picibanil and Adenocarcinoma

To determine the feasibility, safety and histological change of preoperative endoscopic ultrasound-guided fine-needle injection (PEU-FNI) of immature DCs (iDCs) with OK-432 in pancreatic cancer patients.. Nine patients enrolled in the trial (DC group) and were compared with 15 patients operated on without iDC injection (non-DC group). Adverse events of PEU-FNI and postoperative complications were evaluated according to CTC-AE ver.3.0 and the Clavien-Dindo classification/ISGPF definition, respectively. Histological changes within the tumor and lymph nodes were evaluated by immunohistochemical examination of infiltrating inflammatory cells (CD4+, CD8+, Foxp3+ and CD83+).. There were no severe toxicities following PEU-FNI, except for one transient grade 3 fever, and there were no significant differences in the incidence of postoperative complications between the two groups. Colliquative necrosis and diffusely scattered TUNEL-positive cells were observed at the injection sites. CD83+ cells significantly accumulated in the regional lymph nodes of the DC group as well as Foxp3+ cells in the regional and distant lymph nodes. The two DC group patients, one of which was stage IV with distant lymph node metastasis, survived more than 5 years without requiring adjuvant theraphy.. PEU-FNI was feasible and safe, and further study needs to confirm and enhance antitumor responses.

Topics: Adenocarcinoma; Aged; Antineoplastic Agents; Combined Modality Therapy; Dendritic Cells; Endoscopic Ultrasound-Guided Fine Needle Aspiration; Feasibility Studies; Female; Humans; Immunohistochemistry; Injections, Intralesional; Lymph Nodes; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Pancreatic Neoplasms; Picibanil; Preoperative Period

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

We conducted a phase II study of OK-432 intrapleural administration followed by systemic chemotherapy using cisplatin with gemcitabine to determine their combined effects on non-small cell lung cancer (NSCLC) with pleuritis carcinomatosa. Between December 1999 and October 2001, 15 patients were registered in the study. Fourteen patients had an Eastern Cooperative Oncology Group performance status (PS) of 1, and one patient had a PS of 2. Ten patients had adenocarcinoma, one had squamous cell carcinoma, and four had malignant mesothelioma. Patients underwent thoracocentesis and received an OK-432 intrapleural injection. They were then treated every three weeks with chemotherapy consisting of 80 mg/m2 cisplatin on day 1 and 1000 mg/m2 gemcitabine on days 1 and 8. Thirteen patients received two or more courses of chemotherapy. Grade 3 or 4 neutropenia, anemia and thrombocytopenia occurred in five, two and three patients, respectively. Non-hematological toxicities were mild, except for one patient who experienced a grade 3 elevation of transaminase and two patients who experienced grade 3 nausea. Of the 15 patients, one achieved partial response (PR), 13 a stable disease (SD) rating, and one a progressive disease (PD) rating, and the overall response rate was 6.7%. The median survival time was 13.5 months and the one-year survival rate was 60.0%. In conclusion, OK-432 intrapleural administration followed by cisplatin and gemcitabine systemic chemotherapy did not reduce patients' tumors but did prolong their survival time. A large-scale phase II study of the efficacy of this combination therapy is required.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Cisplatin; Deoxycytidine; Female; Gemcitabine; Humans; Lung Neoplasms; Male; Mesothelioma; Middle Aged; Picibanil; Pleural Neoplasms; Survival Rate; Treatment Outcome

Although a few reports indicated some benefit to survival, the effect of adjuvant therapy for the patients with resected lung cancer was still controversial. The aim of our study was to evaluate survival advantage of CDDP-based adjuvant therapy compared with short-term immunochemotherapy.. prospective randomized trial.. from 1990 through 1994, 94 patients were registered. Forty-seven patients were randomly assigned to each group, i.e., CDDP-based therapy group (CB Group, CDDP+VDS+tegafur+OK-432 or CDDP+OK-432+mediastinal irradiation) or immunochemotherapy group (IC Group, tegafur+OK-432). PATIENTS in both groups were followed at 4-month intervals with the routine follow-up program of our department.. No significant difference was observed between the patients' characteristics of two groups. Compliance of the regimen in each group was 79% in CB Group and 85% in IC Group. No treatment-related death was observed. Five-year survival rates of CB Group and IC Group were 49% and 51%, and 5-year disease-free survival rates were 46% and 44%, respectively. There were no statistical differences between the two groups. Furthermore, no survival differences could be found between CB Group and IC Group in any subgroup of patients.. Both of these regimens were feasible. However, we have not observed any survival benefit in the CB Group in any subgroup, so far. Induction therapy, new chemotherapeutic agents, or anti-angiogenetic a agents may improve the survival of surgically treated lung cancer patients.

Topics: Adenocarcinoma; Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Carcinoma, Large Cell; Carcinoma, Squamous Cell; Cisplatin; Drug Therapy, Combination; Female; Humans; Immunotherapy; Lung Neoplasms; Male; Middle Aged; Picibanil; Pneumonectomy; Postoperative Care; Prospective Studies; Radiotherapy, Adjuvant; Survival Rate; Tegafur

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

A prospective randomized study to compare the effectiveness of pleurodesis by two new sclerosing agents: OK-432 and mitomycin C were conducted in 53 patients with malignant pleural effusion caused by lung cancer. None of the patients received concomitant systemic chemotherapy or radiation therapy during the study. After complete drainage of pleural fluid, the patients were allocated randomly to receive 10 Klinische Einheit units of OK-432 or 8 mg of mitomycin C by intrapleural injection at weekly intervals. The treatment was terminated if the pleural effusion disappeared or the patients had received four consecutive procedures. There were 26 patients who received pleurodesis with OK-432 and 27, with mitomycin C. Patient characteristics in the two treatment groups (age, sex, histologic type, performance status, and prior treatment before pleurodesis) were compatible. These results showed that pleurodesis with OK-432 achieved a higher complete response rate (73%) than that of mitomycin C (41%). The rates of objective treatment response (complete response plus partial response) were comparable in both groups (88% for OK-432 and 67% for mitomycin C). The average number of intrapleural injections needed to achieve complete response was fewer in the OK-432 group (1.9 +/- 0.9) than in mitomycin C group (2.8 +/- 0.9). There was no significant difference in the median survival of the patients who received pleurodesis with OK-432 (5.8 months) or mitomycin C (5.1 months). However, the effusion-free period in the OK-432 group was significantly longer than that in the mitomycin C group (7.0 months versus 1.5 months). Patients who underwent OK-432 pleurodesis had a higher complication rate (80%) than did those in the mitomycin C group (30%). Transient febrile reaction was the most common reaction encountered. The immunologic study in OK-432 group showed an increase in peripheral leukocyte count and decrease in the OKT4/OKT8 ratio. The mitomycin C group had a mild reduction in peripheral blood leukocyte count and no significant change in the OKT4/OKT8 ratio. It was concluded that pleurodesis with OK-432 is an effective alternative treatment for malignant effusion in patients with lung cancer.

Topics: Adenocarcinoma; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Female; Humans; Immunity, Cellular; Lung Neoplasms; Male; Middle Aged; Mitomycin; Neoplasm Staging; Picibanil; Pleural Effusion; Prospective Studies; Tissue Adhesions

Fifty-one patients with stage III and IV ovarian adenocarcinoma underwent initial cytoreductive surgery at Kurume University Hospital between January 1982 and October 1985. They were assigned postoperatively by randomized trials to immunochemotherapy or chemotherapy alone. Of all 51 patients, long-term results of immunochemotherapy for 43 patients were evaluated versus radicality of initial cytoreductive surgery. As a result, the group of patients treated with immunochemotherapy tended to have a better prognosis than the group of patients treated with chemotherapy alone, whereas no statistical difference was observed between the two groups. Moreover, no significant difference was observed in the monitoring of OKT 4/8 ratio between the two groups. However, immunochemotherapy produced a favorable prognosis in the patients with residual disease of greater than 2 cm in diameter at initial surgery. In conclusion, these data suggested that immunochemotherapy may have some impact on survival of patients with ovarian adenocarcinoma.

Topics: Adenocarcinoma; Chemotherapy, Adjuvant; Female; Follow-Up Studies; Humans; Ovarian Neoplasms; Picibanil

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

A study of postoperative adjuvant chemotherapy according to cell type, combined with immunotherapy using PSK and OK-432 was conducted in 178 lung cancer patients who had undergone resection. BRM (PSK or OK-432) was selected by randomization. Chemotherapy was mainly performed with VCR, MMC, and MTX except for small cell carcinoma. Of the total number of lung cancer cases, 113 were evaluable. Four-year survival rates were 36.7% for the OK-432 group, 55.9% for the PSK group and 34.7% for the control group, with significant differences among these three groups. Survival rates for stage III showed significant differences between immunochemotherapy groups, (OK-432 group, PSK group) and the chemotherapy group. Postoperative administration of immunomodulators is therefore considered to contribute to the improved survival of patients in lung cancer.

Topics: Adenocarcinoma; Adult; Aged; Biological Products; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Humans; Lung Neoplasms; Male; Middle Aged; Picibanil; Pneumonectomy; Postoperative Period; Prognosis; Proteoglycans; Random Allocation

The main reason for unfavourable surgical outcome of lung cancer is latent distant metastases over looked during surgery, which ultimately cause recurrence, or death of the patients even in cases undergoing curative surgery. This fact necessitates the indispensable use of systemic adjuvant therapy in patients under going surgery for lung cancer. There have been mary reports concerning the clinical efficacy of surgical adjuvant chemotherapy for non-small cell lung cancer using various kinds of drugs in various treatment modalities, but the results have been controversial. During the past eleven years, we have used postoperative chemotherapy in three ways over three different periods: in the earliest period, short-term combined chemotherapy (STCC) was used, in the middle period, intermittent long-term combined chemotherapy (ILTCC) was used in combination with immunotherapy for a randomized group, and in the latest period, when continuous long-term combined chemotherapy (CLTCC) with immunotherapy was employed. A comparison was then made between these three kinds of treatment groups. In Comparing of the results obtained for the earliest and middle periods, ILTCC showed a significantly improved beneficial effect over STCC in terms of further increased survival rate. Furthermore, by randomized study, it was clarified that the favourable effect of ILTCC was further improved by concomitant use of immunotherapy. CLTCC with immunotherapy carried out in the latest period seemed to be prevent early recurrences in patients with stage I or II who underwent curative surgery, even though a short-term observation period of for 20 months was employed. It is conceivable that the latest treatment modality used will exerted best the most favourable beneficial effect in comparison with the two early treatments. A review of the literature was presented along with a discussion of the clinical value of chemotherapy and immunochemotherapy as a surgical adjuvant.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Carbazilquinone; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Clinical Trials as Topic; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Female; Fluorouracil; Humans; Lung Neoplasms; Male; Middle Aged; Mitomycin; Mitomycins; Nimustine; Nitrosourea Compounds; Picibanil; Pneumonectomy; Postoperative Care; Random Allocation

Pleural effusion is a common complication in patients with malignant neoplasm. A randomized controlled study of intrapleural instillation of Adriamycin (control group, 30 patients) and Adriamycin Nocardia rubra cell wall skeleton (N-CWS group, 26 patients) with tube thoracostomy was performed in 55 patients with malignant pleural effusion due to primary lung cancer. The response rates for control of pleural effusion were 73.4% in the N-CWS group and 46.1% in the N-CWS group. These results suggest that intrapleural instillation using a combination of anti-cancer agent and immunopotentiator is an effective treatment for malignant pleurisy. Cardiac tamponade secondary to cancer is a life-threatening complication requiring immediate treatment. Twenty-four patients with malignant pericardial effusion were treated by intrapericardial instillation of anti-cancer drugs, such as Carbazilquinone, Mitomycin-C or ACNU, with pericardial drainage. The range of survival time from the instillation of anti-cancer drug was 3-365 days (average days). In only 4 patients, reaccumulation of pericardial effusion was recognized. There were no serious complications with this procedure. It was considered that local instillation of anti-cancer agents with pericardial drainage was a useful therapeutic modality for malignant pericarditis.

Topics: Adenocarcinoma; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; BCG Vaccine; Bleomycin; Carcinoma, Squamous Cell; Cell Wall; Doxorubicin; Drainage; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mitomycin; Mitomycins; Nimustine; Nitrosourea Compounds; Nocardia; Pericardial Effusion; Picibanil; Pleural Effusion; Random Allocation

The choice of an optimal sclerosant for pleurodesis for malignant pleural effusion remains controversial. This retrospective clinical study compared the efficacy and safety of two sclerosants; talc slurry (talc-s) and OK-432.. We compared the characteristics, 30/90-day success rates, and adverse events in patients with lung adenocarcinoma who underwent pleurodesis by using either OK-432 or talc-s. Propensity score matching was used to compare the two scelrosants.. Ninety-four patients (mean age=71.6±9.6 years) were included in this retrospective study, of whom 64 received OK-432 and 30 received talc-s. Seventy-three patients (77.6%) were initially diagnosed with clinical stage IV lung cancer, with a 28.7% epidermal growth factor receptor mutation frequency. The propensity score-matched cohort included 26 patients from each group. The 30-day success rates for OK-432 and talc-s were 80.7% and 76.9%, respectively (odds ratio: 1.26, 95% confidence interval: 0.33-4.77, p=0.73). Neither the overall incidence of adverse events nor the 90-day success rates differed significantly. Multivariate logistic regression revealed that the predictors of 30-day success were lower drainage volume on the previous day, particularly <250mL/day, the presence of full lung expansion, and pre-therapy with an epidermal growth factor receptor-tyrosine kinase inhibitor. The median post-pleurodesis survival time was 6.9 months, which was not significantly different between the study groups.. Propensity score-matched analyses showed that pleurodesis using OK-432 and talc-s demonstrated comparable efficacy and safety profiles in patients with lung adenocarcinoma. This indicated that OK-432 could be a viable alternative to talc-s in this procedure.

Topics: Adenocarcinoma; Aged; Female; Humans; Lung Neoplasms; Male; Picibanil; Pleural Effusion, Malignant; Pleurodesis; Propensity Score; Regression Analysis; Sclerosing Solutions; Talc

Radiofrequency ablation therapy (RFA) is a radical treatment for liver cancers and induces tumor antigen-specific immune responses. In the present study, we examined the antitumor effects of focal OK-432-stimulated dendritic cell (DC) transfer combined with RFA and analyzed the functional mechanisms involved using a murine model. C57BL/6 mice were injected subcutaneously with colon cancer cells (MC38) in their bilateral flanks. After the establishment of tumors, the subcutaneous tumor on one flank was treated using RFA, and then OK-432-stimulated DCs were injected locally. The antitumor effect of the treatment was evaluated by measuring the size of the tumor on the opposite flank, and the immunological responses were assessed using tumor-infiltrating lymphocytes, splenocytes and draining lymph nodes. Tumor growth was strongly inhibited in mice that exhibited efficient DC migration after RFA and OK-432-stimulated DC transfer, as compared to mice treated with RFA alone or treatment involving immature DC transfer. We also demonstrated that the antitumor effect of this treatment depended on both CD8-positive and CD4-positive cells. On the basis of our findings, we believe that combination therapy for metastatic liver cancer consisting of OK-432-stimulated DCs in combination with RFA can proceed to clinical trials, and it is anticipated to be markedly superior to RFA single therapy.

Topics: Adenocarcinoma; Adjuvants, Immunologic; Animals; Catheter Ablation; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cell Movement; Colorectal Neoplasms; Combined Modality Therapy; Dendritic Cells; Female; Interferon-gamma; Lymphatic Metastasis; Lymphocyte Depletion; Lymphocytes, Tumor-Infiltrating; Mice; Mice, Inbred C57BL; Phagocytosis; Picibanil; Subcutaneous Tissue; T-Lymphocyte Subsets; Tumor Burden

Focal ground-glass opacity (GGO) on computed tomography has been reported in several disorders including inflammatory disease and primary neoplastic lesion of the lung. We report a case of malignant melanoma of the nasal cavity metastatic to the lungs in which multiple pulmonary nodules showed GGO. Lung biopsy specimen demonstrated melanoma cells proliferating in a lepidic fashion along the thickened alveolar wall simulating bronchioloalveolar carcinoma. Metastatic lung tumor showing GGO is uncommon.

Topics: Adenocarcinoma; Adenocarcinoma, Bronchiolo-Alveolar; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Chemotherapy, Adjuvant; Dacarbazine; Diagnosis, Differential; Female; Humans; Lung Neoplasms; Melanocytes; Melanoma; Middle Aged; Nasal Cavity; Nose Neoplasms; Picibanil; Tegafur; Tomography, X-Ray Computed; Uracil

We investigated the effectiveness and complications of intrathoracic infusion with a combination of cisplatin, OK-432, and minocycline for malignant pleural effusion. All patients were hospitalized with chest tube drainage of pleural effusion until the daily drainage volume was less than 100 ml. Twenty-five mg of minocycline, 1 to 3 KE of OK-432, and 5 to 10 mg of cisplatin were instilled into the pleural space. The administration was repeated until drainage effusion disappeared. Therapeutic effect was evaluated according to the following criteria: (1) excellent, no fluid reaccumulation for at least 4 weeks as determined by chest radiogram and clinical evaluation; (2) effective, fluid reaccumulation less than 50% of original effusion with no need of thoracentesis for symptomatic relief within 4 weeks after treatment; and (3) failure, reaccumulation of more than 50% of the original effusion requiring thoracentesis to relieve symptoms within 4 weeks of treatment. Twelve patients with malignant effusion received the combination treatment; 11 patients had primary lung cancer and one had metastatic lung tumor from cancer of the rectum. In all cases, the histology or cytology revealed adenocarcinoma. Eleven of the 12 patients had an excellent response with relief of clinical symptoms. The remaining case failed to show any improvement. Complications such as local pain, fever, nausea, and vomiting were mild and transient. We conclude that combination administration of low-dose minocycline, OK-432, and cisplatin into the thoracic cavity for malignant effusion is an effective alternative treatment with the potential for improvement of the general condition and reduced morbidity.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Dose-Response Relationship, Drug; Drainage; Drug Administration Schedule; Female; Humans; Infusions, Intralesional; Lung Neoplasms; Male; Middle Aged; Minocycline; Picibanil; Pleural Effusion, Malignant; Thoracic Cavity

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

Adoptive immunotherapy using OK-432-activated mononuclear cells (OK-MCs) offers cell-mediated and cytokine-mediated pathways for antitumor activity. The effectiveness of direct intratumoral administration of OK-MCs via a catheter/reservoir system was studied in patients with malignant brain tumors. Seventeen patients, 12 with malignant glioma, four with metastatic adenocarcinoma, and one with primary sarcoma of the brain, were treated by OK-MC therapy (1.0 to 11.2 x 10(7) cells/person) between June 1989 and April 1999. The OK-MC therapy was given to patients with tumors progressing despite previous cytoreductive surgery, radiation, or chemotherapy. Adverse effects seen after the therapy were fever in 10 patients, seizure in two patients, and hypotension in one patient. Evaluation by computed tomography or magnetic resonance imaging revealed that seven patients showed no change including three with minor response, and 10 showed progressive disease. Adoptive immunotherapy using OK-MC was safe and well tolerated, but the therapeutic potential is limited.

Topics: Adenocarcinoma; Adult; Aged; Brain Neoplasms; Combined Modality Therapy; Female; Glioma; Humans; Immunotherapy, Adoptive; Male; Middle Aged; Monocytes; Picibanil; Sarcoma; Treatment Outcome

An interferon-gamma (IFN-gamma)-inducing molecule (OK-PSA) has been purified from OK-432 by an affinity chromatographic technique performed on cyanogen bromide-activated Sepharose 4B-bound TS-2 monoclonal antibody, which neutralizes IFN-gamma-inducing activity of OK-432. OK-PSA has striking anti-tumor activity in vivo and in vitro. In the current study, the liposomes were used to improve the delivery of the agent (OK-PSA) to effector cells and to increase the therapeutic effect. Significantly less OK-PSA encapsulated into liposomes (Lipo-OK-PSA) than OK-PSA alone (1/100 or less of OK-PSA alone) was required to induce IFN-gamma, tumor necrosis factor-alpha (TNF-alpha), TNF-beta, interleukin-1 beta (IL-1 beta), natural killer, and lymphokine-activated killer activities by human peripheral blood mononuclear cells and mouse spleen cells. Furthermore, higher levels of these activities were detected in peripheral blood mononuclear cells and mouse spleen cells treated with Lipo-OK-PSA than in those treated with OK-PSA. All of these activities induced by Lipo-OK-PSA were almost completely neutralized by anti-asialo-GM1 antibody and complement (p < 0.001). In in vivo experiments, Lipo-OK-PSA elicited striking anti-tumor activity on syngeneic Meth-A tumor-bearing and colon 26-bearing BALB/c mice and on salivary gland tumor-bearing nude mice far better than did OK-PSA. Furthermore, high levels of natural killer and lymphokine-activated killer activities and a significant increase in the number of cells positive for asialo-GM1, IFN-gamma, TNF-alpha, or IL-1 beta were detected in the spleen cells derived from the animals given Lipo-OK-PSA compared with those given saline. These findings clearly indicate that OK-PSA plays an important role in the anti-tumor efficiency of OK-432, and that, for the most part, liposome encapsulation of this molecule markedly accelerates its effect mediated by asialo-GM1-positive cells (mainly natural killer cells).

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cells, Cultured; Cytokines; Cytotoxicity, Immunologic; Drug Carriers; G(M1) Ganglioside; Humans; Interferon-gamma; Interleukin-1; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Leukocytes, Mononuclear; Liposomes; Lymphotoxin-alpha; Mice; Mice, Inbred BALB C; Picibanil; Salivary Gland Neoplasms; Sarcoma, Experimental; Spleen; Streptococcus pyogenes; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha

Docetaxel is an anti-tumor agent which promotes the congregation and stabilization of microtubules, there by preventing cell division. It is reported to have anti-tumor activity against breast or non-small cell lung carcinomas which have been resistant to other anti-tumor agents. On the other hand, it causes peripheral edema and effusion in the pleural or peritoneal cavities. Thus, pleural or peritoneal effusions, which require drainage have been considered to be contraindications for the administration of docetaxel. OK-432 is an agent which causes adhesion by evoking a local inflammatory reaction. We experienced two cases of recurrent breast carcinoma with malignant pleural effusion. We successfully managed their pleural effusion with the intrapleural administration of OK-432. Thereafter, we safely administered docetaxel, and obtained good outcomes. The present paper also discussed the synergistic action between these agents.

Topics: Adenocarcinoma; Antineoplastic Agents; Antineoplastic Agents, Phytogenic; Breast Neoplasms; Docetaxel; Drug Administration Schedule; Female; Humans; Middle Aged; Neoplasm Recurrence, Local; Paclitaxel; Picibanil; Pleura; Pleural Effusion, Malignant; Taxoids

The effective treatment of unresectable pancreatic cancer remains to be elucidated. We report herein a patient who underwent a local injection of a mixture of OK-432, fibrinogen and thrombin. Tumor size and tumor markers significantly decreased following this procedure. Local injection therapy with OK-432, fibrinogen and thrombin may be a promising treatment for unresectable pancreatic cancer.

Topics: Adenocarcinoma; Drug Therapy, Combination; Fibrinogen; Humans; Injections, Intralesional; Pancreatic Neoplasms; Picibanil; Thrombin

In order to study the clinical usefulness of biological response modifiers (BRMs) in eliminating malignant solid tumors, we have investigated the effect of various combination therapies on the murine Colon26 solid tumor model. When the tumor-bearing mice were treated with chemotherapeutics, G-CSF and OK-432 (streptococcal preparation), the tumors completely disappeared from all of the treated mice. When these survivors were rechallenged with Colon26 tumor cells on Day 120, all of them survived without showing any sign of recurrence or metastases. The results indicate that mice with malignant solid tumors, which can not be cured using chemotherapeutics alone, may be completely healed with a combination immuno-chemotherapy. During the course of this combination therapy, study, it was found that there was a clear positive correlation between immunosuppressive acidic protein (IAP) levels and tumor sizes. Suppressor macrophages (sM phi) which produce IAP were found to be decreased in bone marrow and spleen of treated mice. This suggests that the combination therapy may make the mice recover from a suppressed immune state caused by sM phi. In conclusion, the combination therapy with chemotherapeutics and BRMs could cure the solid tumor-bearing mice very effectively through not only synergistic direct tumor cell destruction but also indirect immunomodulation of the host.

Topics: Adenocarcinoma; Animals; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Cisplatin; Colonic Neoplasms; Cyclophosphamide; Cytotoxicity, Immunologic; Epirubicin; Female; Granulocyte Colony-Stimulating Factor; Immunologic Factors; Macrophages; Mice; Mice, Inbred BALB C; Mitomycin; Neoplasm Proteins; Picibanil; Recombinant Proteins; Tumor Cells, Cultured

This paper delineates which lymph nodes should be dissected due to the high frequency of metastasis associated with different types of primarily lesions of the thoracic esophagus. In cancer involving the upper third of the esophagus (Iu), lymph flow was found to be primary from the superior mediastinal area to the cervical area; in that involving the middle third (Im), it was broadly distributed from the superior, middle, and inferior mediastinal region to the cervical and abdominal regions; and in that involving the lower third (Ei), it tended to extend from the inferior mediastinal region to the abdominal region, with single primary metastatic nodes also being noted in this area. The significance of the "top" nodes, namely, the nodes located along the right recurrent laryngeal nerve in the upper portion of the thorax, was also investigated, and it was confirmed that the prognosis for patients with metastases to both the top nodes and other nodes was unfavorable. An immunohistochemical study on mediastinal lymph flow using the anti-Su-Ps antibody demonstrated interactions between top nodes and cervical and/or thoracic nodes.

Topics: Adenocarcinoma; Carcinoma, Squamous Cell; Esophageal Neoplasms; Female; Humans; Lymph; Lymph Node Excision; Lymphatic Metastasis; Male; Middle Aged; Picibanil; Postoperative Complications

A 61-year-old female was admitted to our hospital because of a mass in right lateral chest wall and chest pain. Chest X-P and CT scans showed a right chest wall tumor and pleural effusion. Biopsy specimen from the chest wall tumor revealed an adenocarcinoma, not a mesothelioma, based on immunohistochemical study. Cancer cells were also detected in pleural effusion. Imaging diagnostic analysis could detect no primary tumor in lung field or other organs. High levels of CA125 were noticed: 9,610 U/ml in serum and 37,600 U/ml in pleural effusion, respectively. Finally, there was a possibility that the chest wall tumor might be a metastatic lesion from undetected ovarian cancers, so three cycles of combined chemotherapy (CDDP+ADM+CPA) were done. CDDP plus OK-432 was also injected two times intrapleurally. After chemotherapy, the chest wall tumor and effusion disappeared and the serum CA125 level decreased to the normal range.

Topics: Adenocarcinoma; Antineoplastic Combined Chemotherapy Protocols; CA-125 Antigen; Cisplatin; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Female; Humans; Middle Aged; Picibanil; Remission Induction; Thoracic Neoplasms

A simple and highly reproducible mouse colonic cancer model with mesenteric lymph node (MLN) metastasis was established by injecting COLON-26 tumor cells into lymphatic nodules in the tip of vermiform appendix of BALB/C mice. In this model, antitumor effect of orally administered OK-432 was examined. OK-432 was given orally at three different periods: before injection of COLON-26 cells (Protocol-A), early after injection of COLON-26 cells (Protocol-B), and late after injection of COLON-26 cells (Protocol-C). As a result, MLN metastasis was significantly suppressed and survival rate was significantly improved in every protocol as compared to mice without OK-432 administration. Then, in vivo anti-tumor activities of MLN cells and splenic lymphocytes were evaluated by Winn assay. Tumor neutralizing activity against syngenic COLON-26 cells was induced in the MLN cells after OK-432 administration and the effector cells were found in CD4-positive T lymphocytes because MLN cells treated with anti-L3/T4 and anti-LFA plus complement lost their anti-tumor efficacy. In conclusion, oral administration of OK-432 appears to be an effective immunotherapy against colonic cancer especially in the prevention and the treatment for MLN metastasis.

Topics: Adenocarcinoma; Administration, Oral; Animals; Antineoplastic Agents; Colonic Neoplasms; Immunotherapy; Lymphatic Metastasis; Male; Mesentery; Mice; Mice, Inbred BALB C; Nitrosomethylurethane; Picibanil

A patient with navel metastasis from ovarian carcinoma was treated by immunotherapy and neo-adjuvant intraarterial infusion chemotherapy (OK-432 i.c., VP-16 25 mg/body x 10 days po, CDDP 100 mg/m2 iA, CPM 200 mg x 3 days/body i.v., THP 50 mg/m2 iA). Maximal blood concentration of THP was 1.081 micrograms/ml at 1 hour intraarterially and 0.091 microgram/ml at 2 hour intravenously. THP concentration of arteria is ten times higher than that of venous. And the area under the curve (AUC) of THP is 3.46 micrograms/ml/hr intraarterially and 0.43 microgram/ml/hr at intravenous. Two courses of the neo-adjuvant intraarterial chemotherapy were done. One month after, the first operation was performed. Each tissue platina concentration is 9.72 micrograms/ml is 9.72 micrograms/cm3 uterus cervix, 7.10 micrograms/cm3 uterus corporis, 5.72 micrograms/cm3 left ovarium, 2.64 micrograms/cm3 right ovarium, 0.52 microgram/cm3 paraaortic lymph node. After the immuno-chemotherapy, the metastatic tumor appeared remarkably smaller and the main tumor regained normal size and we achieved the optimal operation successfully. This patient was treated with double platina chemotherapy by intraperitoneal infusion using implantable reservoir access after the first operation (VP-16 200 mg/m2 i.p. D1, CDDP 100 mg/m2 ip D1, CBDCA 300 mg/m2 i.v. D3). This patient can keep the state of cytological complete remission for more than four months after the second look operation. Now she continues maintenance immuno-chemotherapy from a home doctor.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Cyclophosphamide; Doxorubicin; Etoposide; Female; Humans; Immunotherapy; Infusion Pumps, Implantable; Neoplasm Staging; Ovarian Neoplasms; Picibanil; Remission Induction

The effect of OK432 on hepatic metastasis, induced by inoculating 1 x 10(6) ACL-15 cells from a rat colon adenocarcinoma cell line into the ileocolic vein of male F344 rats, was investigated in this study. Metastases were detected 14 days after inoculation in the control rats, however, pretreatment 3 days prior to the tumor cell inoculation with an anti-asialoGM1 antibody, which eliminates natural killer (NK) cell activity in vitro, increased the number of hepatic metastases, shortened the survival time, and decreased the NK activity of the nonparenchymal liver cells (NPC). In contrast, pretreatment with OK432 2 days prior to tumor inoculation significantly decreased the number of hepatic metastases, prolonged the survival time, and augmented the NK activity of the NPC, although treatment with OK432 3 or 7 days after inoculation did not decrease the number of hepatic metastases. Moreover, NPC from the OK432-pretreated rats had a marked antitumor effect against ACL-15 cells in the Winn's neutralization test. The results of this study indicate that pretreatment with OK432 before tumor cell inoculation inhibits hepatic metastasis in this experimental model, possibly by augmentating liver-associated NK activity.

Topics: Adenocarcinoma; Animals; Colonic Neoplasms; Killer Cells, Natural; Liver; Liver Neoplasms; Male; Neoplasm Transplantation; Neutralization Tests; Picibanil; Rats; Rats, Inbred F344; Spleen; Tumor Cells, Cultured

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

Recently, cases of postoperative chylothorax have increased concomitantly with the increase in number of aggressive thoracic surgery. Chylothorax was complicated on the 6 th postoperative day in a 69-year-old male who underwent right lower lobectomy with mediastinal lymph node dissection for adenocarcinoma of the lung. After the leaking point from thoracic duct was confirmed by lymphangiography and chest CT, OK-432 1.5 KE was instilled into the intrapleural space through a intrathoracic tube. By this procedure, the chylous fistulas were completely cured. Application of OK-432, even in such a small dose as 1.5 KE, appeared very useful for the treatment of postoperative chylothorax.

Topics: Adenocarcinoma; Aged; Chylothorax; Humans; Instillation, Drug; Lung Neoplasms; Male; Picibanil; Pleura; Pneumonectomy

The effect of intrapleural injection of OK-432, a streptococcal preparation, for management of carcinomatous pleural effusion was investigated in patients with non-small cell lung cancer (NSCLC). Ten patients, including 5 men and 5 women with performance status 2-3(ECOG) and average age of 66.4 years, received OK-432 for different times after the tumor burden in effusion was relieved with adequate drainage. The response rate was 100% in terms of decreased reaccumulation of pleural fluid, improvement of general status, and disappearance of tumor cells in the fluid. The adverse effects of this treatment were mild-including fever, chills, chest pain and nausea-and all were tolerable to patients. Median survival time was 4.5 months after treatment. This preliminary report indicates that intrapleural injection of OK-432 is an effective alternate method for management of carcinomatous pleural effusion to improve the quality of life for terminally ill cancer patients.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Carcinoma, Non-Small-Cell Lung; Female; Humans; Lung Neoplasms; Male; Middle Aged; Picibanil; Pleural Effusion; Time Factors

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

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

Intratumor injections of an immune modulator, OK-432, were administered to a 61-year-old man with inoperable lung adenocarcinoma. He received intratumor injections of OK-432, 20 K.E., twice weekly, under chest ultrasound guidance. A total dose of 240 K.E. was given in a six-week period. The tumor size decreased during a six-month follow-up period after the OK-432 injections. The immunologic profile of the patient showed neutrophilia, a decrease in the lymphocyte count in the peripheral blood and an increase in immunoglobulins after the OK-432 injections. The peripheral T-lymphocyte subsets showed a significant reduction in cytotoxic T cells and a decrease in the OKT4/OKT8 ratio. Histologic examination of the tumor after OK-432 injections showed extensive desmoplastic fibrosis. There was no evidence of lymphocyte infiltration. Intratumor injections of OK-432 may be an alternative for local control of inoperable lung cancer.

Topics: Adenocarcinoma; Fibrosis; Humans; Lung Neoplasms; Male; Middle Aged; Picibanil

OK-432 (5 KE), an immunomodulatory agent prepared from an attenuated strain of Streptococcus pyogenes, was dissolved in 1 ml of aprotinin (1000 KIE) and mixed with 80 mg of fibrinogen containing Factor XIII. A single intratumoral injection of the mixture was performed preoperatively under endoscopy in 20 patients with colorectal carcinoma. Postoperative histopathologic examinations revealed the formation of fibrin fibers at the site of injection and marked infiltration of inflammatory cells into the tumor stroma on the day after injection; the formation of granulomas containing many giant cells after 4 to 7 days; and extensive regression of tumor tissue after 14 days. This study suggests that the high concentration of exogenous fibrinogen gelatinized enough to trap OK-432 in tumor stroma and that OK-432 induced granulomatous hypersensitivity to degenerate tumor stroma, thereby causing regression of the tumors.

Topics: Adenocarcinoma; Aprotinin; Drug Combinations; Drug Synergism; Factor XIII; Fibrinogen; Humans; Immunotherapy; Injections; Picibanil; Rectal Neoplasms; Sigmoid Neoplasms

The effects of OK-432 on artificial liver metastasis of tumor-bearing mice were assessed using murine colon adenocarcinoma MCA-38 in C57 BL/6 mice. OK-432 injection into the spleen reduced the liver metastases. In gastro-intestinal cancer patients, the effects of OK-432 injection into the spleen were assessed with functional T cell subsets. The treatment resulted in an increase in the number of cytotoxic T cells, but a decrease in the suppressor T cells. The facts suggested that OK-432 injection into the spleen had an ability to prevent liver metastases.

Topics: Adenocarcinoma; Animals; Colonic Neoplasms; Injections; Leukocyte Count; Liver Neoplasms; Lymphocyte Subsets; Male; Mice; Mice, Inbred C57BL; Picibanil; Receptors, Interleukin-2; Spleen; T-Lymphocytes, Regulatory

We assessed the feasibility of the sequential multimodal treatment including neoadjuvant chemotherapy for far advanced ovarian cancer patients not amenable to a standard modality because of poor medical status. Seven consecutive advanced ovarian cancer patients presented with massive ascites (5 with pleural effusion). Based on the priming theory, immunotherapy with OK432 (s.c. priming with 0.2 KE of OK432 followed by a local injection with 10KE of OK432) was successfully applied to a carcinomatous effusion. Thereafter, patients were treated with 4-6 courses (13-20 wks) of "low-dose consecutive CP (CPM 500 mg/m2, day 1; CDDP 10 mg/m2, day 1-7), which delivered 1CR, 5PR and 1NC (tumor regression rate: 30-100%). Subsequently, the patients underwent radical surgery including small/large bowel resection, splenectomy and diaphragma resection in addition to hysterectomy, bilateral adenectomy and omentectomy, with tumor resectability being 100% in 4 cases and 90% < (residual 2 cm) in 3. Postoperatively, patients received intraperitoneal (IP) chemo-immunotherapy and were followed up with IP washing cytology through an implanted reservoir. Mean survival time was 17.1 months (10-32) with the follow up interval being 10-32 months. Four patients with complete tumor resection are alive with no evidence of disease for 14-32 months. Among 3 incomplete patients, 2 with persistent/recurrent disease received further IP chemotherapy and the remaining one died of the disease at 15 months from the start of therapy. Thus, the present multimodality indicates the possibility of a "cure" for far advanced ovarian cancer patients with poor performance status.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Cisplatin; Cyclophosphamide; Female; Fluorouracil; Follow-Up Studies; Humans; Hysterectomy; Immunotherapy; Middle Aged; Ovarian Neoplasms; Ovariectomy; Picibanil; Prognosis; Survival Rate

In cases of advanced ovarian cancer, intermittent CDDP therapy (ICDDPT) was applied after the first operation and induction chemotherapy, and its efficacy and limit were studied. One cycle of this therapy involved consecutive 5 day CDDP treatment (25-30mg/body/day). The therapy was repeated at intervals of 3 months. In many cases, ovarian cancer was histologically rated as epithelial adenocarcinoma. The study included 18 cases in total. ICDDPT was applied to 13 cases in which no tumor mass was detected by second look operation (SLO) or which showed clinical remission after operation. Only 3 of these 13 cases showed recurrence, and all these 13 are still living. Of the 5 cases in which SLO disclosed a tumor mass or which did not show remission after the first operation, 2 died. When the survival rate after ICDDPT was compared by the Kaplan-Meier method with that of controls without CDDP therapy, the effectiveness of ICDDPT was demonstrated. The survival rate could therefore be improved by ICDDPT. The therapy particularly improved the long term prognosis of SLO negative cases and cases in clinical remission. It seems necessary to repeat this therapy for a long period to achieve satisfactory results. In SLO positive cases and cases without clinical remission, the therapy had only a limited effect.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Middle Aged; Ovarian Neoplasms; Picibanil; Postoperative Care; Prognosis; Survival Rate; Tegafur

Much effort has been developed to control of multiple liver metastases of colo-rectal cancer, but the results of various therapies are not necessarily satisfactory. We report here a 73-year female with advanced rectal cancer and multiple liver metastases (H3), who showed a complete response to hepatic arterial infusion of mitomycin C using "Infuse-a-port". Hepatic arterial infusion of chemotherapeutic agents using totally implantable reservoir might be one of the most potent therapies for non-resectable liver metastasis of colo-rectal cancer.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Female; Hepatic Artery; Humans; Infusion Pumps; Infusions, Intra-Arterial; Injections, Subcutaneous; Liver Neoplasms; Mitomycin; Picibanil; Rectal Neoplasms; Tegafur

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

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

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

Recombinant interleukin-2 (rIL-2) was administered intraperitoneally for 15 days, 2 days after intraperitoneal administration of Streptococcal preparation OK-432 to a patient of peritonitis carcinomatosa occurred eight months after second look operation, in which residual tumor could not be removed completely. The patient had been maintained by hemodialysis three times a week for over ten years. Combination chemotherapy using CDDP and Ifosfamide, or CDDP and THP-Adriamycin had not been effective to control rapidly increasing ascites. Negative cytological exam, was achieved on day 7 and ascites disappeared by day 15. No severe side effects including fluid retention were observed. Fever up was controllable by Indomethacin. Flow cytometric analysis revealed dominant (73%) CD4+, CD29+ helper inducer subset, while CD4+, CD45RA+ was 6%, in the lymphocytes in ascites on day 8. It was suggested that intraperitoneal administration of rIL-2 after OK-432 was safe and effective for peritonitis carcinomatosa with chronic renal failure.

Topics: Adenocarcinoma; Adult; Biological Products; Female; Humans; Immunization, Passive; Infusions, Parenteral; Interleukin-2; Kidney Failure, Chronic; Killer Cells, Lymphokine-Activated; Ovarian Neoplasms; Peritoneal Neoplasms; Picibanil

We had demonstrated that the NK cell mediated cytotoxicity of murine spleen cells could be augmented by in vivo priming and subsequent in vitro challenge with a streptococcal preparation OK432, and the cell surface phenotype of induced killer cells was Thy-1+, asialo GM1+, suggesting that the activated cells were of NK lineage (OK-NK cell). We had also clarified that IL-2 played a major role in inducing the OK-NK cells via the production of IFN-gamma. In this study, we examined the effect of adoptive transfer of OK-NK cells on syngeneic tumors in mice. Mice were implanted with SP2 myeloma cells intraperitoneally (i.p.), or C26 colon adenocarcinoma cells subcutaneously to make the models of peritonitis carcinomatosa or solid tumor, and the OK-NK cells were transferred i.p. or intratumorally, adoptively. By the adoptive transfer of OK-NK cells, 92% of mice bearing SP2-tumor had be cured. The tumor growth of C26-solid tumor was inhibited, and the survival rate of mice bearing C26-tumor was significantly increased. The intratumoral remnants of 125I-labelled OK-NK cells were 61, 27 and 8% at 4, 12 and 36h after intratumoral transfer, respectively. By multiple transfer of OK-NK cells, the antitumor effect was more effectively augmented than that of a single transfer. Results in this study suggested that OK-NK cells could be useful for the therapy of cancer patients.

Topics: Adenocarcinoma; Animals; Biological Products; Cell Survival; Female; Immunization, Passive; Killer Cells, Natural; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Multiple Myeloma; Picibanil; Tumor Cells, Cultured

TILs can be isolated and expanded in vitro in the presence of RIL-2. The resulting cells are highly cytotoxic in vitro and in vivo against a variety of tumor targets. Although most of the TILs bear T cell antigens on their cell surface, recent evidence suggests that natural killer (NK) cells may be part of the overall population of infiltrating cells. Based upon this evidence, we have evaluated the effects of Picibanil (OK-432), a well-known inducer of NK cell and T cell cytotoxicity, on TILs. OK-432 was administered intravenously at a dose of 100 micrograms, previously determined to be optimal for NK stimulation, to tumor-bearing animals. Two days later, control and experimental animals had their tumors harvested and processed in order to grow their TILs in vitro in complete medium containing RIL-2 at a final concentration of 1,000 U/ml. The following observations were made: 1) a greater than 300% increase in overall TIL number compared to controls on day 10 of culture returning to normal by day 30; 2) a marked increase in the percent of cells expressing cytotoxic and differentiation antigens in the experimental group compared to controls, such increase seen mostly from day 7 to day 10; 3) a marked increase in the cytotoxic activity of the experimental TILs against an NK-sensitive tumor target, the YAC-1 lymphoma, throughout the period of growth of the TILs (3-4 times controls) and to a lesser extent against an NK-resistant tumor target. These findings may have potential application, in immunotherapeutic trials against human tumors and may help to understand the reasons for the effectiveness of OK-432 in vivo against selected murine tumors.

Topics: Adenocarcinoma; Animals; Antigens, Differentiation, T-Lymphocyte; Biological Products; Cell Division; Cells, Cultured; Female; Fluorescent Antibody Technique; Lymphoma; Mice; Mice, Inbred C57BL; Neoplasms, Experimental; Picibanil; Premedication; Sarcoma, Experimental; T-Lymphocytes, Cytotoxic; Up-Regulation

A 42-year-old man was admitted because of huge retrovesical mass. The organ from which the tumor originated was unknown. The biopsy specimen showed poorly differentiated adenocarcinoma. The tumor increased rapidly and could not be resected because of peritoneal dissemination. The mass fully occupied the abdominal space with marked dyspnea. Fortunately, a marked decrease in the tumor size was noted by neo-MFC without any side effect. Therefore, the patient could enjoy a daily life until he died suddenly of cardiac failure 8 months after first admission. Retrovesical tumor is usually discovered at advanced stage because of lack of symptoms. For recovery of good performance status combined chemotherapy with relatively mild side effect must be selected and administered for a long time.

Topics: Adenocarcinoma; Adult; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Humans; Male; Mitomycin; Mitomycins; Neoplasm Staging; Picibanil; Tegafur; Urinary Bladder Neoplasms

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

Topics: Adenocarcinoma; Administration, Oral; Aged; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Humans; Injections, Intralesional; Male; Picibanil; Remission Induction; Sigmoid Neoplasms; Sigmoidoscopy; Tegafur; Uracil

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

To examine the carcinogenetic and growth inhibitory effects of OK-432, large-bowel carcinoma was induced experimentally in rats by intrarectal injection of N-methyl-N-nitrosourea (MNU), and OK-432 was administered intradermally. Rats were sacrificed after six months and the large intestine was cut into serial sections. Histopathologic examination and analysis of the infiltrating mononuclear cells, using monoclonal antibodies, were performed. The average rate of carcinogenesis per rat was 15.7 +/- 8.5 in the MNU alone group (n = 10) and 8.3 +/- 3.5 in the MNU and OK-432 group (n = 6). The invasion was deeper than the muscularis propria in 16 out of 157 lesions (10.2 percent) in the MNU alone group and in one out of 50 lesions in the MNU + OK-432 group (2.0 percent) (P less than 0.05). When time of appearance of atypical glands or carcinomas were compared in the MNU alone and MNU + OK-432 group, carcinogenesis was found to be delayed in the MNU + OK-432 group. In the investigation of infiltrating mononuclear cells using monoclonal antibodies, there were increases in helper T cells in both the MNU alone and MNU + OK-432 groups, but there was little difference between the two groups. The results of this study suggest that the suppression of experimental carcinogenesis in the large bowel by the concomitant administration of OK-432 with MNU, may be due to the enhanced activation or prolonged activated state of immunocompetent cells, which appear via antigen recognition, by OK-432.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Animals; Biological Products; Intestinal Neoplasms; Male; Methylnitrosourea; Picibanil; Rats; Rats, Inbred Strains; Time Factors

An IgG2a mouse monoclonal antibody (MoAb) to the human salivary gland adenocarcinoma cell line HSG, 5B/10, has been generated in our laboratory. In the current study, the antitumor effects mediated by MoAb 5B/10 in human salivary gland adenocarcinoma (HSG)-bearing nude mice or the antibody-dependent cell-mediated cytotoxicity (ADCC) against HSG cells using human peripheral blood mononuclear cells (PBMC) as effector cells were examined. In addition, effects of the streptococcal preparation OK-432 on the growth of HSG tumors or on the MoAb 5B/10-mediated cellular cytotoxicity were studied. MoAb 5B/10 mediated an ADCC reaction against HSG cells that were insensitive to NK cells but not to the reaction of antibody and complement-mediated cytotoxicity. The coexistence of MoAb 5B/10 and OK-432 caused marked augmentation of cytotoxic effects. Treatment of OK-432-stimulated PBMC with antiasialo Gm1 antiserum plus complement but not with silica particles resulted in a significant decrease of cytotoxic effects as compared with relevant controls. the nude mice inoculated intraperitoneally with HSG cells and treated with MoAb 5B/10, OK-432, or (especially) a combination of the two had significantly prolonged survival times as compared with untreated controls. Moreover, spleen cells from the tumor-bearing mice treated with OK-432 alone or a combination of MoAb 5B/10 and OK-432 were found to carry high levels of effector cell activity in the MoAb 5B/10-mediated cytotoxicity assay using HSG cells as targets.

Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; Biological Products; Cells, Cultured; Chromium Radioisotopes; Combined Modality Therapy; Female; G(M1) Ganglioside; Glycosphingolipids; Humans; Leukocytes, Mononuclear; Mice; Mice, Nude; Neoplasm Transplantation; Picibanil; Salivary Gland Neoplasms; Silicon Dioxide; Spleen

We had demonstrated that the NK cell mediated cytotoxicity of murine spleen cells could be augmented by in vivo prime and subsequent in vitro challenge with the streptococcal preparation OK432, and the cell surface phenotype of induced killer cells was Thy 1+, asialo GM1+, suggesting the activated NK cells (OK-NK cell). The culture supernatants of spleen cells with OK432 possessed the activity of IL-2 and IFN-gamma, and the IL-2 played a major role to induce the OK-NK cells via the production of IFN-gamma. In this study, we examined the effect of adoptive transfer of OK-NK cells on tumor-bearing mice. The mice were implanted SP2 myeloma cells intraperitoneally (i.p.), or C26 colon adenocarcinoma cells subcutaneously (s.c.) to make the models of peritonitis carcinomatosa or solid tumor, and the OK-NK cells were transferred i.p. or i.t., adoptively. By the adoptive transfer of OK-NK cells, the 92% of mice bearing SP2-tumor had be cured. The tumor growth of C26-solid tumor was inhibited, and the survival rate of mice bearing C26-tumor was increased, significantly. The intratumoral remnants of 125I-labelled OK-NK cells were 61.27 and 8% after intratumoral transfer, respectively. By multiple transfer of OK-NK cells the anti-tumor effect was more augmented than that of a single transfer. Thus we recognized the anti-tumor effect of adoptive transfer of OK-NK cells on tumor-bearing mice, and suggested that OK-NK cells could be useful for the therapy of cancer patients.

Topics: Adenocarcinoma; Animals; Biological Products; Female; Immunization, Passive; Killer Cells, Natural; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Multiple Myeloma; Neoplasms, Experimental; Picibanil

The combination therapy of local administration of OK-432 and radiation was performed for two patients with lower bile duct carcinoma. Initially, 10KE of OK-432 was given locally, and irradiation was performed according to the schedule of 180-200 rad/5 fractions/week and given 5,000-5,220 rad totally. One case received 5KE of OK-432 locally 17 days after first injection. Both cases showed complete response and survived 4 months and 59 months without any sign of recurrence, respectively.

Topics: Adenocarcinoma; Aged; Bile Duct Neoplasms; Biological Products; Combined Modality Therapy; Humans; Injections; Male; Picibanil; Radiotherapy Dosage; Remission Induction

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

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

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

Immunocytochemical techniques were used to clarify the local inhibitory effects of a streptococcal immunopotentiator, OK-432, against solid malignant tumor growth. Natural killer (NK) cells and fibronectin were chosen as immunostaining markers to demonstrate the antitumor effects. Immunocytochemical staining was performed by the avidin-biotin-peroxidase complex method. These investigations demonstrated that (1) local administration of OK-432 seems to promote a marked induction of NK cells and fibroblasts around or entering into the cancerous lesions and (2) the cancer cell-killing effect of NK cells and the fibronectin-enriched stromal reaction augmented by the injection of OK-432 suggest at least the possibility of protection against neoplastic growth with invasion and the spread of distant or nodal metastases of solid carcinomas.

Topics: Adenocarcinoma; Antibodies, Monoclonal; Biological Products; Female; Head and Neck Neoplasms; Humans; Immunoenzyme Techniques; Lymphatic Metastasis; Male; Middle Aged; Neck; Picibanil; Thyroid Neoplasms

An immunoglobulin M mouse monoclonal antibody (MAb) to the streptococcal preparation OK-432, TS-1, was generated. The TS-1 antigen is a carbohydrate epitope. This antigen is stable upon fixation and embedding in paraffin. The tissue and cellular OK-432 localization in human salivary adenocarcinoma-bearing nude mice given OK-432 intratumorally was examined by various methods according to the immunological procedures using the purified TS-1 MAb. The presence of OK-432 antigen recognized by TS-1 MAb was clearly observed in the tumor as well as the spleen and lung 24 or 48 h after OK-432 administration, whereas transfer of OK-432 from the site of injection to the organs, such as liver and kidney, was rarely seen. The presence of OK-432 antigen in some immunocompetent cells, as defined by Mac-1 antigen or asialo GM1 antigen, was observed by the double-antibody labeling technique in the tumor and spleen from tumor-bearing nude mice. Moreover, interaction between OK-432 and macrophages or natural killer (NK) cells in relation to expression of interferon (IFN) in tumor-bearing nude mice given OK-432 was observed. Consequently, significant increases of Ia-positive or Ia-negative macrophages, NK cells as well as IFN-alpha/beta- or IFN-gamma-positive cells in the tumor and/or spleen were found when compared with those without OK-432 administration.

Topics: Adenocarcinoma; Animals; Antibodies, Monoclonal; Biological Products; Female; Humans; Killer Cells, Natural; Macrophages; Mice; Mice, Nude; Neoplasm Transplantation; Picibanil; Salivary Gland Neoplasms; Transplantation, Heterologous

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

Chemotherapy and administration of OK-432 were performed concomitantly in 49 cases of inoperable primary lung cancer, and the Su-PS skin reaction was measured. In the group of patients under 60 years of age, the maximum diameter of the reaction after chemotherapy tended to be large, and evaluation of the results showed that the maximum diameter tended to be large in the group showing tumor contraction effects. In a comparison of the prognosis between the group which survived for less than 6 months and that which survived for 6 months or longer, there was no significant difference between them before administration of OK-432, but when the maximum reaction diameter after chemotherapy was compared, that in the group which survived for 6 months or longer was significantly stronger (p less than 0.05). The Su-PS skin reaction at the time of administration of OK-432 is therefore considered to be a useful immunological parameter for predicting the results of treatment and also for prognosis.

Topics: Adenocarcinoma; Adult; Aged; Biological Products; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Humans; Lung Neoplasms; Male; Middle Aged; Picibanil; Polysaccharides, Bacterial; Prognosis; Skin; Skin Tests; Streptococcus pyogenes; Tuberculin Test

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

In order to study the role of immune skin reactions (DNCB, PPD, Su-PS reaction) in progressive lung cancer, various investigations were conducted, in particular during the administration of OK-432, and the following results were obtained. Before and after chemotherapy, only a slight decrease in the skin reactions was noted. Su-PS reaction was intensified by the administration of OK-432, but other skin reactions were not changed after 3 months, being only slightly intensified by long-term administration. At the time of remission achieved through radiochemotherapy during administration of OK-432, Su-PS reaction was intensified compared to the level before treatment, and a lowering tendency was noted at the time of recurrence. PPD reaction presented a similar tendency, but DNCB reaction did not show this trend. Concerning the relationship between skin reaction and survival period, the positive DNCB reaction group before treatment had a significantly extended survival period compared to that of the negative group. During administration of OK-432, Su-PS reaction was most useful at all timings, while PPD reaction occurred during the intermediate period. Upon observing the Su-PS reaction after 3 months of treatment, the prognosis was excellent in cases with erythema of 10 mm or more. However, no such tendency was noted for the PPD reaction. Thus, for understanding the pathologic state and prognosis of patients with progressive lung cancer, the Su-PS reaction was most useful during intra dermal administration of OK-432, the PPD reaction was moderately useful, but the DNCB reaction produced different results. Therefore, for the evaluation of prognosis, it was considered essential to select and combine the skin reactions according to the examination timing and treatment schedule.

Topics: Adenocarcinoma; Biological Products; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Dinitrochlorobenzene; Humans; Lung Neoplasms; Picibanil; Polysaccharides, Bacterial; Skin; Skin Tests; Streptococcus pyogenes; Tuberculin Test

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

We studied the effect of intraperitoneal injection of OK-432 on the growth of original tumor mass in patients with malignant ascites and a possible mechanism of reduction of tumor volume. Sixteen patients with valuable original tumor mass and a large amount of ascites caused by gastro-intestinal cancer were studied. Tumor cells were separated from ascitic fluids and cultured in vitro before the study. Lymphocytes were collected from the fluids at varying intervals after intraperitoneal injection of OK-432 and cultured 24 hours in vitro. Effect of the culture supernatant on ascites-derived autologous tumor cell growth was examined in vitro using microplate assay. The results were as follows. 1) Reduction of tumor mass more than four weeks was found in 4 of 16 cases. 2) Before OK-432 injection, the culture supernatant from ascites-derived lymphocytes did not inhibit autotumor cell growth in vitro. But, the supernatant from lymphocytes which were collected from the ascites after OK-432 injection markedly inhibited tumor growth in all of 4 tumor mass reduction cases. In 12 non-reduction cases the supernatant slightly inhibited tumor growth only in 2 cases. 3) A similar growth inhibitory factor was detected in the mixed culture-supernatant of peripheral blood lymphocytes and OK-432 in vitro. 4) Preliminary studies indicated that the tumor growth inhibitory factor might be different from tumor necrosis factor and interferons. These results indicate that ascites-derived lymphocytes-producing factor may play an important role in reduction of tumor mass volume in patients with cancerous ascites.

Topics: Adenocarcinoma; Adult; Aged; Biological Products; Chronic Disease; Female; Gastrointestinal Neoplasms; Humans; Injections, Intraperitoneal; Male; Middle Aged; Peritonitis; Picibanil

Carcinomas produce large amounts of prostaglandin (PG) E2, which play an important role in suppression of non-specific cellular immune reaction in tumor-bearing individuals. PG synthesis inhibitor can restore the immune activity against tumors. The anti-tumor activity of indomethacin was investigated in CDF1 mice (BALB/c X DBA/2) implanted intraperitoneally with mouse colon adenocarcinoma 26 (5 X 10(5) or 2 X 10(5) cells) in a model study to prevent peritoneal recurrence after surgery for gastrointestinal cancers. Oral administration of indomethacin (0.002% water solution as drinking water) depressed and inhibited the disseminated tumor growth in the abdominal cavity, and prolonged the survival time, resulting in 30-50% cures of mice. The treatment combined with a small intraperitoneal dose of Picibanil (OK-432) (0.5 mg/kg twice weekly), which activates macrophages in the abdominal cavity, cured 90% of mice. An intraperitoneal dose of 16,16-dimethyl-PGE2 (5 micrograms/mouse, daily) reduced the anti-tumor activity of indomethacin. The results suggest that indomethacin treatment relieved the endogenous(tumor cell- and macrophage-produced) PGE2-mediated immunosuppression. It is postulated that PG-synthesis inhibitor in combination with chemotherapeutic agents, immunotherapeutic agents and low dose radiation, may provide a good therapeutic tool to prevent the development of peritoneal carcinomatosis, particularly in the cases having a small number of residual cancer cells or micrometastases in the abdominal cavity after surgery.

Topics: Adenocarcinoma; Animals; Anti-Inflammatory Agents, Non-Steroidal; Colonic Neoplasms; Dinoprostone; Drug Therapy, Combination; Immune Tolerance; Indomethacin; Mice; Mice, Inbred Strains; Neoplasm Recurrence, Local; Peritoneal Neoplasms; Peritonitis; Picibanil; Prostaglandins E

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

A patient with relapsed primary pulmonary carcinoma (T2N0M0 Stage II adenocarcinoma) showing contralateral metastasis after 4 postoperative years was given Carboquone (CQ), Cisplatin (CDDP) and OK-432, and positive therapeutic results were obtained. However, aggravation ensued and so UFT was given in combination with the above chemotherapy, resulting in repeatedly good results. The details of this case of relapsed pulmonary carcinoma, which was resistant to chemotherapy but showed positive therapeutic results with combined use of UFT, are reported.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Carbazilquinone; Cisplatin; Female; Humans; Lung Neoplasms; Neoplasm Recurrence, Local; Picibanil

A combination of OK-432 and high-dose Carboquone (12-22 mg/m2) was administered to 17 patients with unresectable non-small cell lung cancer. The response rate was 42.9% (CR-1, PR-5) among 14 patients in whom measurement of tumor diameter was possible. With regard to hematologic adverse effects, 13 patients had a WBC count of less than 3,000, and 6 patients had a platelet count of less than 50,000. Duration of WBC nadir was not longer than 3 days, and there were no cases of infectious complication or bleeding tendency. Other side effects were all transient.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Carbazilquinone; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Female; Humans; Lung Neoplasms; Male; Middle Aged; Picibanil

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

We evaluated various immunologic parameters in patients with papillary and follicular carcinomas of the thyroid gland. Our studies included examinations of peripheral blood lymphocytes and skin reactions to selected antigens. Preoperative peripheral blood tests were found to be normal except for an elevated percentage of IgG X Fc+ T-cells (T gamma). Skin reactions (phytohemagglutinin, purified protein derivative) were greater preoperatively than postoperatively. In postoperative cases without tumor recurrence, absolute numbers of T-cells and lymphocytes were reduced. OK-432 is a biologic response modifier of a streptococcal preparation and was used as immunotherapy in postoperative patients. This therapy seemed to augment the absolute numbers of T-cells and lymphocytes as well as purified protein derivative skin reactions in the patients without tumor recurrences. In the patients with postoperative tumor recurrences, there was an abnormal reduction in the percentage of T-cells and in the absolute numbers of T-cells and lymphocytes. OK-432 treatment was not significantly effective in normalizing this reduction.

Topics: Adenocarcinoma; Adolescent; Adult; Aged; B-Lymphocytes; Carcinoma, Papillary; Female; Humans; Lymphocyte Activation; Lymphocytes; Male; Middle Aged; Picibanil; Skin Tests; T-Lymphocytes; Thyroid Neoplasms

Topics: Adenocarcinoma; Aged; Biological Products; Cell Cycle; Cytotoxicity, Immunologic; Female; Glycoproteins; Humans; Lung Neoplasms; Lymphoma; Male; Middle Aged; Picibanil; Pleural Effusion; Tumor Necrosis Factor-alpha

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

To evaluate the efficacies of various administration routes of the streptococcal preparation, OK-432, we studied the lymphocyte proliferation responses to lectins in patients with malignancies. OK-432 was administered intravenously (I.V.), intramuscularly (I. M.) or intradermally (I.D.) for 2 weeks. Lymphocyte proliferation responses to concanavalin A, PHA and SuM (crude extract of OK-432) were studied before and after OK-432 administration. Enhanced responses were observed in 7 out of 9 patients (77.8%) in the I.V. group compared with 3 out of 7 (44.2%) in the I.M. group and 4 out of 9 (44.4%) in the I.D. group. Ratios of stimulation index (S.I.) after administration over S.I. before administration were highest in the I.V. group. These results suggest that I.V. administration of OK-432 is most effective for stimulating host immune systems.

Topics: Adenocarcinoma; Adult; Aged; Biological Products; Carcinoma, Squamous Cell; Concanavalin A; Female; Humans; Infusions, Parenteral; Lung Neoplasms; Lymphocyte Activation; Male; Middle Aged; Phytohemagglutinins; Picibanil

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

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 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

Topics: Adenocarcinoma; Antineoplastic Agents; Biological Products; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Humans; Lung Neoplasms; Male; Picibanil; Prognosis

We studied effects of OK-432 on the bone marrow and peripheral blood cells of lung cancer patients. The nuclear cell count of bone marrow increased in 5 to 7 patients upon intravenous treatment with OK-432 compared with 3 of 6 patients who were intramuscularly treated with OK-432. Serial neutrophil counts of bone marrow increased in all 7 patients treated intravenously compared with 3 of 6 patients treated intramuscularly. The mean nuclear cell count or the serial neutrophil count of bone marrow in intravenously treated patients was significantly higher than the pretreatment values (p less than 0.001). In the peripheral blood picture, the difference in white blood cells or neutrophils before and after intravenous treatment was also statistically significant (p less than 0.01). There was no change in the erythrocytic series count of bone marrow and the hemoglobin count. Our results support the superiority of intravenous OK-432 treatment over intramuscular treatment in the growth-accelerating effect on bone marrow cells, especially regarding the neutrophil series.

Topics: Adenocarcinoma; Adult; Aged; Biological Products; Bone Marrow; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Cell Division; Female; Humans; Infusions, Parenteral; Leukocyte Count; Lung Neoplasms; Male; Middle Aged; Neutrophils; Picibanil

Ten patients with carcinomatous pleural effusions were treated with single intrapleural (i.pl.) injections of the streptococcal preparation OK432 on day 0 and the effects of i.pl. OK432 on the lysis of fresh or cryopreserved autologous tumor cells isolated from the pleural effusions were observed on day 7. In eight patients tumor cells in the effusions had decreased or disappeared by day 7. The other two patients, however, had no clinical evidence of therapeutic benefit from i.pl. OK432. Effusion tumor cells were relatively resistant to lysis by autologous lymphocytes when tested in a 4-h 51Cr-release assay. Positive reactions were recorded for blood and effusion lymphocytes in two of ten untreated patients. Injection of OK432 i.pl. resulted in an induction or augmentation of cytotoxicity against autologous tumor cells and K562 in the effusions of seven of ten subjects by day 7. In contrast, autologous tumor killing activity of blood lymphocytes was not always modified by i.pl. OK432. Purification of large granular lymphocytes (LGL) by discontinuous Percoll gradient centrifugation enriched autologous tumor killing activity, with no reactivity in LGL-depleted, small T lymphocytes. Significant lysis of autologous tumor cells was observed with effusion LGL from seven of ten untreated patients. Seven days after i.pl. OK432 injection, effusion LGL expressed enhanced cytotoxicity against autologous effusion tumor cells, whereas T cells were still not cytotoxic to autologous tumor cells on day 7. The frequency of LGL among effusion lymphocytes was not altered by i.pl. OK432. Adherent effusion cells were not involved in lysis of autologous effusion tumor cells in either untreated or OK432-treated patients. In vitro treatment of blood and effusion lymphocytes with OK432 induced an enhancement of autologous tumor-killing activity in patients who subsequently responded to i.pl. OK432 treatment. OK432 augmented in vitro autologous tumor killing activity of LGL, whereas T cells failed to lyse autologous tumor cells even after in vitro activation with OK432. These results indicate that i.pl. administration of OK432 to cancer patients will result in an augmentation of autologous tumor killing activity of LGL in the pleural effusions, and that this could be responsible for the antitumor activity of i.pl. OK432 therapy.

Topics: Adenocarcinoma; Adult; Aged; Biological Products; Carcinoma, Squamous Cell; Cell Adhesion; Cytotoxicity, Immunologic; Humans; Immunotherapy; Killer Cells, Natural; Lung Neoplasms; Middle Aged; Picibanil; Pleural Effusion; T-Lymphocytes

A combination immunochemotherapy regimen containing cisplatin (20 mg, days 1-5), peplomycin (20 mg, days 2, 9, 16), +/- vinblastine (5 mg, days 1, 2), and picibanil (3-5 KE/week) was performed in twelve patients with advanced or recurrent uterine and ovarian cancers under intravenous hyperalimentation (IVH), except one patient receiving peplomycin by a continuous infusion method using IVH bag (10 mg/day for 5 days). This regimen was repeated every three weeks. Five (71.4%) of seven evaluable patients showed partial response. No patients yielded the complete disappearance of disease. No severe and lethal pulmonary or renal dysfunction occurred and all was well tolerated. In a regimen without vinblastine, myelosuppression, especially thrombocytopenia, occurred later compared to the regimen including vinblastine.

Topics: Adenocarcinoma; Aged; Biological Products; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Drug Therapy, Combination; Female; Humans; Immunotherapy; Middle Aged; Ovarian Neoplasms; Peplomycin; Picibanil; Uterine Cervical Neoplasms; Uterine Neoplasms; Vinblastine

Twelve patients with carcinomatous pleural effusions were treated with single intrapleural (i.pl.) administration of OK432 on day 0 and the effects of i.pl. OK432 on natural killer (NK) cell activity were followed on day 7. Two patients showed no clinical evidence of therapeutic benefit from i.pl. OK432. In the other 10 patients, pleural effusions and/or tumor cells in the effusions had decreased or disappeared by day 7. NK cell activity was markedly low or absent in pleural effusions of untreated patients due to the presence of adherent effusion cells capable of suppressing the maintenance and interferon-induced augmentation of NK cell activity. I.pl. injection of OK432 resulted in enhancement of NK cell activity and abrogation of NK suppressor cell activity in the effusions. On the other hand, blood NK cell activity was not consistently altered by i.pl. OK432. In vitro treatment of effusion mononuclear cells from untreated patients with OK432, but not with interferon, augmented NK cell activity. In addition, adherent effusion cells of untreated patients lost their NK suppressor function following in vitro OK432 treatment. These results suggest that i.pl. administration of OK432 will result in augmentation of NK cell activity and reduction of NK suppressor cell activity in pleural effusions, which could be responsible for the antitumor activity of i.pl. OK432.

Topics: Adenocarcinoma; Adult; Aged; Biological Products; Carcinoma, Squamous Cell; Female; