are several problems to be solved, which are; 1) preoperative diagnostic accuracy of the depth of cancer invasion, 2) possibility of reoperation because of sm invasion or lymphatic or venous invasion in final histology, 3) possibility of postoperative stenosis after laparoscopic intragastric mucosal resection for the lesion near the cardia, 4) incidence of metachronous multiple gastric cancer. In conclusion, if the indication is properly selected, these laparoscopic procedures are curative and minimally invasive treatment for early gastric cancer.

[Assessment of function preserving gastrectomy for early gastric cancer]

Year 1998
Isozaki H. Nomura E. Tanigawa N.
Dept. of General and Gastroenterological Surgery, Osaka Medical College, Japan.
To assess function preserving gastrectomy for early gastric cancer, the effectiveness of a reduction of the extent of gastrectomy, preservation of pylorus, and preservation of vagus nerve was evaluated. Postoperative physical results after pylorus-preserving gastrectomy with preservation of vagus nerve (group I, 32 cases), 2/3 distal gastrectomy with preservation of vagus nerve (group II, 12 cases), 2/3 distal gastrectomy without preservation of vagus nerve (group III, 21 cases) and 4/5 distal gastrectomy without preservation of vagus nerve (group IV, 81 cases), were investigated. Postoperative/ preoperative body-weight ratio in groups I (96.6%) and II (97.4%) was significantly higher than in groups III (92.2%) or IV (89.5%). The patients in groups I and II had fewer abdominal symptoms than in group IV. The gastric emptying pattern of patients in group I was slower than in the other groups. Contraction of the gallbladder in groups I and II was better than in group IV. The serum concentration of cholecystokinin after meals was low in group I, but increased rapidly in the other, groups. Reducing the extent of gastrectomy, preserving the pylorus, and preserving the vagus nerve, resulted in preservation of physical status after gastrectomy.

[Extended gastric surgery: is paraaortic lymph node dissection essential for advanced gastric cancer?]

Year 1998
Aikou T. Natsugoe S. Hokita S.
First Dept. of Surgery, Kagoshima University School of Medicine, Japan.
We retrospectively analyzed the clinicopathological findings and prognosis in patients who underwent paraaortic lymph node (No. 16) dissection. No. 16 metastasis was histologically found in 61 of 640 patients (9.5%). Almost all of the patients had tumors in the upper third of the stomach or the whole stomach. In the patients who had a total of ten or less lymph node metastases after curative resection. No. 16 metastases were found at the site of either the left or right side of the abdominal aorta. Conversely, No. 16 metastases occurred in both left and right sides of the abdominal aorta in patients with 11 or more lymph node metastases in total. The five-year survival rate of patients with histologically proven No. 16 metastasis was 21%. The indication for No. 16 lymphadenectomy should be decided by not only the number of No. 16 lymph node metastases but also by the total number of removed lymph node metastases. When D4 lymph node dissection was compared with D2 lymph node dissection in the patients without No. 16 involvement on histology, the prognosis of the former was superior to the latter in the patients with a tumor in the upper and middle part of the stomach. In order to evaluate the efficacy of prophylactic D4 lymphadenectomy, randomized clinical trial between D4 and D2 should be performed. It is also important that the indication for No. 16 lymph node dissection should be decided on the individual patients according to the objective data based on a retrospective study.

[Chemotherapy of gastric cancer]

Year 1998
Konishi T. Teruya M. Kawahara M. Itoh A. Asakura R. Araki S. Hojo K. Nouchi T. Takeda Y.
Department of Surgery, Showa General Hospital, Tokyo, Japan.
At present curative resection is the only radical treatment for gastric cancer, although recently developed combination chemotherapy shows increased activity in treating locally advanced and metastatic disease. Among several combination regimens, those based on biochemical modulation, such as sequential methotrexate/5-fluorouracil or low-dose CDDP/5-fluorouracil, are thought to provide increased efficacy with decreasing adverse reactions in unresectable gastric cancer. Therefore, a prospective randomized clinical trial comparing the prognosis of patients receiving adjuvant multi-agent chemotherapy with those treated only surgically should be pursued for estimation of the clinical benefit of these agents.

[International perspectives on the treatment of gastric cancer]

Year 1998
Kobori O. Sano T. Horikoshi Y.
Dept. of Surgery, International Medical Center of Japan, Tokyo, Japan.
Our experience of treatment of gastric cancer in European and developing countries suggested the necessity of the establishment of both operative and chemotherapeutic modalities. These modalities should be first based on theoretically convincing data and secondarily well analyzed from the viewpoint of cost-effectiveness.

[Phase I study of orally administered UFT plus l-leucovorin]

Year 1998
Horikoshi N. Aiba K. Kanamaru R. Hasegawa K. Takeda S. Taguchi T. Niitani H. Furue H. Kurihara M. Ogawa M. Abe T.
Cancer Chemotherapy Center, Cancer Institute Hospital, Japanese Foundation for Cancer Research.
A Phase I study of UFT plus l-LV was conducted in 29 patients (pts) with G.I. cancer on a multicenter cooperative study. UFT and l-LV were given orally in two divided doses for 28 consecutive days, followed by a 14 day-rest period. UFT was fixed in three doses, 250, 313 and 375 mg/m2/day, and l-LV was increased in dose from 25 to 50 and to 100 mg/body/days. Dose-limiting toxicities were anorexia, diarrhea, and nausea/vomiting. The maximum tolerated dose of UFT was 375 mg/m2/day, and l-LV 25 mg/body/day. Severe myelotoxicity was not observed. There were three responders (PR) out of 21 pts with measurable disease at UFT doses of 313 mg/m2/day and l-LV 50 and 100 mg/body/day. Responses observed were abdominal mass (rectal ca), liver metastasis (pancreas ca) and metastasis of liver and lymph-node (gastric ca). As a result of pharmacokinetics, plasma concentrations of 5-methyl-THF were maintained > 1.0 microM for over 5 hours that was considered to have a modulating effect on the plasma concentration. In doses of 50 mg and 100 mg/body/day of l-LV. No accumulations in plasma were observed in patient treated in 28 days by l-LV/UFT therapy. It was suggested UFT and l-LV did not interfere with each other's absorption. A Phase II study is recommended, with doses of 313 mg/m2/day of UFT and 50 or 100 mg/body/day of l-LV.

