picibanil and Stomach-Neoplasms

OK-432 has been used as a cancer treatment for 40 years, and the immunostimulatory effects of OK-432 therapy have been intensely investigated in Japan. Recently, it has received attention as a possible booster for cancer vaccine treatments. Our previous meta-analysis based on summary measures revealed a significant improvement in the survival of patients with curatively resected gastric cancer. However, it is impossible to exclude the possibility of bias due to several prognostic factors.. We collected individual data for patients with stage III or stage IV gastric cancer after curative resection from 14 trials that were identified in a previous meta-analysis. Immunochemotherapy with OK-432 was compared with treatment with standard chemotherapy on an intention-to-treat basis. The primary end point was overall survival. Stratified survival analyses were performed with the trial as the stratification factor. Subgroup analyses were also performed according to the potential prognostic factors, which included pathological factors, splenectomy, and delayed-type hypersensitivity.. There were 796 and 726 patients in the OK-432 and control groups, respectively. The median overall survival was 42.6 months for the OK-432 group and 32.3 months for the control group. The overall hazard ratio was 0.88 (95 % confidence interval 0.77-1.00, p = 0.050). No factor showed a statistically significant interaction in the subgroup analyses.. The results suggest that immunochemotherapy treatment with OK-432 could have a borderline significant effect for patients with stage III or stage IV gastric cancer after curative resection.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Female; Humans; Immunotherapy; Male; Middle Aged; Picibanil; Randomized Controlled Trials as Topic; Stomach Neoplasms; Survival Analysis

Non-specific immunopotentiators, such as polysaccharide K (PSK), also known as OK-432, induce anti-tumor effects via immunological responses. The efficacy of combination immunochemotherapy using these immunopotentiators has been examined by multiple previous studies. The survival benefits of immunochemotherapy for patients with curative resections of gastric cancers are not widely accepted. To clarify this issue, we performed a meta-analysis to evaluate the effect of immunochemotherapy on survival in patients with curative resections of gastric cancer. For this study, we compared the results of chemotherapy and immunotherapy using the biological response modifier PSK as an immunopotentiator. The meta-analysis included 8,009 patients from eight randomized controlled trials after central randomization. The overall hazard ratio for eligible patients was 0.88 (95% confidence interval, 0.79-0.98; P = 0.018) with no significant heterogeneity [chi (2)(8) for heterogeneity = 11.7; P = 0.16]. The results of this meta-analysis suggest that adjuvant immunochemotherapy with PSK improves the survival of patients after curative gastric cancer resection.

Topics: Adjuvants, Immunologic; Antineoplastic Agents; Chemotherapy, Adjuvant; Humans; Immunotherapy; Picibanil; Polysaccharides, Bacterial; Randomized Controlled Trials as Topic; Stomach Neoplasms; Survival Analysis

Postoperative hepatic lymphorrhea is a very rare complication after abdominal surgery. Hepatic lymphorrhea, not containing chyle, involves an internal lymph fistula between the lymphatic channels toward the cisterna chyli and the peritoneal cavity. Over the past 20 years, 17 cases have been reported in Japan. Here, we report a further case, of a patient with successfully treated intractable hepatic lymphorrhea following gastrectomy for early gastric cancer. We review 18 cases, including the present case, with respect to the management of postoperative lymphorrhea refractory to conventional medical treatment.

Topics: Aged; Ascites; Fistula; Gastrectomy; Humans; Ligation; Liver; Lymph Node Excision; Lymphocele; Male; Picibanil; Postoperative Complications; Recurrence; Sclerotherapy; Stomach Neoplasms; Time Factors

The most effective treatment for gastric cancer is complete surgical resection with lymphadenectomy. However, a number of patients experience recurrence of the cancer even after curative surgery. This review focuses on comparative trials studying the use of adjuvant therapy with chemotherapy plus immunotherapy in the treatment of patients with curatively resected gastric cancer. Preoperative and intraperitoneal therapy, and therapy for advanced or recurrent gastric cancer are also discussed. At present, some subset analyses of adjuvant trials have shown favorable results suggesting that the biological response modifiers (BRMs), PSK or OK-432, add a benefit to chemotherapy. For advanced gastric cancer, although gastric cancer cells are generally not very sensitive to most of the currently available chemotherapeutic agents, it has been reported that biochemical modulation with treatments including low-dose cisplatin + 5-FU (fluorouracil) have high response rates and exert an immunomodulatory effect especially when used in combination with BRMs. The impact of splenectomy and some of the promising newly developed drugs are discussed.

Topics: Adjuvants, Immunologic; Antibiotics, Antineoplastic; Antineoplastic Agents; Chemotherapy, Adjuvant; Humans; Immunologic Factors; Mitomycin; Picibanil; Proteoglycans; Splenectomy; Stomach Neoplasms

Topics: Adjuvants, Immunologic; Clinical Trials as Topic; Combined Modality Therapy; Humans; Immunocompetence; Lentinan; Picibanil; Proteoglycans; Stomach Neoplasms

Topics: Adjuvants, Immunologic; Chemotherapy, Adjuvant; Clinical Trials as Topic; Gastrectomy; Humans; Meta-Analysis as Topic; Picibanil; Postoperative Care; Proteoglycans; Stomach Neoplasms; Treatment Outcome

Considerable controversy surrounds the management of gastric cancer and this has largely overshadowed recent progress in our understanding of the epidemiology and molecular pathogenesis of the disease, and improvements in diagnostic and staging techniques. Differences identifiable in the molecular pathogenesis of the 'intestinal' and 'diffuse' types of gastric cancer may help to unravel the biological behaviour of variants and ultimately influence therapeutic strategies. Endoscopic ultrasound is well established as being accurate for T staging and the introduction of laparoscopy, with or without ultrasound, is obviating unnecessary laparotomy in non-bleeding, non-obstructed patients. Controversies in surgery encompass the role of laparoscopic surgery in early gastric cancer, the extent of lymphadenectomy including para-aortic nodal dissection, resection of en bloc contiguous organ involvement, pancreatosplenectomy, left upper abdominal evisceration, and modes of reconstruction (pylorus-preserving gastrectomy, pouch formation) to enhance quality of life. Whereas adjuvant chemotherapy does not impact favourably on survival, emphasis has now shifted to neoadjuvant (induction) chemotherapy to downstage the disease. Preoperative regional chemotherapy and intra-operative hyperthermic chemotherapy or irradiation may prove to be of benefit in patients with resectable disease, but some scepticism still exists as to the usefulness of biological response modifiers (e.g. OK432, PSK) for adjuvant treatment. Ethical issues relating to cultural differences in Asia sometimes mitigate against adequate trial design (e.g. a surgery-alone control group or a no adjuvant therapy treatment group may be considered inappropriate) and this has understandably hindered acceptance in Western countries of the value of current management practices in Asia. These issues and the need for ongoing well-conducted randomized trials with prospective subset analysis are now being addressed.

Topics: Antineoplastic Combined Chemotherapy Protocols; Asia; Chemotherapy, Adjuvant; Combined Modality Therapy; Contraindications; Gastrectomy; Humans; Immunologic Factors; Immunotherapy; Intraoperative Period; Laparoscopy; Lymph Node Excision; Picibanil; Proteoglycans; Stomach Neoplasms; Treatment Outcome

The 5-year survival rate of patients with advanced gastric cancer who undergo curative resection is gradually increasing and currently ranges between 67.1% to 76.4% at the five major cancer centers in Japan. A belief that minimal residual disease has a high probability of being cured with adjuvant therapy prompted Japanese investigators to develop the D2 dissection with extended lymphadenectomy, more detailed pathologic staging, perioperative chemotherapy, and chemoimmunotherapy. This review focuses on comparative trials performed in Japan studying the use of adjuvant therapy with either chemotherapy alone or chemotherapy plus immunotherapy in the treatment of patients with curatively resected gastric carcinoma. Preoperative and intraperitoneal therapy also has been evaluated. At present, however, no chemotherapy has been shown to impact favorably on the survival of gastric cancer patients, whereas the biological response modifiers, PSK or OK-432, seem to add some benefit to chemotherapy in the adjuvant setting. Carefully designed randomized controlled trials with sufficient size which include a surgery-alone control arm are the only way to establish the efficacy of adjuvant therapy.

Topics: Antibiotics, Antineoplastic; Antineoplastic Agents; Carcinoma; Chemotherapy, Adjuvant; Gastrectomy; Humans; Immunologic Factors; Immunotherapy; Japan; Lymph Node Excision; Neoplasm Staging; Neoplasm, Residual; Picibanil; Proteoglycans; Randomized Controlled Trials as Topic; Stomach Neoplasms; Survival Rate

Two immunotherapeutic methods were developed as adjuvant therapy for gastrointestinal malignancies, one using oral administration of a streptococcal preparation, OK-432, and the other with adoptive immunotherapy (AIT), local transfer of IL2-cultured and autologous lymphocytes, combined with local preadministration of OK-432. Tsuchitani and Nio in our laboratory have revealed experimentally that oral OK-432 stimulates tumor-specific and non-specific immune mechanisms of gut-associated lymphoid tissues and inhibits the growth of some murine syngeneic tumors that were transplanted into cecal patches. The clinical efficacy of oral OK-432 on gastric cancer patients has been examined by a controlled randomized trial involving a total of about 1000 cases. Oral OK-432 (5KE, once a week) was revealed to be significantly effective in curatively resected group but not effective in non-curatively resected group. Ten consecutive patients with peritoneal dissemination of gastric cancer were treated with intraperitoneal OK-432 and AIT. AIT was performed by transferring autologous lymph node-lymphocytes cultured for 13 days with crude IL2 and tumor-extract. The survival of the treated patients was significantly longer (50% survival period exceeded 1 year) than that of historical control (95 cases, 50% survival period was 5 months). These immunotherapeutic methods are expected to be useful for multidisciplinary therapy of gastric cancer by a combination of each method with other therapeutic methods.

Topics: Biological Products; Clinical Trials as Topic; Combined Modality Therapy; Humans; Immunization, Passive; Picibanil; Random Allocation; Stomach Neoplasms

The chemical structure and characteristics, the antitumour activity, the antibacterial, antiviral, antifungal, antiparasitic activities, immunological properties and mode of action of immunomodulators of microbial origin, especially antitumour polysaccharide lentinan, have been discussed immunopharmacologically in comparison with pachymaran, schizophyllan, DiLuzio's yeast glucan, Coriolus preparation PS-K, Streptococcal preparation OK-432, Nocardia rubra cell wall skeleton N-CWS together with BCG and Corynebacterium parvum. Lentinan exerts its inhibitory action not only on allogeneic tumours but also on syngeneic and autologous tumours, and prevents chemical and viral carcinogenesis. The phase III randomized control study of lentinan in cancer patients with gastric and colo-rectal cancer showed the clinical efficacy of lentinan in prolonging the life span and improving host immune responses. Experimental and clinical application demonstrated the advantage of N-CWS over BCG-CWS, and a recent study on OK-432 showed similar results to those obtained with C. parvum. In future work on microbial immunomodulators, it will be essential to find a parameter of the host-tumour relationship which will indicate the protocol for application of immunomodulators, and to find a new-type of selective immunostimulant. For this purpose, exhaustive studies on lymphokines, monokines and lymphocyte tropic hormones are indispensable.

Topics: Adjuvants, Immunologic; Animals; Bacteria; BCG Vaccine; Blood Proteins; Carbohydrate Conformation; Chemical Phenomena; Chemistry; Colonic Neoplasms; Fungi; Glucans; Humans; Immunotherapy; Infections; Lentinan; Lymphocytes; Macrophage Activation; Neoplasms, Experimental; Picibanil; Polysaccharides; Proteoglycans; Rectal Neoplasms; Sizofiran; Stomach Neoplasms; Structure-Activity Relationship

Splenectomy is often performed in patients who undergo total gastrectomy for cancer of the upper stomach. Although splenectomy facilitates lymph node dissection of the splenic hilum and recent reports advocate spleen preservation, the role of the spleen is not fully elucidated in gastric cancer treatment. This prospective randomized study was performed to evaluate the role of the spleen in immunological function in gastric cancer patients who underwent total gastrectomy and received postoperative immunochemotherapy. Forty-five patients with gastric cancer were randomly allocated to four groups: 1. splenectomy without immunotherapy (OK-432 administration), 2. splenectomy with immunotherapy, 3. spleen preservation without immunotherapy, 4. spleen preservation with immunotherapy. Postoperative immunological function of these patients was compared among the four groups. NK cell activity of the peripheral blood lymphocytes (PBL) in spleen-preserved patients who received immunotherapy was significantly higher for 24 weeks after surgery than that of the splenectomized patients with and without OK-432 administration. IL-2 production of PBL in spleen-preserved patients with immunotherapy was significantly higher between 4 and 24 weeks after surgery compared with that of the splenectomized patients without immunotherapy. The results suggest that spleen preservation might be beneficial in patients with less advanced gastric cancer who receive postoperative immunochemotherapy after total gastrectomy.

Topics: Adenocarcinoma; Antineoplastic Agents; Disease-Free Survival; Female; Gastrectomy; Humans; Immunotherapy; Interleukin-2; Lymph Node Excision; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Picibanil; Prospective Studies; Spleen; Splenectomy; Stomach Neoplasms; Treatment Outcome

To investigate, by a multi-institutional randomized trial, the prognostic significance of the augmentation of tumour-infiltrating lymphocytes (TILs) by preoperative intratumoral injection of OK-432 (OK-432 it), a bacterial biological response modifier, in patients with gastric cancer. The 10-year survival and disease-free survival were examined and analysis of the factors showing survival benefit was performed. 370 patients who had undergone curative resection of gastric cancer were enrolled in this study and followed up for 10 years postoperatively. Patients were randomized into either an OK-432 it group or a control group. Ten Klinishe Einheit (KE) of OK-432 was endoscopically injected at 1 to 2 weeks before the operation in the OK-432 it group. Both groups received the same adjuvant chemoimmunotherapy consisting of a bolus injection of mitomycin C (0.4 mg kg(-1) i.v.) and administration of tegafur and OK-432 from postoperative day 14 up to 1 year later. Tegafur (600 mg day(-1)) was given orally and OK-432 (5 KE/2 weeks) was injected intradermally for a maintenance therapy. The TILs grades in resected tumour specimens and presence of metastasis and metastatic pattern in dissected lymph nodes were examined. Multivariate analysis was performed to determine the efficacy of OK-432 it on prognostic factors. All patients were followed up for 10 years. The overall 5- and 10-year survival rates and disease-free survival rates of the OK-432 it group were not significantly higher than those of the control group. However, OK-432 it significantly increased the 5- and 10-year survival rates of patients with stage IIIA + IIIB, moderate lymph node metastasis (pN2), and positive TILs. OK-432 it was most effective at prolonging the survival of patients who had both positive TILs and lymph node metastasis. The OK-432 it group with positive TILs showed a significant decrease in metastatic lymph node frequency and in the number of lymph node micro- metastatic foci when compared to the control group. This study showed that only one time preoperative OK-432 it, particularly when it triggers TILs, is effective for reduction of regional lymph node metastasis. OK-432 it probably acts partly by eliminating micro-metastatic foci in lymph nodes. Preoperative intratumoral injection of OK-432 is technically very easy and has no serious adverse effects, so it is a promising form of neoadjuvant immunotherapy for advanced gastric cancer.

Topics: Adult; Aged; Disease-Free Survival; Female; Humans; Lymphatic Metastasis; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Picibanil; Prognosis; Stomach Neoplasms

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.

Topics: Adjuvants, Immunologic; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Colonic Neoplasms; Disease-Free Survival; Drug Combinations; Humans; Middle Aged; Picibanil; Rectal Neoplasms; Stomach Neoplasms; Survival Rate; Tegafur; Uracil

Eleven patients with liver metastasis from gastric cancer were treated by intermittent arterial infusion using OK-432 and recombinant IL-2 in combination with anticancer drugs. The direct effects for liver metastasis were PR 3 (response rate 30%), MR 2, NC 3, PD 1 and NE 1. Papillary adenocarcinoma showed a highly effective rate. The mean survival period was 326 days and the 50% survival period was 318 days. Out of 4 patients who underwent surgical resection for metastatic liver tumor, one showed recurrence, and the other is now healthy without any sign of recurrence for 8 years after the operation. In 7 patients with liver metastasis from colorectal cancer, intermittent arterial infusion therapy using Leucovorin, CDDP and 5-FU was performed. The direct effects were CR 2, PR 1, MR 1, PD 2, NE 1; the mean survival period was 478 days, and the 50% survival period 556 days. Out of 8 patients who underwent liver resection for metastasis, all patients remained alive for 687 mean survival days without liver recurrence. No severe side effects were noted in either therapy.

Topics: Adenocarcinoma, Papillary; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Hepatic Artery; Humans; Immunotherapy; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Interleukin-2; Leucovorin; Liver Neoplasms; Male; Middle Aged; Picibanil; Recombinant Proteins; Stomach Neoplasms

The streptococcal agent OK-432 is used widely as a potent biologic response modifier. Accumulated evidence suggests that OK-432 exerts antineoplastic effects by a direct cytotoxic or inhibitory effect on tumor cells. The clinical efficacy of OK-432 has been reported for various tumors. In this randomized Phase III study, the authors compared 5-fluorouracil (5-FU), doxorubicin, mitomycin C, and the intradermal administration of OK-432 (FAM-P) with the standard FAM regimen in patients with gastric carcinoma who underwent curative resection.. From May 1988 until November 1991, a total of 99 patients were entered into this randomized trial. The patients were stratified according to the American Joint Committee on Cancer stage of disease (i.e., Stage IB, II, and III). Fifty patients were treated with the FAM regimen here and throughout text.: 5-FU, 750 mg intravenously (i.v.), on Days 1, 8, 29, and 36; doxorubicin, 30 mg/m2 i.v., on Days 1 and 29; and mitomycin C, 10 mg/m2 i.v., on Day 1. Forty-nine patients received the FAM-P regimen: 5-FU, 750 mg i.v., on Days 1, 8, 29, and 36; doxorubicin, 30 mg/m2 i.v., on Days 1 and 29; mitomycin C, 10 mg/m2 i.v., on Day 1; and OK-432 5.0 Klinishe Einheit (clinical unit) injected intradermally weekly.. The survival difference was statistically significant between the patients receiving the FAM and FAM-P regimens (5-year survival of 52% vs. 62%; P = 0.04). A comparison between disease free survival in FAM and FAM-P patients showed a borderline advantage for the FAM-P group (P = 0.053). When Stage IB, Stage II, and Stage III patients were analyzed separately, the difference in survival between two regimens was significant in Stage III patients (P = 0.049) and the disease free survival was of borderline significance (P = 0.06), but not in patients with Stage IB and II disease. The significant toxicity of OK-432 was mild fever, which was controlled with acetaminophen.. The results of this study show that OK-432 may be an active, well tolerated agent for the treatment of curatively resected gastric carcinoma. However, these findings should be confirmed by a multicenter randomized study with a large sample size.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Disease-Free Survival; Doxorubicin; Female; Fluorouracil; Humans; Immunotherapy; Male; Middle Aged; Mitomycin; Picibanil; Stomach Neoplasms

We previously reported that the antitumor effect of OK-432, a streptococcal preparation, was markedly augmented when this agent was injected into tumors together with fibrinogen. In order to elucidate the effect of this treatment on the spleen, we assessed splenic function in gastric cancer patients receiving preoperative local immunotherapy with OK-432 and fibrinogen. Immunohistochemical studies of the spleen at 7 days after intratumoral injection therapy revealed numerous macrophages phagocytizing OK-432 in the splenic sinuses. Phenotypic analysis of splenocytes by flow cytometry revealed an increase in the CD4/CD8 ratio and in the expression of HLA-DR, CD25, and Leu M3 by splenic T cells of the patients treated with OK-432 plus fibrinogen when compared to patients treated with OK-432 alone or untreated patients. Splenic T cells from patients treated with OK-432 plus fibrinogen showed significantly higher cytotoxicity against Daudi and K562 cells than T cells from control patients (p < 0.05), and culture of these splenic T cells with recombinant IL-2 induced the expansion of lymphokine-activated killer cells. These results demonstrate that local immunotherapy with a mixture of OK-432 and fibrinogen effectively augumented splenic antitumor immunity in gastric cancer patients.

Topics: Antineoplastic Agents; CD4-Positive T-Lymphocytes; Female; Fibrinogen; Humans; Immunotherapy; Killer Cells, Lymphokine-Activated; Male; Middle Aged; Picibanil; Spleen; Stomach Neoplasms

To evaluate the efficacy of adjuvant immunochemotherapy, especially the long-term administration of HCFU to patients with noncuratively resected and unresected gastric cancer, a randomized controlled study was conducted by 16 institutions in Hokkaido. After surgery, 185 patients were divided into two groups using the envelope method; group A (84 patients) treated by MMC (4 mg, twice a week, total 1 mg/kg)+OK-432 (or PSK): group B (101 patients) treated with MMC+OK-432+HCFU (600 mg, per day). The 5- and 10-year survival rates were 9.8 and 3.1% in group A, and 11.1 and 11.1% in group B (p=0.062). Better survival rates were obtained in those cases with unresected, S3, or peritoneal dissemination in group B. These results suggested the long-term administration of HCFU was effective for noncuratively resected and unresected gastric cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Chi-Square Distribution; Combined Modality Therapy; Fluorouracil; Follow-Up Studies; Humans; Immunotherapy; Japan; Mitomycin; Picibanil; Stomach Neoplasms

The influence of intratumor administration of OK-432 on the tumor-selective antitumor effect of 5'-DFUR was studied in 49 patients with advanced gastric cancer. The patients were divided into 4 groups that received oral 5'-DFUR, intratumor OK-432, oral 5'-DFUR plus intratumor and intracutaneous OK-432, or no therapy before operation. Using surgical specimens, the PyNPase activity and 5-FU content were measured, and the localization of PyNPase was determined immunohistologically. The results were as follows: 1) 5'-DFUR therapy decreased intratumor PyNPase activity whereas administration of OK-432 increased it. 2) PyNPase activity was higher in cancer tissue than in normal tissue for all groups. 3) The 5-FU content of cancer tissue was higher in patients receiving OK-432 plus 5'-DFUR than in patients receiving 5'-DFUR alone. 4) In the resected tumors, PyNPase was mainly localized in the cancer cells of some patients and in the stromal cells of others. Thus, the localization of PyNPase showed two major patterns.

Topics: Antineoplastic Agents; Floxuridine; Humans; Injections, Intralesional; Isomerism; Pentosyltransferases; Picibanil; Prodrugs; Pyrimidine Phosphorylases; Stomach Neoplasms

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Humans; Immunologic Factors; Injections, Intralesional; Mitomycin; Picibanil; Preoperative Care; Stomach Neoplasms; Tegafur

In order to evaluate the biological response after intraperitoneal administration of OK-432 and CDDP, we studied the changes of cytokine levels in ascitic fluid. A total of 53 gastric cancer patients were included in this study. OK-432 20KE was administered in 7 patients and CDDP was administered in 4 patients intraperitoneally during operation. The IL-6, IL-8, TNF-alpha and sTNF RI levels in ascitic fluid were measured from 0 to 5 postoperative day. These results were compared with those obtained from the control groups (42 patients). The ascitic level of IL-6 increased immediately after operation, then gradually decreased. The elevations of IL-6 from 0 to 5 postoperative day were remarkably higher in the OK-432 treated group, and those on 0 and 1 postoperative days were remarkably lower in CDDP treated group than in the control group. Similarly, the ascitic level of IL-8 elevated soon after operation and then decreased gradually. In the OK-432 treated group, the ascitic level of IL-8 was significantly higher than in the control group from 0 to 2 postoperative day. Ascitic TNF-alpha was detectable only in the ascites soon after operation in the OK-432 treated group. The ascitic level of sTNF RI peaked on 2 postoperative day in the control and the OK-432 treated group and 1 postoperative day in the CDDP treated group. There were no significant differences between these groups.

Topics: Aged; Ascitic Fluid; Cisplatin; Cytokines; Female; Gastrectomy; Humans; Infusions, Parenteral; Interleukin-8; Male; Middle Aged; Picibanil; Stomach Neoplasms; Tumor Necrosis Factor-alpha

The preoperative intratumoral injection with OK-432 (Picibanil, Chugai Pharmaceutical Co., Tokyo, Japan), an immunomodulatory agent prepared from an attenuated strain of streptococcus pyogenes, activates the regional immune system and causes degeneration of cancer tissue in carcinoma of the stomach.. A multi-institutional randomized trial of OK-432 to determine its clinical usefulness was conducted. Three hundred and ninety-five patients with gastric cancer were assigned randomly either to receive or not to receive a preoperative intratumoral injection of OK-432. Among them, 277 patients with advanced cancer were treated by common postoperative chemoimmunotherapy consisting of mitomycin C, tegafur, and OK-432. All patients were followed for at least 5 years.. The adverse effects of OK-432 injected intratumorally predominantly were mild fever, anorexia, and abdominal pain, however, no treatment was required for these symptoms. Overall, there were no differences in outcome between the OK-432 and control groups. However, analysis based on stage showed that a preoperative intratumoral injection of OK-432 significantly improved the 5-year survival rate of patients with Stage III cancer (P = 0.0229), at 47.7% for the OK-432 group and 27.5% for the control group. In subset analysis, when the 5-year survival of patients with and without tumor infiltrating lymphocytes (TIL) was compared, OK-432 injected intratumorally had a significant positive effect on the group showing a moderate to marked number of TIL (P = 0.0438).. These results showed that the intratumoral injection of OK-432 may improve survival of patients with Stage III gastric cancer. Cancer 1994;3097-3103.

Topics: Adjuvants, Immunologic; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Injections; Male; Middle Aged; Mitomycin; Neoplasm Staging; Picibanil; Premedication; Stomach Neoplasms; Survival Rate; Tegafur

The effects of postoperative immunochemotherapy including the streptococcal preparation OK-432 on the rate of peritoneal recurrence and survival time after curative resection were studied in 36 patients with gastric cancer. Patients randomized to group B received 18 months of a therapy that is widely used in Japan for patients with gastric cancer: mitomycin C (MMC) and UFT, a combination of tegafur and uracil in a molar ratio of 1:4. Patients randomized to group A received the same drugs given to group B plus an intraperitoneal injection of OK-432 on postoperative day 0 and intradermal injections of OK-432 for 18 months at 2-week intervals. There were no differences between the two groups in any known prognostic factor or dose of any drug received, except for OK-432. There was no difference in the toxicity rates between the groups. The concomitant administration OK-432 and anticancer drugs significantly decreased the rates of peritoneal recurrence and lengthened survival time (P < 0.05).

Topics: Adjuvants, Immunologic; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Drug Administration Schedule; Female; Gastrectomy; Humans; Injections, Intradermal; Injections, Intraperitoneal; Male; Middle Aged; Mitomycin; Neoplasm Recurrence, Local; Neoplasm Staging; Peritoneal Neoplasms; Picibanil; Postoperative Care; Prognosis; Prospective Studies; Stomach Neoplasms; Survival Rate; Tegafur; Treatment Outcome; Uracil

We studied the effects on survival time of postoperative immuno-chemotherapy, including the streptococcal preparation OK-432, in patients with gastric cancer and synchronous peritoneal dissemination. The patients were prospectively randomized and a valid statistical assessment could be made for 109. Patients randomized to group B received therapy that is widely used in Japan to treat patients with gastric cancer: mitomycin C (MMC) and UFT, a combination of tegafur and uracil in a molar ratio of 1:4, for 1 year. Patients randomized to group A received the same drugs as were given to group B patients plus OK-432 i.p. for 7 days, beginning on postoperative day 0, and OK-432 by intradermal injection for 1 year, at 2-week intervals. There were no differences between the two groups in any known prognostic factor or in the dose of any drug administered except for OK-432. There was no difference in the toxicity rate between the groups. In this negative trial, there was no improvement in survival time with the addition of OK-432 to MMC and UFT for patients with gastric cancer and peritoneal dissemination.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Drug Administration Schedule; Female; Humans; Injections, Intradermal; Injections, Intraperitoneal; Male; Middle Aged; Multivariate Analysis; Peritoneal Neoplasms; Picibanil; Prospective Studies; Stomach Neoplasms; Survival Analysis; Treatment Outcome

Results of 6589 gastric cancer operations at the Department of Surgery, Seoul National University Hospital, from 1970 to 1990 were reported. About two thirds (76.6%) were advanced gastric cancer (stages III and IV). The 5-year survival rate of operated stage III gastric cancer was only 30.6%, with frequent recurrence. Conversely, cell-mediated immunities of advanced gastric cancer patients were significantly decreased. Therefore, to improve the cure rate and to prevent or delay recurrence, curative surgery with confirmation of free resection margins and systematic lymph node dissection of perigastric vessels were performed and followed by early postoperative immunotherapy and chemotherapy (immunochemosurgery) in stage III patients. To evaluate the effect of immunochemosurgery, two randomized trials were studied in 1976 and 1981. In first trial, 5-fluorouracil, mitomycin C, and cytosine arabinoside for chemotherapy and OK 432 for immunotherapy were used. The 5-year survival rates for surgery alone (n = 64) and immunochemosurgery (n = 73) were 23.4% and 44.6%, respectively, a significant difference. In the second trial, there were three groups: group I, immunochemosurgery (n = 159); group II, surgery and chemotherapy (n = 77); and group III, surgery alone (n = 94). 5-Fluorouracil and mitomycin C for chemotherapy and OK-432 for immunotherapy were administered for 2 years. The 5-year survival rate of group I was 45.3%, significantly higher than the 29.8% of group II and than the 24.4% of group III. The postoperative 1-chloro-2.4-dinitrobenzene test, T-lymphocyte percentage, phytohemagglutinin- and con-A-stimulated lymphoblastogenesis and the antibody-dependent cell-mediated cytotoxicity test showed more favorable values in the immunochemosurgery group. Therefore, immunochemosurgery is the best multimodality treatment for advanced gastric cancer.

Topics: Anastomosis, Surgical; Antibody-Dependent Cell Cytotoxicity; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Fluorouracil; Gastrectomy; Humans; Immunotherapy; Jejunostomy; Leukocyte Count; Male; Middle Aged; Mitomycin; Neoplasm Staging; Picibanil; Prognosis; Skin Tests; Stomach Neoplasms; Survival Rate; T-Lymphocytes

We studied the effect of early postoperative chemotherapy, including 5-fluorouracil (5-FU) for 5 days for patients with gastric cancer following noncurative resection. The study was prospectively randomised and controlled, and 162 (87.1%) of 186 were eligible candidates for statistical assessment. Patients randomised to group A received therapy that is used widely to treat patients with gastric cancer in Japan; mitomycin C (MMC), OK-432, UFT and PSK. Patients randomised to group B received the same drugs given to group A plus 5-FU bolus injections for 5 days, beginning on postoperative day 2. There were no differences in prognostic factors and doses of the drugs prescribed, except for 5-FU. There was no difference in the toxicity rate between the groups. Generalised Wilcoxon test revealed a P value of 0.169, and the 50% survival rate improved 1.4-fold in patients with gastric cancer treated with early postoperative chemotherapy of MMC, OK-432 plus 5-FU injection.

Topics: Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Fluorouracil; Humans; Male; Middle Aged; Mitomycin; Picibanil; Prospective Studies; Proteoglycans; Stomach Neoplasms; Tegafur; Uracil

We previously found that the ability to generate cytotoxic cells induced by in vitro activation of peripheral blood mononuclear cells (PBM) with OK-432, a bacterial immunopotentiator, was markedly increased following intravenous administration of a single dose of mitomycin C (MMC) in cancer patients. On the basis of this clinical finding, we designed a treatment regimen that consisted of MMC 12 mg/m2 intravenously on day 1 and OK-432 5 Klinische Einheit (KE) intradermally on days 6, 8, and 11, when the generation of OK-432 activated killer cells had been shown to be significantly augmented. Then, it was followed by long-term tegafur. Fifteen patients with stage III gastric carcinoma who had undergone curative resection were treated with the above regimen. The survival of these patients was significantly better than that of 26 comparable stage III patients concurrently treated with MMC 12 mg/m2 alone, followed by long-term tegafur (P less than 0.01). The results indicate that OK-432 combined with MMC may be effective against stage III gastric carcinoma, when these agents are used probably in an appropriate combination.

Topics: Carcinoma; Combined Modality Therapy; Female; Humans; Male; Middle Aged; Mitomycin; Picibanil; Stomach Neoplasms; Survival Rate

The current study was designed to compare the effects of oral administration of the streptococcal preparation, OK-432, as an adjuvant immunotherapy versus those of intradermal administration of OK-432 on the survival of patients after surgery for gastric cancer. The patients were stratified into two groups after surgery: a curative surgery stratum and a palliative surgery stratum. Then the patients in each stratum were randomly assigned into three groups: an oral placebo group, an oral OK-432 group, and an intradermal OK-432 group. All of the patients were given fluoropyrimidines orally in combination with OK-432 or placebo for 2 years after surgery. A total of 1011 patients were registered between 1982 and 1985, and 970 patients were eligible for statistical analysis. The survival rate of the oral OK-432 group was significantly higher than those of the other two groups after curative surgery. There were no significant difference in the survival rates between the three groups after palliative surgery, however. The effect of oral OK-432 was quite pronounced in patients after curative surgery for stage II to IV gastric cancer, especially in those patients with regional node involvement. Furthermore, it was found that the spleen is necessary for effective immunotherapy with oral OK-432, because the survival rate of the oral OK-432 group was significantly improved in patients whose spleens were preserved, when compared with splenectomized patients. These results demonstrate that oral adjuvant immunotherapy with OK-432 is beneficial after curative surgery for gastric cancer.

Topics: Administration, Oral; Adult; Aged; Combined Modality Therapy; Double-Blind Method; Female; Humans; Immunotherapy; Injections, Intradermal; Male; Middle Aged; Picibanil; Stomach Neoplasms; Survival Rate

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.

Topics: Adjuvants, Immunologic; Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Female; Gastrectomy; Humans; Lymphocyte Activation; Male; Middle Aged; Mitomycin; Mitomycins; Multicenter Studies as Topic; Picibanil; Postoperative Care; Prospective Studies; Proteoglycans; Randomized Controlled Trials as Topic; Stomach Neoplasms; Survival Rate; Tegafur

A cooperative study on surgical adjuvant immunochemotherapy for prevention of postoperative recurrence of gastric cancer was carried out by Kondo's group from July 1974 to December 1977. A total of 848 patients with gastric cancer underwent curative resection were eligible. Of 848 patients, 819 cases with complete description of patient's background were evaluable: Group A (surgery + MMC + 5-FU:chemotherapy) 253 cases, group B (surgery + MMC + 5-FU + OK-432 or PSK:immunochemotherapy) 282 and group C (surgery alone) 284. The 5-year corrected survival rates of total cases using Cox's proportional hazard model were 76.2% with group A, 73.6% with group B and 73.3% with group C. And the 10-year survival rates were 67.6% with group A, 64.3% with group B and 63.9% with group C. The difference in survival rate among groups A, B and C was not statistically significant. In the evaluation of prognostic factors by Cox's proportional hazard model, level of curative resection, extent of resection, histological stage and Kajitani's classification had an influence upon survival rates, in which degrees of metastasis in lymph node and serous infiltration were also involved. The significance of postoperative adjuvant immunochemotherapy has not been clarified.

Topics: Adjuvants, Immunologic; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Fluorouracil; Gastrectomy; Humans; Japan; Mitomycin; Mitomycins; Neoplasm Recurrence, Local; Picibanil; Prognosis; Proportional Hazards Models; Prospective Studies; Proteoglycans; Stomach Neoplasms; Survival Rate

A biological response modifier, OK-432 (Picibanil) administered by injection has been used for cancer immunotherapy. The present study was designed to determine the optimal dose and frequency of oral administration of OK-432. Ninety-one stomach cancer patients were randomly assigned into 7 groups and were administered a placebo or OK-432 at a dose of 5, 20 or 40 KE, once or 3 times a week before their operation (5 KE X 1/W, 20 KE X 1/W, 40 KE X 1/W, or X3/W). ++Missregistration excluded 3 patients and the data of 88 patients were analysed. There was no significant difference in the background status of the patients in each group. The NK activity of PBL was augmented by the administration of 40 KE X 1/W or 20 KE X 3/W and that of RNL was augmented by the administration of 5 KE X 3/W or 40 KE X 1/W, in conjunction with an increase in the number of % positive cells of leu 11a+ or leu 19+ analysed by flow cytometry. The killing activity of PBL, RNL, or MNL against allogeneic lined gastric cancer cells (KATO III) was not augmented by the oral administration of OK-432 for one week. The skin reactivity to Su-PS or PPD, serum levels of tumor markers, or serum levels of immunoglobulins did not help in determining the optimal dose or its frequency. These results suggest that 5 KE X 3/W may be the optimal regimen to augment the antitumor immunity of RNL.

Topics: Administration, Oral; Aged; Biological Products; Biomarkers, Tumor; Clinical Trials as Topic; Double-Blind Method; Female; Humans; Immunoglobulins; Immunotherapy; Killer Cells, Natural; Leukocyte Count; Male; Middle Aged; Picibanil; Stomach Neoplasms

The present study was designed to determine the optimal dose and frequency of oral administration of a biological response modifier, OK-432 (Picibanil), which has been used for cancer immunotherapy by injection. Ninety one stomach cancer patients were randomly assigned into 7 groups and were administered a placebo or OK-432 at a dose of 5, 20 or 40KE, once or 3 times a week before operation (5KE X 1/W, 20KE X 1/W, 40KE X 1/W, or X 3/W). Misregistration excluded 3 patients and the data of 88 patients were analysed. There was no significant difference in the background status of the patients in each group. In the 1st report, we already showed that 5KE X 3/W might be the optimal regimen to augment the natural killer (NK) activity of regional lymph node lymphocyte (RNL). In the 2nd report, we searched for the optimal regimen to augment the antitumor immunity of T lymphocytes. The proliferative response of RNL to SuPR (protein derived from OK-432) was augmented in all the groups administered OK-432. The responsiveness of PBL to autologous tumor extract enhanced by IL-2 was augmented by 5KE X 1/W, and that of RNL was augmented by 5KE X 3/W. The killer/suppressor (Leu2+15-/Leu2+15+) ratio in RNL increased in all the groups administered OK-432 especially in 20KE X 3/W group. Oral administration of OK-432 augmented both non-specific and the specific antitumor immunity of PBL as well as RNL, and 5KE X 3/W may be the optimal regimen to augment the antitumor immunity, especially of RNL.

Topics: Administration, Oral; Adult; Aged; Biological Products; Clinical Trials as Topic; Double-Blind Method; Humans; Leukocyte Count; Lymphocyte Activation; Middle Aged; Picibanil; Stomach Neoplasms; T-Lymphocytes

Pre- and postoperative intradermal administration of OK-432 enhanced the SU-PS skin reaction in patients with gastric cancer, but failed to prevent a fall in the NK activity induced by the operation. The change in NK activity was not associated with a change in the proportion of Leu 7-positive cells, but was related to Leu 11a-positive cells. Intradermal injection of OK-432 increased the proportion of Leu 7-positive cells in the patients in whom they accounted for less than 20% of lymphocyte population. The case was the same with Leu 11a-positive cells. Intravenous injection of OK-432 tended to increase suppressor-inducer T cells (CD4+2HA+ cells), B cells and Leu 7-positive cells. Particularly, the proportions of OK-M1-positive cells and MHC class II antigen-positive cells increased in all patients. Immunotherapy with OK-432 given intravenously at a dose of 0.1 KE appeared to be safe because no side effects were essentially observed.

Topics: Combined Modality Therapy; Drug Administration Schedule; Humans; Immunotherapy; Injections, Intravenous; Lymphocyte Subsets; Picibanil; Postoperative Care; Preoperative Care; Stomach Neoplasms

A streptococcal preparation, OK-432, was orally administered at a dose of 5 KE to patients with gastric or colorectal cancer for 7-14 days before their operations, and its immunomodulatory effects on peripheral blood lymphocytes (PBL), regional node lymphocytes (RNL) and tumor infiltrating lymphocytes (TIL) were assessed. The group treated with OK-432 included 8 gastric and 6 colorectal cancer patients, and the control group included 8 gastric and 8 colorectal cancer patients. The NK cell activity of PBL was significantly augmented by the oral administration of OK-432, and the proportions of Leu 7+ and Leu 11+ cells in PBL also increased. The responses of PBL and TIL to autologous tumor extracts in the presence of interleukin-2 were enhanced after the oral administration of OK-432. The proportion of OKT8+ cells in PBL increased after treatment with oral OK-432, whereas the proportion in RNL significantly decreased. These results indicate that oral OK-432 affects NK and T cells and may augment the antitumor immunity of patients with gastrointestinal cancer.

Topics: Administration, Oral; Adult; Colorectal Neoplasms; Female; Humans; Immunity, Cellular; Immunotherapy; Interleukin-2; Killer Cells, Natural; Lymph Nodes; Lymphocytes; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Picibanil; Stomach Neoplasms

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

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cytarabine; Drug Administration Schedule; Fluorouracil; Humans; Japan; Mitomycin; Mitomycins; Multicenter Studies as Topic; Picibanil; Random Allocation; Stomach Neoplasms; Tegafur; Telephone

The Gastric Cancer Immunochemotherapy Study Group, constituted of 412 institutions, carried out six independent trials simultaneously from 1978 to 1981. A total of 4,456 cases were subjected to the study, from which 826 cases (18.5%) were excluded due to the violence of entry criteria. Curative gastrectomy, followed by a combination of mitomycin C (MMC), Ftorafur (FT)and Krestin (PSK) produced better postoperative survivals than either combination of MMC and FT, or MMC and PSK (5-year survival rate: 71.7% in MMC + FT + PSK, 64.1% in MMC + PSK, and 58.5% in MMC + FT). In the subset of patients with negative nodes (n(-)), and with involved serosa by histological examination (ps(+)), a combination of FT and PSK after gastrectomy seemed to be more favorable for the post-operative survivals than the single use of either drug. Four drug combinations of MMC, FT, PSK and Picibanil (OK-432) also had a clinical benefit in the group of patients with poorly differentiated adenocarcinoma, compared with chemotherapy alone. These results, though there are biases due to excluding 18.5% of cases, suggest some clinical benefits in the control of cancer relapse after surgery. The conclusion should be confirmed by a further elaborate trial.

Topics: Adjuvants, Immunologic; Aged; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Combined Modality Therapy; Gastrectomy; Humans; Japan; Male; Mitomycin; Mitomycins; Multicenter Studies as Topic; Neoplasm Recurrence, Local; Picibanil; Proteoglycans; Stomach Neoplasms; Tegafur

In order to augment antitumor immunity of gut-associated lymphoid tissue in digestive organ cancer, oral administration of various biological response modifiers were studied using mice transplanted with cecal tumor. Among them OK-432 was the most effective and clinical application of oral OK-432 was studied. Autoradiogram and immunofluorescence studies showed the absorption of orally administered OK-432 from the gut. In phase I study oral OK-432 was much less toxic than other administration routes. Phase II study showed that oral OK-432 at various doses augmented antitumor immunity of the lymphocytes of peripheral blood and regional lymph node. In a multi-institutional study on postoperative adjuvant immunotherapy, 1011 gastric cancer patients were accumulated and randomized to compare the effects of oral and intradermal OK-432. In patients who underwent curative operation, 1-, 2- and 3-year survival rates (%) were 95, 88 and 82 for oral OK-432 group (n = 255), 88, 83 and 80 for the placebo group (n = 260), and 89, 79 and 73 for intradermal OK-432 group (n = 261). There was significant differences among cumulative survivals of three groups, and this life-prolonging effect of oral OK-432 was remarkable for stage II or III patients. These results demonstrate that oral immunotherapy with OK-432 is useful as an immunotherapy of digestive organ cancers.

Topics: Administration, Oral; Biological Products; Combined Modality Therapy; Digestive System; Humans; Immunotherapy; Lymphoid Tissue; Picibanil; Stomach Neoplasms; Survival Rate

Many BRMs (biological response modifiers) have been used for post-operative immunochemotherapy. And their usefulness were also reported. Nevertheless it is still unknown that which route, how much doses and which timing are the most effective to administer these drugs. We used BRMs intratumorally and preoperatively. To reconfirm the efficacy of intratumoral injection therapy randomized study was performed in gastric carcinoma. Three hundred and ninety-five cases were entered, 199 cases in group A which were treated preoperatively with OK-432 intratumorally and 196 cases in group B which were control, respectively. In the cases which had marked infiltration of lymphoid cells in tumor sites, the two year survival rate of group A was significantly better than that of group B (p less than 0.05). On the study of recurrent forms, the distal lymph node metastasis was markedly decreased in group A. The ratio of metastasis to the distal lymph nodes in group A was 5-10% lesser than that in group B on the each depth of tumor invasion. The ratio of lymph nodes metastasis was almost similar in the each group, but the number of metastatic lymph nodes was significantly reduced in high grade tumor infiltrated cases in group A (p less than 0.005). These results suggest that preoperative endoscopically intratumoral administration of OK-432 suppresses the lymph node metastasis and improves the postoperative survival rate.

Topics: Biological Products; Combined Modality Therapy; Gastroscopy; Humans; Lymphatic Metastasis; Picibanil; Stomach Neoplasms; Survival Rate

A total of 48 patients with gastric cancer were randomly assigned to receive either endoscopic injections of OK-432 plus systemic treatment with intravenously administered 5-fluorouracil and intradermally injected OK-432 (group A) or systemic therapy alone (group B). Morphologic improvement occurred in 7 of the 22 patients in group A. In one patient the tumor mass disappeared completely. In group B morphologic improvement occurred in only 2 of the 26 patients. The survival rate throughout the 24-month period was significantly (P less than 0.01) higher in group A than in group B patients. Thus, local administration of OK-432 by endoscopic injection is effective and is recommended for the treatment of patients with advanced gastric cancer.

Topics: Administration, Oral; Administration, Topical; Aged; Biological Products; Clinical Trials as Topic; Female; Fluorouracil; Gastroscopy; Humans; Injections, Intradermal; Injections, Intravenous; Male; Middle Aged; Picibanil; Prognosis; Random Allocation; Stomach Neoplasms

To evaluate the effectiveness of adjuvant immunochemotherapy in advanced adenocarcinoma of stomach, patients who had undergone radical subtotal gastrectomy for stage III gastric carcinoma were randomized to receive immunochemotherapy or not. For immunotherapy, streptococcus pyogenes preparation (picibanil) was given intramuscularly every week and for chemotherapy, either MFC (mitomycin-C, 5-fluorouracil and cytosine arabinoside) regimen or FME (5-fluorouracil and methyl-CCNU) regimen was given. Immunotherapy was started at the 4th or 5th postoperative day and chemotherapy was started at the 8th to 10th postoperative day. To evaluate the immune status of patients, various immune parameters such as 1-chloro-2, 4-dinitrobenzene (DNCB) test, T-lymphocyte count, PHA- and concanavalin-A stimulated lymphoblastogenesis and antibody dependent cellular cytotoxicity (ADCC) activity were checked before operation and 3 to 4 months after operation. One hundred and thirty-eight patients were chosen for study during a 5-year period. Seventy-four patients received postoperative immunochemotherapy and 64 patients received no further anticancer therapy following operation. All patients had been followed at least for 5 years since they underwent operation. Survival rate and immune status were compared between two groups. Patient characteristics and preoperative values for immune status of two groups were similar to each other. Five-year survival rate of postoperative immunochemotherapy group was 44.6%, whereas that of surgery alone group was 23.4%. The difference is statistically significant (p less than 0.05). All the postoperative values of immune parameters showed more favourable data in the postoperative immunochemotherapy group.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Clinical Trials as Topic; Combined Modality Therapy; Cytarabine; Female; Fluorouracil; Follow-Up Studies; Gastrectomy; Humans; Korea; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Random Allocation; Semustine; Stomach Neoplasms; T-Lymphocytes; Time Factors

Our cooperative study group carried out a controlled study of MQF-OK therapy with tegafur (FT) (group A) and with UFT (group B), a compound of FT and uracil in the molar ratio of 1:4, on various advanced gastrointestinal cancers. From January 1985 to May 1987, 91 patients were entered into this study, and 11 cases were ineligible for the protocol (11%). Fifty of 80 cases had advanced gastric cancer, 30 had pancreatic cancer or other cancers, such as colon cancer, and biliary tract cancer. They were divided into group A or B at random. There was no difference in the patient characteristics between group A and B. In gastric cancer, 23 of 50 cases were randomized into group A and 27 cases into group B. Two cases in group A (8.7%) and 7 cases in group B (25.9%) showed PR. The response rate of group B was better than that of group A, but the value of P by Kruskal-Wallis test was 0.27. Thirteen of the 30 other cancers were randomized into group A and 17 cases into group B. Three cases in group A and B, respectively, showed PR. There was no significant difference between the two groups in terms of antitumor effect, prolongation of life or side effects. In conclusion, it was suggested that the MQF-OK therapy with UFT was beneficial for the Remission Induction Therapy in advanced gastric cancer.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carbazilquinone; Clinical Trials as Topic; Double-Blind Method; Female; Fluorouracil; Gastrointestinal Neoplasms; Humans; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Remission Induction; Stomach Neoplasms; Tegafur; Uracil

It is well known that some kinds of immunological functions, s.c. NK activity, IFN or IL-2 production of spleen cells are decreased in mice with protein calorie malnutrition (PCM) compared with those of well-nourished mice. In this study, nutritional conditions of cancer bearers were demonstrated to have serious influence on the effects of immunochemotherapeutic agents as shown herewith. (1) Intra-tumoral 5-FU concentration was lower in PCM mice or starved mice than in mice fed a normal diet. (2) Transplanted mammary tumor, MM-48, was paradoxically grown in PCM mice after 7 days i.p. injection of OK-432 or Lentinan, but the tumor burden was relatively decreased after the same treatment in N-group mice. (4) The life prolongation effect of rIL-2 and OK-432 against ascitic hepatic carcinoma, MH-134, was recognized in C 3H/He mice. On the other hand, there was no observable effect by sequential i.p. injection of PCM mice sera together with rIL-2 and OK-432. (5) Clinically, a randomized study of advanced or recurrent gastric cancer patients treated with MMC and FT(MF) with or without Lentinan was performed. Excellent end-point results were obtained only in Lentinan-administered patients with normal protein levels, but no such effects were noted in patients with low protein levels (below 5.9 g/dl). These findings suggest that the nutritional environment of the cancer bearing host has an important role in the effect of some kinds of BRMs.

Topics: Animal Nutritional Physiological Phenomena; Animals; Antineoplastic Agents; Biological Products; Humans; Interleukin-2; Lentinan; Mice; Mice, Inbred C3H; Neoplasms, Experimental; Nutritional Physiological Phenomena; Picibanil; Polysaccharides; Stomach Neoplasms

Two immunotherapeutic methods were developed as adjuvant therapy for gastrointestinal malignancies, one using oral administration of a streptococcal preparation, OK-432, and the other with adoptive immunotherapy (AIT), local transfer of IL2-cultured and autologous lymphocytes, combined with local preadministration of OK-432. Tsuchitani and Nio in our laboratory have revealed experimentally that oral OK-432 stimulates tumor-specific and non-specific immune mechanisms of gut-associated lymphoid tissues and inhibits the growth of some murine syngeneic tumors that were transplanted into cecal patches. The clinical efficacy of oral OK-432 on gastric cancer patients has been examined by a controlled randomized trial involving a total of about 1000 cases. Oral OK-432 (5KE, once a week) was revealed to be significantly effective in curatively resected group but not effective in non-curatively resected group. Ten consecutive patients with peritoneal dissemination of gastric cancer were treated with intraperitoneal OK-432 and AIT. AIT was performed by transferring autologous lymph node-lymphocytes cultured for 13 days with crude IL2 and tumor-extract. The survival of the treated patients was significantly longer (50% survival period exceeded 1 year) than that of historical control (95 cases, 50% survival period was 5 months). These immunotherapeutic methods are expected to be useful for multidisciplinary therapy of gastric cancer by a combination of each method with other therapeutic methods.

Topics: Biological Products; Clinical Trials as Topic; Combined Modality Therapy; Humans; Immunization, Passive; Picibanil; Random Allocation; Stomach Neoplasms

Nutritional deficiencies are believed to be instrumental in producing reduced immune responses in a variety of animal species. Malnutrition may result in an increase or a decrease in immune functions, depending upon its degree, and also the timing and severity of the nutritional protein deprivation. Our experimental data suggest that there is a significant impairment of cytotoxic activity against K-562 and of the ability of spleen cells to produce interferon in protein-deprived mice in comparison with control mice. Paradoxically accelerated tumor growth after administration of OK-432 or Lentinan was also noted in protein-deficient tumor-bearing mice. In addition, a clinical randomized study of advanced or recurrent gastric cancer patients treated with MMC and FT(MF) with or without lentinan was performed. We recognized excellent end-point results only in the lentinan-treated patients with normal protein levels, while no effect of this agent was seen in patients with low serum protein levels (below 5.9/dl). Aggressive postoperative chemotherapy for cases with distant lymph node metastasis was performed under active nutritional support without any depression of metabolic and immunological states, resulting in a good 5-year survival rate (36.9%).

