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Serum vitamin D binding protein (Gc protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of colorectal cancer patients was lost or reduced because Gc protein is deglycosylated by serum alpha-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Deglycosylated Gc protein cannot be converted to MAF, leading to immunosuppression. Stepwise treatment of purified Gc protein with immobilized beta-galactosidase and sialidase generated the most potent macrophage-activating factor (GcMAF) ever discovered, but it produces no side effect in humans. Macrophages treated with GcMAF (100 microg/ml) develop an enormous variation of receptors and are highly tumoricidal to a variety of cancers indiscriminately. Administration of 100 nanogram (ng)/ human maximally activates systemic macrophages that can kill cancerous cells. Since the half-life of the activated macrophages is approximately 6 days, 100 ng GcMAF was administered weekly to eight nonanemic colorectal cancer patients who had previously received tumor-resection but still carried significant amounts of metastatic tumor cells. As GcMAF therapy progressed, the MAF precursor activities of all patients increased and conversely their serum Nagalase activities decreased. Since serum Nagalase is proportional to tumor burden, serum Nagalase activity was used as a prognostic index for time course analysis of GcMAF therapy. After 32-50 weekly administrations of 100 ng GcMAF, all colorectal cancer patients exhibited healthy control levels of the serum Nagalase activity, indicating eradication of metastatic tumor cells. During 7 years after the completion of GcMAF therapy, their serum Nagalase activity did not increase, indicating no recurrence of cancer, which was also supported by the annual CT scans of these patients.

Protein-bound polysaccharide K is an immunotherapeutic agent that promotes apoptosis by inhibiting nuclear factor-kappaB activation in cancer cells. We previously showed that oncogenic beta-catenin activates nuclear factor-kappaB and inhibits apoptosis by up-regulating beta-transducin repeat-containing protein. We investigated whether the activation state of beta-catenin in the primary tumor is associated with differences in survival rates of patients with colon cancer undergoing immunochemotherapy with 5-fluorouracil plus polysaccharide K vs. chemotherapy with 5-fluorouracil alone.We assessed the activation states of beta-catenin and nuclear factor-kappaB in the primary tumors of 202 colon cancer patients, and analyzed the data in terms of the clinicopathologic characteristics and survival of patients undergoing the two forms of adjuvant therapy.We found two distinct patterns of nuclear accumulation of activated beta-catenin in the tumor cells: diffuse nuclear accumulation in 89 cases (44 percent) and selective nuclear accumulation at the tumor invasion front in 18 cases (9 percent). Nuclear factor-kappaB activation was found in 64 cases (32 percent). In patients with diffuse nuclear accumulation-type beta-catenin activation, immunochemotherapy significantly improved recurrence-free survival, cancer death survival, and overall survival rates compared with patients receiving chemotherapy alone. No survival benefit was found in cases with nuclear accumulation at the tumor invasion front-type beta-catenin activation or no activation. Similarly, immunochemotherapy favored the survival of patients with nuclear factor-kappaB activation. Multivariate analysis established the TNM stage and administration of polysaccharide K as independent prognostic factors in the patients with diffuse nuclear accumulation-type beta-catenin activation.The presence of diffuse nuclear accumulation-type beta-catenin activation identifies patients with colon cancer who respond better to immunotherapy with polysaccharide K.

The benefits of immunochemotherapy employing the biological response modifier polysaccharide K (PSK) for patients with curatively resected colorectal cancer was reassessed by means of a meta-analysis of data with center randomization from 1,094 patients enrolled in three clinical trials. In all three trials, patients were followed up for at least 5 years after surgery and enrollment of the last patient and outcomes for standard chemotherapy were compared with those for chemotherapy plus PSK. The endpoints were overall survival and disease-free survival; and intent-to-treat analysis was performed without patient exclusion. Data were analyzed using the weighted average of the individual log hazard ratios. The overall survival risk ratio for all eligible patients was 0.71 (95% confidence interval (CI) : 0.55-0.90; P=0.006), and the disease-free survival risk ratio was 0.72 (95% CI: 0.58-0.90; P=0.003). The results of this meta-analysis suggest that adjuvant immunochemotherapy with PSK can improve both survival and disease-free survival of patients with curatively resected colorectal cancer.

The selection of a trial design is an important issue in the planning of clinical trials. One of the most important considerations in trial design is the method of treatment allocation and appropriate analysis plan corresponding to the design. In this article, we conducted computer simulations using the actual data from 2158 rectal cancer patients enrolled in the surgery-alone group from seven randomized controlled trials in Japan to compare the performance of allocation methods, simple randomization, stratified randomization and minimization in relatively small-scale trials (total number of two groups are 50, 100, 150 or 200 patients). The degree of imbalance in prognostic factors between groups was evaluated by changing the allocation probability of minimization from 1.00 to 0.70 by 0.05. The simulation demonstrated that minimization provides the best performance to ensure balance in the number of patients between groups and prognostic factors. Moreover, to achieve the 1 percentile for the p-value of chi-square test around 0.50 with respect to balance in prognostic factors, the allocation probability of minimization was required to be set to 0.95 for 50, 0.80 for 100, 0.75 for 150 and 0.70 for 200 patients. When the sample size was larger, sufficient balance could be achieved even if reducing allocation probability. The simulation using actual data demonstrated that unadjusted tests for the allocation factors resulted in conservative type I errors when dynamic allocation, such as minimization, was used. In contrast, adjusted tests for allocation factors as covariates improved type I errors closer to the nominal significance level and they provided slightly higher power. In conclusion, both the statistical and clinical validity of minimization was demonstrated in our study.

Background: The metastatic potential of tumors is dependent on the cell to cell adhesion by cell surface carbohydrate antigens. Thus, expression of sialyl Lewis a , which is one of the important molecules of cell surface carbohydrates, may serve as a prognostic marker of aggressive and metastasizing tumor growth. However, the prognostic value of sialyl Lewis a expression in colon cancer is still controversial. Methods: In this study, we investigated the expression of sialyl Lewis a antigen in 233 colon cancer specimens from patients who were registered in a prospective adjuvant immunochemotherapy clinical trial. The clinical course and the prognosis of the patients were evaluated after all the immunohistochemical analyses had been performed. Results: Sialyl Lewis a expression levels were correlated with both overall survival (P= 0.0006) and disease-free survival (P = 0.004) in all patients with the log-rank test. This result could be assumed to have been influenced by the difference in the metastatic preponderance in a high versus low sialyl Lewis a expression in the tumor cells. Conclusion: This prospective study in a randomized controlled trial suggests that sialyl Lewis a expression levels may serve as an indicator of the metastatic potential of colon cancer cells, which would strongly predict the prognosis.

The efficacy of a biological response modifier polysaccharide K in adjuvant immunochemotherapy was evaluated in primary colon cancer patients with macroscopic Dukes' C after curative resection. Employing the minimization method using three factors (lymph node metastases, preoperative serum CEA level, and institution), 446 patients were allocated into groups P and C. Group P received immunochemotherapy, oral PSK (3 g per day) followed by oral 5-FU (200 mg/body per day), while group C received only intermittent chemotherapy, oral 5-FU (200 mg per day) followed by 4-week rest. Both groups received ten courses. Survival for cancer death was significantly higher in group P than in group C, but there was no difference in 7-year disease-free survival or overall survival had. Repeated alternating administration with PSK followed by 5-FU can improve survival for cancer death.

Many studies on postoperative carcinoembryonic antigen (CEA) and/or carbohydrate antigen (CA)19-9 monitoring after operation for gastric cancer have been reported, but most have been retrospective.A nationwide observational study was implemented in 135 leading institutions in Japan to evaluate the significance of CEA and/or CA19-9 in postoperative monitoring for recurrence in patients with advanced gastric cancer. Three hundred and twenty-one patients examined in this analysis underwent radical gastrectomy at one of Japan's leading institutions between November 1993 and March 1996 and had been followed up for at least 5 years. Serum levels of CEA and CA19-9 were examined preoperatively and every 3 months postoperatively, with diagnostic imagings, such as chest X-ray, computed tomography (CT), and ultrasonography also being performed every 3 months.Recurrence was observed in 120 patients (peritoneum, 48; liver 16; lymph node, 16; multiple sites, 25; and others, 12). Sensitivities of CEA and either CEA or CA19-9, or both, for recurrence were 65.8% and 85.0%, respectively, both of which values were significantly higher than the preoperative positivities (28.3% and 45.0%, respectively). In most patients with high preoperative levels CEA and/or CA19-9, these tumor markers increased again at recurrence. Recurrent diseases were detected between 5 months after detection by diagnostic imagings and 12 months before detection by diagnostic imagings (mean of 3.1 +/- 3.6 months before detection by diagnostic imagings) and between 10 months after detection by diagnostic imagings and 13 months before detection by diagnostic imagings (mean of 2.2 +/- 3.9 months before detection by diagnostic imagings) by CEA and CA19-9 monitorings, respectively.These results suggest that CEA and/or CA19-9 monitoring after operation was useful to predict the recurrence of gastric cancer, especially in almost all the patients with high preoperative levels of these markers.

SUMMARY: The benefits of immunochemotherapy with a penicillin-treated, lyophilized preparation of Streptococcus pyogenes, OK-432 (Picibanil), were reassessed in patients with resected non-small-cell lung cancer through a meta-analysis based on data from 1,520 patients enrolled in 11 randomized clinical trials. All 11 trials were started before 1991, and the subjects had been followed up for at least 5 years after surgery and randomization. In these trials, standard chemotherapy was compared with the same therapy plus OK-432. The endpoint of interest was overall survival, and analysis was based on intent-to-treat population without patient exclusion. Data were analyzed using the Mantel-Haenszel method. The 5-year survival rate for all eligible patients in the 11 trials was 51.2% in the immunochemotherapy group versus 43.7% in the chemotherapy group. The odds ratio (OR) for overall survival was 0.70 (95% CI = 0.56-0.87, p = 0.0010). Analysis of four trials in which central randomization was performed also reconfirmed a significantly longer survival time for the immunochemotherapy group (OR = 0.66, 95% CI = 0.44-1.00, p = 0.049). Based on these results of meta-analysis, it is postulated that postoperative adjuvant immunochemotherapy using OK-432 might improve the survival of patients after resection of non-small-cell lung cancer.

The role of the spleen in tumor immunology is still controversial in that it can either enhance or suppress the antitumor immune response depending on the tumor-bearing host. To clarify this biphasic effect of the spleen, a clinical evaluation of splenectomy in conjunction with immunotherapy and the host immune status was performed in gastric cancer patients. The effect of splenectomy and immunotherapy in 253 gastric cancer patients enrolled in a prospective randomized trial (SIP) was analyzed using the Cox's proportional hazards model in terms of the covariate interaction of the preoperative immunosuppressive acidic protein (IAP) level. In patients with high IAP levels (>580 microg/ml) with predicted negative antitumor immune reactions, splenectomy improved the prognosis. In patients with lower IAP values, conversely, the preservation of the spleen and immunotherapy demonstrated a significant benefit to survival. The spleen was shown to have a biphasic activity in terms of its antitumor immune response depending on the IAP level of the patient. The effect of immunotherapy is significantly influenced by the activity of spleen cells. The preoperative IAP level is therefore considered to be a possible indicator for the effectiveness of splenectomy and immunotherapy in curatively resected gastric cancer patients.