[Sequential chemotherapy with methotrexate and 5-fluorouracil for advanced gastric cancer]

Year 1998
Iwamoto S. Kimoto M. Mure T. Onuma E. Yamamoto Y. Iki K. Yoshida K. Tadaoka Y. Majima T. Kawasaki S. Kubozoe T. Tsunoda T.
Dept. of Surgery, Kawasaki Medical School.
Sequential chemotherapy with methotrexate and 5-fluorouracil (MTX/5-FU) for advanced gastric cancer was given 29 patients. The procedure consisted of weekly MTX 100 mg/m2 (i.v.) followed three hours later by 5-FU 600 mg/m2 (i.v.) with leucovorin rescue on each of the following two days. Nine of 28 patients (32.1%) showed partial response to this treatment. Response rates were 28.6% in the 21 cases with poorly differentiated adenocarcinoma and 42.9% in the 7 cases with well- or moderately-differentiated adenocarcinoma. This procedure was especially effective for primary lesions (PR 9/20: 45%) and lymphnode metastases (CR 4 + PR 4, 8/17: 47.1%). Side effects were mild leukopenia and G-I symptoms such as nausea, diarrhea and loss of appetite, except in 1 patient who died of severe myelosuppression with sepsis. We concluded that sequential MTX/5-FU therapy is fairly effective and the adjuvant chemotherapy of choice for advanced or recurrent gastric cancer with not only poorly differentiated adenocarcinoma but also well- or moderately-differentiated adenocarcinoma.

[Concentrations of 5-fluorouracil (5-FU) in serum and tissues at venous injection of tegafur or 5-FU--clinical study on colorectal cancer]

Year 1998
Kojima T. Suzumura K. Kanemitsu T. Miyashita A. Inamura Y. Owa Y. Naruse T.
First Dept. of Surgery, Aichi Medical University.
Tissue and serum concentrations of 5-fluorouracil (5-FU) after daily slow venous injection of tegafur or 5-FU for 5 days were measured. The serum concentration of 5-FU elevated to the highest level 6 hours after the venous injection (mean: 30 ng/ml). Compared with the tegafur injection, the serum concentration of 5-FU elevated to a higher peak level 6 hours after the 5-FU injection (mean: 827 ng/ml). The serum concentration of 5-FU after the tegafur injection tended to be maintained longer than after the 5-FU injection. When tegafur was injected, the concentration of 5-FU in cancer tissue or lymphnodes was significantly higher than in normal tissue. On the other hand, no significant difference was detected among the concentrations of 5-FU in the above three tissues when 5-FU was injected. Moreover, a significantly higher concentration of 5-FU in lymphnodes was caused by the tegafur injection compared to the 5-FU injection.

[Effect of granisetron in preventing emesis due to anti-cancer drug (CDDP) administration pulmo-mediastinal malignancies--comparison of simultaneous infusion with the conventional method of administration]

Year 1998
Nakahara K. Minami M. Yasumitsu T. Ikeda M. Ohta M. Nakamura K. Akashi A. Kido T.
Dept. of Surgery, Otemae Hospital.
For patients with pulmo-mediastinal malignancies, the antimetic effect of granisetron was studied in the following two ways. Firstly in the standard method, 40 micrograms/kg of granisetron was infused for 30 minutes, 30 minutes before CDDP infusion. Secondly, in the simultaneous method, granisetron was mixed with CDDP in a 500 microliters infusion bottle, and then infused over 0.5-3 hours. Over a 24-hour time course, significantly effective rates (nausea less than mild, and vomiting 2 times less) were 72.7% in the simultaneous group (n = 22) and 52.6% in the standard group (n = 19). The non-effective rates were 18.2% and 15.8%, respectively. Although the results were not statistically significant, the simultaneous method is easier to perform and it seems to confer a slightly better clinical outcome than the conventional method.

[A CR case of amylase-producing tumor treated by hyperthermochemotherapy]

Year 1998
Kan K. Naitoh K. Tsuruta A. Mizuta N. Ohmori K. Kawachi H. Amaike H. Yanada M. Ohmori Y.
Dept. of Surgery, Kyoto Prefectural Yosanoumi Hospital.
A 64-year-old female who was diagnosed with an amylase-producing tumor of unknown origin was treated by hyperthermochemotherapy. The patient was admitted with a complaint of abdominal fullness due to ascites. Laboratory examination showed high levels of serum amylase and tumor markers, including CA15-3, CA 125 and CA 72-4. Laparotomy showed peritoneal dissemination with histological findings of adenocarcinoma of unknown origin. After laparotomy, she was given hyperthermia combined with chemotherapy using carboplatin (CBDCA), mitomycin C (MMC) and doxifluridine (5'-DFUR). Hyperthermia (13.56 MHz radiofrequency for 40-50 min) was performed a total of six times within one and a half months. The total doses of CBDCA and MMC were 450 mg and 24 mg, respectively, and 600 mg of 5'-DFUR was orally administered every day. By these combined treatments, ascites disappeared and serum levels of amylase and all tumor markers were decreased and normalized. MRI and echo examination also showed complete disappearance of peritoneal metastasis. Two and a half years after the treatment, the patient is alive without any evidence of recurrence, which suggests that this combined therapy is one of the useful modalities for peritoneal dissemination as well as an inoperable tumor itself.

[A case of advanced gastric cancer successfully treated by UFT and CDDP followed by surgical resection proving cancer cell disappearance in the stomach]

Year 1998
Muramoto M. Matsugaki K. Ogino K. Azuma M. Inukai A. Akao M. Nakai T. Manabe T.
Dept. of Surgery, Inabe Kosei Hospital.
A patient with advanced gastric cancer responded remarkably to UFT combined with CDDP. UFT was administered orally for 28 consecutive days at a dose of 400 mg/m2, and CDDP was injected intravenously for a day at a dose of 100 mg/m2. Surgical resection proved the histological disappearance of cancer cells in stomach.