Topics: Adjuvants, Immunologic; Animals; Esophageal Neoplasms; Humans; Lentinan; Mice; Mice, Inbred C3H; Neoplasms; Nutrition Disorders; Picibanil; Stomach Neoplasms

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

Topics: Biological Products; Drug Therapy, Combination; Humans; Mitomycin; Mitomycins; Picibanil; Postoperative Care; Proteoglycans; Stomach Neoplasms; Tegafur

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Combined Modality Therapy; Female; Gastrectomy; Humans; Male; Middle Aged; Picibanil; Stomach Neoplasms

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

Topics: Female; Humans; Lymphatic Metastasis; Lymphocyte Activation; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Postoperative Period; Proteoglycans; Random Allocation; Stomach Neoplasms; Suppressor Factors, Immunologic; Tegafur

The effect of postoperative immunochemotherapy with mitomycin C (MMC), 5-fluorouracil (5-FU) and OK-432 was evaluated as an adjuvant therapy after curative resection for gastric cancer. Immediately after surgery, patients were randomly allocated to the following three treatments: (A) chemotherapy with MMC and 5-FU (32 cases); (B) chemoimmunotherapy with MMC, 5-FU and OK-432 (33 cases); and (C) surgery alone as control (34 cases). There were no significant differences in the background factors influencing survival time among the groups, and there was no dose-distribution of chemotherapeutic agents between groups A and B. While the differences were not statistically significant, the survival rate and disease-free interval of group B were better than those of groups A or C. Side effects such as gastroenteric disorder, leukopenia (less than 3,000/mm3), thrombocytopenia (less than 7 X 10(4)/mm3) and increase of serum transaminase level (GPT greater than or equal to 100 units) were less frequently observed in group B than in group A. The results of the present study seemed to indicate that chemoimmunotherapy with OK-432 may be effective for surgical adjuvant therapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Combined Modality Therapy; Female; Fluorouracil; Gastrectomy; Humans; Lymph Node Excision; Lymphatic Metastasis; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Postoperative Period; Random Allocation; Stomach Neoplasms

A remarkable improvement of prognosis has been obtained in surgery for patients with gastric cancer in Japan. This is attributed to the standardization of prophylactic lymphadenectomy and the prescription of adjuvant anticancer chemotherapy. Postoperative long-term cancer chemotherapy (PLCC), available from 1970, using MMC, Tegafur and PSK in addition to curative surgery has prolonged the survival time of patients with serosal and/or secondary lymphatic metastasis. To confirm the efficacy of adjuvant chemotherapy on a wide basis, the Cooperative Study Group of Surgical Adjuvant Chemotherapy for Gastric Cancer was organized in 1975. The first and the second study revealed that postoperative bolus injection of MMC and long-term administration of Tegafur improved the survival rate of patients with stage III and lymphatic with serosal metastasis. The third pilot study showed that immunotherapy using PSK and/or OK-432 with anticancer drugs might be effective for gastric cancer. To promote extensive investigations of a large number of patients, the Japanese Foundation for Multidisciplinary Treatment of Cancer was founded in 1980, and the first study suggested that immunochemotherapy using MMC, Tegafur, PSK and OK-432 is effective for gastric cancer. Efficacy of MMC and Tegafur treatment was obtained in some types, such as female cases, those with undifferentiated adenocarcinoma of Borrmann types II and IV and those given curative resection. It is therefore necessary to seek a proper regimen for each type of patient for the concept of Type-oriented Therapy (TOT).

Topics: Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Humans; Lymph Node Excision; Mitomycin; Mitomycins; Picibanil; Postoperative Care; Proteoglycans; Stomach Neoplasms; Tegafur

Immuno-chemotherapeutic effects on the growth of MM-48 mammary tumor were studied in syngeneic C3H/He mice fed diets containing a low (D), normal (N) or arginine-supplemented (NA) protein content. The serum protein levels were 5.7 g/dl in N-mice and 3.7 g/dl in D-mice, respectively. On the other hand, no difference was seen between the two groups, with regard to intra-tumoral protein concentrations. The natural killer (NK) activity of spleen cells was significantly lower in D-mice than in N-or NA-mice. Augmentation of NK activity was detected following the i.p. injection of OK-432 or LENTINAN, while no augmentation was recognized in D-mice. Interferon production of cultured spleen cells was significantly reduced in D-mice, and significantly increased in NA-mice compared with N-mice. NK activity was markedly augmented at 7 days after bilateral oophorectomy in N-mice. Both NK and IFN titers were significantly reduced following administration of estradiol every 7 days. The growth of MM-48 tumor was inhibited by daily administration of OK-432 or LENTINAN in N-mice. However, the tumor growth was paradoxically accelerated after administration of the same drugs in D-mice. These findings indicated that the nutritional or endocrine environment of cancer-bearing mice plays an important role in the effect of some kinds of BRMs. A clinical randomized study of advanced and recurrent gastric cancer patients treated with MMC and FT (MF) with or without LENTINAN, was then performed. We recognized excellent end-point results only in LENTINAN-administered patients with normal protein levels, while no effect of LENTINAN was seen in patients with low protein levels (below 6.0 g/dl).

Topics: Animals; Combined Modality Therapy; Endocrine Glands; Female; Fluorouracil; Humans; Lentinan; Mammary Neoplasms, Experimental; Mice; Mice, Inbred C3H; Neoplasms; Neoplasms, Experimental; Nutritional Physiological Phenomena; Picibanil; Stomach Neoplasms

A prospective randomized trial of surgical adjuvant chemoimmunotherapy was conducted in patients who had undergone palliative gastrectomy for previously untreated advanced stomach cancer. Immediately after surgery, one hundred and forty-seven patients were randomized to receive either chemoimmunotherapy with FT-207 plus OK-432 (group A) or chemotherapy with only FT-207 (group B). The number of patients subjected to this analysis was 134 cases (group A: 70 cases, group B: 64 cases) because thirteen patients were excluded. FT-207 was administered orally and OK-432 was administered intracutaneously. There were no differences in the background factors influencing survival time between the two groups. While the survival rate of group A patients was higher than that of group B patients, the difference in the survival rate between the two study groups was not statistically significant. However, in patients with less differentiated cancer (poorly differentiated adenocarcinoma, signet-ring cell carcinoma) the survival rate of group A patients was significantly (p less than 0.05) higher than that of group B patients. The results of the present study show that OK-432 administered intracutaneously is effective in elevating the survival rate of patients receiving chemotherapy with FT-207 for advanced stomach cancer (especially for less differentiated cancer).

Topics: Administration, Oral; Aged; Biological Products; Clinical Trials as Topic; Combined Modality Therapy; Female; Fluorouracil; Gastrectomy; Humans; Injections, Subcutaneous; Male; Middle Aged; Picibanil; Postoperative Care; Prospective Studies; Random Allocation; Stomach Neoplasms; Tegafur

An analysis of 3,630 gastric cancer cases from 412 institutions who were treated with 6 randomly-assigned protocols was carried out to study the effect of daily PSK and Futraful administration and the adjuvant effect of PSK and/or Picibanil (OK 5 KE) combined with MMC and FT. Evaluation of immunochemotherapy was made on the basis of three-year survival rates and immunoparameters. The most positive results were found in survival rates favoring the combined therapy (FT + PSK) over single administration (FT) to relatively early-stage patients (30%, difference), PSK, MMC and FT combination (10%), and PSK, OK, MMC and FT (22%), over single chemotherapy alone. Serum alpha-2 globulin levels, indicative of immunosuppression, were lower in PSK-administered cases. The overall findings indicated that PSK and/or OK with MMC and FT are effective in prolonging the lives of post-operative patients.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biological Products; Humans; Mitomycin; Mitomycins; Multi-Institutional Systems; Picibanil; Postoperative Care; Proteoglycans; Stomach Neoplasms; Tegafur

Fifty-eight patients with stage IV gastric carcinoma were studied for the 24-month survival rate after receiving immunochemotherapy (Mitomycin-C + FT 207 + OK 432 + PSK, 29 cases) and chemotherapy Mitomycin-C + FT 207, 29 cases). There were no differences in the background factors influencing survival time between the two groups. The survival rate of the immunochemotherapy group was higher than, that of chemotherapy group throughout the observation period, in addition to statistical significance in some periods. The 50% survival rate was 10 months, in the chemotherapy group and 18 months in immunochemotherapy group. The difference in survival between the nonresected cases with immunochemotherapy and the resected cases with chemotherapy was smaller than that between nonresected cases and resected cases of the chemotherapy or immunochemotherapy group. These results suggested that possibility that immunochemotherapy prolonged the survival of patients with stage IV gastric carcinoma.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Combined Modality Therapy; Female; Humans; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Proteoglycans; Random Allocation; Stomach Neoplasms; Tegafur

A controlled clinical trial of surgical adjuvant immunochemotherapy of gastric cancer was started in July, 1974 involving twelve institutes (Chairman; T. Kondo) in Japan. Patients with gastric cancer undergone curative resection were eligible. These patients were divided into 3 groups; Group A, mitomycin C (MMC) + 5-fluorouracil (5-FU): Group B, MMC + 5-FU + PSK or MMC + 5-FU + OK-432; and Group C, surgery alone. Of 1412 patients accumulated up to December 1977, 848 cases were evaluable: Group A-264 cases, group B-290 and group C-294. Side effects such as leukopenia, thrombopenia, elevated GOT and GPT, albuminuria and digestive disorders, were observed in 54 cases (20.5%) of group A and in 59 cases (20.3%) of group B. The 3-year survival rates of total cases were 79.2% with group A, 77.0% with group B and 85.2% with group C. The 2-year survival rates of histological stage II cases were 93.4% with group A, 90.5% with group B and 80.7% with group C. The difference in survival rate between A and C (12.7%) was statistically significant (p less than 0.05). The efficacy was not related to the histological type of gastric cancer. Adjuvant immunochemotherapy using OK-432 was significantly effective on a 1-year survival rate of stage IV gastric cancer.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Female; Fluorouracil; Gastrectomy; Humans; Male; Middle Aged; Mitomycin; Mitomycins; Neoplasm Recurrence, Local; Picibanil; Postoperative Care; Proteoglycans; Stomach Neoplasms

Topics: Adult; Aged; Ascites; Biological Products; Clinical Trials as Topic; Female; Humans; Intestinal Neoplasms; Intestine, Large; Leukocyte Count; Male; Middle Aged; Palliative Care; Picibanil; Prognosis; Skin Tests; Stomach Neoplasms; T-Lymphocytes

Postoperative immunochemotherapy with mitomycin C (MMC), 5-fluorouracil (5-FU) and OK-432 was evaluated as adjuvant therapy for curative resection in the cases of gastric cancer. One hundred and twenty-two patients (28 were excluded) were randomly assigned to 3 groups: Group A-MMC and 5-FU (28 cases); Group B-MMC, 5-FU and OK-432 (33 cases); Group C-control (33 cases). There were no differences in the back ground factors influencing survival time among each group. Group B showed better results in survival rate and disease free interval as compared with Group A or C. Minor and reversible side effects such as enterogastric disorder, leukopenia (less than 3000/mm3), thrombo cytopenia (less than 7 X 10(4)/mm3) and elevation of serum transaminase (S-GPT greater than or equal to 100 unit) were equivalently observed in frequency in each Group A and B, but they were milder in Group B than Group A.

Topics: Aged; Biological Products; Drug Therapy, Combination; Female; Fluorouracil; Humans; Immunotherapy; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Stomach Neoplasms

It is first mentioned that there is a method of evaluation for the effect on immunochemotherapy as an adjuvant and supporting therapy to surgery. The availability of clinical immunotherapy with surgical treatment was studied by using some prospectively randomized trials. The results were summarized as follows; A combined modality therapy of nonspecific and host mediate immunotherapy and chemotherapy as an adjuvant to surgery was effective on long survival, and the therapy had simultaneously a protective effect of toxicity based on some chemotherapeutic agents. The therapy was effective on the patients who had rather immunologically high response such as curatively or non-curatively resected case than those of nonresectable case. In some combination, combined modality therapy may have not effect, so it should be used under paying attention to the points that are type and dose of agents, timing and interval of administration, and combination method of surgical, chemical and immunological treatments.

Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Fluorouracil; Gastrectomy; Humans; Mitomycin; Mitomycins; Picibanil; Prospective Studies; Stomach Neoplasms; Tegafur

Topics: Administration, Oral; Animals; Biological Products; Clinical Trials as Topic; Female; Humans; Mice; Picibanil; Skin Tests; Stomach Neoplasms; Tuberculin Test

A randomized trial of surgical adjuvant chemoimmunotherapy was conducted in patients who had undergone palliative gastrectomy for previously untreated advanced stomach cancer. First, all patients received the same induction chemoimmunotherapy with MFC (mitomycin C, 5-fluorouracil, and cytosine arabinoside) plus OK-432 for 6 weeks after surgery. The patients were then randomized to receive either chemoimmunotherapy with MFC plus OK-432 (group A) or immunotherapy with OK-432 alone (group B) for maintenance. The survival rate of patients was significantly higher in group B (44 cases) than in group A (39 cases) during the first 9 months after the start of induction therapy (P less than 0.05). A further division of patients in terms of carcinoma histology revealed a difference in survival rate only in patients with an undifferentiated histology (poorly differentiated adenocarcinoma and signet-ring cell carcinoma), and not in those with a differentiated histology (papillary, tubular, and mucinous adenocarcinomas). These results indicate that simple immunotherapy with Ok-432 is better for maintenance than chemoimmunotherapy involving MFC, particularly in patients with undifferentiated gastric carcinomas.

Topics: Antineoplastic Agents; Biological Products; Cytarabine; Drug Therapy, Combination; Female; Fluorouracil; Gastrectomy; Humans; Male; Middle Aged; Mitomycins; Palliative Care; Picibanil; Random Allocation; Stomach Neoplasms

Percutaneous balloon pericardiotomy and intrapericardial instillation seemed to be less invasive and effective treatments for refractory pericardial effusion. A 65-year-old man who suffered from refractory pericardial effusion associated with gastric cancer and had been hospitalized three times for pericardiocentesis, complained of dyspnea at rest and visited our emergency room. Echocardiography showed a large amount of pericardial effusion all around the heart and signs of cardiac tamponade. Percutaneous balloon pericardiotomy was performed and pericardial effusion turned to pleural effusion. We performed left thoracocentesis. One week later, massive pericardial effusion localized only around the right heart appeared, and pericardiocentesis was performed again. After another month, pericardial effusion around right heart appeared again and intrapericardial instillation with OK-432 (Picibanil) was tried. After the procedure, the pericardial effusion did not increase, and he has had few symptoms for 2 months as an outpatient.

Topics: Aged; Antineoplastic Agents; Cardiac Tamponade; Echocardiography; Humans; Male; Pericardial Effusion; Pericardiectomy; Picibanil; Pleural Effusion, Malignant; Stomach Neoplasms

We report a very rare case of double cancer involving palatal malignant melanoma and gastrointestinal stromal tumor (GIST), a rare tumor of the gastrointestinal tract originating from a primitive mesenchymal cell. After chemotherapy, radiation therapy, and treatment with interferon and OK-432, the GIST was resected and the melanoma disappeared. The patient has had no evidence of recurrent tumor, and the patient's clinical course has been uneventful for 1 year. This is probably the first report of synchronous double cancer involving oral malignant melanoma and GIST.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Female; Gastrointestinal Stromal Tumors; Humans; Interferon-beta; Melanoma; Neoplasms, Multiple Primary; Palatal Neoplasms; Picibanil; Stomach Neoplasms

A sixty-eight-year-old man was operated on for Stage IV gastric cancer with total gastrectomy and D3 lymph node dissection. The right gastric artery was filled with tumor thrombosis, but tumor tissue was left on the cut stump. Intraoperative ultrasonic liver scanning revealed the suspected metastatic images. Mitomycin C 20 mg dissolved in glue was then pasted at the artery cut stump. Although intraarterial infusion of adriamycin 20 mg, systemic methotrexate + 5-FU alternative therapy and daily medication of UFT-E 400 mg were administered, liver metastasis developed in follow-up CT scans 6 months later. Since 9 months after operation,continuous intraarterial infusion of 5-FU 250 mg/24 hours for 7 days was given biweekly, and was repeated 44 times for the next 27 months. This chemotherapeutic modality purged the liver metastasis. The patient has now survived 7 years 3 months with no therapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Doxorubicin; Drug Combinations; Floxuridine; Fluorouracil; Gastrectomy; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Lymph Node Excision; Lymph Nodes; Lymphatic Metastasis; Male; Methotrexate; Mitomycin; Neoplasm Staging; Picibanil; Proteoglycans; Stomach Neoplasms; Tegafur; Uracil

Locoregional administration of the streptococcal preparation OK-432 is effective in treating malignant ascites from gastric cancer. In order to enhance the efficacy, we conducted a pilot study of locoregional immunotherapy for malignant ascites using host-oriented doses of OK-432. Moreover, action mechanisms of OK-432 were further explored in view of the T-helper type 1 (Th1)-Th2 concept. Gastric cancer patients with cytologically determined malignant ascites were locoregionally administered with OK-432. The dose of OK-432 was selected according to the delayed-type hypersensitivity (DTH) reaction levels to OK-432. Cytokine production profiles of ascites cells were determined using whole ascites assay by stimulation with OK-432. IL-10 mRNA expression was analyzed using RT-PCR. It was found that a positive clinical response was observed in 37 of the 51 (73%) patients with the DTH-oriented approach, showing a significantly higher efficacy than traditional dosage methods using empirical doses (31/58, 53%) (p=0.0487). The DTH-oriented administration of OK-432 produced adverse effects such as fever elevation (p<0.0001) and abdominal pain (p=0.0013) to a significantly lesser extent compared with the traditional treatment. Analysis of the action mechanism of OK-432 revealed that the DTH reaction in responders (19+/-6 mm) was stronger than that in non-responders (6+/-4 mm) (p<0.0001). Tumor necrosis factor (TNF)-alpha production of ascites cells was also higher in responders (3943+/-1247 pg/ml) than in non-responders (1217+/-939 pg/ml) (p=0.0002). There was a significant positive correlation (p=0.0085) between the levels of DTH reaction and TNF-alpha production of ascites cells, but not of blood cells. Responders appeared to polarize on the Th1 axis when clinical responses were plotted on Th1-Th2 dimensions according to the cytokine production profiles of TNF-alpha, IFN-gamma, IL-4 and IL-6 of ascites cells. In vitro culture with IL-2 of ascites cells after OK-432 administration demonstrated an almost clonal expansion of CD4+ lymphocytes, which produced TNF-alpha and IFN-gamma, but did not produce IL-4 or IL-6. IL-10 mRNA expression was detectable in ascites cells from non-responders before treatment. These results suggest that the DTH-oriented locoregional administration of OK-432 may be both effective and less toxic in treating malignant ascites from gastric cancer, showing a possibility of the tailored immunotherapy for malignant ascites. Th1 dysfunction exists

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Ascites; Female; Humans; Hypersensitivity, Delayed; Immunotherapy; Interleukin-10; Male; Middle Aged; Picibanil; Pilot Projects; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stomach Neoplasms; Th1 Cells; Th2 Cells; Tumor Necrosis Factor-alpha

It is very important to control the Th2-dominant condition in cancer patients while they are undergoing immunotherapy. OK-432 powerfully guides Th1 cytokine, but sometimes it can not eliminate the Th2 dominant state in cancer patients, which is needed to induce Th2 cytokine. Premedication with combined LTN and OK-432 is an effective therapy for controlling the Th1/Th2 balance. We tried administering LTN and OK-432 in the pleural or peritoneal cavity for patients with malignant effusion. Of all 9 lesions of the 8 cases, 6 showed complete remission and 1 showed partial response. The level of IL-12 (p70) and IFN-gamma in the pleural effusion or ascites of the combination group was higher than the OK-432 only group. In conclusion, LTN and OK-432 combined therapy appears to be an effective local treatment.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Female; Humans; Immunotherapy; Interferon-gamma; Interleukin-10; Interleukin-12; Lentinan; Male; Middle Aged; Picibanil; Pleural Effusion, Malignant; Stomach Neoplasms

The case of a patient who developed intractable massive ascites caused by hepatic lymphorrhea derived from surgical injury to the hepatoduodenal ligament is presented. OK-432 was injected intraperitoneally through a catheter advanced to near the hepatoduodenal ligament, so as to expose this site to a high concentration of OK-432. Under ultrasound guidance, it was difficult to reach this site due to massive ascites, and so we performed this procedure under CT and fluoroscopic guidance using a unified CT and angiography system. Subsequently, local administration of OK-432 on five separate occasions resulted in resolution of the ascites. We ascribe this favourable result to the use of this unified CT and angiography system to advance the catheter to the suitable site, making possible the local administration of OK-432.

Topics: Antineoplastic Agents; Ascites; Fluoroscopy; Gastrectomy; Humans; Injections, Intraperitoneal; Male; Middle Aged; Picibanil; Postoperative Complications; Radiography, Interventional; Stomach Neoplasms; Tomography, X-Ray Computed

We evaluated intraperitoneal cytology during surgery as a significant predictor of survival and tried to establish strategies for preventing peritoneal carcinomatosis.. The study included 236 patients with gastric carcinoma macroscopically invading the serosa who underwent intraperitoneal cytological examination during surgery. In the 215 resected patients, the relationship between cytological positivity for cancer cells and various clinicopathologic features was analyzed. Additionally, postoperative survival was assessed in relation to the positivity of intraoperative cytology.. Cancer cells were positive [Cy+] in 78 (33.1%) of 236 patients who underwent cytological examinations. Among 73 patients with peritoneal metastases, 53 patients (72.6%) were Cy+, as were 25 (15.3%) of the 163 patients without peritoneal metastases. Multivariate analysis indicated that peritoneal metastasis (p = 0.0001) and the depth of tumor invasion (p = 0.0069) were significant factors correlated with Cy+. Among patients with curative surgery, the 5-year survival rate of the Cy+ group was 22.2%, which was worse (p = 0.0004) compared with that of the Cy(-) group (60.9%). Among Cy+ patients, the survival rate of the group treated with intraperitoneal administration of mitomycin C (MMC) and OK-432 was better (p = 0.0108) than that of the historical control group.. These results suggest that intraperitoneal cytological examination can be a significant prognostic factor for gastric carcinoma with serosal invasion. In addition, dissemination of cancer cells in the peritoneum may be controlled by intraperitoneal immunochemotherapy with MMC and OK-432.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Signet Ring Cell; Combined Modality Therapy; Female; Gastrectomy; Humans; Intraoperative Care; Liver Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Mitomycin; Peritoneal Cavity; Peritoneal Neoplasms; Picibanil; Postoperative Care; Stomach Neoplasms; Survival Rate

Both 5-fluorouracil and doxorubicin are commonly used agents in chemotherapy of gastric cancer in adjuvant setting as well as metastatic disease. In a variety of malignancies, high expression of multidrug resistance-associated protein1 and P-glycoprotein has been associated with resistance to doxorubicin, whereas 5-fluorouracil resistance has correlated with the level of thymidylate synthase expression. We evaluated the expression of multidrug resistance-associated protein1, P-glycoprotein, and thymidylate synthase using immunohistochemistry in 103 locally advanced gastric cancer patients (stage IB-IV) who underwent 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection and investigated the association between their expression and clinicopathologic characteristics including prognosis of the patients. While high expression (> or =5% of tumour cells positive) of multidrug resistance-associated protein1 and P-glycoprotein was observed in 70 patients (68%) and 42 patients (41%), respectively, 65 patients (63%) had primary tumours with high expression (> or =25% of tumour cells positive) of thymidylate synthase. There was a significant association between multidrug resistance-associated protein1 and P-glycoprotein expression (P<0.0001) as well as P-glycoprotein and thymidylate synthase expression (P<0.0001). High multidrug resistance-associated protein1 and P-glycoprotein expressions were associated with well and moderately differentiated histology (P<0.0001 and P=0.03, respectively) and intestinal type (P<0.0001 and P=0.009, respectively). High multidrug resistance-associated protein1 expression correlated with lymph node metastasis (P=0.037), advanced stage (P=0.015), and older age (P=0.021). Five-year disease-free survival and overall survival of total patients were 55.2% and 56.2%, respectively, with a median follow-up of 68 months. There were no significant differences in disease-free survival and overall survival according to the expression of multidrug resistance-associated protein1 (P=0.902 and P=0.975, respectively), P-glycoprotein (P=0.987 and P=0.955, respectively), and thymidylate synthase (P=0.604 and P=0.802, respectively). Concurrent high expression of these proteins (high multidrug resistance-associated protein1/P-glycoprotein, high multidrug resistance-associated protein1/thymidylate synthase, high P-glycoprotein/thymidylate synthase) did not correlate with disease-free survival or overall survival. Even high expre

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; ATP Binding Cassette Transporter, Subfamily B, Member 1; Chemotherapy, Adjuvant; Combined Modality Therapy; Disease-Free Survival; Doxorubicin; Drug Resistance, Multiple; Drug Resistance, Neoplasm; Female; Fluorouracil; Gastrectomy; Humans; Immunotherapy; Lentinan; Life Tables; Male; Middle Aged; Mitomycin; Neoplasm Proteins; Picibanil; Stomach Neoplasms; Survival Analysis; Thymidylate Synthase

We examined the usefulness of preoperative chemotherapy using 5-FU and low-dose CDDP in patients with stage IVb gastric cancer. Between 1996 and 1998, seven patients with stage IVb gastric cancer who received preoperative chemotherapy achieved complete or partial response. One course of the chemotherapy was as follows: arterial or venous infusion of 5-FU (500 or 250 mg/day on day 1-5) and low-dose CDDP (5-10 mg/day on day 1-5) for three weeks. In addition to preoperative chemotherapy, biological response modifiers such as OK-432 and lentinan were used. We evaluated the response with abdominal or chest CT and tumor markers. Although preoperative chemotherapy did not improve the survival rate significantly, the prognosis of these patients seemed to be relatively good. Only slight side effects were found. These results suggest that preoperative chemotherapy using 5-FU and low-dose CDDP may be useful for patients with stage IVb gastric cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Administration Schedule; Female; Fluorouracil; Gastrectomy; Humans; Lentinan; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Staging; Picibanil; Preoperative Care; Prognosis; Stomach Neoplasms; Survival Analysis

We have experienced two cases of unresectable advanced gastric cancer effectively treated by chemo-immunotherapy. One case was of a 68-year-old male patient diagnosed as having inoperable advanced gastric cancer with liver and lung metastasis. This patient was treated by combined chemo-immunotherapy of MMC 10 mg/M, 5'-DFUR 800 mg/day and OK-432 5 KE/2W. At 6 months later, a computed tomography (CT) scan and upper gastrointestinal (GI) series revealed that the metastatic liver tumors and stomach lesion were remarkably decreased in size, and endoscopic biopsy confirmed no cancer cells in the stomach lesion. Moreover, the metastatic lung tumor had disappeared on chest X-ray. The other case was of a 68-year-old female patient with unresectable advanced gastric cancer treated by combined administration of MMC 10 mg/M, 5-FU 200 mg/day and OK-432 5 KE/2W. At 2 months after commencing the treatment, there was a reduction in the serum carcinoembryonal antigen (CEA) level. At 6 months later, the CEA had decreased to normal, the primary and metastatic sites had completely disappeared on CT, and endoscopic biopsy confirmed no cancer cells in the stomach lesion. This patient has survived to date for 5 years and 6 months after commencing the treatment. These results suggested that combined chemo-immunotherapy of MMC, antimetabolite, and OK-432 was an effective treatment for unresectable advanced gastric cancer.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Fluorouracil; Humans; Immunotherapy; Male; Mitomycin; Picibanil; Radiography; Stomach Neoplasms

Locoregional administration using OK-432 was evaluated in treating malignant effusion. Positive clinical responses were seen in 19 (52%) of 36 gastric cancer patients, and in 9 (90%) of 10 colon cancer patients (p < 0.05), indicating its clinical benefit in treating malignant effusion of colon cancer. Fever elevation was observed in 43 (93%) patients and local pain occurred with 9 (20%) of 46 administrations. Immunological analysis for responder patients with rectal cancer revealed that OK-432 induced autologous tumor-reactive CD 3+ CD 4+ TCRV beta 20+ killer lymphocytes. The TCR gene analysis permitted us to clone a V beta 20 CDR 3 sequence, by which positive bands were shown in 3 (75%) of 4 responders and negative bands in 3 (100%) of 3 non-responders. It is suggested that cross-antigenicity exists between OK-432 and colon cancer, and that genetic analysis using the TCRCDR 3 sequence makes it possible to predict responder patients to OK-432 immunotherapy.