Background: Oral 5-fluorouracil and its prodrugs (tegafur, carmofur) is now being studied for adjuvant chemotherapy of curatively resected colorectal cancers.To evaluate the effect of these oral fluoropyrimidines (o-FPs), an individual patient data (IPD) meta-analysis of randomized clinical trials was performed in Japan as an inter-trialist group study. Methods: Data from the three clinical trials in which postoperative adjuvant therapy with o-FPs was compared with surgery alone in patients with colorectal cancer were sought. IPD from a total of 4960 patients with follow-up periods of at least 5 years were analyzed. Results: The results of the meta-analysis on an 'intention to treat' basis demonstrated a significant benefit of o-FPs in terms of the disease-free survival (DFS) of the total patients [risk ratio (RR) 0.830,95 % confidence interval (CI) 0.742-0.929, P = 0.001J. o-FPs were also demonstrated to be effective for survival in rectal cancer (RR 0.857, 95% CI 0.734-0.999, P = 0.049) and in Dukes'C colorectal cancer (RR 0.828,95 % CI 0.711-0.965, P= 0.016). Conclusion: The results suggest the advantage of long term o-FPs, possibly with the injection of mitomycin C, for prognosis for curatively resected colorectal cancer patients.

A large-scale retrospective study was undertaken to evaluate the association between preoperative plasma carcinoembryonic antigen (CEA) levels and the prognosis of 2768 gastric cancer patients who underwent curative gastrectomy between 1983 and 1984 at 66 leading medical institutions in Japan. Postoperative follow-up was at least 5 years. Preoperative plasma CEA levels were also analysed against other prognostic factors. Preoperative plasma CEA levels showed strong correlations to the degree of lymph node metastasis ( P P = 0.004) and the histopathology of the gastric cancer ( P P

BACKGROUND Immunosuppressive acidic protein (IAP) has been reported to have close correlation with the impairment of host immune response. To evaluate the significance of IAP in clinical studies, the prognostic value of preoperative IAP was investigated in clinical trials of patients with gastric carcinoma after curative resection. METHODS An appropriate IAP threshold value of 580 μg/mL was determined using Cox's proportional hazards model. Five-year survival rates were estimated for high and low IAP groups in three different clinical studies. Meta-analysis was performed based on individual patient data, and summarized hazard ratios were estimated using a stratified proportional hazards model. RESULTS Meta-analysis of the three clinical trials demonstrated that patients with preoperative IAP levels above the threshold had significantly poorer cancer related survival (P = 0.0039) and absolute survival (P = 0.0023), even after adjustment for the major prognostic factors. CONCLUSIONS Gastric carcinoma patients with an IAP value above the threshold level of 580 μg/mL have a higher risk of cancer death and absolute death than patients with an IAP value below the threshold value.

In a phase III randomized trial of adjuvant chemotherapy for gastric cancer, interinstitutional differences were analyzed. A trial of three regimens: mitomycin C, 5-fluorouracil(5-FU) and CA (MFC) + continuous oral 5-FU (Group C); MFC + continuous oral UFT(tegafur and uracil) (Group B); and MF + UFT (Group C) after operation was conducted in 466 patients with gastric cancer (stage II and III) at four hospitals in Japan (CIH, CAD, ACC and NCC). Patients were stratified by the institution, stage, and tumor size (8 cm). The 5-year survival rates were in the order of Group A (79.0%)B (70.0%)C (61.0%) (P = 0.1228) in total, A (95.0%)B (80.0%)C (58.0%) (P0.05) at CAD (82 patients), ACB at CIH (215), CAB at ACC (95), and BAC at NCC (78). The survival rate of patients with S2(serosal exposure), 8 cmand N0-1 cancer was higher at CIH than at the other institutions. The interinstitutional differences in patient characteristics and surgical technique were more powerful than the differences among the three groups.

In Japan the standard adjuvant treatment after resection of gastric cancer is intravenous mitomycin plus oral fluorouracil. We have assessed the efficacy of protein-bound polysaccharide (PSK) in addition to standard chemotherapy in patients who had undergone curative gastrectomy at 46 institutions in central Japan. 262 patients were randomly assigned standard treatment alone or with PSK. The minimum follow-up time was 5 years (range 5-7 years). PSK improved both the 5-year disease-free rate (70 7 vs 59 4% in standard treatment group, p=0 047) and 5-year survival (73·0 vs 60·0%, p=0·044). The two regimens had only slight toxic effects, consisting of nausea, leucopenia, and liver function impairment, and there were no significant differences between the groups. The treatments were clinically well tolerated and compliance was good. Addition of PSK to adjuvant chemotherapy with mitomycin and fluorouracil is beneficial as treatment after curative gastrectomy.

A mouse monoclonal antibody V-715 was raised against fresh colon cancer tissues. Biochemical analysis elucidated that the antigen defined was adenosine deaminase binding protein (ADBP). In colon cancer cell lines, V-715 was positive in 8 out of 16 differentiated cancers and in 2 out of 8 poorly differentiated cancers. In frozen sections, ADBP was expressed in 17 out of 33 differentiated colon cancers, but none of 4 poorly differentiated colon cancers. In normal colon, the expression was observed in epithelium. In gastric cancers, ADBP was expressed in 10 out of 15 differentiated cancers, but weakly or only heterogenously expressed in 2 out of 8 poorly differentiated cancers. In normal gastric mucosa, ADBP was mainly detected in the foveolar epithelium, but was weakly or not expressed in the deep gastric glands. Carcinoid tumors and malignant lymphoma of the stomach did not express ADBP. These results suggest that ADBP may act as a marker of enterocytic differentiation in normal and neoplastic gastrointestinal cells, and might be exploitable in clinical and pathological diagnosis of gastrointestinal cancers. © 1993 Wiley-Liss, Inc.