[A case of advanced gastric cancer with virchows metastasis responding remarkably to combination chemotherapy of low-dose CDDP and 5-FU]

Year 1998
Kajihara K. Ishikawa H. Akama F. Ninomiya H. Shigeta K. Sano I. Nakamura Y. Iwasaki K.
Dept. of Surgery, Sasebo City General Hospital.
The patient was a 72-year-old female who had Stage IVb advanced gastric cancer with Virchow's and paraaortic lymph node metastases. She was considered nonresectable and placed on neoadjuvant chemotherapy consisting of low-dose CDDP and 5-FU. After 1 course of administration, Virchow's metastasis disappeared, and the tumor was remarkably reduced in size. However, this chemotherapy was interrupted by toxicity of grade 3 appetite loss, nausea and vomiting, so that total gastrectomy and splenectomy were performed, which were non-curative operation because of paraaortic lymph node metastases. Histopathological examination of the section of the primary tumor revealed that cancer cells had almost disappeared, and only a few atypical cells remained in the granulation tissue. Eleven months after the surgery, there has been no progression of Virchow's and paraaortic lymph node metastases. Combination chemotherapy of low-dose CDDP and 5-FU appears useful as an inductive approach to advanced gastric cancer.

[A case of multiple liver metastasis of gastric cancer responding to hepatic arterial infusion chronotherapy]

Year 1998
Kobayashi I. Yokomori T. Iesato H. Ouya T. Ohwada S. Morishita Y.
Dept. of Surgery, Ojiya General Hospital.
A 64-year-old man underwent total gastrectomy and placement of the hepatic arterial catheter for advanced gastric cancer with multiple liver metastasis. After the operation, repeated hepatic arterial infusion chemotherapy was performed. Treatment consisted of a 5-day course of continuous arterial infusion of 5-FU. (500 mg/body), leucovorin (21 mg/body) intravenous infusion at 4:00 p.m. on days 1-5, mitomycin C (2 mg/body) arterial infusion at 9:00 a.m. on day 5, and cisplatin (40 mg/body) arterial infusion at 4:00 p.m. on day 5. A total of 13 courses of this chemotherapy diminished liver metastasis. During this therapy, the patient's condition was good, with no experience of nausea or leukopenia.

[Two patients with obstructive jaundice due to intra-abdominal lymph-node metastases of gastric cancer responding to combination chemotherapy with 5-FU and CDDP]

Year 1998
Mochizuki F. Fujii M. Kasakura Y. Imai S. Kanamori N. Kasahara M. Yamagata M. Iwai S.
3rd Dept. of Surgery, Nihon University School of Medicine.
Combination chemotherapy with 5-FU and CDDP was given to two patients with obstructive jaundice due to intra-abdominal lymph-node metastases of advanced and recurrent gastric cancer. One patient was a primary case associated with lymph-node metastases of portal fissure and periaorta, and the other was a recurrent case associated with lymph-node metastases of hepatoduodenal ligament and periaorta. The regimen consisted of 5-FU 1,000 mg/ m2 (day 1-5, continuous infusion) and CDDP 100 mg/m2 (day 3, 1 hr drip infusion). The interval was from the 6th to 21st day. The response to chemotherapy showed shrinking of intra-abdominal lymph-nodes and reopening of the biliary tract. The patients could be discharged from the hospital without PTBD tube and enjoyed a better quality of life (QOL). This therapy is thought to be effective against obstructive jaundice due to intra-abdominal lymph-node metastases of advanced and recurrent gastric cancer.

[The effect of hepatic arterial infusion chemotherapy on the prognosis after hepatectomy for hepatocellular carcinoma]

Year 1998
Takagi K. Koyama T. Hasegawa M. Manabe K.
Dept. of Surgery, Niigata Prefectural Central Hospital.
The effect of hepatic arterial infusion chemotherapy on the prognosis after hepatectomy for hepatocellular carcinoma was investigated in patients with risk factors for recurrence. The risk factors for recurrence after hepatectomy were defined to be metastasis in the liver (+), portal tumor embolus (+), and tumor larger than 5 cm in diameter. Out of 87 patients with hepatocellular carcinoma who underwent an operation in the past 7 years in our hospital, 60 survived for more than 1 year and were enrolled in our study. Thirty-eight of them showed one or more risk factors for recurrence, and were considered to be the high-risk group. These 38 patients were divided into two groups: one group of 19 treated by hepatic arterial infusion chemotherapy using mitoxantrone, and the other group of 19 given no treatment. The survival rates and non-recurrence rates were compared between the two groups. The survival rates after 1 and 3 years for the group treated by hepatic arterial infusion chemotherapy were 94.7% and 54.7%, respectively. The survival rates for the non-treated group were 53.9% and 32.8%, respectively (p = 0.012). The non-recurrence rates after 1 year and 3 years were 94.7% and 44.2% for the treated group and 52.6% and 23.6% for the non-treated group (p = 0.005), respectively. The survival rates and non-recurrence rates after 3 years in the treated group were significantly higher (p = 0.012, 0.005), respectively. It was concluded, therefore, that post-operation hepatic arterial infusion chemotherapy improved the prognosis of the high-recurrence probability group.

[Early phase II study of TAT-59 in patients with advanced or recurrent breast cancer--a multicenter dose finding study]

Year 1998
Aoyama H. Tominaga T. Abe O.
Dept. of Surgery, National Nagoya Hospital.
A dose finding early phase II study of TAT-59, a new triphenylethylene derivative, was performed in patients with advanced or recurrent breast cancer. TAT-59 was given orally for over 8 weeks at a daily dose of 10 mg, 20 mg or 40 mg/day. Thirty-six, 38 and 35 patients were eligible in the group treated with 10, 20 and 40 mg of TAT-59, respectively. The proportion of patients obtaining a complete or partial response with 10 mg/day, 20 mg/day and 40 mg/day of TAT-59 was 28.6% (10/35), 28.6% (10/35) and 25.8% (8/31) in the evaluable cases, respectively. The median duration of initial response with TAT-59 was 38.5 days, 26.5 days and 25.6 days, respectively. The frequent adverse reactions observed in all dosing groups included hot flashes, anorexia, nausea and vomiting, sweating, and abnormal values in liver function tests. In these adverse reactions, the incidence of hot flashes, which might be caused by the pharmacologic function of TAT-59 was 0.0% (0 of 35), 2.9% (1 of 35) and 10.0% (3 of 30) in the evaluable cases receiving 10 mg, 20 mg and 40 mg of TAT-59, respectively. In conclusion, it was recommended that the optimal dose in terms of efficacy and adverse reactions should be 20 mg/day.