Topics: Adult; Aged; Antineoplastic Agents; Ascitic Fluid; ATP-Binding Cassette Transporters; Colorectal Neoplasms; Complementarity Determining Regions; Female; Humans; Immunotherapy; Male; Middle Aged; Picibanil; Pleural Effusion, Malignant; Receptors, Antigen, T-Cell; Reverse Transcriptase Polymerase Chain Reaction; Stomach Neoplasms

We attempted to clarify the accumulation of radiolabeled lymphocytes to tumors and regional lymph nodes in patients with gastric carcinoma. The effects of oral administration of OK-432 were also studied. Five patients with gastric cancer and one who underwent endoscopic mucosal resection, were entered in the study. Prior to the tracer study in 3 patients with gastric cancer, 5 KE of OK-432 was administered for 2 days. Peripheral mononuclear cells were separated and labeled with [111] In-tropolone. After the resection of stomach, tumor tissue, normal gastric mucosa, regional lymph nodes, and non-regional lymph nodes were dissected and radioactivity was measured by a gamma-counter. Accumulation of lymphocytes to the tumor tissue and n1 lymph node station was more than two times that in the normal gastric mucosa and ten times that in non-regional lymph nodes. Accumulation of lymphocytes to the n2 station was strongly enhanced by oral administration of OK-432.

Topics: Administration, Oral; Antineoplastic Agents; Humans; Lymph Nodes; Lymphocytes; Picibanil; Radionuclide Imaging; Stomach Neoplasms

Adoptive immunotherapy (AIT) for non-hematological malignancies, using HLA-matched donor lymphocytes, has been rarely reported. For a 35-year-old male patient with peritoneal disseminated advanced gastric cancer, we performed AIT using lymphocytes from his HLA-matched 37-year-old brother and a streptococcal preparation, OK-432, as an antigen. After the donor had been immunized by intradermal administration of OK-432, OK-432-reactive lymphocytes were induced in vitro and transferred to the patient intravenously with OK-432. Low-dose systemic immunochemotherapy, using interleukin-2, 5-fluorouracil and cyclophosphamide, was concurrently administered with AIT. As a result, the Schnitzler metastasis in the patient reduced in size without any significant graft-versus-host-related complications. One of the effector mechanisms of therapeutic benefit was suggested to be cytokine release from the transferred OK-432-reactive lymphocytes. Our findings suggest the safety and efficacy of AIT using lymphocytes from an HLA-matched sibling and OK-432 as an antigen. Further studies to investigate the use of tumor-associated antigen and an HLA-matched sibling's lymphocytes for AIT of advanced cancer are warranted.

Topics: Adenocarcinoma, Scirrhous; Adult; Fatal Outcome; Histocompatibility Testing; Humans; Immunotherapy, Adoptive; Lymphocytes; Male; Picibanil; Stomach Neoplasms; Transplantation, Homologous

OK-432, a killed preparation of Streptococcus pyogenes, as well as Bacillus Calmette-Guerin (BCG) and Corynebacterium parvum are all known biological response modifiers. To examine the immunomodulatory effects of OK-432, natural killer cell activity and cytokine production by peripheral blood mononuclear cells (PBMCs) were assessed in 32 patients with gastric cancer. Skin tests for Streptococcus pyogenes A-3Su (Su-PS) and BCG were performed in all patients. Other nutritional and immunological parameters were also determined. OK-432-treated PBMCs showed a significant increase of cytotoxicity against K562 cells (p < 0.01). Increased levels of interferon-gamma (IFN-gamma), tumor necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL-2) were found in the supernatants of cultures treated with OK-432 in 29 (90.6%), 20 (62.5%), and 8 (25.0%) out of 32 patients, respectively. Natural killer cell activity, IFN-gamma production, and the Su-PS skin test were positively correlated (p < 0.01). In contrast, the BCG test and other markers were not correlated with natural killer cell activity and IFN-gamma production. These results suggest that the Su-PS skin test could predict OK-432-induced natural killer cell activity and IFN-gamma production in patients with gastric cancer, and was therefore useful to determine whether patients were responders to OK-432.

Topics: Adjuvants, Immunologic; Adult; Aged; Antineoplastic Agents; Cytotoxicity, Immunologic; Female; Humans; K562 Cells; Killer Cells, Natural; Leukocytes, Mononuclear; Male; Middle Aged; Picibanil; Stomach Neoplasms

A 67-old man was referred to our hospital because of dyspnea on exertion and severe hypoxia. He had been given, tegafur and OK 432 for seven years following an operation for gastric cancer. Pulmonary hypertension was noted by right heart catheterization. The findings of a transbronchial lung biopsy resulted in a diagnosis of pulmonary veno-occlusive disease. Pulmonary hemodynamic studies were performed for five different agents: nifedipine, beroprast sodium (PGI2), nitroglycerin, theophylline, and isosorbide dinitrate. However, none of these agents showed significant effects on pulmonary arterial pressure or pulmonary vascular resistance. Treatment with glucocorticoid relieved the patient's symptoms without any apparent effect on pulmonary hemodynamics. The long-term administration of anticancerous agents (tegafur) were thought to have caused pulmonary veno-occlusive disease to develop in this patient.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Humans; Male; Picibanil; Pulmonary Veno-Occlusive Disease; Stomach Neoplasms; Tegafur; Time Factors

Eighty gastric cancer patients with peritoneal dissemination were analyzed to evaluate the effect of intraperitoneal chemo- and/or immunotherapy on abdominal ascites. Among them, 19 were treated with intraperitoneal chemo- and/or immunotherapy, and 21.1% of them showed decreased ascites and better QOL. Patients treated with intraperitoneal administration with OK-432 showed good survival. Among patients with OK-432 administration, those receiving postoperative chemotherapy showed better survival than those given immunochemotherapy. Conversely, among patients with chemotherapy, those given postoperative immunochemotherapy showed better survival than those on chemotherapy. Patients with HLA-type I and III, and those with preoperative normal immune status showed good response when they received intraperitoneal therapy.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Antineoplastic Agents; Cisplatin; Female; Humans; Immunity, Cellular; Immunotherapy; Infusions, Parenteral; Male; Middle Aged; Mitomycin; Peritonitis; Picibanil; Stomach Neoplasms; Survival Rate

A thirty three-year-old male complaining of vomiting was diagnosed as having type 3 advanced gastric cancer of upper stomach and multiple liver metastasis, and had undergone total gastrectomy. The conclusive stage was P2H2n4se stage IVb. Intraoperatively, ethanol injection was performed for the liver metastasis under ultrasonography, and CDDP 100 mg was injected into the intra-abdominal cavity. Postoperative adjuvant therapy was added using oral fluorouracil and OK-432. Then we utilized FP chemotherapy (consisting of 5-FU and cisplatin) and radiotherapy for the bone metastasis. The patient survived 4 years and 4 months with good quality of life.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Ethanol; Fluorouracil; Gastrectomy; Humans; Injections, Intralesional; Liver Neoplasms; Male; Picibanil; Stomach Neoplasms; Tegafur; Uracil

We analyzed 30 endoscopically treated patients with early gastric cancer in terms of the utility of endoscopic ultrasonography (EUS) and the evaluation of prognosis. Endoscopic therapy for early gastric cancer included strip biopsy, laser irradiation, and OK-432 injection. Examination of the depth of cancer invasion in the strip biopsy specimens showed that the diagnostic accuracy of EUS was 85.7%. Complete resection rate in strip biopsy was 82.8%, and the patients with incompletely resected cancer were successfully treated with laser irradiation and/or OK432 injection. The prognosis of the patients treated with strip biopsy was good. Three patients died of causes other than gastric cancer. Local recurrence and a heterochronous new lesion developed in six patients, but all of these cases were successfully treated with additional strip biopsy. All but one patient treated with laser irradiation and/or OK 432 injection survived during the study period. These results suggest that EUS is useful in determining the indication of endoscopic therapies and that prognosis is good in patients with early gastric cancer treated endoscopically.

Topics: Aged; Aged, 80 and over; Endoscopy, Gastrointestinal; Female; Follow-Up Studies; Humans; Laser Therapy; Male; Middle Aged; Picibanil; Prognosis; Retrospective Studies; Stomach Neoplasms; Ultrasonography

We report a very rare case of small cell carcinoma of the stomach. A 69-year-old man, complaining of epigastric discomfort, was admitted to our hospital. Gastric endoscopy showed a Borrmann type 3 tumor at the lesser curvature of the cardia. Multiple liver metastases were observed in CT-scan, and total gastrectomy and cannulation to the hepatic artery were carried out. Macroscopically it was gastric cancer with P0H3N1T3M0, Stage IV b, histologically small cell carcinoma, intermed, INF gamma, ss, ly1, v3, n1(+), ow(-), aw(-). Immunochemotherapy was carried out, but liver metastases developed. The prognosis of this disease is very poor, resulting from rapidly developing metastases and invasion, in spite of treatments such as gastrectomy, chemotherapy and radiotherapy. More effective treatments are needed.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Small Cell; Chemotherapy, Adjuvant; Cisplatin; Gastrectomy; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Male; Neoplasm Invasiveness; Picibanil; Stomach Neoplasms; Tegafur; Uracil

Prognostic factors, such as preoperative status, intraoperative findings, and postoperative treatments, were evaluated in 61 patients with peritoneal metastasis from gastric cancer treated in our facility between 1979 and 1991. Since 1986, 23 patients have been treated with OK-432-combined adoptive immunotherapy (AIT). OK-432-combined AIT is a sequential treatment via a catheter inserted into the abdominal cavity, using a streptococcal preparation, OK-432, followed by the transfer of lymphocytes cultured with T cell growth factor and sonicated tumor extract. A univariate analysis showed that six factors consisting of: (1) age, (2) resection of primary lesion, (3) grade of peritoneal metastasis or serosal invasion, (4) chemotherapy, (5) OK-432, and (6) OK-432-combined AIT influenced survival. The survival of the patients given OK-432-combined AIT (median survival time; MST = 7.5 months) was significantly (P = 0.0267) longer than that of those not receiving OK-432-combined AIT (MST = 4.3 months). A multivariate analysis showed that the most significant factors associated with survival were chemotherapy, resection of the primary lesion, and OK-432-combined AIT. Since these three factors are all therapeutic procedures, the use of combination therapy including OK-432-combined AIT is thus expected to prolong the survival of gastric cancer patients with peritoneal metastasis.

Topics: Adult; Aged; Aged, 80 and over; Combined Modality Therapy; Female; Humans; Immunotherapy, Adoptive; Male; Middle Aged; Peritoneal Neoplasms; Picibanil; Prognosis; Regression Analysis; Retrospective Studies; Stomach Neoplasms; Survival Rate

A 68-year-old female patient with unresectable advanced gastric cancer was treated by combined administration of MMC (10 mg/month), 5-FU (200 mg/day) and OK-432 (5KE/2 weeks). Two months after starting the treatment, there was a diminution in the serum CEA level. Six months later, the CEA had decreased to the normal level, primary and metastatic sites completely disappeared and no cancer cell was confirmed by endoscopic biopsy. The patient has survived for 33 months of a state of complete response.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Mitomycin; Picibanil; Remission Induction; Stomach Neoplasms

It has been demonstrated that natural killer (NK) cell activity of lymphnode lymphocytes (LNL) is very low and hardly augmented by interferon. In this study, OK-432 was injected into the gastric cancer mass through endoscopy one week before the operation, through which NK activity of LNL was significantly increased. A single cell assay could divide the OK-432-injected patients into two groups; responder and non-responder. In responders, the increased activity induced by OK-432 was found also in the distal lymphnodes.

Topics: Adjuvants, Immunologic; Cytotoxicity, Immunologic; Humans; Killer Cells, Natural; Lymph Nodes; Lymphocytes; Picibanil; Stomach Neoplasms

Twenty two surgical specimens of gastric cancer resected after administration of OK-432 for the skin reaction test were examined to determine whether the cancer cells had the same antigens as OK-432, a product of hemolytic streptococcus cells. When the tissues were stained by the PAP method with anti-Su streptococcus antibody used as the primary antibodies, the common antigens were demonstrated in 10 (45.5%) of the 22. The presence or absence of the common antigens was independent of the degree of skin reaction to OK-432, and the relations of the common antigens to other host responses were not clear in this study. This is the first report for the presence of such common antigens between human gastric cancer and OK-432.

Topics: Adult; Aged; Aged, 80 and over; Antigens, Neoplasm; Female; Humans; Leukocytes, Mononuclear; Lymphocytes, Tumor-Infiltrating; Macrophages; Male; Middle Aged; Neoplasm Staging; Picibanil; Skin Tests; Staining and Labeling; Stomach Neoplasms

The response of peripheral blood lymphocytes to the streptococcal preparation OK432 was examined in vitro in 193 gastric cancer patients. When the patients were divided by stimulation index (SI) into two groups, SI > or = 20 and SI < 20, the response rate of SI > or = 20 group of stage IV was 37.5%, and higher than those of the other stages (p < 0.05). In the relationship between SI and the survival period in stage III, the SI > or = 20 group showed longer survival than the SI < 20 group (p < 0.05). There was no statistically significant difference in survival between SI > or = 20 and SI < 20 in stage IV, but no member of the SI < 20 group survived more than 2 years, whereas the five-year survival of the SI > or = 20 group was 38.9%. In the overall survival of stage III and IV, the SI > or = 20 group showed longer survival than the SI < 20 group (p = 0.001). The lymphoproliferative responses to OK432 decreased in very advanced gastric cancer patients and this might lead to poor prognosis.

Topics: Cell Division; Female; Humans; In Vitro Techniques; Lymphocytes; Male; Picibanil; Predictive Value of Tests; Prognosis; Stomach Neoplasms; Survival Analysis

We evaluated the effects of chemotherapy given postoperatively with and without immunomodulators on the survival of patients who had undergone resection for gastric cancer. We conducted a retrospective survey of data on 963 Japanese patients treated at our department of surgery between 1965 and 1987. Data related to the duration of postoperative survival were calculated for those who received chemotherapy, i.e. an individualized combination of various agents given with or without the immunomodulators PSK, a protein extract of the fungus Coriolus versicolor, and/or OK-432, a preparation of an attenuated strain of Streptococcus (immunochemotherapy). Postoperative immunochemotherapy was more often prescribed for patients with advanced disease. The survival of patients who received immunochemotherapy was shorter than that of patients who received only chemotherapy. In a subgroup of patients adjusted for disease stage, the survival of those on chemotherapy versus immunochemotherapy did not differ significantly at any stage. For optimal results, a protocol for postoperative immunochemotherapy needs to be designed and investigated prospectively and according to the stage of gastric cancer. The stage III gastric cancers seem amenable to a favorable response.

Topics: Adjuvants, Immunologic; Aged; Combined Modality Therapy; Female; Humans; Immunologic Factors; Male; Middle Aged; Picibanil; Proteoglycans; Retrospective Studies; Stomach Neoplasms; Survival Analysis; Treatment Outcome

A sixty-eight-year-old male patient was diagnosed as having inoperable advanced gastric cancer with liver and lung metastasis. The patient was treated by combined chemo-immunotherapy of MMC 10 mg/M, 5'-DFUR 800 mg/day and OK-432 5 KE/2 W. Six months after commencing chemotherapy, CT-scan and upper GI series revealed that metasized liver tumors and stomach lesion were remarkably decreased in size and no cancer cell was confirmed by endoscopic biopsy. Further, the metastatic lung tumor has disappeared on chest X-ray. The patient had been well without any evidence of tumor re-progression for over one year, but from July the liver tumor began to metastasize again and the patient eventually died of liver metastasis on Jan. 1, 1993.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Drug Administration Schedule; Floxuridine; Humans; Immunotherapy; Liver Neoplasms; Lung Neoplasms; Male; Mitomycin; Picibanil; Stomach Neoplasms

In order to evaluate the biological response after intraperitoneal administration of OK-432, we studied the changes of cytokine levels in ascitic fluid. In 6 advanced gastric cancer patients with peritoneal dissemination or extensive lymph node metastases, OK-432 20 KE was administered intraperitoneally during operation and the IL-6, IL-8 and IFN-gamma levels in ascitic fluid were measured from 0 to 5 postoperative days. These results were compared with those obtained from non-OK-432 administered control groups (17 cases). The ascitic level of IL-8 increased immediately after operation and gradually decreased. In the OK-432 treated group, the elevation of IL-8 on 0 and 1 postoperative days was remarkable, and there were statistically significant differences with the control group. Similarly, the ascitic level of IL-6 elevated soon after operation and then decreased gradually. In the OK-432 treated group, the ascitic level of IL-6 was significantly higher than in the control group after 3 postoperative days. There were no differences in changes of ascitic IFN-gamma levels between the groups. From these results, IL-6 and IL-8 appeared to be induced in ascitic fluid by intraperitoneal administration of OK-432.

Topics: Ascitic Fluid; Cytokines; Humans; Infusions, Parenteral; Interferon-gamma; Interleukin-6; Interleukin-8; Lymphatic Metastasis; Picibanil; Stomach Neoplasms

Nine gastric cancer patients with simultaneous liver metastases were given intermittent transarterial administration of chemotherapeutics (adriamycin, mitomycin C or 5-fluorouracil) and biological response modifiers (BRM; OK-432 and interleukin (IL) -2) after gastrectomy. In terms of direct antitumor effect on liver metastases, a partial response was observed in 4 of 9 cases (44%). In addition, the concentration of 3 kinds of cytokines such as IL-6, tumor necrosis factor (TNF) -alpha and interferon (IFN) -gamma in the peripheral blood sera was measured immediately before and after transarterial administration of agents. While the concentration of IL-6 increased by BRM, chemotherapeutics could not alter the level of IL-6. As for TNF-alpha and IFN-gamma, no particular changing pattern was observed after transarterial administration. Furthermore, natural killer (NK) activity of peripheral blood mononuclear cells was measured. Administration of either BRM or BRM in combination with chemotherapeutics caused a decrease in NK activity, whereas chemotherapeutics did not. Flow cytometric analysis using 3 kinds of monoclonal antibodies (Anti-CD16, CD56 and CD57) revealed that the proportion of subset of both highly activated NK cells (CD16+.CD56+.CD57-) and moderately activated NK cells (CD16+.CD56+.CD57+) reduced after administration of BRM.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cytokines; Doxorubicin; Fluorouracil; Humans; Immunotherapy; Injections, Intralesional; Interleukin-2; Killer Cells, Natural; Liver Neoplasms; Mitomycin; Picibanil; Stomach Neoplasms

CDDP, 5-FU and LCV are administrated for recurrent gastric carcinoma in our hospital. We have been attempting translumbar local injection of a suspension of OK-432 and Lipiodol into the para-aortic lymph nodes or their surrounding areas for patients with para-aortic lymph node metastases when it was confirmed that the patient had a recurrence. This emulsion gradually degraded successively in the body. In this paper, we report the translumbar local injection method and its effective use in a case with para-aortic lymph node recurrence of gastric carcinoma.

Topics: Aorta; Female; Humans; Injections, Intralesional; Injections, Spinal; Lung Neoplasms; Lymphatic Metastasis; Middle Aged; Picibanil; Stomach Neoplasms

The effects of oral administration of OK-432 on immune reactivities of gut associated lymphoid tissue (GALT) were studied in patients with gastric cancer. The lymphocytes of peripheral blood, regional lymph nodes and spleen in patients with gastric cancer were measured by using different monoclonal antibodies and flow cytometry. OKT3, OKT4, OKT8, OKM1, OKT4+2H4+, OKT4+2H4-, OKT8+Leu15+ and OKT8+1Leu5- were used as monoclonal antibodies. The NK activity, Interleukin-2 production and Interleukin-2 receptor were also measured. After oral administration of OK432, 1) little change was found in peripheral blood and spleen, 2) the percentages of OKT3, OKT4, OKT4+2H4- and the ratio of OKT4/OKT8 were increased in proximal regional lymph nodes, and 3) the percentages of OKT8 and OKT8+Leu15- in regional lymph nodes were not changed. These results suggest that the helper T cell activity and the antitumor immunity of regional lymph nodes were elevated by oral administration of OK-432.

Topics: Administration, Oral; Aged; Antibodies, Monoclonal; CD4-CD8 Ratio; Female; Humans; Immunotherapy; Interleukin-2; Male; Middle Aged; Picibanil; Preoperative Care; Stomach Neoplasms; T-Lymphocyte Subsets

A human monoclonal antibody, YJ-37 (IgM) was generated through the fusion of human B lymphoblastoid cell line HO-323 with the regional lymph node lymphocytes from a colonic cancer patient who was treated with a local immunotherapy. This antibody was purified and conjugated with biotin, after which direct immunohistochemical staining was performed. The results revealed that YJ-37 selectively reacted with colonic cancer (7/19), gastric cancer (3/6), endometrial cancer (1/2) and colonic adenoma (7/13), but not with normal epithelia. Membrane immunofluorescence and FACS analysis also showed that YJ-37 bound to tumor cell surfaces. Furthermore, the chemical structure of the antigen defined by YJ-37 was analyzed by means of thin-layer chromatography immunostaining and ELISA. The results indicated that YJ-37 reacted with sialylated lacto-series carbohydrate chains, which have been reported to accumulate in cancer cells.

Topics: Adenoma; Antibodies, Monoclonal; B-Lymphocytes; Carbohydrate Conformation; Carbohydrate Sequence; Cell Fusion; Cell Line; Colonic Neoplasms; Endometrial Neoplasms; Enzyme-Linked Immunosorbent Assay; Female; Fibrinogen; Glycolipids; Humans; Immunotherapy; Lymph Nodes; Lymphocytes; Molecular Sequence Data; Picibanil; Stomach Neoplasms

The possible use of spleen-derived mononuclear cells (SPMC) for the intentional and economical adoptive immunotherapy of cancer patients was studied. SPMC were obtained from spleens resected surgically from patients with gastric cancer or idiopathic thrombocytopenic purpura (ITP). When SPMC were cultured in recombinant interleukin 2 (rIL2), SPMC, in the form of interleukin-activated killer spleen cells (IL-SP) proliferated in six of eight cases. CD8+ lymphocytes were the major expanding cell population in most SPMC cultures and IL-SP showed a significant cytolytic activity against cultured tumor cells during cell proliferation. When cultured with a streptococcal preparation, OK-432, for 24 to 48 h, SPMC showed cytotoxic activity against tumor cells and were expressed as OK-432 activated killer spleen cells (OK-SP). The effects of supernatants from IL-SP and OK-SP on tumor cell growth were also examined. The supernatants from IL-SP and OK-SP significantly inhibited cell growth in 3 and 10 out of 11 cases, respectively, while those from OK-SP showed higher growth inhibitory activity than those from IL-SP. The results of this study indicate the potential of SPMC as effector cells for the adoptive immunotherapy of cancer patients.

Topics: Adult; Aged; Female; Humans; Immunotherapy, Adoptive; Interleukin-2; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Lymphocyte Subsets; Male; Middle Aged; Neoplasms; Picibanil; Spleen; Stomach Neoplasms

Twenty-four patients with liver metastases from gastric or colorectal cancer were treated with OK-432-combined adoptive immunotherapy (AIT). Lymphocytes isolated from regional lymph nodes or peripheral blood were cultured with medium containing T cell growth factor and sonicated tumor extract antigen (SE-Ag) for 9-13 days. The cultured lymphocytes were transferred mainly through the hepatic artery after the administration of OK-432, a streptococcal preparation. Sixteen of the 24 patients received a low dose of anti-cancer agents between the OK-432 injection and cell transfer. When cultured without SE-Ag, regional lymph node lymphocytes (RLNL) showed significantly (P < 0.05) higher cytotoxic activity against autologous tumor cells and, on the contrary, lower cytotoxic activity against K562 than peripheral blood lymphocytes (PBL). When cultured with SE-Ag, cytotoxicity of RLNL against autologous tumor cells was nearly equivalent to that of PBL. The blastogenesis of fresh PBL to SE-Ag was significantly (P < 0.05) augmented after the OK-432-combined AIT. Two patients showed complete response and 4 patients showed partial response among 19 patients who had evaluable lesions. Five patients whose liver metastases were resected were treated with OK-432-combined AIT as an adjuvant therapy. To date they are alive without recurrence in the liver.

Topics: Adult; Aged; Antigens, Neoplasm; Colorectal Neoplasms; Female; Humans; Immunotherapy, Adoptive; Interleukin-2; Liver Neoplasms; Lymphocyte Activation; Male; Middle Aged; Picibanil; Stomach Neoplasms

We have established a metastatic model of human gastric cancer using orthotopic transplantation of histologically intact tissue in nude mice, and have used this model to evaluate the effects of immunochemotherapy using OK-432, 5-fluorouracil (5-FU) and mitomycin C (MMC) against SC-I-NU, a human stomach cancer line. One-quarter or one-half maximum tolerated doses (MTDs) of 5-FU or MMC resulted in a significant reduction of stomach tumor growth, while liver metastases were not reduced, possibly due to suppression of natural killer (NK)-cell activity by both drugs. On the other hand, when combined with OK-432, half MTDs of 5-FU and MMC significantly reduced liver metastases, with synergistic reduction of stomach tumor growth, possibly reflecting a rescue of NK-cell activity by treatment with OK-432. This metastatic model of human stomach cancer shows that locally growing and metastatic tumors may have different chemosensitivities, and provides the opportunity to test both with various treatment regimens.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Count; Combined Modality Therapy; Disease Models, Animal; Drug Screening Assays, Antitumor; Fluorouracil; Humans; Immunotherapy; Killer Cells, Natural; Liver Neoplasms, Experimental; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Mitomycin; Neoplasm Transplantation; Picibanil; Spleen; Stomach Neoplasms; Transplantation, Heterologous

Intraperitoneal and pleural immunotherapy has been used as an effective therapy for malignancy. Recently we treated two patients with peritonitis and pleuritis due to cancer by intraperitoneal and pleural administration of IFN-gamma, OK-432 and antitumor agents. One patient with gastric cancer (stage IIIb) was treated with intraperitoneal administration of IFN-gamma and OK-432 in combination with intraarterial infusion of MMC, ADM, 5-FU and CDDP. Two months later, ascites and pleural fluid diminished. Another patient with ovarian carcinoma (stage IV), was administered IFN-gamma, OK-432 and CDDP into ascites with general medication of CDDP and Epi-ADM. Two months later, her ascites and tumor size decreased. This patient was treated with palaplatin every two months for the ten months and hysterosalpingecctomy and tumorectomy of Douglas pouch were performed at the sixteenth month. The histopathological examination of resection from this patient showed complete necrotic tissue of tumor. Endogenous cytokine therapy with intraperitoneal and pleural administration of IFN-gamma for priming and OK-432 for eliciting in combination with antitumor agents may be effective treatment for malignant peritonitis and pleuritis.

Topics: Adenocarcinoma, Mucinous; Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Epirubicin; Female; Humans; Infusions, Intravenous; Infusions, Parenteral; Interferon-gamma; Male; Middle Aged; Ovarian Neoplasms; Peritonitis; Picibanil; Pleural Effusion; Pleurisy; Stomach Neoplasms

We investigated whether tumor cell lysis by LAK cells was augmented by treatment with OK432 in vitro. NK and LAK activity against K562 cells was not enhanced by their treatment with OK432. In contrast, the susceptibility of OK432-treated Daudi and KATO-III cells to lysis by LAK cells was enhanced. Succinate dehydrogenase activity and RNA synthesis were impaired in Daudi and KATO-III cells by treatment with OK432, and moreover the expression of HLA Class I antigen and beta 2-microglobulin was inhibited in OK432-treated KATO-III cells. Thus, it is suggested that the enhancement of the susceptibility of OK432-treated tumor cells with regard to succinate dehydrogenase activity, RNA synthesis, and HLA Class I antigen expression.