H‐15 (HT‐29‐15) is an IgG1 mouse monoclonal antibody (mAb) to a cell surface antigen (molecular mass, 200,000 daltons) present on virtually all colorectal cancers and also in normal pancreatic ducts and bile ducts, but not in other normal tissues. The biological distribution and imaging characteristics of iodine‐131 (l31I)‐labeled mAb H‐15 were studied in 5 primary colorectal cancer patients and 9 patients with local recurrence of colorectal cancer. H‐15 mAb labeled with 0.5‐10 mCi of 131I was administered 7 to 8 days before surgery at 4 dose levels, ranging from 0.2 to 6 nig. Selective mAb H‐15 localization to tumor tissues was demonstrated in 6 of 12 patients with antigen‐positive tumors: in two patients, recurrent tumors were negative to H‐15 mAb, although the primary tumors were positive. In six patients with positive radioimaging, tumor:normal tissue ratios ranged from 2.05 to 5.35 and tumor:serum ratios from 1,18 to 2.73. The clarity of images seems to correlate well with the latter ratios. Technetium‐99 (99mTc)‐albumin blood pool studies in selected cases showed that local recurrence of colorectal cancers was hypovascular, emphasizing the selective localization of mAb H‐15 despite poor blood flow distribution in the tumors. The results altogether demonstrated that radioimmnnodetection with 131I mAb H‐15 is valuable for differentiating recurrent colorectal cancer from granuloma formation after surgery.

悪性リンパ腫に対する研究の進歩にともない, 胃悪性リンパ腫に対しても新しい観点での治療法の導入が試みられている.胃悪性リンパ腫のなかでも新しい知見が得られている表層拡大型 (表拡型) リンパ腫を今回研究対象とした.1965年から1990年までに手術した胃悪性リンパ腫102例のうち表拡型リンパ腫は26例であった.26例のうち深達度sm 19例, 腫瘍最大径20cm以上10例, リンパ節転移陽性11例, R2の郭清23例, 全摘術19例であった.10生率は86.8%と高く, 再発死亡は1例のみであった.リンパ節郭清, 切除範囲が適切であれば予後は良好と考えられた.24例の組織型がIsaacsonら1)によるMALTリンパ腫 (mucosa-associated lymphoid tissue lymphoma) であり, 中村ら2) によるRLH (reactive lymphoreticular hyperplasia) はMALTリンパ腫であると考えられるようになっている.表拡型リンパ腫の認識は胃悪性リンパ腫の理解において重要な意味をもつものと考えられる.

A total of 103 patients with advanced gastric carcinoma were randomized after curative surgery to receive an alternate administration of carbazilquinone (CQ) and PSK (Krestin) or carbazilquinone alone. Each course of therapies started 1 week after the surgical operation and therapy schedules consisted of 9 courses. In each course of 6 weeks, CQ (2 mg/m2/week) was administered on day 0, 8, and 15. In combined immunochemotherapy group, PSK was given orally in 3-divided doses of 2 g/m2/day from the day of the third CQ administration for consecutive 4 weeks. Estimated survival rate and cumulative survival curve were compared utilizing the data up to 7 years after the operation. There was no overall significant difference in survival rates between the CQ plus PSK group and the CQ alone group, but a group of patients whose disease was classified as S1 + S2(N1-2) survived significantly longer when treated with the combination of CQ and PSK. Neither in more advanced cases (greater than S3 or greater than N3) nor in cancers of early stages, the addition of PSK provided an additive effect. The favorable result obtained in one subgroup treated with PSK, suggests that the use of this agent in treating gastric cancers should be carefully evaluated in terms of serosal infiltration and nodal metastasis.

症例は66歳男性.1989年8月27日, 腹痛, 嘔吐, 発熱が出現.8月28日, 他院に急性腹症として緊急入院し, 胃内視鏡内視鏡生検, computed tomographyなどにより, 胃癌および癌性腹膜炎と診断された.9月19日, 当院へ転院.当院の胃生検では癌は証明されなかったが, 上部消化管造影などでBorrmann4型胃癌と診断し, 10月6日, 手術を施行した.切除標本では胃大弯側に穿孔部を認め, その外側に炎症性肉芽腫が存在した.それとは別に小弯に潰瘍性病変が存在し, その中にアニサキス虫体と思われる異物を認めた.摘出標本の検索では胃癌は存在せず, 両病変ともにアニサキスによるものと診断した.本症例は, アニサキスにより胃に潰瘍性病変を形成し, さらに, 別な部分に胃穿孔を起こしたというきわめてまれな症例であり, さらに, 術前に画像検査および病理組織検査で癌と診断されたという点でも示唆に富む症例であった.

Hepatocellular carcinomas occasionally grow into the bile duct, evidencing itself in symptoms such as obstructive jaundice and abdominal pain. This report discusses a case of small liver cancer grown into the bile duct which was marked by an initial symptom of r-hypochondral pain. In December 1988, a 60-year-old male experienced attacks of abdominal pain similar to that caused by gallstones and came to our hospital. Computed tomography showed liver cirrhosis and a tumor in the left intrabileduct combined with dilatation of its peripheral ducts. Endoscopic retrograde cholangiography (ERC) also revealed a polyp-like tumor in the left bile duct. Cytology of the bile showed the presence of adenocarcinoma. Based on these examinations, a diagnosis was at first made as an intrahepatic cholangiocarcinoma, and surgery was performed. During surgery, a tumor of 2 cm in diameter was found on the surface of the left lateral lobe of the liver. With the diagnosis of hepatocellular carcinoma, combining with initial bile duct tumor, left hepatic lobectomy was performed. Out surface of the excised material showed that the tumor exposed on the surface was connected to the intrabileduct tumor. The final pathological diagnosis resulted in the hepatocellular carcinoma which had grown into the bile duct.