[Hepatic arterial infusion chemotherapy (HAI) for advanced hepatocellular carcinoma inefficacious with transcatheter arterial embolization (TAE)]

Year 1998
Takayama W. Asano T. Kobayashi S. Nakagouri S. Kenmochi T. Okazumi S. Takeda A. Fukunaga T. Iwasaki K. Shutou K. Matsuzaki H. Aoyama H. Shinotou K. Kouno T. Isono K.
Second Dept. of Surgery, Chiba University School of Medicine.
For 6 patients with advanced hepatocellular carcinoma (HCC) in whom TAE was inefficacious, we tried hepatic arterial infusion chemotherapy. 5-FU 500 mg/day + CDDP 10 mg/day was administered during 5 days. The AFP level was decreased for 4 patients, and 2 patients showed a partial response in CT image. These 2 patients have been alive over 22 and 18 months, respectively. These results suggest that 5-FU + CDDP HAI might be a useful treatment of HCC inefficacious with TAE.

[Combination of transcatheter arterial infusion of SMANCS and embolization (SMANCS-TAE) for hepatocellular carcinoma--second report]

Year 1998
Hirashima N. Itazu I. Nukaya H. Kimura H. Hasegawa I. Yoshimizu T. Nemoto S. Sakakibara K.
Dept. of Gastroenterology, Chukyo Hospital.
Patients with unresectable hepatocellular carcinoma (hepatoma) with hypervascularity were treated by SMANCS-TAE. A superselective catheterization technique was used to inject gelatin sponge particles after administration of SMANCS. In 30 patients of first hepatoma treated by SMANCS-TAE. Grade 4 was obtained after 1.7(1-3) courses. The 2-year survival rate was 22%. Some of the 24 patients of second hepatoma treated by SMANCS-TAE have survived over 2 years. Sixteen patients with advanced hepatoma (Vp2-3 or T4) were treated only by SMANCS injection, but none survived over 1 year. SMANCS-TAE appears to have the same potential and safety as L-TAE, when used selectively. Moreover, we can reduce the course of treatment and obtain good QOL for hepatoma patients except in advanced cases.

[Adjuvant chemotherapy with UFT or UFT with OK-432 to patients with gastric and colorectal cancer. Kanto Adjuvant Study Group]

Year 1998
Konishi T. Idezuki Y. Watanabe H. Haga S. Ushirokouji Y. Shinohara K. Shibusawa M. Bandai Y. Hiraishi M. Murata N. Yabe K. Yamamura T. Yumoto S. Gunji A. Nishigaki M.
No information.
In Japan, long-term oral therapy with tegafur in combination with immunopotentiators is commonly used as adjuvant therapy after curative resection of gastric or colorectal can for gastric and colorectal cancer. When the outcome was analyzed in terms of the relative performance (R.P.) and the individual dose intensity (I.D.I.) of OK-432, gastric cancer patients with a R.P. of 0.5 or higher tended to have a better survival curve. There were no marked differences in lymphocytes subsets, except that the Leu 7 level at 3 months after gastric cancer resection was significantly higher (p < 0.05) in group B than in group A. Thus, no inhibition of the anticancer effect of UFT was noted during long term combination therapy with UFT and an immunopotentiator as postoperative adjuvant therapy for patients who underwent curative resection of gastric or colorectal cancer. The results suggest that UFT combined with long-term OK-432 maintenance therapy may contribute to improve survival rates in gastric cancer patients.

[The evaluation of weekly hepatic arterial infusion of high-dose 5-FU for liver metastases from colorectal cancer]

Year 1998
Hata Y. Morita S. Noda Y. Kawasaki R. Morita Y. Awatani T. Horimi T.
Dept. of Radiology, Kochi Municipal Central Hospital.
A study was conducted on weekly infusion of high-dose 5-FU through the hepatic artery for liver metastases from colorectal cancer. In the evaluation of 38 cases, no CR and 16 PR were to control the extrahepatic metastases is a subject for forthcoming study.

[Combination effect of granisetron plus corticosteroid for prevention of cisplatin-induced emesis: a cross-over study comparing methylprednisolone and dexamethasone]

Year 1998
Tanaka K. Sekine M. Serikawa T. Sanada H. Shichiri K. Fujimori R.
Dept. of Gynecology and Obstetrics, Akita Red Cross Hospital.
Granisetron (G) is an effective antiemetic drug that is used to prevent cisplatin-induced emesis, although it is less effective for delayed emesis. To enhance the antiemetic effects of granisetron, corticosteroid analogues such as methylprednisolone (M) and dexamethasone (D) were employed in a study of patients treated with cisplatin (CDDP). We investigated the clinical response and urinary excretion of 5-hydroxyindole acetic acid (5-HIAA), the main metabolite of serotonin, in 31 patients with ovarian cancer or uterine endometrial cancer who received CAP therapy (CDDP 75 mg/m2) in a 3-day cross-over trial comparing G + M and G + D treated patients. Both regimens were and delayed emesis than G + D. We conclude that G + D is a more efficacious combination than G + D in protecting patients from CDDP-induced acute and delayed emesis.