Topics: Antigens, Neoplasm; Antigens, Surface; Burkitt Lymphoma; DNA, Neoplasm; Humans; Immunotherapy, Adoptive; Killer Cells, Lymphokine-Activated; Leukemia, Myeloid, Acute; Neoplasms, Experimental; Phenotype; Picibanil; RNA, Neoplasm; Sensitivity and Specificity; Stomach Neoplasms; Succinate Dehydrogenase; Tumor Cells, Cultured

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Humans; Immunotherapy; Korea; Neoplasms; Picibanil; Stomach Neoplasms

Peripheral blood lymphocytes (PBL) of gastric cancer patients in advanced stages showed lymphokine activated killer (LAK) activities comparable to those of healthy donors, suggesting potential applicability of LAK cells induced from PBL stimulated with recombinant interleukin-2 (rIL-2) in adoptive immunotherapy (AIT) for gastric cancer. In order to generate a large number of LAK cells from PBL, lymphocytes were cultured with both rIL-2 and phytohemagglutinin (PHA). In this culture, the numbers of cells increased to a greater extent than those in culture with rIL-2 alone but cytotoxic activity did not augment, thus suggesting that this procedure would not afford sufficient clinical effects. On the other hand, a large number of LAK cells with high anti-tumor activities were efficiently induced from spleen cells of the patients by culture of rIL-2; hence clinical usefulness of these LAK cells is anticipated. In regional lymph node lymphocytes (RLNL) cultured with rIL-2, the cytotoxic activities were lower than in those induced in PBL, and a characteristic increase of CD8 + CD11 + suppressor T cells was observed after incubation with rIL-2. Nevertheless, an increase of CD4 + 4B4 + helper inducer T cells was also observed in RLNL after the culture with rIL-2. Furthermore, high cytotoxic activities were induced in RLNL in some cases in which metastasis to the regional lymph nodes was not detected. When gastric cancer patients were pretreated with biological response modifiers (BRM), especially with Lentinan, LAK cells from PBL showed higher NK and LAK activities as compared with those of patients without BRM pretreatment.

Topics: Adult; Aged; Antigens, Surface; Cytotoxicity Tests, Immunologic; Female; Humans; Immunologic Factors; Immunotherapy, Adoptive; Interleukin-2; Killer Cells, Lymphokine-Activated; Lentinan; Lymph Nodes; Lymphocytes; Male; Middle Aged; Phytohemagglutinins; Picibanil; Spleen; Stomach Neoplasms

We have reported the intratumoral injection of OK/fbg is a very effective immunotherapy for colorectal cancer. In this study, we injected OK/fbg into gastric cancer. Histopathological examinations revealed the formation of fibrin fibers, marked infiltration of inflammatory cells and regression of tumor tissue. Seven days after injection, cytotoxicity of splenic lymphocytes was significantly high and HLA-DR, CD25+ splenic lymphocytes were increased. But there was no significant change in peripheral blood and lymph node lymphocytes. On the contrary, several hours after injection, cytotoxicity and surface markers were changed in peripheral blood and lymph node lymphocytes. However, there was no change in splenic lymphocytes. We suppose that activation of splenic lymphocytes was caused by activation of peripheral blood and regional lymph nodes.

Topics: Chemotherapy, Adjuvant; Cytotoxicity, Immunologic; Fibrinogen; Humans; Immunotherapy; Injections, Intralesional; Lymphocyte Activation; Macrophages; Picibanil; Spleen; Stomach Neoplasms

Nineteen patients with metastatic liver tumor (9 of gastric cancer, 5 of colon cancer, 2 of pancreatic cancer, one each of mammary cancer, cholecystic cancer, carcinoid of biliary tract) and one patient with primary liver cancer were treated by endogenously induced LAK therapy consisting of transhepatic arterial infusion with ADM or MMC for induction therapy and OK-432 and rIL-2 (TGP-3) for immunotherapy. The following results were obtained. 1) Clinical response for liver tumor showed no CR but 8 cases of PR, for an overall response rate of 42.1%. 2) Reduced tumor marker value was noted in 76.5% cases, and 50% survival term became 349 days after the therapy. 3) Many CD4 and CD8 positive mononuclear cells had infiltrated around liver tumor after therapy by immuno-histochemical staining of surface marker. 4) NK activity of peripheral blood lymphocytes was markedly reduced soon after the therapy and continued for about 4-7 days, while in cases of combined subcutaneous administration with OK-432, NK activity showed only a slight decrease.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colonic Neoplasms; Doxorubicin; Drug Administration Schedule; Humans; Interleukin-2; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Liver Neoplasms; Mitomycin; Picibanil; Stomach Neoplasms; Survival Rate

The effects of OK-432, a streptococcal preparation, administered intratumorally (OK-432 i.t.) on the change of lymphocyte subsets of regional lymph nodes were investigated in 26 gastric cancer patients. The results were as follows: 1) In the proximal lymph nodes, both non-metastatic and metastatic lymph nodes, and the proportion of CD3+ cells were slightly increased. 2) In the proximal lymph nodes without metastasis, the proportion of CD4+2H4+ cells and CD4+4B4- cells was increased about 10%. 3) In 4 of 15 patients who had metastatic lymph nodes macroscopic changes of the tumor and necrosis of metastatic lymph nodes by OK-432 i.t. were observed. In these lymph nodes CD8-CD11+ cells increased over 40%. These data suggested that the lymph node lymphocyte reaction by OK-432 i.t. may differ between metastatic lymph nodes and non-metastatic lymph nodes.

Topics: Flow Cytometry; Gastroscopy; Humans; Immunotherapy; Injections, Intralesional; Lymph Nodes; Lymphatic Metastasis; Lymphocyte Subsets; Picibanil; Stomach Neoplasms

Out of 79 cases dealt with reservoir, a response was obtained in 31% of 51 assessable cases. When assessed by cumulative survival with Kaplan-Meier method, the 50% survival was 8 months for total cases and prolonged to 21 months for responsive cases. However, eventually re-hospitalization was required for almost all cases. Although oral nutrition was impossible because of poor general condition, there were many patients who refused re-hospitalization and wished to continue treatment at home. In the present study, in 5 such cases the usefulness of home parenteral nutrition (HPN) combined with chemotherapy was determined. All the five patients in this study had gastric cancer with metastases and recurrent lesions in the liver or lymph node, or localized or with peritoneal spread. The site of the reservoir was within the artery in 4 cases and in the abdominal cavity in 1 case. The chemotherapy was multidrug-combination therapy consisting of 5-FU, MMC, CDDP and EPIR. In 4 cases local hyperthermia was added. In 3 out of the 5 cases (3 out of 7 lesions), a partial response (PR) was obtained. The mean dwelling period of the reservoir was 349.2 days for all cases, but longer than 400 days for 3 cases in which PR was obtained. For HPN, a catheter was inserted through the internal cervical vein, and 750-1,500 kcal/day was administered intermittently during night or constantly for 24 hours. In cases in which PR was obtained with chemotherapy and in those in which the reservoir for HPN was been in place before the terminal stage, the reservoir could be used for administration for a prolonged period. The mean dwelling period of the reservoir was 179.8 days and the duration of home stay was 121.2 days. All of the patients were classified as PS2 or higher and pronounced improvement in PS was obtained after HPN in only 1 case. Four out of the 5 patients were satisfied with receiving treatment at home. However, since HPN is associated with many problems such as sudden worsening in general condition, cancer pain and great burden to families, the solution to these problems remains.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Epirubicin; Female; Fluorouracil; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Infusions, Parenteral; Male; Middle Aged; Parenteral Nutrition, Home Total; Picibanil; Stomach Neoplasms; Survival Rate

Although 58 patients with peritonitis carcinomatosa underwent multidisciplinary therapy over the last 5 years in our department, about half of them died within 3 months after treatment. In addition, the prognosis was poor for gastric and colon cancer patients, who had macroscopic peritoneal dissemination. Therefore intraoperative intraperitoneal administration of either BRM or anticancer drugs was performed for the microscopic peritoneal dissemination of the cancer, and the immunological response in the peritoneal cavity was examined. In terms of subpopulation of peritoneal exudate cells, neutrophil leucocytes were predominant and thereafter lymphocytes increased. As for the cytokines in the exudate from peritoneal cavity, the concentration of interleukin-6 peaked within 24 hours after administration, followed by a gradual decrease, while the concentration of interferon-gamma was detectable at more than 24 hours after operation, followed by a gradual increase. Tumor necrosis factor-alpha was also detectable in the exudate. Its concentration decreased when both OK-432 and MMC were administered, but it increased when CDDP was administered. The above results indicated that preventive intraoperative intraperitoneal administration of BRM and anticancer drugs should bring about individual immunokinetic modulation in tumor bearing host and both cytokines and immunocytes could play an important role in locoregional tumor immunity.

Topics: Cisplatin; Humans; Immunotherapy; Infusions, Parenteral; Mitomycin; Pancreatic Neoplasms; Peritonitis; Picibanil; Stomach Neoplasms

Lymphocyte subpopulations of the spleen were assayed in 26 patients with gastric cancer and 5 patients with benign disease using two-color flow cytometric analysis. The ratio of Leu 2a+.Leu 15+ cells, or suppressor T cells, in the gastric cancer patients was about 6 per cent, being higher than that in the patients with benign disease (p less than 0.05). There were fewer Leu 7+.Leu 11- cells, or natural killer-NK-cells, in the gastric cancer patients in stage III or IV than in those with stages I or II (p less than 0.05). The ratio of Leu 3a+.Leu 8- cells, or helper T cells, in the stage IV patients accounted for about 15 per cent of the splenic lymphocytes, which was less than that seen in the patients in stages I or II (p less than 0.05). The ratio of Leu 2a+.Leu 15- cells, or cytotoxic T cells, was approximately twice that of suppressor T cells. The pre-operative administration of lentinan plus OK-432 increased the ratio of Leu 4+.HLA-DR+ cells, or activated T cells, and cytotoxic T cells (p less than 0.05 and p less than 0.01, respectively). The above results suggest that lymphocyte subpopulations in the spleen may have more immunosuppressive potential in proportion with the stage of gastric cancer, but that this reduced immune state may be altered when lentinan and OK-432 are given to these patients.

Topics: Adult; Aged; Female; Flow Cytometry; Humans; Immunologic Factors; Lentinan; Male; Middle Aged; Neoplasm Staging; Picibanil; Spleen; Stomach Neoplasms; T-Lymphocyte Subsets

Lymphocyte infiltration into a tumor has been regarded as an expression of host immunity against cancer, but tumor-infiltrating lymphocytes (TIL) have little or no cytotoxicity. This study examined two different approaches to augment this low cytotoxicity. Firstly, biological response modifiers (OK-432, PSK) were injected into gastric cancer intralesionally. Intralesional injection of OK-432 or PSK significantly augmented the cytotoxicity of TIL. By the injection of OK-432, the ratio of OKT8-, Leu7-positive cells were increased in the TIL subset. In the second approach, TIL of gastric or pulmonary cancer patients were cultured with interleukin-2 (IL-2) in vitro. Co-culturing with IL-2 augmented the low cytotoxicity of TIL, and broad-reactive lymphokine-activated killer (LAK) cells were generated from TIL.

Topics: Cytotoxicity, Immunologic; Humans; Immunologic Factors; Injections, Intralesional; Interleukin-2; Lung Neoplasms; Lymphocyte Subsets; Lymphocytes, Tumor-Infiltrating; Picibanil; Proteoglycans; Stomach Neoplasms; Tumor Cells, Cultured

When peripheral blood mononuclear cells (PBMC) were incubated with a streptococcal preparation, OK-432, for 24 h, PBMC acquired cytolytic activity against cultured and fresh human tumor cells. Such PBMC were called OK-432-activated mononuclear cells (OK-MC). OK-MC produce several kinds of cytokines such as interferon alpha (IFN alpha), IFN gamma, and tumor growth inhibitory factor (TGIF) both in vitro and in vivo. OK-MC-produced cytokines also inhibited the growth of cultured and fresh human tumor cells. The growth inhibition was examined by human tumor clonogenic assay using a double-layer agar technique. The results indicate that two pathways of anti-tumor activity are induced in OK-MC, i.e., cell-mediated and cytokine-mediated.

Topics: Adenocarcinoma; Burkitt Lymphoma; Colonic Neoplasms; Cytokines; Cytotoxicity, Immunologic; Growth Inhibitors; Immunologic Factors; Leukocytes, Mononuclear; Picibanil; Stomach Neoplasms; Tumor Cells, Cultured; Tumor Stem Cell Assay

The effects of OK432, a streptococcal preparation, administered either orally (PO-OK432) or intratumorally (IT-OK432) on the immuno-reactivities of regional lymph nodes were investigated in gastric cancer patients. Although native lymph node lymphocytes (LNL) from untreated patients did not show any cytotoxicities against K562 and Raji cells, enhanced activities were found in LNL from patients administered OK432. Augmenting effects on the cytotoxicities of LNL by in vitro additional OK432, interleukin 2 or gamma-interferon were remarkable in the patients given IT-OK432. Moreover, the cytotoxicities of peripheral blood lymphocytes were augmented in vitro more strongly in patients given IT-OK432 than in those given PO-OK432. Flow cytometric analysis of LNL revealed a decrease in CD4+ cells by PO-OK432 and an increase in CD8+ cells by IT-OK432. An increase in CD4+2H4+ cells and a decrease in CD4+2H4- cells were observed in the patients given OK432, though CD8+CD11+ cells decreased by PO-OK432 while CD8+CD11+ cells increased by IT-OK432. Thus, it is suggested that LNL reactive to OK432 immunotherapy may differ between PO- and IT-OK432, and that the immunoreactivities of local lymph nodes and systemical immuno-reactivities may be highly potentiated by IT-OK432 rather than PO-OK432.

Topics: Administration, Oral; Adult; Aged; Carcinoma; Cytotoxicity, Immunologic; Female; Humans; Immunity, Cellular; Injections, Intralesional; Lymph Nodes; Male; Middle Aged; Picibanil; Stomach Neoplasms

A comparative clinical study was conducted with an addition of vitamin A added to the auxiliary chemotherapies after surgical operation of gastric cancer. The OK-432 + MMC + Tegafur therapy (hereafter referred to as Group A) and the OK-432 + MMC + Tegafur + vitamin A therapy (Group B) were administered. The results were as follows. 1) The survival rate was slightly higher in Group B, although there was no significant difference between the two. 2) As to the rate of recurrence, it was significantly lower in Group B (p less than 0.05). The results above have suggested that additional vitamin A to the auxiliary chemotherapies after operation of gastric cancer can possibly be lower the recurrence rate, contributing to the prolongation of life.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Gastrectomy; Humans; Lymphatic Metastasis; Male; Middle Aged; Mitomycin; Mitomycins; Neoplasm Metastasis; Picibanil; Postoperative Care; Stomach Neoplasms; Survival Rate; Tegafur; Vitamin A

A 61-year-old male diagnosed as Borrmann type 3 advanced gastric cancer was operated, but could not be resected because of the invasion to the pancreas and the lymph nodes metastases. So, local administration of OK-432 20 KE, intra-abdominal administration of CDDP 50 mg, and long-term intermittent intravenous administration of MMC a total amount of 1480 mg, and oral administration of UFT were performed. As the result of this therapy, the tumor was reduced in size. Three years and seven months after the operation, he feels well. Because of this combined therapy, his renal function was made worse.

Topics: Adenocarcinoma; Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Humans; Infusions, Parenteral; Injections, Intralesional; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Remission Induction; Stomach Neoplasms; Tegafur; Uracil

Arterial infusion therapy was used for 97 patients with AMF therapy. Forty were unresectable, 30 non-curatively resected and 22 recurrent gastric cancers. 5-fluorouracil (5-FU) was administered by arterial continuous infusion, adriamycin (ADM) and mitomycin C (MMC) by bolus infusion in the hospital, and continuous arterial 5-FU infusion and ADM low dose intermittent bolus infusion chemotherapy (AF therapy) was used for outpatients. The clinical effectiveness was evaluated. One year cumulative survival rate of primary case by Kaplan Meier method was 21.6%, and that of recurrent gastric cancer was 4.5%. The median survival periods were 7 months in primary cases and 4 months in recurrent cases. In primary cases, the arterial infusion therapy was more effective in non-curatively resected cases than in unresectable ones. Intraperitoneal administration of cisplatin with AF intraarterial infusion therapy (AF-CDDP therapy) was applied in 11 cases with 9 primary and 2 recurrent cases. The clinical effectiveness of each was evaluated. One-year cumulative survival rate of primary case by Kaplan-Meier method was 28.6% and the median survival periods were 10 months. AF-CDDP therapy was considered more effective for unresectable gastric cancer with carcinomatous peritonitis. In conclusion, our method is considered to be advantageous in the treatment of carcinomatous peritonitis of gastric cancer patients.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Fluorouracil; Humans; Infusions, Intra-Arterial; Infusions, Parenteral; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Stomach Neoplasms

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Ascitic Fluid; Cisplatin; Female; Humans; Infusions, Parenteral; Lymphocyte Subsets; Male; Middle Aged; Peritonitis; Picibanil; Postoperative Period; Prognosis; Stomach Neoplasms

Local injection of BRM (OK-432 or Lentinan) around the cancer lesions via endoscope was performed on 66 gastric cancer patients preoperatively, and the regional lymph node lymphocytes in the surgical specimens were examined on T-cell subset, production of IL-2, and responsiveness to IL-2. The results were as follows: 1) In the metastatic lymph nodes, proportions of T-lymphocyte subsets, production of IL-2 and responsiveness to IL-2 did not change after local administration of OK-432 or Lentinan. 2) In the non-metastatic lymph nodes, percentage of CD4+4B4+ cells were significantly increased and production of IL-2 was markedly augmented after local injection of OK-432. On the other hand, percentage of CD8+CD11- cells were significantly increased and production of IL-2 was markedly enhanced after the local injection of Lentinan. These data suggested that the antitumor response of the non-metastatic lymph node lymphocytes was augmented after the local injection of OK-432 or Lentinan.

Topics: Adult; Aged; Female; Humans; Immunologic Factors; Injections, Intralesional; Interleukin-2; Lentinan; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Picibanil; Stomach Neoplasms; T-Lymphocyte Subsets; T-Lymphocytes

The effect of OK-432 on suppressor inducer T cells in the generation of suppressor cells was investigated to determine its mechanism of action as an immunopotentiating agent. Suppressor cell activities induced by sera from patients with advanced cancer (stage III, IV or recurrence) were found to be as high as those induced by Con-A. Suppressor activity induced by Con-A or serum from cancer patients resided in CD8+ T cells, although CD4+ T-cells were required for the induction of suppressor cells. Significant increases in the CD4+2H4+ T cell population after stimulation with either Con-A or sera from the advanced cancer patients were observed when compared with stimulation by normal serum. Stimulation with Con-A induced suppressor cells as well as a significant increase of CD4+2H4+ T-cells. The presence of OK-432 during the generation of suppressor cells, however, significantly reduced the suppressor activity and apparently blocked the increase of CD4+2H4+ T-cells. Thus, it is suggested that OK-432 may interfere with the induction of suppressor cells through the blocking of CD4+2H4+ suppressor inducer T-cells.

Topics: Antibodies, Monoclonal; Biological Products; Complement System Proteins; Concanavalin A; Flow Cytometry; Humans; In Vitro Techniques; Lymphocyte Activation; Phenotype; Picibanil; Staining and Labeling; Stomach Neoplasms; T-Lymphocytes, Helper-Inducer; T-Lymphocytes, Regulatory

The endogenous induction of tumor necrosis factor serum (TNS) for cancer immunotherapy was undertaken in the immediate postoperative period using Lentinan as the primer and OK-432 as the inducer. The changes in several immunological markers of the blood were assayed and compared with a control group to clarify the effects of this treatment. Plasma TNF-alpha levels were elevated two to three hours after eliciting treatment. The neutrophil count was elevated on the 7th postoperative day (POD) and the natural killer (NK) cell activity was transiently suppressed on the 1st POD, but NK cells possessing a high activity (Leu7-CD16+) were preserved until the 7th POD. Helper/inducer (CD4+) and killer cells (CD8+ CD11-) tended to increase, and suppressor (CD8 bright+ CD11+) cells tended to decrease in the induction group. There was no difference in the levels of prostaglandin E2 (PGE2) between the groups, but a marked elevation of interferon-gamma was evident on the 1st POD in the induction group. This treatment may be useful as postoperative adjuvant immunotherapy for cancer due to its ability to induce cytokines and activate host immune mechanisms.

Topics: Aged; Antigens, CD; Biomarkers, Tumor; Carcinoma, Hepatocellular; CD4-Positive T-Lymphocytes; Esophageal Neoplasms; Female; Humans; Immunotherapy; Interferons; Lentinan; Leukocyte Count; Liver Neoplasms; Male; Middle Aged; Pancreatic Neoplasms; Picibanil; Postoperative Period; Remission Induction; Stomach Neoplasms; T-Lymphocytes, Regulatory; Tumor Necrosis Factor-alpha

This study was undertaken in order to evaluate the effect of intraoperative intraperitoneal (i.p.) administration of CDDP on patients who underwent gastrectomy for gastric cancer with peritoneal dissemination, compared with MMC or OK-432 i.p. administration group and untreated group. The median survival time was 11 months in CDDP i.p. group (35 patients), 8 months in MMC or OK-432 Ip group (33 patients) and 7 months in untreated group (25 patients). 1- and 2-year survival rates were 30.4% and 12.1% for MMC or OK-432 i.p. group, and 28% and 8% for untreated group, while in CDDP i.p. group, the rates were higher at 46.4% and 14.7%, respectively (CDDP i.p. group vs. untreated group, p less than 0.05). In vitro chemosensitivity test by succinate dehydrogenase inhibition (SDI) test supported the clinical results. CDDP had higher sensitivities than MMC and ADM on poorly differentiated cases as well as peritoneal dissemination cases. Our results suggest that intraoperative i.p. administration of CDDP was useful for the treatment of gastric cancer with peritoneal dissemination.

Topics: Adult; Aged; Ascitic Fluid; Cisplatin; Female; Gastrectomy; Humans; Intraoperative Care; Male; Middle Aged; Mitomycin; Mitomycins; Peritoneal Cavity; Picibanil; Stomach Neoplasms; Survival Rate

This report describes a 55-year-old man who had a curative operation for leiomyosarcoma of the stomach 6 years ago. Unresectable liver metastases was discovered during the second laparotomy and successfully treated by intra hepato-arterial chemotherapy, which included MMC, ADM and Therarubicin with Infuse-A-Port. He remains well presently with a decrease in the size of the liver metastases and no metastasis to any other organs upon investigation by an abdominal CT 2 years and 2 months after the second laparotomy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Fluorouracil; Hepatic Artery; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Leiomyosarcoma; Liver Neoplasms; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Stomach Neoplasms

In order to improve the prognosis, intraoperative intraperitoneal administration of both mitomycin C and OK-432 was performed for the peritoneal dissemination of gastric cancer. Some 74 of 469 patients of gastric cancer, who underwent surgical treatment over the last 7 years in our department, had peritoneal dissemination and 24 of them were treated with the drugs described above. However, there was no significant difference between treated group and controlled untreated group. No severe side effects were noted except for moderate pyrexia. It is still too early to determine the effect of this treatment because of both the short duration of follow-up and the small number of analyzed cases. In the future, we are planning to apply this treatment to selected cases, for which a histological diagnosis will be made intraoperatively by use of irrigation cytology and/or stamp biopsy.

Topics: Adult; Aged; Biological Products; Female; Gastrectomy; Humans; Infusions, Parenteral; Intraoperative Care; Male; Middle Aged; Mitomycin; Mitomycins; Neoplasm Seeding; Peritoneal Neoplasms; Picibanil; Prognosis; Stomach Neoplasms; Survival Rate

An autopsy case of hemolytic uremic syndrome after treatment with antineoplastic agents for advanced gastric carcinoma is reported. A 70 year-old woman underwent partial gastrectomy for gastric carcinoma on April 16, 1987 (P0H0S2N4, Stage IV). She was treated with Mitomycin C (MMC), UFT, OK-432 and PSK as post operative chemotherapy. Total doses were 60 mg of MMC, 33.9 g of UFT, 55 KE of OK-432 and (507 g) of PSK. She suffered from occult blood in urine in September 1987, thrombocytopenia and anemia in October, edema and hypertension in November and died due to acute renal failure and pulmonary failure on December 5, 1987. It seemed that the cause of death was hemolytic uremic syndrome induced by antineoplastic agents.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Hemolytic-Uremic Syndrome; Humans; Mitomycin; Mitomycins; Picibanil; Proteoglycans; Stomach Neoplasms; Tegafur; Uracil

Forty-three patients with advanced cancer were evaluated for the changes of absolute counts of peripheral blood lymphocytes and lymphocyte subsets during chemotherapy or chemoimmunotherapy. In 27 patients who did not respond to the therapy, whole lymphocytes, T cells, helper/inducer T cells and NK cells decreased significantly in number. In contrast, they showed little decrease in 16 cases responded to the therapy. In situ immunohistochemical analysis of the tumor infiltrating lymphocytes was performed on the carcinoma tissues obtained from 25 gastric cancer patients. T cell infiltration, in which helper/inducer T cells were predominant over suppressor/cytotoxic T cells, and NK cell infiltration were found in most of the tissues comprised various carcinoma types of histology. Furthermore, an analysis of a gastric cancer patient treated with systemic administration of 3 BRMs and intratumoral injection of OK-432 indicated that infiltration of cytotoxic T cells and NK cells augmented by cytokines such as IFN-gamma produced from activated helper/inducer T cells and NK cells. Therefore, it is suggested that movements of helper/inducer T cells and NK cells relate to the response to chemotherapy and participate in prognosis of advanced cancer patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Colonic Neoplasms; Esophageal Neoplasms; Female; Humans; Immunologic Factors; Injections, Intralesional; Interferon-gamma; Killer Cells, Natural; Leukocyte Count; Lymphocytes; Male; Middle Aged; Neoplasms; Picibanil; Remission Induction; Stomach Neoplasms; T-Lymphocytes, Helper-Inducer

In patients with gastric cancer invading the serosa, there is often peritoneal dissemination. In an attempt to control such peritoneal recurrences, OK-432, a compound composed of penicillin G-treated, attenuated Streptococcus pyogens of human origin, was administered intraperitoneally at the time of gastrectomy. The non-specific antitumor activity of the peritoneal macrophages was investigated for its cytostatic activity against the cultured human lung cancer cell line, QG-90. OK-432 given intraperitoneally significantly increased the number of the peritoneal macrophages (p less than 0.05), and also enhanced the cytostatic activity (p less than 0.01). On the basis of these findings, OK-432 IP after gastrectomy was given to 13 of 68 patients with gastric cancer invading the serosa and who underwent curative resection. The five-year survival rate of patients given the drug was 63.5%, while the rate was 52.9% in those not given the drug. OK-432 IP seemed to be effective when lymph node involvement was nil or limited to around the area of the stomach. The peritoneal recurrence rate was, however, not affected by OK-432 IP. Elevation of body temperature and some dehydration were the only observed side effects of OK-432. In attempts to control peritoneal recurrences in patients with gastric cancer invading the serosa, randomized controlled trials on OK-432 IP are now being designed.