5年間臨床像がほぼ変わらず, さらにはいわゆる早期の下部胆管癌であった1例を経験した.症例は51歳の男性で主訴は心窩部痛. 1985年総胆管切石術が施行された際, 下部胆管の腫 瘍が指摘された. そのときは生検の結果adenomaであり, 患者の希望もあったので経過観察となった. 今回1990年1月心窩部痛があり, 諸検査の結果同部位の腫瘍が痛みの原因と診断され当院に紹介入院した. 術前の生検では, 一部異型度が強いpapillary adenomaと診断されたが, 癌の可能性も否定できず, 臨床症状があることから膵頭十二指腸切除を施行した. 病理組織検査ではfibromascular layerに一部浸潤したadenocarcinomaであった. 下部胆管腫瘍に対する術前診断と手術適応について考察した.

An immunohistochemical analysis of the expression of Lewis(a), Lewis(b), and sialated Lewis(a) blood group antigens was performed on specimens of human non-involved stomach (n = 91), early gastric cancers (n = 41), and advanced gastric cancers (n = 50). In non-involved stomach, Lewis(a) and Lewis(b) were detected mainly in surface epithelium, although sialated Lewis(a) was scarcely expressed. These blood group-related antigens were rarely observed in deep glands. In gastric cancers, Lewis(a) showed a tendency to be expressed in well or moderately differentiated carcinomas, and this was observed to be more marked in advanced tumors. There was no obvious difference in positive ratios of Lewis(b) between degrees of differentiation of the cancers. Sialated Lewis(a) was not detected in early cancers, and its frequent expression in well- or moderately differentiated, advanced carcinomas suggested an association with both cancer differentiation and progression. These results indicate that knowledge of the expression of blood group antigens may help interpret the antigenic alterations occurring in the course of carcinogenesis, differentiation, and progression of gastric cancers.

症例は, 66歳の男性で腹痛と発熱を主訴に来院.諸検査の結果, 胆嚢総肝管瘻を合併した胆嚢癌の胆管浸潤, または胆管癌の胆嚢浸潤と診断し, 胆嚢, 胆管切除, 肝門部胆管十二指腸吻合を施行した.切除標本を検索すると, 胆嚢と総肝管は広く交通し, 瘻孔を形成しており, 腫瘍は胆嚢頚部に茎を持ち, 結節状に発育しこの瘻孔を通って総肝管内に突出していた.なお, 一部胆嚢体部で胆嚢粘膜からさらに肝床に直接浸潤していた.腫瘍と周囲組織との接合点は茎の部位と, 肝床への浸潤部のみであり, 他の胆嚢粘膜, 瘻孔壁, および総肝管粘膜との間には連続性はなかった.また胆嚢内および胆管内には同一の形状の混合石が存在していた.病理組織学的には, papillary adenocarcinomaで, リンパ節転移はなかった.以上より, この腫瘍は, 胆嚢癌で, 胆石症に続発して形成された胆嚢総肝管瘻を通じて胆管内に発育進展したものと考えられた.

H-15は大腸癌培養細胞HT胃29の細胞表面に発現している分子量200 Kdの糖蛋白に対するモノクローナル抗体で, 認識する抗原決定基はシアル化LewisaとCross Reactivityを有している.H-15は, 血清学的, 免疫組織学的検索で, 大腸癌細胞表面に高率に検出され, 他癌や正常組織ではほとんど存在していないことが証明されている.抗体を放射性ヨードでラベルし, ヌードマウス移植ヒト大腸癌に投与したところ, 鮮明な腫瘍画像が得られた.大腸癌症例における臨床応用では, 0.2～10mgの抗体を0.2～10m Ciの131Iでラベルし, ガンマカメラを用いて抗体の局在を検討した.抗体投与による重篤な副作用はなく, 肝転移20例中4例, 局所病変8例中3例において, 直接腫瘍画像を描出することができた.

BACKGROUND: Oral carmofur, either as a single or in combination with other chemotherapeutic agents, has been used as adjuvant chemotherapy for curatively resected colon cancer patients. Past trials and meta-analyses indicate that it is somewhat effective in extending survival of patients with this cancer. The objective of this study was to perform a reappraisal of randomized clinical trials conducted in this regard. METHODS: We designed an individual patient-based meta-analysis of relevant clinical trials to examine the benefit of oral carmofur for curatively resected colon cancer in terms of overall survival (OS) and disease-free survival (DFS). RESULTS: We analyzed individual patient data of three randomized clinical trials, which met the predetermined inclusion criteria. These three trials had a combined total of 2152 patients, carmofur as adjuvant chemotherapy compared with surgery-alone, 5 years follow-up, intention-to-treat-based analytic strategy and similar end points (OS and DFS). In a pooled analysis, 5 year OS rates were 80.4 and 76.4%, and 5 year DFS rates 76.9 and 71.0%, respectively, in carmofur and surgery-alone group. Oral carmofur had significant advantage over surgery-alone in terms of both OS [pooled hazard ratio, 0.82; 95% confidence interval (CI) = 0.68-0.99; P = 0.043] and DFS (pooled hazard ratio, 0.77; 95% CI = 0.65-0.91; P = 0.003). CONCLUSIONS: This individual patient-based meta-analysis demonstrated that oral carmofur significantly improves both OS and DFS in patients with curatively resected colon cancers.