[A case report of esophageal carcinoma with grade 3 response by preoperative chemotherapy using CDDP/5-FU/LV]

Year 1998
Bando K. Onda M. Miyashita M. Takahashi Y. Takita M. Matsutani T. Okawa K. Sasajima K. Ujihara Y. Takubo K. Yamashita K.
First Dept. of Surgery, Nippon Medical School.
A 67-year-old man was diagnosed as having a type 3 advanced esophageal carcinoma by barium swallow and endoscopy. Biopsy specimens showed well-differentiated squamous cell carcinoma with positive immunostaining for p53, C-erb B-2 and negative for bcl-2. Two courses of chemotherapy using 5-FU, leucovorin and CDDP were performed before operation. Because no cancer cells were present in the surgical specimens, the effect was evaluated as grade 3. This neoadjuvant chemotherapy may be effective for esophageal carcinoma with a possible apoptosis mechanism.

[Advanced gastric cancer curatively resected following combined neoadjuvant chemotherapy--report of a case]

Year 1998
Koike N. Ohwada S. Ogawa T. Kawashima K. Takeyoshi I. Sato Y. Kamiyama H. Morishita Y.
Second Dept. of Surgery, Gunma University School of Medicine.
An advanced gastric cancer patient with T3N1M0 successfully underwent a curatively total gastrectomy combined with distal pancreatectomy and lymphnode dissection following ELF-P combined chemotherapy. The patient received two courses of etoposide (75 mg/m2, Day 1-5, i.v.), leucovorin (30 mg/body, Day 2-5, i.v.), 5-FU (500 mg/m2, Day 2-5, i.v.) and CDDP (60 mg/m2, Day 1, i.v.). A partial response for the primary lesion and lymphnode metastasis was obtained, and a successful curative resection of the stomach was performed. No drug adverse responses occurred. The effect of ELF-P chemotherapy was confirmed with grade 1b by histopathological examinations. Neoadjuvant chemotherapy with ELF-P may be useful as an inductive approach for advanced gastric cancer.

[A case of gastric cancer with peritonitis carcinomatosa and malignant biliary stenosis treated by intraperitoneal CDDP and MMC with UFT therapy]

Year 1998
Takayanagi N. Danjo Y.
Dept. of Internal Medicine, Shiraoi Town Hospital.
A 55-year-old man, who complained of vomiting, was diagnosed as having a Borrmann type 3 gastric cancer (T3N3P2H0M0: Stage IVb). He was treated by distal gastrectomy. After four months, PTCD was applied for malignant biliary stenosis due to lymphnode metastasis. Since ascites due to peritonitis carcinomatosa developed about six months after operation, UFT therapy combined with CDDP 50 mg and MMC 10 mg intraperitoneally were performed. The patient became gradually less aware of subjective symptoms after chemotherapy. Three months later, he enjoyed a good general condition and all of the fixed tubes were removed. This chemotherapy seemed effective to support his quality of life.

[Successful treatment of pseudomyxoma peritonei using combination chemotherapy of intraperitoneal low-dose CDDP and oral 5-DFUR administration]

Year 1998
Ohta Y. Shima Y. Sasaki N. Nishida T. Yamayoshi T. Adachi A.
Dept. of Surgery, Tagawa City Hospital.
We report a case of pseudomyxoma peritonei treated with combination chemotherapy. A 73-year-old woman was diagnosed as having psuedomyxoma peritonei originated from the vermiform appendix. Appendectomy was performed, and 10 mg of MMC was administered intraperitoneally. From day 7, 600 mg/day of 5'-DFUR was orally given for 2 years, and 20 mg of CDDP once a month was intraperitoneally administered seven times. The patient has been doing well with no evidence of tumor recurrence for two years after operation. Combination chemotherapy with CDDP and 5'-DFUR, as a biochemical modulation therapy, has fewer side effects and leads to better quality of life of patients. We recommend a combination chemotherapy with low-dose CDDP and 5'-DFUR for patients in poor general condition.

[Preoperative chemotherapy for advanced colorectal carcinomas--comparison of histological effect between UFT + leucovorin tablet and UFT alone]

Year 1998
Maruyama M. Kudo T. Kuwabara H. Yoshida T. Sugano N. Ebuchi M.
Dept. of Surgery, Tokyo Metropolitan Ohkubo Hospital.
The authors analyzed the histological effect of preoperative chemotherapy for 41 colorectal advanced cancer patients using resected specimens. Twenty patients in the UFT + LV group received 400 mg/day of UFT and 30 mg/day of leucovorin for 10-14 days just before the operations. Twenty-one patients with UFT alone received UFT 400 mg/day during the same period. Only one patient in the UFT + LV group developed the side effect of mild leukocytopenia. The histological effect of the UFT + LV group was superior to that of the UFT alone group (p = 0.03). The number of Grade 1a and 1b in the UFT + LV group was 14 (60.9%) and 7 (30.4%), while in the UFT group 16 (66.7%) and 2 (8.3%). Histological examination revealed no lesions which showed Grade 2 and 3 in both groups. There was the tendency for the histological effect in moderately differentiated adenocarcinomas to be superior to that in well-differentiated adenocarcinomas in both group. The histological effect in metastatic lymph nodes was superior to that in the original colorectal lesions in both groups. This suggests preoperative chemotherapy with UFT + LV and UFT could achieve the clinical down-staging of advanced colorectal cancer.

[Continuous intraportal chemotherapy for prevention of metachronous hepatic metastasis in colorectal cancer]

Year 1998
Adachi W. Watanabe H. Yazawa K. Koide N. Koike S. Mihara M. Nakata S. Kajikawa S. Kuroda T. Amano J.
Second Dept. of Surgery, Shinshu University School of Medicine.
Fifty-five colorectal cancer patients who had continuous intraportal chemotherapy between 1990 and 1993 (treated group) and 130 colorectal cancer patients who did not have portal chemotherapy between 1982 and 1993 (untreated group) were studied to clarify the effects of continuous intraportal chemotherapy on the prognosis. After a catheter was placed in the portal vein through the right gastroepiploic vein at the time of radical operation, 10 mg of MMC was continuously infused for 4 hours at operation and 500 mg/day of 5-FU was continuously infused for 7 days postoperatively. The toxicities of this therapy were not serious. The five-year survival rate was 65.3% in the treated group and 65.6% in the untreated group. The five-year disease-free survival rate was 69.8% in the treated group and 58.6% in the untreated group, with no significant difference. In stage II patients, however, the five-year disease-free survival rate in the treated group was slightly higher than in the untreated group (90.0% vs 70.3%, p = 0.073), and the rate of hepatic recurrence in the treated group was significantly lower than in the untreated group. These results suggest that continuous intraportal chemotherapy may prevent metachronous hepatic metastases in stage II colorectal cancer patients.