Topics: Adenocarcinoma; Cell Count; Cytotoxicity, Immunologic; Gastrectomy; Humans; Intraoperative Period; Macrophages; Peritoneal Lavage; Peritoneal Neoplasms; Phagocytosis; Picibanil; Stomach Neoplasms

A 78-year-old female was diagnosed as having an early gastric cancer of II a (+II c) type with probable sm invasion by gastroscopic examination. Endoscopic polypectomy was carried out due to advanced age, severe ischemic heart disease, and refusal of surgical treatment. Most of the cancerous tissue were removed endoscopically, but biopsy specimens after polypectomy showed some tumor cells leaving at the excisional site. She was treated with local injection of OK-432 endoscopically, PSK orally, Tegafur rectally, and Lentinan intravenously. After about 7 months' treatments, biopsy specimens revealed no residual cancer cells. The total doses administered up to cure for cancer were 70 KE of OK-432, 141 g of PSK, 99 g of Tegafur, and 45 mg of Lentinan. The combination therapy with massive removal of cancer tissue by endoscopy, local injection of anti-cancer agent to residual cancerous lesion and systemic immunochemotherapy will be available and recommendable for poor risk patients with early gastric cancer.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Female; Gastroscopy; Humans; Immunotherapy; Injections; Lentinan; Picibanil; Proteoglycans; Stomach Neoplasms; Tegafur

The production of a tumor growth inhibitory factor (TGIF) was induced in human peripheral blood mononuclear cells (PBMC) by a streptococcal preparation, OK-432, in vitro. The antitumor effect of locally injecting PBMC treated with OK-432 into the tumor site was studied. PBMC were collected from patients with gastric cancer 5 to 12 days before their operation, and cultured with OK-432 for 24 hr in vitro. After the culture, the PBMC were washed thoroughly to eliminate the OK-432. The washed PBMC went on producing TGIF for more than 72 hr in vitro in the absence of OK-432. A small number of TGIF-producing PBMC, approximately 10(7) cells, were injected around the lesion under endoscopic observation. A remarkable antitumor effect was observed in 2 out of 10 cases of resectable gastric cancer. Histological examinations indicated that the antitumor effect is due to antitumor cytokines such as TGIF produced by PBMC rather than to the OK-432-activated PBMC themselves.

Topics: Adenocarcinoma; Aged; Biological Products; Female; Humans; Leukocytes, Mononuclear; Male; Middle Aged; Picibanil; Stomach Neoplasms; Tumor Cells, Cultured

Although regional lymph node lymphocytes (LNL) are thought to be a barrier of the immunological surveillance, their natural cytotoxicity is strongly suppressed. In this study, an immunopotentiator OK-432 (10K.E.) was injected into gastric cancer lesions under endoscopy 1 week before operation, and the effects on the cytotoxicity of LNL were examined by single cell assay. This assay is characterized by assessment of killer cell frequency in preventing the killer cells from recycling by their fixation in agarose, and by direct microscopic observation of both binding and killing phases. NK sensitive cell line K562 was used as target cells. By intratumoral injection of OK-432, the killer cell frequency of LNL in 8 out of 20 cases was elevated to almost equal level as that of peripheral blood lymphocytes. In clinical stages these 8 cases belonged to early stages (stage I 7 cases, stage II 1 case). In LNL subsets of OK-432 injected cases, the percentage of OKT8 positive cells was decreased and the ratio of OKT4 and OKT8 was significantly increased compared with non-injected group.

Topics: Adult; Aged; Biological Products; Female; Humans; Injections, Intralesional; Killer Cells, Natural; Lymph Nodes; Male; Middle Aged; Picibanil; Stomach Neoplasms

The efficacy and safety of endoscopic therapy was investigated prospectively in 42 patients with 44 early gastric cancers who were not candidates for surgery. Thirty-five of the 44 lesions (80%) were treated by endoscopic therapy alone. Adequate tumor resection was possible in lesions less than 2 cm in diameter, in those of the protruding, flat, and erosive types, and in those located in the antrum. None of the 35 patients who were judged completely cured by the initial therapy developed recurrence or lymph node metastases in the follow-up period (range, 3-114 months; mean, 37 months). Therefore, endoscopic therapy appears effective in the treatment of patients with early gastric cancer when the risks of surgery are too high.

Topics: Aged; Aged, 80 and over; Biopsy; Female; Follow-Up Studies; Gastroscopy; Humans; Laser Therapy; Male; Middle Aged; Picibanil; Stomach Neoplasms

Twenty-four patients with advanced stomach cancer were treated with OK-432 combined adoptive immunotherapy [AIT] as prophylaxis or therapy against peritoneal metastases. Lymphocytes isolated mainly from regional lymph nodes were cultured for 9-13 days with T cell growth factor and sonicated tumor extract. OK-432 administration and cell transfer were performed via a catheter inserted into the abdominal cavity at surgery. The proliferation rate of regional lymph node lymphocytes was higher than that of peripheral blood lymphocytes (p less than 0.01). Cultured regional lymph node lymphocytes expressed CD25 and CD4+45R- more frequently than those of peripheral blood lymphocytes. On the other hand, cytotoxic activity of regional lymph node lymphocytes were slightly lower than that of peripheral blood lymphocytes. These results suggest that regional lymph node lymphocytes could be used in AIT because of their different function from that of peripheral blood lymphocytes. Survival of the patients with peritoneal metastasis at primary laparotomy was higher than that of the historical control group (4-9 months after surgery). These results show that OK-432 combined adoptive immunotherapy appears to be a new therapeutic approach to peritoneal metastases from stomach cancer.

Topics: Adult; Aged; Aged, 80 and over; Female; Humans; Immunization, Passive; Killer Cells, Lymphokine-Activated; Lymph Nodes; Lymphocyte Activation; Male; Middle Aged; Peritoneal Neoplasms; Picibanil; Stomach Neoplasms

The influence of OK-432 on the activation of UFT, consisting of tegafur and Uracil, was examined in patients with gastric cancer and colonic cancer. In 14 gastric cancer and 15 colonic cancer cases, to which UFT 400 mg/day and OK-432 2KE 2/W were administered orally and intra-muscularly for 2 weeks preoperatively until surgical treatment, intratumor 5-fluorouracil (5-FU) concentration was measured and compared with that of patients who given UFT 400 mg/day orally for 2 weeks (15 gastric cancer and 15 colonic cancer cases). As the results, in the groups of patients given OK-432, the concentration in gastric cancer tissue was 0.093 +/- 0.067 microgram/g and that in colonic cancer was 0.098 +/- 0.058 microgram/g. Both values exceeded 0.05 microgram/g which is considered to be the effective intratumor 5-FU concentration. No difference was observed in these cases given UFT alone. The ratio of intratumor 5-FU concentration vs. that of normal tissue was 2.5 for gastric cancer and 2.7 for colonic cancer and the ratio of tumor vs. serum 5-FU concentrations was 8.5 for gastric cancer and 10.9 for colonic cancer. No difference was also observed in these values in cases given UFT alone. From above results, it seemed that the clinical dose of OK-432 2KE 2/W had no influence on the activation of UFT, so that the combination therapy of UFT and OK-432 was found to be clinically useful.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biological Products; Biotransformation; Colonic Neoplasms; Fluorouracil; Humans; Lymphatic Metastasis; Picibanil; Stomach Neoplasms; Tegafur; Tissue Distribution; Uracil

In the present study, we measured in vitro production of IFN-gamma induced by OK432 in peripheral mononuclear cells (PMC) and investigated the relationship between the skin reaction to Su-Ps, an extract of Streptococcus Pyogenes, and purified protein derivative (PPD) and the productibility of IFN-gamma in patients with gastric and esophageal cancers. PMC isolated with the Ficoll-conray centrifugation technique were adjusted to 10(6) cells/ml in RPMI-1640 medium supplemented with 10% fetal calf serum and incubated over 7 days at 37 degrees C in the presence of OK432 at 0.17 KE/ml in microculture plates. IFN-gamma secreted in the supernatants was measured consecutively during the observation period with radioimmunoassay. The results are summarized as follows. 1. The production of IFN-gamma in PMC from patients with negative skin reaction to Su-Ps and PPD was significantly decreased as compared with the value obtained from patients who were positive in these skin tests (p less than 0.001). 2. In vitro production of IFN-gamma induced by OK432 was significantly correlated with the degree of skin tests to Su-Ps and PPD as well (r = 0.48, r = 0.41, p less than 0.01, respectively). Thus, it is concluded that the assay of IFN-gamma produced in PMC cultures is useful to evaluate the immunological status of patients with cancer.

Topics: Bacterial Proteins; Biological Products; Esophageal Neoplasms; Female; Humans; Interferon-gamma; Leukocytes, Mononuclear; Male; Mitogens; Picibanil; Skin Tests; Stomach Neoplasms; Tuberculin Test; Tumor Cells, Cultured

A combined therapy with OK-432. mitomycin C (MMC) and 5-fluorouracil (5-FU) by administration through hepatic arterial infusion was performed in three patients with liver metastasis from gastric cancers. A catheter was introduced into hepatic artery by laparotomy. The dosage was 250 mg/day for 5-FU continuously, 10 mg/week for MMC and 5 KE/week for OK-432, respectively. Two cases with advanced gastric cancer and synchronous hepatic metastasis were treated by hepatic arterial infusion after surgical removal of primary lesion. Metastatic lesion in liver was completely eliminated. Another case with metastatic liver tumor from gastric cancer was also treated by the same protocol. The reduction rate of this case was 70% by CT scan. These results suggested that combined therapy with OK-432, MMC and 5-FU by hepatic arterial infusion is a good modality for liver metastases from gastric cancers.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Remission Induction; Stomach Neoplasms

We report a case of advanced gastric cancer with Virchow's node metastasis which responded to concomitant plasma exchange and immunochemotherapy. Plasma exchange was conducted three times in total (once a week) using a membrane type plasma separator, with fresh frozen plasma as exchange fluid. Immunochemotherapy was performed simultaneously using MMC, FT and OK-432. By the end of the third plasma exchange, Virchow's node was confirmed by palpation and ultrasonic examination to have vanished. Diminution of the gastric cancer, and improvement of stenosis of the stomach were confirmed under endoscopy. We surmised that plasma exchange eliminated the immunosuppressive substances in serum, and intensified the anticancer effects of MMC and FT, resulting in the disappearance of the Virchow's node and diminution of the gastric cancer itself.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Combined Modality Therapy; Humans; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Mitomycin; Mitomycins; Neck; Picibanil; Plasma Exchange; Remission Induction; Stomach Neoplasms; Tegafur

Described is the case of an 88-year-old male suffering from advanced hemorrhagic gastric cancer who, because of surgical risk factors, was conservatively treated with immuno-chemotherapy in the form of suppositories containing ftorafur (FT-207) and Picibanil (OK-432). The patient showed marked clinical improvement from this therapy. However, his advanced age and other associated complications kept us from performing further examinations, such as an upper-G-I series and a gastrofiberscopy. A year and 4-months later, the patients died of pneumonia and subsequently was autopsied. Macroscopically, his gastric tumor was found to have completely disappeared and had been replaced by a yellowish-white scar tissue. Microscopically, no cancer cells were found in the examined specimens or in the regional lymph nodes.

Topics: Adenocarcinoma; Aged; Aged, 80 and over; Biological Products; Cicatrix; Combined Modality Therapy; Humans; Lymph Nodes; Male; Picibanil; Remission Induction; Stomach Neoplasms; Suppositories; Tegafur

OK-432 has been injected endoscopically into 4 patients with an unresectable esophageal or gastric cancer. Three months after the initial injection, a remarkable improvement in the symptoms and a reduction of the tumor size was recognized in all 4 patients. This study indicates that an OK-432 injection provides considerable benefits to patients with an advanced esophageal or gastric cancer.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Aged; Aged, 80 and over; Biological Products; Carcinoma, Squamous Cell; Combined Modality Therapy; Esophageal Neoplasms; Esophagoscopy; Gastroscopy; Humans; Injections; Male; Middle Aged; Picibanil; Remission Induction; Stomach Neoplasms

A 70-year-old male with unresectable stage IV gastric cancer was locally administered OK-432 on operation. During the 3rd year following the operation, primary lesion was notably reduced by endoscopic picture, and ro cancerous tissue was detected by biopsy. In addition, serum levels of AFP and CEA were markedly decreased. The patient has survived for 3 years 6 months after operation.

Topics: Adenocarcinoma, Papillary; Aged; Biological Products; Combined Modality Therapy; Humans; Injections; Intraoperative Care; Male; Picibanil; Remission Induction; Stomach Neoplasms

Topics: Antineoplastic Combined Chemotherapy Protocols; Biological Products; Breast Neoplasms; Colonic Neoplasms; Humans; Immunity, Cellular; Immunotherapy; Middle Aged; Picibanil; Stomach Neoplasms

In eleven patients with gastric cancer who could not be operated on because of advanced age, refusal of surgery, or the presence of complications, the streptococcal preparation OK-432 was administered, both intradermally and by direct injection into the tumor under endoscopic guidance. Via gastric x-ray and endoscopic examinations, the tumor was observed to disappear in two cases-one advanced cancer and one early gastric cancer endoscopically. Particularly in the latter case repeated biopsies revealed no evidence of cancer cells. All patients developed fever after intratumor injection, but in no case was it necessary to discontinue administration, and no other serious side effects were noted. The endoscopic injection of OK-432 appears to be a safe and useful form of therapy for gastric cancer unsuitable for surgery.

Topics: Adenocarcinoma; Aged; Biological Products; Female; Gastroscopy; Humans; Male; Picibanil; Stomach Neoplasms

The concept of BRM includes both immunotherapeutic agents and cytokines. We have tested the effects of various kinds of immunopotentiators on gastric cancer patients in terms of (1) the effects on postoperative survival, (2) the effects on tumor size and (3) immunological effects. The results obtained showed that immunopotentiators produced favorable effects. Cytokines should also be evaluated from the same standpoints as those for immunopotentiators.

Topics: Adjuvants, Immunologic; Cell Wall Skeleton; Humans; Lentinan; Mucoproteins; Mycolic Acids; Picibanil; Stomach Neoplasms

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

Topics: Adult; Aged; Cytotoxicity, Immunologic; Esophageal Neoplasms; Humans; Interferon Type I; Interleukin-2; Killer Cells, Natural; Middle Aged; Picibanil; Spleen; Stomach Neoplasms; T-Lymphocytes, Regulatory

Reported herein is the case of a terminal patient with advanced gastric cancer who was shown an extremely effective response to immunochemotherapy. The patient, a 62-year-old female, was determined as having a gastric cancer, Borr. type 2, originating in the pyloric antrum. The tumor was found to be H3P3S2N2 (stage IV), and its histology revealed a mucus-producing papillary adeno-carcinoma, ss gamma, n(+), ly2, and V1. Thus the patient underwent a distal gastrectomy, and was given an operative administration of MMC, followed by postoperative immunochemotherapy with FT 207 and OK 432. Consequently, no ascites were noticed throughout the recuperative course, and repeated CT scannings of the hepatic metastatic lesions, revealed a remarkable regression. Two years after this operation, she resumed normal daily life. Further, her preoperatively elevated tumor markers have returned to normal.

Topics: Adenocarcinoma, Papillary; Biological Products; Combined Modality Therapy; Female; Gastrectomy; Humans; Middle Aged; Picibanil; Postoperative Care; Pyloric Antrum; Stomach Neoplasms; Tegafur

In 8 cases of advanced and/or relapsed gastric cancer (7 cases advanced, 1 case relapsed), we undertook combination chemotherapy with systemic administration of cisplatin and celiac arterial infusion of carboquone intermittently under continuous administration of OK-432 i.m. and UFT p.o. The male to female ratio was 5 to 3 and the age distribution from 53 to 77 years (mean age, 70 years.) Eight cases were divided into the following histological types: 1 papillary adenocarcinoma, 1 well-differentiated tubular adenocarcinoma, 3 moderately differentiated tubular adenocarcinomas, and 3 poorly differentiated adenocarcinomas. Complete response (CR) was obtained in one case, partial response (PR) in four cases, minor response (MR) in two cases, and no change (NC) in one case. The response rate was 62.5%. CR was noted in a relapsed case. The median survival time from the beginning of the chemotherapy was 8 months (ranging from 6 to 13 months). The major toxicity was bone marrow suppression, but there were no cases of serious renal damage.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow; Carbazilquinone; Celiac Artery; Cisplatin; Drug Evaluation; Female; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Neoplasm Recurrence, Local; Picibanil; Remission Induction; Stomach Neoplasms; Tegafur; Uracil

A SU-polysaccharide skin test (SU-PS test) has been employed and studied as a parameter for monitoring the immunological status of OK-432 treated patients who had undergone a curative gastrectomy for a gastric cancer in stages II and III. The median diameter of the erythema (SU-PS value) was found to have no relation to the number of lymphocytes and the serum protein level and was depressed by combined chemotherapy. The SU-PS value was significantly higher in patients not given a splenectomy than in patients who had undergone a patients splenectomy. The spleen is considered the essential organ to focus on in OK-432 immunotherapy.

Topics: Aged; Biological Products; Female; Humans; Immunotherapy; Leukocyte Count; Male; Middle Aged; Picibanil; Polysaccharides, Bacterial; Postoperative Period; Skin Tests; Splenectomy; Stomach Neoplasms; Streptococcus

OK-432, a compound composed of penicillin-G-treated, attenuated Streptococcus pyogenes of human origin, was administered by intratumoral injection (IT) to 15 of 49 patients with Stage III gastric carcinoma, at the time of preoperative endoscopic examination. The 5-year survival rate of patients given IT was 73.3%, whereas the rate was only 36.5% in those not given IT (P less than 0.05). A study of recurrent cases revealed a significantly low incidence of peritoneal recurrence in the group on OK-432 IT (P less than 0.01). In previous work, the authors noted a favorable prognosis of patients with Stage III gastric carcinoma and with a marked infiltration of Langerhans' cells (LC) in the tumor tissues. All of the 49 in the current study were thus examined immunohistochemically, using anti-S-100 protein antibody, the objective being to clarify the relationship between OK-432 IT and the density of LC. The density of LC among those given IT was significantly increased as compared with those not given IT (P less than 0.05). The results of this study suggest that OK-432 IT may lead to augmentation of the density of LC in tumor tissues and hence prevent peritoneal recurrences in patients with Stage III gastric carcinoma.

Topics: Adenocarcinoma; Biological Products; Drug Evaluation; Gastroscopy; Humans; Langerhans Cells; Neoplasm Proteins; Peritoneal Neoplasms; Picibanil; S100 Proteins; Stomach Neoplasms; Streptococcus pyogenes

The therapeutic effect of OK-432 induced endogenous TNF on tumor bearing mice and cancer patients was investigated. OK-432 (10 KE/mouse) was administered intraperitoneally to Balb/c mice 7 days prior to the transplantation of Meth A cells (1 x 10(6)/mouse) into the abdominal cavity. And at day 1 of tumor inoculation, 1 KE/mouse of OK-432 was administered intraperitoneally. The significant prolongation of life span was observed in these mice. On the basis of these observation, therapeutic effect of endogenous TNF on cancer patients was clinically evaluated. OK-432 was administered intraperitoneally or intrapleurally to cancer patients with peritonitis carcinomatosa or pleuritis carcinomatosa 4 times (10KE each) every other day and 50KE of OK-432 was readministered with the interval of 7 days. An appreciable activity of TNF was detected in peritoneal fluids or pleural effusion, and the significant decreasing of these fluids was observed. It is therefore concluded that these therapeutic approach may well be taken into account in treatment of cancer.

Topics: Aged; Animals; Ascitic Fluid; Biological Products; Breast Neoplasms; Cytotoxicity, Immunologic; Female; Humans; Immunotherapy; L Cells; Lung Neoplasms; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplasms; Picibanil; Sarcoma, Experimental; Stomach Neoplasms; Tumor Necrosis Factor-alpha

An 83-year-old patient with advanced gastric cancer was given repeated endoscopic administration of OK-432 combined with systemic immunochemotherapy. The cancerous lesion gradually regressed following the treatment, and remarkable degeneration was observed in many tumor cells. Detailed immunohistochemical examination revealed that Leu 7-positive cells had markedly infiltrated the cancerous tissue. This finding suggests that NK cells may play an important role in tumor regression induced by intratumoral OK-432 therapy.

Topics: Adenocarcinoma; Aged; Biological Products; Humans; Injections; Killer Cells, Natural; Male; Picibanil; Stomach Neoplasms

Gastric endoscopy could be an useful procedure in treating patients with early gastric cancer in certain conditions. We treated 24 patients with gastric cancer for whom no surgery was indicated because of serious complications or patient's refusal. Endoscopic local injection (ELI) with Mitomycin C (MMC), 5-fluorouracil (5-FU), and Picibanil (OK-432) was performed in 16 patients and polypectomy in 8 patients as radical treatment for primary gastric cancer. Of the 16 cases, ELI was effective in 9 cases of early gastric cancers, consisting of 4 cases with complete response (CR), additional 4 with a partial response (PR), but was ineffective in the remaining of all 3 cases of advanced cancers. ELI with MMC + 5FU was performed in 8 cases with an excellent response; 3 cases with CR and 3 cases with PR; 5 patients are alive, with the longest survival period of 54 months, and 2 patients died of other diseases. On the other hand, ELI with OK-432 was carried out in remaining 8 cases with no effective results, showing only 1 case with CR and another case with PR. Polypectomy was effective for 8 protruding type of early gastric cancers with the longest cancer-free period of 31 months. At present, although preoperative evaluation of the depth and range of cancer invasion is difficult, we would like to emphasize that ELI and polypectomy are procedures worthy to be attempted in patients with early gastric cancers with no nodal metastases for surgery is not indicated.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Gastroscopy; Humans; Male; Middle Aged; Mitomycins; Picibanil; Stomach Neoplasms

Topics: Adult; Aged; Biological Products; Cells, Cultured; Female; Humans; Interferons; Interleukin-1; Interleukin-2; Lymphocytes; Male; Middle Aged; Picibanil; Stomach Neoplasms

The IFN producing activity of RLNL and PBL was studied in cancer patients using K562, PHA-P and OK-432 as inducers. In response to K562, IFN production was significantly greater in the PBL than in the RLNL, and the titer was about equal in the PBL and RLNL when OK-432 was used as an inducer. On the contrary, the amount of IFN produced by PHA-P was significantly higher in the RLNL than in the PBL. There was no definite relationship recognized between tumor progression and IFN productivity in the cases studied.

Topics: Adult; Aged; Cell Line; Colonic Neoplasms; Female; Humans; Interferons; Leukemia, Erythroblastic, Acute; Lymph Nodes; Lymphocytes; Male; Middle Aged; Phytohemagglutinins; Picibanil; Rectal Neoplasms; Stomach Neoplasms

Intratumoral administration of 5 K.E. OK-423 was given every other day for a patient with an abdominal wall recurrence of gastric cancer. After a total dose of 465 K.E. the abdominal tumor turned necrotic and its demarcation was monitored. Finally, the tumor separated and fell from the abdominal wall. Histologically, marked infiltration of neutrophils, lymphocytes, and macrophages were observed in the cancerous tissue. Clinically, local pain lessened and the serum CEA level decreased. PPD and PHA skin tests were markedly stimulated. A long term small-dose intratumoral administration of OK-432 seemed to be effective for a local recurrence of gastric cancer.

Topics: Abdominal Muscles; Adenocarcinoma; Adult; Biological Products; Humans; Male; Picibanil; Soft Tissue Neoplasms; Stomach Neoplasms

Multiple-drug (OK-432, PSK and SPG) immunotherapy and chemotherapy provided remission of symptoms for 36 months in a patient aged 21 years suffering scirrhous gastric carcinoma associated with carcinomatous peritonitis in which direct infiltration to the pancreas, retroperitoneum and the left colon was observed. A remarkable improvement with time was observed by endoscopic and roentgenographic observation, and a substantial improvement was also observed in the NK-cell ratios of lymphocyte subsets of the OKT series in relation to immunologic parameters. A tumor necrosis factor [TNF]-like substance was thought to have been induced by multiimmunotherapy in this case.

Topics: Adenocarcinoma, Scirrhous; Adult; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Carbazilquinone; Glycosaminoglycans; Humans; Male; Mitomycin; Mitomycins; Picibanil; Proteoglycans; Sizofiran; Stomach Neoplasms

A 49-year-old nursery school teacher noticed epigastric discomfort and loss of appetite, and was hospitalized for diagnosis and treatment on Dec. 19, 1984. She was diagnosed to have Borrmann type 4 gastric cancer with Schnitzler's metastasis. After one month's administration of UFTM-O (UFT, mitomycin C, OK-432) subjective symptoms disappeared and improvement of the gastric lesion was demonstrated 2 months later. On Apr. 4, 1985 she was able to return to work, receiving UFTM-O therapy for one year as an outpatient. When ascites appeared in October, UFTM-O was discontinued and a single intraperitoneal administration of cis-platinum was done for peritoneal effusion. Another combination chemotherapy consisting of MTX, 5-FU and OK-432 was started, but she died 3 months later. In consequence, she had been able to live 18 months from the initial diagnosis. Moreover, she was able to enjoy a high quality of life, which meant she was able to return to her work and travel abroad, during the initial two-thirds of the disease period.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Female; Fluorouracil; Humans; Methotrexate; Middle Aged; Mitomycin; Mitomycins; Picibanil; Prognosis; Quality of Life; Stomach Neoplasms; Tegafur; Uracil

It is crucial to define the immunological characteristics of peripheral blood mononuclear cells in order to clarify the physiological state of cancer patients. In this study, we examined prostaglandin E2 (PGE2) and interleukin-1 (IL-1) production by plastic-adherent cells stimulated by lipopolysaccharide (LPS). The secretion of PGE2 and IL-1 into media depended on the dose of LPS. Although the addition of silica resulted in suppression of LPS-induced PGE2 production, it caused augmentation of IL-1 production. The effect of BRM therapy on IL-1 production was evaluated in five cancer patients. The results demonstrated that BRM therapy increased the levels of IL-1 at the late assessment point for 3 patients and their quality of life was improved. These findings suggest that production of IL-1 may be used as a monitor for the effectiveness of biotherapy. The association of PGE2 production with host antitumor response was evaluated in IFN-gamma therapy. The results showed that the PGE2 production ratio increased early in the therapy period and declined gradually, whereas the expression of HLA-DR antigen on monocytes and the level of IL-1 increased during the treatment. The exact mechanism by which BRM activates monocytes is unknown. It is possible that a distinct subpopulation of monocytes is responsible for this effect.

Topics: Biological Products; Cell Adhesion; Cells, Cultured; Colonic Neoplasms; Dinoprostone; Humans; Interleukin-1; Lipopolysaccharides; Lung Neoplasms; Macrophages; Monocytes; Neoplasms; Picibanil; Prostaglandins E; Stomach Neoplasms

Twelve patients with malignant ascites caused by gastro-intestinal cancer were treated by intraperitoneal administration of OK-432. Tumor cells from these patients were separated from ascitic fluid and cultured in vitro before OK-432 therapy. OK-432 was given intraperitoneally one to two times a week at doses ranging from 5 to 20 KE suspended in saline. Mononuclear lymphocytes were collected from the fluid at various intervals throughout the therapy. The effect of ascites-derived lymphocytes on ascites-derived autologous tumor cell growth was studied in vitro using microplate assay. Nine (responders) of 12 patients showed complete disappearance or significant reduction of ascitic fluid. Ascites-derived lymphocytes slightly inhibited autologous tumor cell growth only in one case before OK-432 therapy. Lymphocytes collected from ascites after OK-432 injection significantly inhibited auto-tumor cell growth in all of 9 responders. In 3 non-responders, however, auto-tumor cell growth inhibition was found only in one case. Interestingly, lymphocytes from non-responders significantly inhibited the growth of tumor cells taken from responders. Conversely, lymphocytes from responders did not inhibit non-responder-derived tumor cell growth. These findings imply that auto-tumor killing by OK-432-induced lymphocytes may depend more on the condition of the tumor cells than on the condition of the lymphocytes, and that the measurement of auto-tumor killing activity by ascites-derived lymphocytes may be useful as an indicator in OK-432 therapy.

Topics: Abdominal Neoplasms; Ascites; Biological Products; Cytotoxicity, Immunologic; Drug Evaluation; Humans; Intestinal Neoplasms; Methods; Peritonitis; Picibanil; Stomach Neoplasms; T-Lymphocytes, Cytotoxic

Topics: Adult; Aged; Aged, 80 and over; Biological Products; Carcinoma; Female; Hemolysis; Humans; Injections, Intradermal; Male; Middle Aged; Neoplasm Recurrence, Local; Picibanil; Stomach Neoplasms; T-Lymphocytes

Topics: Adjuvants, Immunologic; Cytotoxicity, Immunologic; Female; Humans; Injections; Interleukin-2; Killer Cells, Natural; Lymph Nodes; Male; Picibanil; Proteoglycans; Stomach; Stomach Neoplasms

In 9 patients with recurrent gastric carcinoma treated with intracutaneous injections of a hemolytic streptococcal preparation of OK-432 (PIC), the T/B cell ratio, the number of IgG-Fc receptor positive (T gamma) cells, the degree of blastoid transformation of lymphocytes in response to concanavalin-A (Con-A) and phytohemagglutinin (PHA), and the activity of natural killer cells (NK) in the thoracic duct lymphocytes (TDL) and peripheral blood lymphocytes (PBL) were measured. In thoracic duct lymph, the T cell to B cell ratio was higher than that found in peripheral blood. The proportion of T gamma cells and the natural killer cell activity was found to be considerably lower in TDL than PBL, though there was a higher degree of blastoid transformation of lymphocytes in response to Con-A and PHA in TDL. After the administration of PIC, there was no significant difference in T/B cell ratios and T gamma cell proportion between TDL and PBL, though the lymphocytic blastoid transformation in response to Con-A and PHA decreased in TDL but not in PBL. PIC administration appeared to augument natural killer cell activity in both TDL and PBL.

Topics: Aged; B-Lymphocytes; Biological Products; Concanavalin A; Humans; Immunotherapy; Killer Cells, Natural; Lymphocytes; Middle Aged; Phytohemagglutinins; Picibanil; Stomach Neoplasms; T-Lymphocytes; Thoracic Duct

A case of synchronous multiple primary neoplasms, an intracranial malignant lymphoma and a gastric carcinoma, is presented. A 63-year-old man was admitted to our hospital with complaints of dizziness and a floating sensation on gait. A CT scan after admission, revealed a well-defined, nodular high density area in the left frontal lobe, which was markedly enhanced by the contrast medium. In order to rule out a metastatic brain tumor, examinations were performed as a consequence, and, the gastric carcinoma was found. A partial removal of the brain tumor and a gastrectomy were performed in two stages. Pathologically, the diagnosis of the brain tumor indicated a malignant lymphoma of large cell type, and that of the gastric carcinoma was an adenocarcinoma. The patient received postoperative irradiation and chemotherapy and was discharged in a good condition. He died of pneumonia 21 months after the operation. Necropsy revealed a marked atrophy of the brain without recurrence of the malignant lymphoma and no recurrence of a gastric cancer.

Topics: Adenocarcinoma; Aged; Brain Neoplasms; Combined Modality Therapy; Gastrectomy; Humans; Lymph Node Excision; Lymphoma; Male; Neoplasms, Multiple Primary; Picibanil; Stomach Neoplasms

Topics: Biological Products; Cells, Cultured; Glycoproteins; Growth Inhibitors; Humans; Monocytes; Picibanil; Stomach Neoplasms; Tumor Necrosis Factor-alpha

It has been assumed that a high dose of OK-432 can be safely injected into tumor tissues or intraperitoneally under general anesthesia. Among 40 patients with advanced carcinoma of the stomach, high doses of OK-432 were injected into the tumor in six and intraperitoneally in 34. Circulatory shock associated with subsequent disseminated intravascular coagulation (DIC) developed within 3 days in one of the former and in two of the latter group. Hypovolemic shock was initially considered to indicate that hypovolemia actually existed in these three patients. However, the shock state with DIC persisted even after the blood volume had been corrected. Gram-negative bacteremia was verified in two of the patients. The shock and DIC seen in these patients could have been attributed to septicemia through either the necrotic tumor or the intestinal wall showing increased permeability as a result of the drug. When and if a high dose of OK-432 is administered locally, the prophylaxis of infection seems to be of crucial importance in order to avoid such complications as those reported above.

Topics: Adult; Aged; Biological Products; Disseminated Intravascular Coagulation; Female; Humans; Injections, Intraperitoneal; Male; Middle Aged; Picibanil; Stomach Neoplasms

Topics: Biological Products; Glycoproteins; Humans; Interferons; Lymphocytes; Picibanil; Stomach Neoplasms; Tumor Necrosis Factor-alpha

Spread of the gastric cancer is multifarious according to its pathological and biophysiological characteristics. The therapeutic strategy was reviewed by the analysis of more than 8.000 cases of gastric cancer treated at Cancer Institute Hospital. Main type of recurrence in early stage cancer was, though seldom, the hematogenous metastasis to the liver. On the other hand, in the advanced cases, macroscopically localized, and histologically well differentiated tumor type easily adhered and invaded to the adjacent organs and structures, and infiltrating and undifferentiated tumor type tended to cause peritoneal dissemination. Lymph node spread was observed in any tumor type, but frequently observed in intermediate type. Invasion to the adjacent organs and limited lymphatic spread can be controlled by wide combined resection of adjacent organs, and extended lymphadenectomy. However, hematogenous metastasis and peritoneal dissemination are difficult to be controlled by surgical intervention. Thus, minor surgery can be directed for small early stage cancer under strict criteria, and wide and extended resection for localized type, and combination of surgery and adjuvant chemotherapy for intermediate and infiltrating tumor types advancing more than stage II.

Topics: Combined Modality Therapy; Gastrectomy; Humans; Lymph Node Excision; Lymphatic Metastasis; Mitomycin; Mitomycins; Neoplasm Invasiveness; Neoplastic Cells, Circulating; Picibanil; Prognosis; Stomach; Stomach Neoplasms

A case of relapsed gastric cancer postoperatively presenting obstructive jaundice due to metastases in the hepatic portal and periaortic lymph nodes and multiple lung metastases was given OK-432 continuously i.m. and UFT p.o., and then generally given cisplatin and massive doses of carboquone i.a. intermittently into the peritoneal cavity. The chemotherapy led to complete remission of the obstructive jaundice and disappearance of the metastases in the lungs and lymph nodes.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Carbazilquinone; Humans; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Picibanil; Portal System; Stomach Neoplasms; Tegafur; Uracil

The enhancement of antitumor effects by combination of biological response modifiers (BRM) was investigated on the basis of their action mechanisms. Experimentally, significant inhibition of tumor growth by combination treatment with BRM, which eliminated immune suppressive mechanisms and in turn enhanced immune responses, was observed. Furthermore, inhibition of tumor growth was observed under conditions of uniform biorhythm in mice and the effect of modification of biorhythm was enhanced by combination with BRM. Clinically, combination treatment of plasma exchange and LAK-cell adoptive immunotherapy was discussed.

Topics: Animals; Humans; Immunization, Passive; Immunotherapy; Interferon Type I; Interleukin-2; Liver Neoplasms, Experimental; Mice; Mice, Nude; Neoplasms; Periodicity; Picibanil; Plasma Exchange; Polysaccharides; Stomach Neoplasms; Vitamins

The influence of a biological response modifier on thoracic lymphocytes was studied clinically and experimentally. The thoracic lymphocytes and peripheral blood were taken from nine cases of gastric cancer relapse before and after the administration of hemolytic streptococci, OK-432 (PIC), for immunological examination. T: B cell ratio, T cell ratio and ADCC activity of the thoracic lymphocytes and peripheral blood were not changed but the NK activities of both were increased. The juvenilization of lymphocytes was reduced but that of the peripheral blood was not changed. The number and the ratio of T cells in the thoracic lymphocytes of Wistar rats were considerably increased by the administration of PIC but they were reduced in the peripheral blood. T-cell subsets of thoracic lymphocytes and peripheral blood were hardly changed by the administration of PIC. In the case immunological treatment, the thoracic lymphocytes and blood lymphocytes should be monitored because their biological specificities are different.

Topics: Animals; B-Lymphocytes; Biological Products; Humans; Leukocyte Count; Lymphocytes; Male; Picibanil; Rats; Rats, Inbred Strains; Stomach Neoplasms; T-Lymphocytes; Thoracic Duct

We examined whether OK-432, a streptococcal preparation, could induce tumor necrosis factor in cancer patients. OK-432 was administered at a dose of 100 KE intratumorally to 4 advanced gastric cancer patients and 10KE intracavitary to 8 patients with malignant pleuroperitoneal effusion. The cytostatic activity of the sera and malignant effusions was assayed by the growth inhibition of L929 cells. OK-432 induced significant cytostatic activity in the sera and malignant effusions. The activity was partially neutralized by the monoclonal antibody against human recombinant tumor necrosis factor. These data suggest that OK-432 induces tumor necrosis factor in the sera and malignant effusions of cancer patients.

Topics: Biological Products; Cytotoxicity, Immunologic; Glycoproteins; Humans; Neoplasms; Peritoneal Neoplasms; Picibanil; Pleural Neoplasms; Stomach Neoplasms; Tumor Necrosis Factor-alpha

Topics: Ascitic Fluid; Biological Products; Colonic Neoplasms; Growth Inhibitors; Humans; Picibanil; Stomach Neoplasms

Using the Su-PS skin test, an attempt was made to evaluate whether or not this reaction could become a useful immune parameter in patients with gastrointestinal cancer. The conclusions were as follows: Late-stage patients with gastric cancer showed a weak response in the Su-PS skin test when examined preoperatively. The skin reaction to Su-PS was shown to become stronger than in the PPD and PHA test when patients received OK-432 treatment. Patients with advanced cancer having longer survival (more than 7 months) showed stronger response in the Su-PS skin test that patients having short survival (less than 6 months). It was suggested that the Su-PS skin test was useful for evaluating the immune response to OK-432 treatment.

Topics: Biological Products; Colonic Neoplasms; Esophageal Neoplasms; Humans; Intradermal Tests; Pancreatic Neoplasms; Phytohemagglutinins; Picibanil; Polysaccharides, Bacterial; Skin Tests; Stomach Neoplasms; Tuberculin Test

Large numbers of neutrophils appear in the peritoneal cavity within a few hours after administration of OK-432 into the peritoneal cavity, and play an important role in the destruction of cancer cells. As OK-432 can activate complement in vitro, it is possible that a chemotactic factor such as C5a is generated and attracts neutrophils into the cavity. We injected OK-432 with fresh human serum preincubated at 37 degrees C for 60 min in order to generate large amounts of complement-derived chemotactic factor. Neutrophils increased in number within a few hours after the injection of OK-432 with preincubated human serum into the peritoneal cavity of a recurrent gastric cancer patient with carcinomatous ascites, and persisted much longer compared with treatment using OK-432 alone. Cancer cells rapidly decreased in number and ascites disappeared two weeks after the treatment with OK-432 and preincubated human serum. It was found that C5a levels measured by RIA initially increased a few hours before neutrophils appeared, and then decreased gradually, after injection of either OK-432 with preincubated human serum or with OK-432 alone. Although complement-derived chemotactic factor might be responsible for attracting neutrophils into the peritoneal cavity, the role of other chemotactic factors should also be investigated.

Topics: Adenocarcinoma; Biological Products; Chemotactic Factors; Complement Activation; Humans; Immunization, Passive; Injections; Neutrophils; Peritoneal Cavity; Peritonitis; Picibanil; Stomach Neoplasms

Serum IAP and ferritin values were measured preoperatively in 83 resectable gastric cancer patients. IAP was significantly higher in them than in normal subjects, and increased gradually with progression of cancer, and the values at stages III and IV were significantly higher than that at stage I. It was significantly higher in the cases of n(+) than in those of n(-), and in the cases of noncurative resection than in those of curative resection. Ferritin was significantly higher in them than in normal subjects and mammary cancer patients, and in males than in females, and the values at stages I and IV were significantly higher than that at stage III. OK-432 was serially administered pre- and postoperatively in 83 cases and only postoperatively in 33 cases. IAP increased markedly at 1 week postoperatively and was reduced gradually at 2 and 4 weeks. Ferritin increased markedly at 1 week after operation and reached the maximum value at 2 weeks and was reduced toward the value of 1 week at 4 weeks. However, these changes showed no significant difference between the both groups.

Topics: Breast Neoplasms; Female; Ferritins; Humans; Lymphatic Metastasis; Male; Neoplasm Proteins; Neoplasm Staging; Picibanil; Postoperative Period; Stomach Neoplasms

This paper describes the morphological and histological changes of gastric cancer following OK-432 injection into and around the lesion under endoscopic observation. Of 10 cases of unresectable gastric cancer, 7 revealed morphological changes and 3 a significant reduction of tumor size. In one of these cases, all the tumor cells disappeared. In 7 cases of resected gastric cancer preceded preoperatively by OK-432 administration, no obvious morphological changes were observed. However, histologically, marked infiltration of inflammatory cells was observed at the site of injection, especially in the submucosal layer. In regional lymph nodes, a lymphocyte predominance pattern which may have resulted from augmentation of T-cell activity was observed in many cases. The results suggested that local OK-432 injection therapy does not have such a marked direct effect on tumor cells, but may be useful as a means of prevention against invasion into the submucosal layer and regional lymph nodes.

Topics: Adenocarcinoma; Adult; Aged; Biological Products; Female; Gastroscopy; Humans; Injections; Male; Middle Aged; Neoplasm Invasiveness; Picibanil; Stomach; Stomach Neoplasms

A 73-year-old female was diagnosed as having gastric cancer (undifferentiated adenocarcinoma), and received gastrojejunal anastomosis as an initial treatment. One year after the operation, she was readmitted to our hospital with the complaint of fullness in her stomach. Physical examination revealed a palpable mass in the epigastric region and ascites. An attempt to induce endogenous TNF was made using OK-432. Four doses of OK-432 (10 KE) were administered intraperitoneally every other day. Seven days after the last administration of OK-432 (10 KE), OK-432 (50 KE) was given at the same site to induce TNF. At 1.5h after the injection of OK-432 (50 KE), 20.8 U/ml and 8.1 U/ml of TNF activity could be detected respectively in the serum and ascites. This is the first report describing the induction of TNF in a cancer patient.

Topics: Adenocarcinoma; Aged; Ascitic Fluid; Biological Products; Female; Glycoproteins; Humans; Picibanil; Stomach Neoplasms; Tumor Necrosis Factor-alpha

Serum IAP values were measured preoperatively in 83 gastric cancer patients. The levels were significantly higher in cases of total, stage III and IV, n (+) and non-curative resection than in normal subjects, stage I, n (-) and curative resection. There was a significant correlation between IAP on the one hand, and IgG FcR (+) T cell, alpha 2-globulin and CEA on the other. OK-432 was serially administered pre- and postoperatively (A) and only postoperatively (B). IAP was examined at one, two and four weeks postoperatively, and the findings were compared. It was increased markedly at one week and was slightly reduced at two and four weeks. These changes in IAP showed no significant differences between groups A and B.

Topics: alpha-Macroglobulins; Carcinoembryonic Antigen; Ferritins; Gastrectomy; Humans; Immunoglobulin Fc Fragments; Lymphocyte Activation; Neoplasm Proteins; Picibanil; Reference Values; Stomach Neoplasms; T-Lymphocytes

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

Topics: Ascites; Biological Products; Digestive System Neoplasms; Humans; Injections, Intraperitoneal; Killer Cells, Natural; Lymphocyte Activation; Lymphocytes; Picibanil; Stomach Neoplasms; T-Lymphocytes, Regulatory; Time Factors

The cell-mediated immunity of gastric cancer subjects was investigated during the postoperative follow-up period from three to 12 months after surgery. The lymphocyte blastogenesis, the T cell count, the lymphocyte count and the lymphocyte percentage were significantly decreased in groups of experimental laparotomy and noncurative gastrectomy, compared with that of nonrecurrent cases after curative gastrectomy. The effects of the administration of immunopotentiators, the streptococcal preparation OK-432, and the protein-bound polysaccharide PSK, were studied in groups of curative gastrectomy. The lymphocyte blastogenesis, the T cell count and the lymphocyte count were slightly elevated in the OK-432 group.

Topics: Biological Products; Humans; Immunity, Cellular; Leukocyte Count; Lymphocyte Activation; Middle Aged; Picibanil; Postoperative Period; Proteoglycans; Stomach Neoplasms; T-Lymphocytes

Lymphocyte infiltration into tumor has been regarded as an expression of host reaction against tumor, but the natural cytotoxicity of tumor infiltrating lymphocytes (TLL) is often very low. In order to augment this low cytotoxicity, TIL of gastric cancer patients were cultured with interleukin-2 (IL-2) in vitro. On the other hand, immunopotentiators (OK432, PSK) were injected into gastric cancer intralesionally under endoscopy. By the in-vitro culture with IL-2, the cytotoxicity of TIL was augmented against both targets of K562 and MNN28 (gastric carcinoma cell line). In particular, the augmentation of cytotoxicity against MKN28 was more obvious in TLL than PBL (peripheral blood lymphocytes). In the ascitic lymphocytes, the in-vitro culture with IL-2 induced autologous tumor cell killing. Intralesional injection of OK432 or PSK augmented the natural cytotoxicity of TIL, and the ratio of OKT8 and Leu7 cells increased in the TIL of OK432-injected group.

Topics: Cell Line; Cytotoxicity, Immunologic; Humans; Interleukin-2; Killer Cells, Natural; Lymphocyte Activation; Picibanil; Proteoglycans; Stomach Neoplasms

Topics: Aged; Biological Products; Colonic Neoplasms; Female; Humans; Injections, Subcutaneous; Macrophage Activation; Male; Middle Aged; Picibanil; Skin; Stomach Neoplasms; T-Lymphocytes

OMF therapy, which is a combination therapy consisting of OK-432 administered locally, Mitomycin C and 5-Fluorouracil, was administered to 50 cases of stomach cancer (52 episodes) preoperatively. Judging the criterion for a positive (+) effect as being the existence of degeneration or necrosis in 1/3-1/2 of carcinomas visible within whole fields, the ratio of histological effectiveness shown by this therapy was 75%. As for its effect on metastatic foci of lymph nodes, when 70 case from an n1 group and 8 from an n2 group with metastatic positive lymph nodes, including 17 cases (4 in Stage II and 13 in Stage III) ablated for curing were studied, a greater than positive (+) effect was shown in 51 out of the total of 78. Consequently the effective ratio was 65%. The survival ratio of 16 cases in Stage III on the 48th month calculated by the Kaplan Meier method was 78.6%. The survival time of 50% of 9 cases in Stage IV (absolute non-curing ablation) was 15 months. Tissue samples were examined constantly after local administration of OK-432. Exudation of neutrocytes was shown on the 1st day, and that of histiocytes, lymphocytes and plasmacytes on the 4th day. At this stage, degeneration of the primary focus or necrotizing change was observed. Interstitial reaction peaked on the 14th day, but histiocytes tended to decrease.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Female; Fluorouracil; Humans; Lymphatic Metastasis; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Preoperative Care; Stomach Neoplasms

Preoperative cancer chemotherapy for gastric cancer was reviewed with special emphasis on histologic findings and survival. Preoperative chemotherapy with intravenous, split administration of MMC 40 mg caused considerable damage to "micro-solitary metastatic foci" in metastatic lymph nodes. In view of the lipid-adsorbing ability of the lymphatic stream, emulsified 5-FU was used orally in 182 patients with gastric cancer; histologic findings revealed that the emulsified 5-FU enhanced the antitumor efficacy for metastatic lymph nodes as well as the primary lesion. However, the 5-year survival rate for gastric cancer patients undergoing preoperative emulsified 5-FU therapy did not differ from the control, with only the exception of patients with Stage III gastric cancer. On the other hand, combined therapy involving preoperative intra-arterial infusion and surgery was carried out in 62 patients with gastric cancer. These preoperative treatments using MMC, 5-FU, VLB, MTX and/or cytosine arabinoside entailed continuous infusion for 15 to 20 hours; the histologic changes observed revealed marked antitumor effects on the primary focus as well as metastatic lymph nodes. The five-year survival rate for the 62 patients was compared with that for 99 patients with gastric cancer in the corresponding period. The survival rate was analyzed based on the degree of serosal invasion. The overall survivals in the 62 patients were higher than those in the controls for the first 3 years. At 4 to 5 years, the survival rates for both the treated and control groups were approximately equal. In patients without serosal invasion, the survival rates were higher in treated cases than in the controls for the first 2 years. Thirty-nine patients with serosal invasion had significantly higher survival rates than the controls for the first 3 years. The survival rates for the treated patients with cancerous infiltration of ther organs were about the same as those for the corresponding control patients.

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Fluorouracil; Humans; Infusions, Intra-Arterial; Infusions, Parenteral; Lymphatic Metastasis; Methotrexate; Mitomycin; Mitomycins; Picibanil; Preoperative Care; Stomach Neoplasms

A 57-year-old woman was referred to our hospital because of epigastric tumor on Jan. 16, 1980. Two advanced gastric carcinomas were recognized in the antrum and the corpus by X-ray and endoscopic examinations. The biopsy diagnosis was poorly differentiated adenocarcinoma. She was treated with FT-207 suppositories and subcutaneous injection of OK-432 without operation because of a suspicion of ascites and Virchow's metastasis. After five months, the tumor of the corpus disappeared, and, after nine months, that of the antrum changed to a scarlike lesion. On July 30, 1981, total gastrectomy with extended nodal dissection was performed. Histological examination revealed complete absence of carcinoma cells in the stomach and regional lymph nodes.

Topics: Adenocarcinoma; Biological Products; Female; Fluorouracil; Gastrectomy; Humans; Injections, Intradermal; Middle Aged; Picibanil; Stomach; Stomach Neoplasms; Suppositories; Tegafur

A 35-year-old woman tuffering from gastric cancer associated with disseminated carcinomatosis of the bone marrow is reported. Total gastrectomy combined with splenectomy and distal pancreatectomy was performed. The patient was treated with mitomycin C, FT-207, OK-432, and PSK. But serum ALP (alkaline phosphatase) and CEA (carcinoembryonic antigen) values showed gradual elevations followed by deterioration of the patient's general condition. Consequently, chemotherapy program consisting of 5-fluorouracil, Adriamycin (intra-arterially), and cisplatin (intravenously) was initiated. Serum CEA and ALP values were considerably improved, and patient was restored to a better condition. She survived 17 months and died of disseminated intravascular coagulation.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Bone and Bones; Bone Marrow; Bone Neoplasms; Cisplatin; Combined Modality Therapy; Doxorubicin; Female; Gastrectomy; Humans; Infusions, Intra-Arterial; Lymph Node Excision; Lymphatic Metastasis; Mitomycin; Mitomycins; Pancreatectomy; Picibanil; Proteoglycans; Radionuclide Imaging; Splenectomy; Stomach Neoplasms; Tegafur

The reaction of skin to 10-micrograms and 20-micrograms quantities of Su-polysaccharide (Su-Ps) were examined in 117 patients with cancer, and the results obtained were as follows. Reaction was a little greater to the 20-micrograms dose than to the 10-micrograms dose, but the two parameters were much correlated with each other. The rates of patients showing positive reactions to each dose were 30.8% for 10-micrograms and 34.2% for 20-micrograms. The reactions were augmented by administration of OK-432. The augmentation of skin reaction by OK-432 was more prominent at 20-micrograms doses than at 10-micrograms doses, therefore appearing to be Su-polysaccharide dose-dependent. The ideal Su-polysaccharide dose for Su-Ps skin reaction thus seemed to be 20-micrograms.

Topics: Breast Neoplasms; Colonic Neoplasms; Female; Humans; Hypersensitivity, Delayed; Intradermal Tests; Male; Neoplasms; Picibanil; Polysaccharides, Bacterial; Skin; Stomach Neoplasms; Streptococcus

The present study was undertaken to determine the adenosine deaminase (ADA) activity of peripheral lymphocytes in patients with gastric cancer, with respect to the cancer progression, the effect of surgery and/or immunotherapy. The gastric cancer patients showed lower lymphocyte ADA activity than did the normal control. The lymphocyte ADA activity did not decrease with the cancer progression. There was a significant correlation between lymphocyte ADA activity and blastogenesis of lymphocyte by phytohemaglutinin or concanavalin A. Six months following gastrectomy, the lymphocyte ADA activity was increased, as compared with the preoperative value. The ADA activity of patients on post-operative OK-432 showed a greater increase, as compared to that of patients not given this treatment. In conclusion, decreased lymphocyte ADA activity in gastric cancer patients might be due to either the cancer bearing status or to the immunological suppression.

Topics: Adenosine Deaminase; Adult; Aged; Concanavalin A; Humans; Lymphocyte Activation; Lymphocytes; Middle Aged; Nucleoside Deaminases; Phytohemagglutinins; Picibanil; Stomach Neoplasms

Topics: Adult; Age Factors; Aged; Cytotoxicity Tests, Immunologic; Esophageal Neoplasms; Female; Humans; Killer Cells, Natural; Leukocyte Count; Male; Middle Aged; Picibanil; Sex Factors; Stomach Neoplasms

The effects of immunochemosurgery on 73 patients with stage III gastric cancer who were treated with radical subtotal gastrectomy followed by immunochemotherapy for 18 months during the 5-year period between 1975 and 1980 were compared to the effects of therapy on 64 patients with stage III gastric cancer treated with radical subtotal gastrectomy alone during the period between 1970 and 1980. For immunotherapy, picibanil (streptococcus pyogenes preparation) was intramuscularly given weekly, and for chemotherapy, either MFC (mitomycin-C, 5-FU, and cytosine arabinoside) regimen I.V. ten times followed by oral 5-FU or FME (5-FU and methyl-CCNU) regimen was given. The percentage of survivors who received postoperative immunochemotherapy compared to that of survivors who received surgery alone differed by approximately 15%. This difference was rather constant with more than 5 years of follow-up. The 5-year survival rate in the immunochemosurgery group was 38.1%, whereas that in the surgery alone group was 24.8%, which was statistically significant (p less than 0.01). Various immune parameter studies such as 1-chloro-2, 4-dinitrobenzene (DNCB) test, T lymphocyte count and percent, PHA- and concanavalin-A-stimulated lymphoblastogenesis, and antibody dependent cellular cytotoxicity (ADCC) activity showed more favorable data in the immunochemosurgery group than in the surgery alone group. The effects of early postoperative immunochemotherapy (immunotherapy from the fourth to fifth postoperative day, and chemotherapy from the eighth to tenth postoperative day) after radical gastrectomy seems to be superior to that of surgery alone for stage III gastric cancer. For stage I and II gastric cancer, radical gastrectomy and postoperative immunotherapy for 3 months would be the best treatment.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Combined Modality Therapy; Cytarabine; Fluorouracil; Gastrectomy; Humans; Immunocompetence; Mitomycin; Mitomycins; Neoplasm Staging; Picibanil; Prognosis; Stomach Neoplasms

Serum ferritin values were measured preoperatively in 83 patients with gastric cancer and were found to be significantly higher than in normal subjects and mammary cancer patients. They were also significantly higher in healthy men than in women and in gastric cancer patients at stages I and IV than in those at stage III. There was no significant correlation between the serum ferritin value and various immunologic parameters. OK-432 serially administered pre- and postoperatively (A) and only postoperatively (B). The ferritin value increased markedly at one week postoperatively, reaching a peak at two weeks; at four weeks, it was reduced toward the value at one week. However, these changes in ferritin value showed no significant difference between groups A and B.

Topics: Blood Transfusion; Breast Neoplasms; Carcinoembryonic Antigen; Female; Ferritins; Gastrectomy; Humans; Leukocyte Count; Lymphatic Metastasis; Lymphocyte Activation; Male; Picibanil; Radioimmunoassay; Reference Values; Stomach Neoplasms

Natural killer cell (NK) activity, together with various nonspecific immunologic parameters, was measured preoperatively, and its changes induced by operative stress were examined in gastric cancer patients. Effect of administration of a nonspecific immunopotentiator, OK-432, was evaluated by postoperative changes in NK activity. Peripheral blood NK activity was measured by 51Cr-release assay against K-562 target cells. It was found that NK activity in the gastric cancer patients was significantly lower than that in healthy subjects. The reduction was specially marked in the cases of cancer at stages I and IV. NK activity in the cases with hepatic or peritoneal metastasis was significantly lower than that in the cases without such metastasis. NK activity in the cases of noncurative gastric resection or non-resection was significantly lower than that in the cases of curative gastric resection. NK activity in the cases of stage IV and "por" in histology was significantly lower than that in the cases of stage IV and "tub1" in histology. In the cases at stages I + II, there was a positive correlation between NK activity and IgG FcR(+) T cell ratio. There was a negative correlation between NK activity and alpha 2-globulin ratio and the correlation was especially significant in the cases at stages III + IV. In the cases at stages III + IV, receiving administration of OK-432 only postoperatively, NK activity was significantly reduced or tended to be reduced at 1 through 4 week(s) postoperatively, while such a reduction was not seen in the cases receiving administration of OK-432 pre- and postoperatively. This phenomenon was more marked in the cases showing a serum albumin level lower than 3.5 g/dl or in the cases undergoing operations longer than 4 hours in duration.

Topics: Adjuvants, Immunologic; Adult; Aged; Biological Products; Cytotoxicity, Immunologic; Female; Humans; Killer Cells, Natural; Leukocyte Count; Lymphocytes; Male; Middle Aged; Neoplasm Staging; Picibanil; Postoperative Period; Serum Albumin; Skin Tests; Stomach Neoplasms

Immunotherapy for gastric cancer has been adopted by any institutes recently. However, immunoparameters which exactly express patients' immune status have not been determined. In this study, the Su-Ps skin test was tried to evaluate whether or not this reaction could become a usable immunoparameter. Conclusions were as follows: 1) Late-stage patients showed a significantly weak response in the Su-Ps skin test compared to early-stage patients when examined preoperatively. 2) Su-Ps skin reaction became stronger after gastrectomy in early-stage patients, while the contrary result was observed in late-stage patients. 3) Postoperative Su-Ps skin tests showed a stronger response than preoperative tests regardless of the patients' stage, when patients received OK-432 treatment. The Su-Ps skin test reaction seemed to be well-correlated with the patients' immune status as above, so that this test can be chosen for evaluation of immunotherapy.

Topics: Humans; Lymphocyte Activation; Phytohemagglutinins; Picibanil; Polysaccharides, Bacterial; Skin; Skin Tests; Stomach Neoplasms; Streptococcus pyogenes; Tuberculin Test

OMF treatment consisting of perifocal administration of OK-432 associated with MMC and 5-FU was applied for 37 lesions of 35 cases including 2 with multiple cancer. The results obtained were as follows lesions. Macroscopical efficacy was rated as "good" in 12 lesions (32.4%), "fair" in 24 lesions (64.9%) and "poor" in 1 case. Histological efficacy was assessed as "++" for 10 lesions (27%), and "+" for 16 lesions (43.2%). Taking "+" or higher histologically as "effective", the efficacy rate was approximately 71%. Efficacy rate for metastatic lymph nodes was approximately 61% in patients who underwent a curative operation. Patients who received non-curative operation showed a certain efficacy to some extent. Twenty-one cases were judged as "S2" at operation. 11 cases as "se", and another 10 cases as 2 cases of "ss beta" and 8 cases of "pm" Histologically . Seven cases of "pm" were considered either as "good" or Histological efficacy as "++" in terms of macroscopical efficacy.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Female; Fluorouracil; Humans; Lymphatic Metastasis; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Preoperative Care; Stomach Neoplasms

We have reported the results of our questionnaires collected from 108 hospitals all over Japan. The mainly used therapies were 5-FU, tegafur, and MMC in singular medications and 5-FU + MMC, MFC and tegafur + MMC in combined medications. The total cases judged as 'effective' in each hospitals were 71. The breakdown is as follows: 1) 'effective for the primary lesion'--47, 33--expansion of affected site proved by radiological and endoscopic views, 6--improvement only by endoscopic findings, 8--shrinkage of palpable tumor size. 2) 'ineffective for the primary lesion'--24, 11--disappearance or decrease in ascites, 13--improvement of sign and symptom. 50% survival period was 2.9 months in ineffective cases and 8.5 months in all effective cases and 10.5 months in effective cases by radiological and endoscopic findings. Draft of the Criteria of Cancer Chemotherapy for Gastric Cancers proposed by Japanese Research Society for Gastric Cancer, which including the evaluation of Borrmann type 4 cancer, was introduced.

Topics: Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Drug Combinations; Fluorouracil; Humans; Mitomycin; Mitomycins; Nimustine; Nitrosourea Compounds; Picibanil; Proteoglycans; Stomach Neoplasms; Tegafur; Uracil

Topics: Adult; Aged; Biological Products; Female; Humans; Intestinal Neoplasms; Leukocyte Count; Male; Middle Aged; Picibanil; Stomach Neoplasms

Nonspecific immunotherapy with OK-432, penicillin and heat treated lyophilized powder of Su-strain of streptococcus pyogens A3, was evaluated in patients with recurrent or unresectable stomach cancer to assess the relative benefit of the preparation administered by different routes. Comparative studies were made of the variation in immunological parameters, the survival rate and the incidence of adverse reactions in two groups of patients with uniform background factors: 24 receiving the preparation intradermally and 18 receiving intramuscular doses of the preparation. In for former group, no serious adverse reaction occurred but more marked improvement was achieved in various immunological parameters examined. The survival rate was significantly higher (P = 0.005) for patients receiving intradermal than those receiving intramuscular doses of the preparation. The results of the present study showed that the preparation is of greater value when it is administered intradermally than intramuscularly.

Topics: Adult; Aged; Agglutination; Biological Products; Female; Humans; Hypersensitivity, Delayed; Injections, Intradermal; Injections, Intramuscular; Leukocyte Count; Male; Middle Aged; Picibanil; Skin Tests; Stomach Neoplasms; T-Lymphocytes

The study group consisted of 35 patients with early gastric cancer, 16 of whom were admitted for preoperative immunotherapy. Ten to 40 K.E. of OK-432 was injected intralesionally by endoscope, and then gastrectomy was performed. After the intralesional injection, fever, nausea, vomiting and epigastralgia occurred. In cancer lesion and regional lymph node, histological findings from OK-432 treated group were compared to those of the control group. Lymphoid cell infiltration at cancer lesion was marked in OK-432 treated group, and degenerated cancer cells were found in 3 cases. On the other hand, lymphoid follicles showed a marked statistical increase in OK-432 treated group. Also the cases with marked lymphoid follicle showed increased numbers of peripheral blood lymphocyte. From the results, intralesional injection of OK-432 may confirm the tumor-associated antigenicity and serves as a useful method to potentiate the specific and/or non-specific immunity in regional lymph nodes.

Topics: Adult; Aged; Antibody Formation; Biological Products; Female; Gastrectomy; Gastroscopy; Humans; Hypersensitivity, Delayed; Injections; Leukocyte Count; Lymph Nodes; Lymphocytes; Male; Middle Aged; Picibanil; Preoperative Care; Skin Tests; Stomach Neoplasms

Topics: Ascites; Biological Products; Humans; Picibanil; Stomach Neoplasms; Streptococcus pyogenes

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Animals; Antineoplastic Agents, Phytogenic; Dogs; Drug Evaluation, Preclinical; Female; Glycosaminoglycans; Male; Picibanil; Sizofiran; Stomach Neoplasms

During the period from Jun. 1973 to Dec. 1981, seven hundred and three patients with primary gastric cancer have undergone gastrectomy at the Surgical Department, Research Institute for Nuclear Medicine & Biology, Hiroshima University. As adjuvant immunochemotherapy, large dose of Mitomycin C was routinely administered; 20 mg on the day of gasrectomy and additional 10 mg on the next day, intravenously. Furthermore, PS-K, a protein-bound polysaccharide, and/or Tegafur were administered for a prolonged period of time. Two hundred and forty of 703 patients were non-curatively resected cases. The factors by which gastrectomy was limited to non-curative resection at the primary gastrectomy were peritoneal dissemintions, liver metastases or invasions to the contiguous organs. Of the 244 patients, 17 were re-laparotomized and at the same time the evaluation of the chemotherapeutic effects was investigated. Of these 17, six patients were administered with large dose OK-432, preparation of Bac. streptococcus hemolyticus, intratumorally or intraperitoneally. In three patients, Intraabdominal patching with Adriamycin (ADM) was performed the direct cytocidal activities and strong stickiness of this drug to the malignant cells. From the findings of relaparotomy, it was suggested that large dose OK-432 administration or ADM patching was effective for peritoneal disseminations.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Female; Humans; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Proteoglycans; Reoperation; Stomach Neoplasms

A short-term intensive chemotherapy (STIC) consisting of large dose of mitomycin C (MMC), tegafur (FT-207), streptococcus preparation picibanil (OK-432) and Krestin (PSK), combined with IVH was performed in 72 patients with advanced gastric cancer. Thirty-three patients were unresectable and 39 patients were recurrent. In this modality, an intensive chemotherapy was able to carry out, maintaining, or increasing in host immunologic parameters and body weight in spite of their disturbed condition in oral food take. Partial response was obtained in 10 of 51 evaluable cases (19.6%) and the survival period on STIC was superior to that on controls. However, no significant difference was observed between the two groups. Four patients had become to be able to take full oral food again by STIC and resulted in the removal of IVH. Hyperglycemia and septicaemia induced by IVH were observed in 9 of 72 patients (12.5%), one died of septicaemia. Full attention should be paid in the management of IVH for patients with advanced cancer.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Humans; Male; Middle Aged; Mitomycin; Mitomycins; Parenteral Nutrition; Parenteral Nutrition, Total; Picibanil; Stomach Neoplasms; Tegafur

In the inoperable Borrmann type 4 Gastric cancer, which is to be used as a synonym of gastric scirrhus clinically, it is regrettable but effect is hardly expected from radiotherapy or immunotherapy, and the treatment relies entirely on chemotherapy. We have reported the results of our questionnaires collected from 108 hospitals (internal medicine-40 and surgical-68) all over Japan to investigate the prevailing circumstances of inoperable Borrmann type 4 gastric cancer. Therapies performed by singular medication were: 1). oral and intravenous 5-FU-33.3%, 2). oral, intravenous and suppository tegafur-27.4% and intravenous MMC-27.4%, of the total 84 methods reported in the field of internal medicine; and 1). administration of 5-FU-29.1%, 2). intravenous MMC-26.8% and 3). tegafur-22%, of the total 127 therapies reported in the surgical field. The therapies performed by combined medications were: 1). 5-FU+MMC-22.6%, 2). MFC-12.1%, 3). tegafur+MMC, and FAM-8.3% (further 29 examples of combination medications consisting of 2-4 preparations), of the total 124 therapies reported in the field of internal medicine; and 1). 5-FU+MMC-22.6%, 2). MFC-12.1% and tegafur+MMC-7.3% (further 37 examples consisting of 2-4 preparations), of the total 124 therapies reported in the surgical field. The total cases judged as 'effective' in all the hospitals were 71. The breakdown is as follows: 1). 'effective for the primary focus'-47 cases/66.7%, expansion of affected site proved by gastric radiogram and endoscopic image-33 cases/46.5%, expansion of affected site proved only by endoscopy-4 cases/5.6%; shrinkage of malignant ulcer and flattening of randwall, disappearance of extra-gastric compression by endoscopic image-2 cases. 2). ineffective for the primary focus'-24 cases/33.8%, of which disappearance of or decrease in ascites-11 cases/15.5%; improvement of anorexia, nausea, vomiting, abdominal fullness, strange epigastric sensation, abnormal evacuation, disappearance of diarrhea etc. and increase in body weight-13 cases. In 50% survival period, the cases in which chemotherapy was judged as entirely ineffective were 283 and the period was 2.9 months. The 50i% survival period for the above-mentioned total effective cases was 8.5 months, of which the 50%r survival period for the effective cases by radiographic and endoscopic findings in the primary focus was 10.65 months showing the prolongation effect of life span. One year survival rate was also 36%. Draft of the Critria of Ca

Topics: Antineoplastic Combined Chemotherapy Protocols; Doxorubicin; Fluorouracil; Humans; Mitomycin; Mitomycins; Picibanil; Stomach Neoplasms; Tegafur

Twelve patients with malignant ascites caused by gastric cancer were treated with intraperitoneal injections of a streptococcal preparation, OK-432. All had resolution of the ascites after OK-432 treatment. Neutrophils, macrophages, and lymphocytes increased in number in ascitic fluid samples. Some of the OK-432-induced inflammatory cells were attached to tumor cells. The absolute number of tumor cells decreased as the number of infiltrating inflammatory cells increased. Infiltrating lymphocytes were mainly E rosette-forming cells. Infiltrating macrophages were in an activated state. The infiltrating neutrophils, lymphocytes, and macrophages could inhibit DNA synthesis of the patient's own tumor cells in the ascitic fluid after OK-432 injection, but not before the injection. These results indicate that OK-432-induced neutrophils, lymphocytes, probably T cells, and activated macrophages may play an important role in tumor cell destruction in ascites. Moreover, as the number of tumor cells decreased, the ascitic fluid protein levels decreased. Decrease of the ascitic fluid protein level may suppress further accumulation of ascitic fluid, and the low protein level in ascitic fluid is likely to facilitate the reabsorption of the fluid into the bloodstream.

Topics: Adenocarcinoma; Aged; Ascites; Biological Products; Chemotaxis, Leukocyte; Female; Humans; Immunity, Cellular; Leukocyte Count; Macrophages; Male; Middle Aged; Neoplasm Recurrence, Local; Neutrophils; Picibanil; Rosette Formation; Stomach Neoplasms; T-Lymphocytes

Intratumoral administration of a large dose of OK-432 has two antitumor functions; a direct cytotoxic effect and an indirect effect through the host reticuloendotherial functions. It has been pointed out that this method, however, occasionally results in shock. Several investigators have suggested the importance of the use of general anesthesia to avoid such shock. In order to explore the hemodynamic effect of intratumoral injection of OK-432, a simulated experiment (OK-432 or saline intramuscular injection) was carried out utilizing 10 anesthetized and 10 unanesthetized dogs. In addition, hemodynamic alterations during the OK-432 administration were studied in nine patients under neuroleptal anesthesia. In both anesthetized and unanesthetized dogs, OK-432 intramuscular injection resulted in a slight decrease of the mean arterial pressure, left ventricular systolic pressure and cardiac output as compared with those of the saline injected dogs. The hemodynamic alterations, however, were minimal and were thought not to cause severe hemodynamic derangements. Clinical experiences also showed no serious hemodynamic effects by the OK-432 intratumoral injections. It was concluded that the OK-432 intratumoral injection appeared not to induce hemodynamic derangement when applied to euvolemic and hemodynamically stable patients.

Topics: Animals; Biological Products; Blood Pressure; Cardiac Output; Dogs; Hemodynamics; Humans; Injections, Intramuscular; Picibanil; Stomach Neoplasms

The mechanism of anti-tumor effect of OK-432 was examined in C3H/He mice transplanted with methylcholanthrene induced fibrosarcomas. Tumor growth was significantly reduced in mice treated with OK-432 daily for 7 days after tumor inoculation. Tumor growth was significantly reduced in Sham-operated mice treated with OK-432 when compared to untreated controls. On the other hand, splenectomized mice failed to respond to OK-432 immunotherapy, suggesting the spleen is an essential organ in host responsiveness to this immunostimulant. Further dissection of the mechanism of OK-432 immunotherapy was achieved by Winn assay with spleen cells taken from mice inoculated with MCA-F (1 X 10(5) cells) and OK-432 for 7 days. Spleen cells from tumor-bearing mice which had been treated with OK-432 further reduced the tumor growth compared with spleen cells from tumor-bearer and such cytotoxic activity was reduced by the spleen cells with treatment of anti-Thy 1. 2 serum plus complement or by 700 rads irradiation before Winn assay, suggesting that OK-432 generated cytotoxic T cell population in vivo.

Topics: Animals; Biological Products; Humans; Killer Cells, Natural; Mice; Mice, Inbred C3H; Picibanil; Sarcoma, Experimental; Spleen; Splenectomy; Stomach Neoplasms

The clinical effect of intratumoral administration of OK-432 was evaluated. The patients with nonresectable advanced cancer were divided into three groups according to administration method of OK-432 at laparotomy: Group I; Intratumoral administration, Group II; Scattering to the abdominal cavity, and Group III; No OK-432, administration. Improvement in suppression of tumor progression was more frequently noticed in the Group I compared to the Group II and III, but there was no significant difference in terms of survival time and rate among the three groups.

Topics: Adenocarcinoma; Aged; Biological Products; Gastroscopy; Humans; Intraoperative Care; Liver Neoplasms; Male; Picibanil; Stomach Neoplasms

Sakata, et al. has already reported that the combination therapy of mitomycin-C, carboquone, 5-fluorouracil and OK-432 (MQF-OK therapy) which had established from animal experiments, was exceedingly effective for inoperable human gastric cancer. In this paper, the effectiveness of MQF-OK therapy for inoperable gastric cancer was compared with that of MFC therapy. To perform this controlled study, a "large area" co-operative study group of cancer chemotherapy, composed of 14 institutions in Aomori and a part of Akita prefectures, was organized. From April 1977 to April 1980, patients were registered and 61 cases were evaluable; 31 out of 61 were treated with MQF-OK therapy (MQF-OK group) and the others with MFC group. The background of the cases, such as sex, age etc, was not different significantly between two groups statistically. According to the response criteria of Japan Society for Cancer Therapy, 18 cases out of 31 cases of MQF-OK group and 9 of 30 cases of MFC group showed "improvement." According to Karnofsky's criteria 17 cases of MQF-OK group and 8 of MFC group showed effectiveness more than I-A, respectively. There was a statistical significance between the two groups (P less than 0.001). By Kaplan-Meier's method, the MQF-OK group survived longer than the MFC group (P = 0.05). The complications, such as leukocytopenia, thrombocytopenia or gastrointestinal complaints, were more frequently found in MQF-OK-432 group than in MFC group (P less than 0.05). But these complications decreased or resolved spontaneously 1 to 4 weeks after the administration of MQF-OK therapy. On these results, MQF-OK therapy was considered excellent method for treatment of inoperable gastric cancer and will be furthermore attempted against other cancers.

Topics: Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carbazilquinone; Cytarabine; Drug Therapy, Combination; Female; Fluorouracil; Humans; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Stomach Neoplasms

We have developed OMF treatment which is consisting of endoscopical injection of OK-432 into the perilesional area of cancer, intraarterial or intravenous injection of mitomycin C by one shot and oral administration of 5-FU, and applied it to the patients with preoperative gastric cancer to whom remarkable macroscopic effects were obtained. We determined its efficacy by establishing a response criteria. Although there were no excellent results, the clinical results were rated as good in 5 lesions (50%) and as fair in 5 lesions (50%) out of 10 lesions in 9 cases. In none of the cases, the treatment was ineffective.

Topics: Aged; Animals; Antibiotics, Antineoplastic; Biological Products; Carcinoma, Ehrlich Tumor; Drug Therapy, Combination; Female; Fluorouracil; Humans; Injections; Male; Mice; Middle Aged; Mitomycin; Mitomycins; Picibanil; Preoperative Care; Stomach Neoplasms

OMF treatment consisting of perifocal administration of OK-432 associated with treatment with MMC and 5-FU was applied for 14 lesions of 13 cases including 1 case of multiple cancer. The results obtained were examined macroscopically and histologically. Macroscopic findings were rated as "good" in 5 lesions (35.8%), "fair" in 8 lesions (57.1%) and "poor" in 1 case. There was no significant difference according to a histologic type. Histologic efficacy was assessed as "++" for 6 lesions (43%), "+" for 6 lesions (43%) and "-" for 2 lesions (14%), suggesting a tendency that higher histologic efficacy be obtained for lesions with a lower degree of differentiation. Taking "+" or higher histologically as "effective", the efficacy rate was approximately 86%. When the macroscopic results were compared with histologic results based on a criteria for assessment established by our group, it was found that the macroscopic efficacy tended to be associated with the histologic efficacy with a consistency rate of approximately 71%.

Topics: Adult; Aged; Biological Products; Drug Therapy, Combination; Female; Fluorouracil; Humans; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Preoperative Care; Stomach; Stomach Neoplasms

Topics: Biological Products; Humans; Leukocyte Count; Picibanil; Skin Tests; Stomach Neoplasms; T-Lymphocytes

A patient with an abdominal tumor and gastric cancer was treated with intraperitoneal OK-432 alone. Her general condition improved and the abdominal mass diminished significantly. The fluoroscopic radiography and gastroduodenal fiberscopic examinations revealed a slight improvement. Four months after the initiation of OK-432 therapy, microscopic examination of the biopsy specimen disclosed degenerated tumor cells with a pronounced accumulation of lymphocytes and large monocytes which were ascertained to be macrophages by the fluorescent antibody technique using anti-macrophage serum. This study revealed one possible mechanism of the antitumor action of OK-432.

Topics: Biological Products; Female; Humans; Injections, Intramuscular; Injections, Intraperitoneal; Leukocyte Count; Lymphocytes; Middle Aged; Picibanil; Radiography; Skin Tests; Stomach Neoplasms

Recently, a streptococcal preparation, OK-432 has been used successfully as an immunopotentiator for immunotherapy in patients with malignant tumors in Japan. In this paper, we report that the administration of OK-432 augments the cytotoxic activity of peripheral blood lymphoid cells against a natural killer (NK) cell-sensitive erythroleukemic cell line, K562, in tumor patients. In patients before or after surgery, sufficient amounts of OK-432 strongly augmented the cytotoxic activity within 3 days after the initial administration of OK-432. Thereafter the levels of cytotoxicity declined rapidly. The administration of a lower dose of OK-432 gave a lower increase in cytotoxicity. Enhanced cytotoxicity occurred with the reintroduction of OK-432 but remained at lower levels of activity. Characterization and fractionation of OK-432-induced effector cells revealed that the augmented cytotoxicity seemed to be carried mainly by NK cells. A low titer of interferon was detected in 3 of 10 patients within 72 hr after the first inoculation of the agent. Furthermore, we discuss the potency of OK-432 for the induction of interferon in detail.

Topics: Adjuvants, Immunologic; Biological Products; Breast Neoplasms; Cell Separation; Cytotoxicity, Immunologic; Humans; Interferons; Lymphoma; Neoplasms; Picibanil; Stomach Neoplasms; Time Factors

Topics: Adult; Aged; Ascites; Biological Products; DNA; Female; Humans; Injections, Intraperitoneal; Lymphocytes; Male; Middle Aged; Picibanil; Rosette Formation; Stomach Neoplasms

Topics: Biliary Tract Neoplasms; Biological Products; Colonic Neoplasms; Humans; Liver Neoplasms; Picibanil; Stomach Neoplasms

OK-432, a streptococcal preparation, was intradermally injected daily into patients with advanced cancer of the stomach or lung for 4 weeks and the effects of OK-432 on the mitogenic responses of cancer patients were followed. The cells involved in the depression of the response of untreated cancer patients were characterized. The cells responsible for impaired responses were nylon wool non-adherent and suppressed the mitogen responses of autologous and allogeneic lymphocytes. These cells lost their suppressive activity during 7 days' culture in vitro. Following OK-432 immunotherapy, mononuclear cells from cancer patients showed increased responses to PHA and Con A, and nylon wool non-adherent cells did not inhibit the mitogen responses. These results suggest that the cells suppressing non-specific mitogen responses are sensitive to in vitro culture, belong to nylon wool non-adherent cells and are lost during 4 weeks of OK-432 therapy.

Topics: Adult; Aged; Biological Products; Cells, Cultured; Humans; Lung Neoplasms; Middle Aged; Mitogens; Neoplasms; Picibanil; Stomach Neoplasms; T-Lymphocytes, Regulatory

Topics: Biological Products; Drug Therapy, Combination; Fluorouracil; Humans; Immunotherapy; Mitomycins; Neoplasm Staging; Picibanil; Stomach Neoplasms

A prospective clinical trial was undertaken in 121 patients with stomach cancer to compare immunochemotherapy with 5-fluorouracil and FT-207 combined with OK-432 or PS-K, immunostimulators, and plain chemotherapy with 5-fluororacil and FT-207. Of the 121 patients who received immunochemotherapy, 67 patients (group A) had undergone curative removal of the tumor. The other 54 patients had undergone noncurative tumor removal or had recurrence after non-curative tumor removal and they were divided into two groups (groups B and C) on the basis of lymphocyte reactivity induced with PHA. Although group A exhibited a significant increase in PHA-induced lymphocyte transformation and a trifling increase in lymphocyte counts, its survival rate within a 36 month period did not differ from that of the peer controls. Group B, composed of 21 patients showing improvement of PHA-induced lymphocyte transformation, significantly prolonged its survival compared to the peer controls. The survival of group C, composed of 33 patients showing a gradual drop in PHA-induced lymphocyte transformation, was not prolonged compared to the peer control patients; and they showed significant decreases in lymphocyte counts. The overall survival of group B and group C was not superior to that of the 48 peer controls.

Topics: Adult; Aged; Antibiotics, Antineoplastic; Biological Products; Dinitrochlorobenzene; Drug Therapy, Combination; Fluorouracil; Humans; Immunotherapy; Lymphocyte Activation; Middle Aged; Phytohemagglutinins; Picibanil; Proteoglycans; Skin Tests; Stomach Neoplasms

Topics: Aged; Antineoplastic Agents; Carbazilquinone; Drug Therapy, Combination; Female; Fluorouracil; Humans; Male; Middle Aged; Mitomycins; Picibanil; Stomach Neoplasms

Topics: Adenocarcinoma; Antineoplastic Agents; Cytarabine; Drug Therapy, Combination; Fluorouracil; Humans; Male; Middle Aged; Mitomycins; Myocardial Infarction; Picibanil; Stomach Neoplasms

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

Topics: Adenocarcinoma; Adenocarcinoma, Papillary; Cytarabine; Drug Therapy, Combination; Fluorouracil; Humans; Hyperplasia; Lymph Nodes; Lymphangitis; Lymphocytes; Mitomycins; Picibanil; Stomach Neoplasms

Topics: Aged; Biological Products; Drug Therapy, Combination; Female; Fluorouracil; Humans; Intestinal Neoplasms; Lung Neoplasms; Male; Middle Aged; Neoplasms; Pancreatic Neoplasms; Picibanil; Stomach Neoplasms; Tegafur