Objective: We conducted a phase I trial of escalating doses of weekly paclitaxel (Taxol) in combinationwithafixedsystemicadministrationof5-fluorouracil(5-FU)inpatientswithadvanced or metastatic gastric cancer. Methods: Patients with advanced or recurrent gastric cancer were treated with escalating doses of weekly paclitaxel as a 60 min intravenous (i.v.) infusion, along with a fixed dose of continuous 5-FUinfusedover5days.Plasmasamplingwasperformedtocharacterizethe pharmacokinetics and pharmacodynamics of paclitaxel. Results: Eighteen patients received combination therapy at four dose levels of weekly Taxol, ranging from 60 to 90 mg/m 2 /week. Dose-limiting toxicities >grade 3 were observed at the 90 mg/m 2 /week dose level. Toxicities included anemia, neutropenia, thrombocytopenia, nausea andalopecia.Twoepisodesofgrade4neutropeniaoccurredintwoofthethreepatientsreceiving this dose. At each dose level, pharmacological studies documented the persistence of significant serum paclitaxel levels over 24 h after drug administration. The maximum tolerated dose (MTD) for this regimen was 90 mg/m 2 /week of paclitaxel for 3 weeks plus 600 mg/m 2 /day of continuous 5-FU for 5 days. Conclusions: The combination of weekly paclitaxel and 5-FU demonstrated an acceptable toxicity profile and feasible pharmacokinetic results suggesting its practical applicability. Based onthesefindings,therecommendeddoseandscheduleforphaseIIstudyofcombinationchemotherapy is paclitaxel 80 mg/m 2 /week · 3 over 4 weeks, and continuous 5-FU 600 mg/m 2 /day · 5 days every 4 weeks.

The expression levels of thymidylate synthase (TS) affect the sensitivity of tumor cells to fluorinated pyrimidine cytotoxic agents and determine the response of patients with colorectal cancer to fluorinated-pyrimidine-based chemotherapy. The correlation between the expression of TS and the prognosis of patients with colorectal cancer was examined in a prospective study. Evaluation of biomarkers including TS expression was performed using tumor specimens from 229 colorectal cancer patients. Immunohistochemical analysis of TS expression was performed using an antibody raised against a C-terminal epitope (D 186 -V 313 ) of the human TS. The intensity of TS staining and the expression of other biomarkers were blindly scored. The five-year survival rates were 63.4% and 85.6% among patients with high and low intratumoral TS expressions, respectively (p=0.0007). Similarly, the disease-free survival (DFS) rate was 51.2% and 80.3% in the high and low TS expression groups, respectively (p=0.0004). In a subset analysis of Dukes' stage C patients, the survival and DFS rates were 44.0% and 40.0% in the high TS expression group, and 73.5% and 67.4% in the low TS expression group, respectively. Significant differences were observed in both survival (p=0.0048) and DFS (p=0.0054) rates. No significant correlation was observed between the expression of other biomarkers and prognosis. Significantly poorer prognosis of curatively resected colon cancer in patients with high TS expression levels in tumor tissue was confirmed by a double-blind prospective study conducted on samples obtained from patients enrolled in an adjuvant immunochemotherapy randomized clinical trial.

Postoperative adjuvant chemotherapy reportedly improves advanced colorectal cancer patients' survival, however, it is necessary to assess what regimens are useful. Doxifluridine (5'-DFUR) is an intermediate of capecitabine approved in Europe and USA to treat metastatic colorectal cancer. 5'-DFUR is metabolized to 5-fluorouracil (5-FU) by thymidine phosphorylase existing in tumor at high concentrations, suggesting high 5-FU levels in tumor tissues and lesser complications. Present study compared usefulness of 5'-DFUR to that of oral 5-FU. Patients were enrolled at 38 centers from April 1993 to September 1996. They had diagnosed colorectal cancer of TNM stages II and III, and underwent macroscopic curative resection. Patients were prestratified into colon or rectum cancer and allocated into either 5'-DFUR (5'-DFUR 460 mg/m 2 /day + PSK 3 g/day) or 5-FU (5-FU 115 mg/m 2 /day + PSK 3 g/day) group by dynamic randomization (stratification factors such as depth of tumor, degree of lymph node metastasis, and location of tumor). Drugs were orally administered daily from postoperative week 2 to 54, with 6 mg/m 2 mitomycin C at operation and following days. Subjects for analysis were 277 in 5'-DFUR and 281 in 5-FU groups. Median follow-up was 6.5 years. Although no differences in overall survival curves were detected, multivariate analysis showed that 5'-DFUR + PSK regimen was a significantly better prognostic factor in patients with Dukes B or C (risk ratio, 1.451; p=0.048); with tumor depth of pT3 or pT4 (risk ratio, 1.568; p=0.020). For patients with advanced colorectal cancer, 5'-DFUR + PSK therapy may possibly be more useful than 5-FU + PSK, but further study is required.

Meta-analysis of 5 studies on postoperative breast cancer cases (2 studies on surgery alone vs. tegafur plus uracil (UFT) and 3 studies on tamoxifen (TAM) alone vs. TAM + UFT) were carried out to evaluate the anticancer drug UFT in oral postoperative adjuvant chemotherapy. Of the 1973 patients enrolled, 1898 were eligible and 75 were excluded (exclusion rate 3.8%). There was no bias in major background factors in either the UFT-treated (965) or non-UFT-treated (933) groups. The reduction in the odds of death and the odds of recurrence were 17 ± 17% (p = 0.33) and 21 ± 11% (p = 0.060), respectively. Multivariate analysis using Cox’s proportional hazards model emphasized the effectiveness of UFT treatment for suppression of recurrence compared with non-treatment with UFT (p = 0.038). Suppression of recurrence was remarkable in the group treated with UFT for 2 years. (the reduction in the odds of recurrence: 23 ± 11%, p = 0.048) Stratified analysis was applied concerning recurrence, and improved results were obtained in premenopausal cases (the reduction in the odds of recurrence: 33 ± 11%, p = 0.019). These results suggested that UFT treatment for 2 years was effective as postoperative adjuvant chemotherapy for stage I – IIIA breast cancer for the prolongation of the reccurence-free survival period.