[Clinical study on the inhibitory effect of a 5-HT3 antagonist, granisetron, for nausea and vomiting induced by chemotherapy (CHOP, VEPA, high-dose ETP) for non-Hodgkins lymphoma]

Year 1998
Sasai Y. Misawa S. Iwai T. Tamura A. Nakazawa N. Ueda Y. Kaneko H. Horiike S. Yokota S. Taniwaki M. Kashima K. Tsuda S. Ookawara Y. Nakao M. Nakagawa H. Fujii H.
Third Dept. of Internal Medicine, Kyoto Prefectural University of Medicine.
The antiemetic effect of granisetron on nausea and vomiting induced by cancer chemotherapy (CHOP, VEPA, VEPA-B, massive dose of ETP) was studied in fifty patients with non-Hodgkin's lymphoma. There was almost no difference in the inhibitory effect by regimen, with the rates of perfect inhibition of nausea and vomiting standing at 55.6% to 60%. Nausea and vomiting was perfectly controlled in 60% of 35 patients receiving CHOP therapy. As a part of this study, a comparison was made of perfect inhibitory effect on nausea and vomiting by potency of chemotherapy under the potency scale of 750 mg/m2 of CPA as 1, revealing no significant difference in the rates of complete inhibition as 71.4% for a drug potency of less than 0.8 vs 52.4% for 0.8 or above (p = 0.26). However, it was clear that the higher the dose of chemotherapy, the lower the rate of complete inhibition. The results confirmed the high efficacy and safety of granisetron in the treatment of nausea and vomiting induced by cancer chemotherapy.

[A case report of advanced breast cancer with remarkable response to chemoendocrine therapy (CTF + MPA)]

Year 1998
Yokota T. Fujii T. Roppongi T. Kanno K. Ogata T.
Dept. of Surgery, Numata National Hospital.
A 59-year-old female complaining of breast tumor with suppurative discharge was diagnosed as having advanced breast cancer (T4cN3M1-StIV), with giant liver metastasis. Seven courses of combined chemoendocrine therapy (CTF + MPA) were used. Following the chemoendocrine therapy, primary tumor, lung, pleural, supraclavicular and parasternal metastasis disappeared, and the liver metastasis was obviously diminished. These effects continued for 1 year 7 months. Although CTF + MPA chemoendocrine therapy is widely used with advanced or recurrent breast cancer, a clearly effective case has almost never been reported. The reason for the remarkable effect in this case was the consistent immunity to breast cancer.

[Breast cancer with liver metastasis responsive to docetaxel: case report]

Year 1998
Oura S. Sakurai T. Yoshimura G. Tamaki T. Umemura T. Kokawa Y.
Dept. of Surgery, Wakayama Medical College Kihoku Hospital.
A 59-year-old female underwent mastectomy for right breast cancer in November 1992. She received tamoxifen and anthracycline-containing chemotherapy as adjuvant therapy. In and after September 1994, she developed loco-regional recurrences five times in total, each of which was treated with surgery and conventional combination chemotherapy. In April 1997, she developed liver metastasis, which was refractory to biochemical modulation therapy (low-dose cisplatin + 5-FU). We, therefore, treated her six times with docetaxel 80 mg, which resulted in partial response of the liver metastasis and brought about a marked decrease in serum CA15-3 levels. Adverse effects of docetaxel were grade 3 alopecia and leucocytopenia. She has been well without re-growth of the liver metastasis for over five months.

[A case of advanced hepatocellular carcinoma responding to suppository of Tegafur]

Year 1998
Kudo K. Arakawa A. Takagi Y. Nishimura R. Yamashita Y. Takahashi M.
Dept. of Radiology, Saishunsou Hospital.
We report a case of advanced hepatocellular carcinoma (HCC) successfully controlled by the suppository administration of Tegafur alone. Five months after initiation of the drug, excellent reduction of tumors and decrease of serum alpha-feto-protein (AFP) level were seen without any side effects. Also, twenty-four months after of the treatment, no regrowth of tumors or increase in the serum AFP level was seen. Because Tegafur is a time-dependent agent, advanced HCC may be controlled by continuous administration for a long period.

[Percutaneous ethanol and acetic acid injection for liver metastasis from colon cancer--two case reports]

Year 1998
Yamamoto S. Iguchi Y. Shibata N. Takesue M. Tsunoda T. Sato K.
Dept. of Medicine, Kawasaki Medical School.
Two cases of liver metastasis from colon cancer were treated by percutaneous ethanol (PEI) and acetic acid (PAI) injection for the recurrent lesion after surgery. Case 1 was a 60-year-old female who received sigmoidectomy with partial hepatectomy, and intraarterial 5-FU infusion was done after surgery. One year later, recurrence of liver tumor was detected, and PEI and PAI were performed for the metastatic lesions of the liver. Tumor regression and histopathological examination revealed coagulative necrosis. The patient died of lung metastasis 2 years and 10 months after treatment. Case 2 was a 58-year-old-male with ascending colon cancer and liver metastasis, who received surgery, and chemotherapy with intraarterial 5-FU infusion was continued. Four months later, recurrence of liver metastasis with elevation of serum CEA was noted. The patient received PEI three times and CEA decreased. Re-operation of hepatectomy revealed complete necrosis at the site of PEI. The patient has been alive for 1 year and 6 months with a new recurrence in the liver and is receiving repeated PEI therapy. PEI and PAI seem to be useful for the treatment of unresectable liver metastasis.

[p53 and Bax protein expression as predictor of chemotherapeutic effect in gastric carcinoma]

Year 1998
Muguruma K. Nakata B. Hirakawa K. Yamashita Y. Onoda N. Inoue T. Matsuoka T. Kato Y. Sowa M.
First Dept. of Surgery, Osaka City University Medical School.
This study was performed to estimate p53 and Bax overexpression as a predictor of the response to chemotherapy of patients with gastric cancer. The subjects were 20 patients with stage IV gastric cancer and 3 with locally recurrent lesions treated with 5-fluorouracil (5-FU) and low-dose cisplatin (CDDP) for 4 weeks. Of the total 23 patients, there were 10 responders: 2 showing complete response (CR) and 8, partial response (PR). Carcinoma biopsy specimens of all were obtained endoscopically with anti-p53 and anti-Bax antibodies. Of the 10 responders, 7 were in the negative p53 staining group, while of the 13 non-responders, 11 were in the positive p53 staining group (p = 0.013). But no correlation was demonstrated between the chemotherapeutic effect and Bax staining alone. Moreover, among the p-53-positive cases, the patients with Bax-negative tumors were all chemoresistant. Therefore, immunohistochemical identification of p-53 and Bax prior to chemotherapy may be a useful predictor for choice of non-responders to chemotherapy.

[Enhanced induction of apoptosis of human colorectal cancer cells after preoperative treatment with 5-fluorouracil its relationship to DNA ploidy pattern]

Year 1998
Yamane N. Makino M. Taniguchi T. Kurayoshi K. Kaibara N.
First Dept. of Surgery, Faculty of Medicine, Tottori University.
We examined the relationship between apoptosis induced by 5-fluorouracil (5-FU) that was given preoperatively to colorectal cancer patients and DNA ploidy pattern, and investigated the cell cycle changes, and the expression of Ki-67. Twenty-nine patients with advanced colorectal cancer were divided into four groups, 3 days, 5 days, 7 days, and 10 days. Groups received continuous intravenous 5-FU at 500 mg/body/day preoperatively. Then, patients were divided into two groups by DNA ploidy pattern, diploid(D) and aneuploid(A). Apoptotic cells were stained by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method. The expression of Ki-67 was examined by immunohistochemical staining. We used flow cytometry (FCM) for analysis of cell cycle distribution. Apoptosis of cancer cells was mostly increased in 7 days 5-FU administration in both D and A groups. The expression of Ki-67 was reduced according to the prolongation of the term of 5-FU administration in both D and A groups. We assessed S-phase fraction (SPF) to evaluate the cell cycle changes by 5-FU. Tumor samples of all patients after injection of 5-FU showed S-phase accumulation. The ratio of SPF (after 5-FU/before 5-FU) was the highest in the 5-day 5-FU administration group in both D and A groups. We concluded that apoptosis and S-phase accumulation were increased, and proliferative activity was decreased by preoperative 5-FU administration in colorectal cancer patients. However, there was no clear correlation between DNA ploidy pattern and these changes.

[Immunohistochemical study on the progression of colorectal cancer--with respect to apoptotic index, expression of apoptosis-related gene products, and labeling index of proliferating cell nuclear antigen (PCNA)]

Year 1998
Watanabe I. Isozaki H. Toyoda M. Ishibashi T. Hara H. Niki M. Gon G. Tenjo T. Kawasaki H. Tanigawa N.
Dept. of General and Gastroenterological Surgery, Osaka Medical College.
To clarify the biological changes in the development and progression of colorectal cancer, immunohistochemical examination was performed with a particular focus on the activity of apoptosis, the expression of apoptosis-related gene products and cell proliferation activity, assessed by the labeling index of proliferating cell nuclear antigen (PCNA). Seventy-six resected specimens of colorectal cancer were used to investigate the expression of apoptosis-related gene products, Bcl-2 protein and PCNA labeling index, as well as the apoptotic index using the TUNEL method. Seventy-five percent of 60 advanced cancer specimens was negative for Bcl-2 protein, and the proportion was higher than that in early cancer specimens. The apoptotic index (AI) in the advanced cancers was significantly higher than in the early stage of cancers. Meanwhile, the percentage of PCNA-positive cells for the advanced cancers was significantly higher than for early cancer. This study demonstrated a decrease in Bcl-2 protein expression, an increase in tumor cell apoptosis, and opposite an increase of cellular proliferation activity in the progression of colon cancer from early to the advanced stage of the disease.

[Analysis of microsatellite alteration in colorectal cancer]

Year 1998
Mizunuma H. Takita K. Ooki S. Onda M. Ando Y. Yoshida T. Tsuchiya A. Abe R.
Dept. of Surgery, Hanawa Kousei Hospital.
We investigated the possible correlation between the microsatellite alterations (replication error: RER, and loss of heterozygosity: LOH) and clinicopathologic factors and survival in colorectal cancer. A total of 78 colorectal cancers was examined for microsatellite alteration at three microsatellite loci containing D2S123, D18S58 and C117-703. RER is considered positive when at least one microsatellite locus is detected. RER was positive in 28.2%, and the respective positivity was 12.8%, 15.3% and 11.5%. The positivity of LOH was 6.4%, 10.3% and 19.2%, in that order. RER-positive cancers were more significantly found in the proximal colon than the distal colorectum. Node-negative colorectal cancers were more noted in RER (+)-positive cancers. Multivariate analysis showed that LOH in D18S58 locus and RER in CI17-703 locus were independent prognostic factors.

[Effect of low-dose CDDP/5-FU therapy on thymidylate synthase content]

Year 1998
Kosaka T. Ueshige N. Sugaya J. Nakano Y. Takashima S.
Dept. of Surgery II, Kanazawa Medical University.
Low-dose therapy consisting of cisplatin plus 5-fluorouracil was given to 20 patients with advanced gastric cancer, and specimens were obtained to evaluate levels of 5-fluorodeoxyuridine (FdUMP) and thymidylate synthase (TS), indices of DNA, and proliferating nuclear cell antigen (PCNA). There was a significant correlation between the levels of FdUMP, total TS and free TS in cancer and in normal gastric mucosa, respectively. Total TS of cancer was higher than that of normal tissue, at 5.3 +/- 4.8 and 3.4 +/- 2.2 pmol/g, respectively. On the other hand, there was no relationship nor difference between The TSIR ratio of cancer and normal mucosa. The FdUMP levels of far advanced cancer showed a tendency to be lower than those of the less advanced one, especially in liver metastasis. The total TS was higher in intestinal type and in INF alpha or beta. The free TS was higher in invasive type, liver metastasis and curability C. The TSIR ratio showed a tendency to be lower in far advanced cases, such as invasive type and INF gamma. The correlation between DNA index and TS values and between PCNA labeling index and TS values were good. These results suggest that TS levels would be a predictor for malignant potential as well as for chemosensitivity.

[Frequent loss of heterozygosity on the long arm of chromosome 21 in human esophageal, squamous cell carcinoma]

Year 1998
Mayama T. Nishihira T. Satomi S. Horii A.
Dept. of Molecular Pathology, Tohoku University School of Medicine.
We investigated human esophageal squamous cell carcinoma using microsatellite markers on the long arm of chromosome 21 (21q) and found frequent loss of heterozygosity (LOH). The frequency of LOH was more than 50% in most of the microsatellite markers examined. Whole chromosome deletion suspected cases were observed in 25% of all cases. No case with microsatellite instability was found. Three common regions of allelic loss were identified. The frequent LOH was observed from early stage in pTNM classification. An unknown tumor suppressor gene in the genesis of esophageal squamous cell carcinoma may exist in 21q.

[Serum carcinoembryonic antigen doubling time in patients with recurrent gastrointestinal carcinoma and its relationship to tumor biology and life expectancy]

Year 1998
Takesue F. Inutsuka S. Nagahama S. Kusumoto H. Korenaga D. Maekawa S. Ikeda T.
Dept. of Surgery, Fukuoka Dental College.
BACKGROUND: The present study was done to determine if carcinoembryonic antigen (CEA) concentration doubling time can predict the course of disease in patients with adenocarcinoma of the gastrointestinal tract and characterize tumor biology. METHODS: CEA doubling times were determined from semilogarithmic plots of CEA concentration time courses in 20 patients with recurrent gastric cancer and 17 with recurrent colorectal cancer. RESULTS: Gastric and colorectal carcinomas showed mean CEA doubling times of 229 days and 85 days, respectively. There were no significant differences with regard to patient age, tumor size, gross appearance and histological differentiation. However, women had shorter CEA doubling times than did men. Flow cytometric analysis showed that tumors with a higher proportion of cells in S-phase (> or = 15%) had significantly shorter CEA doubling times than those with a lower S-phase fraction (< 15%). There was a significant correlation between the CEA doubling time and the length of survival after the initial CEA concentration increase in patients with recurrent gastric and colorectal carcinomas. CONCLUSIONS: CEA doubling time predicts life expectancy in patients with adenocarcinoma of the gastrointestinal tract. Differences in survival time are closely associated with variations in the biological aggressiveness of individual tumors.

[Telomerase activity in colorectal cancer--a semi-quantitative procedure]

Year 1998
Ohki S. Satoh H. Watanabe F. Andoh Y. Nomizu T. Yoshida T. Tsuchiya A. Abe R. Yamaki Y.
Second Dept. of Surgery, Fukushima Medical College.
Telomerase maintains telomere at the end of chromosome and stabilizes chromosome. It is thought to have important roles in cancer progression and cell immortality. We evaluated the role of telomerase expression in colorectal carcinogenesis. Materials included 13 colonic adenomas, 9 early colorectal cancers, 32 advanced colorectal cancers, 5 metastatic tumors, and 30 non-cancerous colon mucosas. The telomerase activity was analyzed using TRAP-eze (Oncor Inc.) for a semi-quantitative method. The positive rate of telomerase activity was 13.3% in non-cancerous colonic mucosa, 15.4% in colonic adenomas, 77.8% in early colorectal cancers, 93.8% in advanced colorectal cancers, and 100% in metastatic tumors; the mean value was 18.0, 29.9, 65.8, 97.0 and 161.3. The correlation between telomerase activity and tumor size, histologic type, or depth of invasion was noted. Sensitivity, specificity and accuracy were on the order of 89%, 98% and 93% at the cut-off level as two times the mean value of non-cancerous mucosa. Telomerase had an important role in carcinogenesis, and progression of colorectal cancer, and it was suggested to be useful for a tumor marker.

[Analysis for predicting the prognostic factors of gastrointestinal tract leiomyosarcoma using MIB-1 and DNA flow cytometry]

Year 1998
Nishio T. Nakagomi H. Mutou S. Miyake T. Hagiwara J. Ashizawa I. Oyama T. Takano K. Tada Y.
Second Dept. of Surgery, Yamanashi Medical University.
PURPOSE: The present study was undertaken to investigate the possibility of determining a prognosis for gastrointestinal tract leiomyosarcoma with the use of DNA analysis and MIB-1 staining. SUBJECTS AND METHODS: Malignant tumors originating in smooth muscle of the gastrointestinal tract, surgically excised from 23 lesions in 17 patients (stomach; 8 cases, 12 lesions; small intestine: 6 cases, 8 lesions; colon: 3 cases, 3 lesions) and embedded in paraffin, were examined. DNA was analyzed using flow cytometry to produce a DNA histogram, and aneuploidy and diploidy were found. MIB-1 staining was done in conformity with the ABC method. RESULTS: 1. An investigation of prognoses using the Kaplan-Meier method revealed a tendency for more favorable prognoses in patients determined to be aneuploid through DNA analysis. However, this was not significantly better than those exhibiting diploidy. 2. All patients who died had a MIB-1 staining positivity rate of over 10%, while all patients who had no recurrence within one year or survived had a MIB-1 staining positivity of less than 10%. 3. No consistent trends were observed between MIB-1 positivity rate and DNA analysis, MIB-1 positivity rate and size of tumor, or DNA analysis and size of tumor. 4. The MIB-1 positivity rate of patients with remote metastases was significantly greater than that of patients with no remote metastases. CONCLUSION: From the fact that patients with MIB-1 positivity rates of greater than 10% had a poor prognosis, while those with rates of less than 10% had a favorable prognosis, we conclude that a MIB-1 positivity rate of 10% is an important value in determining the prognosis of patients with gastrointestinal tract leiomyosarcomas.