We carried out a retrospective evaluation of thymidylate synthase (TS) expression in tumor tissue, and its relation to outcome and response to treatment. The treatment consisted of chemotherapy with tegafur and uracil (UFT). The study group comprised 245 patients with curatively resected Dukes' stage B or C colorectal cancer who were postoperatively enrolled in a controlled study and assigned to receive UFT or no adjuvant chemotherapy. TS expression in tumor tissue was evaluated immunohistochemically with the use of recombinant human TS-specific antibody. Results were as follows. There was no relation between TS expression and the rate of 5-year disease-free survival. Similar results were obtained in both colonic and rectal tumors. The rate of 5-year disease-free survival was significantly higher in the UFT group than in the group receiving no adjuvant chemotherapy ( =0.0055). The difference in survival became more marked among patients whose tumors had diffuse TS expression ( =0.0027). There was no difference in survival between the treatment groups among patients whose tumors had focal TS expression. We conclude that, although unrelated to outcome, TS activity may be useful in predicting the response to adjuvant chemotherapy with UFT in patients with curatively resected Dukes' stage B or C colorectal cancer.

The benefit of immunochemotherapy employing a streptococcal preparation, OK-432 (Picibanil), in patients with curatively resected gastric cancer was reassessed by meta-analysis of data from 1,522 patients enrolled in six clinical trials with central randomization. All six trials began between 1985 and 1993, and patients were followed-up for at least 3 years after surgery and enrollment of the last patient. In these trials, standard chemotherapy was compared with the same chemotherapy plus OK-432. The endpoint was overall survival and intent-to-treat analysis was done without patient exclusion. Data were analyzed using the Mantel-Haenszel method. The 3-year survival rate for all eligible patients in the six trials was 67.5% in the immunochemotherapy group versus 62.6% in the chemotherapy group. The 3-year overall survival odds ratio was 0.81 (95% confidence interval: 0.65-0.99). The treatment effect was shown to be statistically significant (p = 0.044). The results of this meta-analysis suggest that immunochemotherapy after surgery with OK-432 can improve the survival of patients with curatively resected gastric cancer.

To assess the efficacy of 5'-DFUR, an intermediate of capecitabine, for adjuvant treatment of early breast cancer, we conducted an open-labeled multi-center randomized controlled trial to compare postoperative 5'-DFUR treatment with surgery alone. We enrolled 1217 primary breast cancer patients and randomly assigned them into two treatment groups; one received six-month postoperative 5'-DFUR treatment by consecutive or intermittent administration, and the other surgery alone. Follow-up surveys were conducted once a year for all subjects simultaneously and examined their outcome/presence or absence of the cancer recurrence. The central study committee reviewed all follow-up data and judged the recurrence data to be used for the analysis. Eight-year follow-up data showed no significant differences in relapse-free and overall survival between the two groups, and 5'-DFUR treatment regimen showed an extremely high tolerance. Possible explanations are discussed for the finding of no significant survival difference between adjuvant 6-month 5'-DFUR monotherapy and surgery alone in early breast cancer.

Serum vitamin D binding protein (Gc protein) is the precursor for the principal macrophage-activating factor (MAF). The MAF precursor activity of serum Gc protein of colorectal cancer patients was lost or reduced because Gc protein is deglycosylated by serum α-N-acetylgalactosaminidase (Nagalase) secreted from cancerous cells. Deglycosylated Gc protein cannot be converted to MAF, leading to immunosuppression. Stepwise treatment of purified Gc protein with immobilized β-galactosidase and sialidase generated the most potent macrophage-activating factor (GcMAF) ever discovered, but it produces no side effect in humans. Macrophages treated with GcMAF (100 pg/ml) develop an enormous variation of receptors and are highly tumoricidal to a variety of cancers indiscriminately. Administration of 100 nanogram (ng)/human maximally activates systemic macrophages that can kill cancerous cells. Since the half-life of the activated macrophages is approximately 6 days, 100 ng GcMAF was administered weekly to eight nonanemic colorectal cancer patients who had previously received tumor-resection but still carried significant amounts of metastatic tumor cells. As GcMAF therapy progressed, the MAF precursor activities of all patients increased and conversely their serum Nagalase activities decreased. Since serum Nagalase is proportional to tumor burden, serum Nagalase activity was used as a prognostic index for time course analysis of GcMAF therapy. After 32–50 weekly administrations of 100 ng GcMAF, all colorectal cancer patients exhibited healthy control levels of the serum Nagalase activity, indicating eradication of metastatic tumor cells. During 7 years after the completion of GcMAF therapy, their serum Nagalase activity did not increase, indicating no recurrence of cancer, which was also supported by the annual CT scans of these patients.

Background: The purpose of this study is to evaluate the efficacy of postoperative adjuvant chemotherapy using uracil and tegafur (UFT) for colorectal cancer. Methods: In a multicenter trial among 43 institutions for patients who underwent curative resection of Dukes’ B or C colorectal cancer, a surgery alone group (control group) and a treatment group (UFT group) to which UFT was administered at 400 mg/day for 2 years following surgery were compared. A total of 320 patients were registered between March 1991 and April 1994, and 289 of these patients were analyzed as a full-analysis set. Results: The 5-year disease-free survival rate was 75.7% in the UFT group and 60.1% in the control group, respectively, and the stratified log-rank test showed the statistical significance (P=0.0081). This difference was marked in rectal cancer (P=0.0016) and, in particular, the local recurrence was reduced. No significant difference was observed in the 5-year survival rate. The incidence of adverse reactions on administration of UFT was low, and there was no serious adverse reaction. Conclusion: It is suggested that the consecutive administration of UFT at 400 mg/day was an effective and highly safe therapeutic method as postoperative adjuvant chemotherapy for rectal cancer.

To reappraise the benefits of the long supported chemotherapy with carmofur, a meta-analysis based on individual patient data from the three clinical trials was performed by pooling 614 patients from three trials, there is a statistically significant survival benefit (2p=0.032) and disease-free survival (DFS) benefit (2p=0.021) for carmofur; and a highly significant advantage for carmofur in DFS (2p=0.0004) and in survival (2p=0.004) in Dukes' C patients. This IPD meta-analysis strongly suggested an effect of oral carmofur in a long supported chemotherapy for curatively resected colorectal carcinoma.

A randomized controlled comparative study of oral medroxyprogesterone acetate (MPA) 1,200 mg (arm I) and 600 mg (arm II) was conducted in 80 patients with advanced or recurrent breast cancer. There were no significant differences between arm I and arm II in terms of response rate, duration of response and survival, or in terms of incidence and severity of adverse reactions. The lowest serum MPA concentration in responders tended to be higher than that in nonresponders. In the cohort of this study, the lowest concentration in partial response was 17.4 ng/ml, suggesting that this level may be the required minimum serum concentration.

In a previous randomized clinical trial against curatively resected gastric cancer, we compared the effect of immunochemotherapy to chemotherapy and obtained significantly better survival and disease-free survival time (DFS) in a combined therapy group. Although DFS was analysed with a conventional approach in which the onset of relapse was defined as the diagnosis of relapse, we considered it necessary to re-analyse the data and compare the results of an interval-censored approach with the conventional approach, in order to examine whether the conclusion might be altered depending on the approach.

A cyanine photosensitizing dye, platonin, is a potent macrophage-activating agent. Four days after the administration to mice of small amounts of platonin (20–40 ng/mouse), peritoneal macrophages exhibited greatly enhanced Fc-receptor-mediated phagocytic and superoxide-generating capacities. Much higher doses (more than 3000 ng/mouse) did not have this effect. Photodynamic experiments for macrophage activation were performed by exposing mouse peritoneal cells (mixture of macrophages and B and T lymphocytes) to white fluorenscent light (3 J m−2s−1) in media containing various low concentrations of platonin. A short exposure to white fluorescent light (5 s, 15 J m−2) of peritoneal cells in a medium containing 3 ng platonin/ml produced a maximal level of phagocytic capacity of macrophages. Although platonin absorbs light poorly at wavelengths longer than 630 nm, the region of the spectrum in which the tissues are transparent allows reasonable penetration of light. Thus, we designed experiments in which peritoneal cells were exposed to a red fluorescent light (0.5 J m−2s−1). In a medium containing 10 ng platonin/ml with 15 J m−2 red light, a markedly enhanced ingestion activity of macrophages was observed. Photodynamic treatment of peritoneal macrophages alone did not activate macrophages. Thus, participation of nonadherent cells is required for photodynamic activation of macrophages, implying that a macrophage-activating factor is generated within the nonadherent cells and transmitted to macrophages.

Eighty two patients with pathological metastasis to the lymph nodes along the splenic artery (L11) were divided into two groups (pancreato-splenectomy(PS) (+): 19 cases, PS(-):63 cases). Their backgrounds were.not different. Five year survival rate of PS(+) group was 10.5%, and that of PS(-) group was 12.8%. Residual lymph nodes were microscopically detected in the previously dissected pancreas specimen in three out of eight cases studied. Those lymph nodes were few in number, small in size and all of them were cancer negative. From these results, we concluded that dissection of L11 without PS might be a clinically satisfactory procedure against advanced gastric carcinoma.

The prognostic value of immunosuppressive acidic protein (IAP), which is known to suppress various immune responses in cancer patients, was studied in a prospective randomized trial of advanced gastric cancer patients, designed to evaluate the effect of PSK, a kind of biological response modifier with protein-bound polysaccharides. Preoperative serum IAP levels were determined in 228 patients who received radical gastric resection and tests conducted in one laboratory by the single radial immunodiffusion (SRID) method. All patients were followed up for 24 months or more. There was an overall significant difference in disease-free survival time in favour of the PSK-treated group compared with the control group. Preoperative IAP values were strongly associated with disease-free survival time. The statistical analysis to define an appropriate cut-off level for IAP was performed using Cox's proportional hazards model. The most significant difference was observed at the threshold value of 580 micrograms/ml, the hazard ratio being 2.13 with a 95% confidence interval [1.17, 3.88] (P = 0.013). Patients in the PSK-treated group with a preoperative IAP of lower than 580 micrograms/ml showed improved disease-free survival (P = 0.029), however, no significant difference was seen between the two groups when the preoperative IAP exceeded the threshold level. From these results, 580 micrograms/ml is postulated to be the most appropriate threshold value for predicting the prognosis of advanced gastric cancer patients, and it is suggested that PSK would be most effective in patients whose preoperative IAP level is lower than the threshold level.

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

A latent factor, which will be called as “prognostic factor”, is extracted from nine explanatory variables observed mainly at the time of surgery from categorical principal component analysis, and it is shown that the factor has the appropriate meaning of prognosis measured on the postsurgical survival periods. Zero value on the prognostic factor is reflected to about five years on the postsurgical survival periods, and it is shown that positive values (or negative values) on the factor mean elongation more than (or shortening less than) about five years on the postsurgical survival periods. Further, this fact is confirmed by categorical canonical discriminant analysis of the same data. The effect of adjuvant chemotherapy is detected in the interaction with the serosal invasion, and elongation of about 34 months on the survival periods is obtained as the significant difference between the treated group with chemotherapy and the control group, at s1 category in serosal invasion.

胃癌の同時性肝転移241例について術後生存期間からみた各種治療法の有用性を検討した. H1, H2では他因子併存の有無にかかわらず胃切除例の生存期間が長く, H1の5生率はR2 13.6%, R1 17.6%, R0 0%, 非切除0%であった. H1では胃切除のみの症例の5生率10.6%に対して肝転移合併摘除例は20.0%であり, また化学療法 (-) 例の5生率0%に対して全身化学療法例15.0%, 肝動注例23.1%であった. 最近における長期肝動注の成績 (異時性肝転移17例を含む20例の生存期間が407日) も考慮すると, 肝転移が著明でない場合はR1以上の郭清を伴う胃切除と肝転移巣の摘除および肝動注をおこない, 肝転移が著明な場合には肝動注を中心とする治療を選択すべきと思われる.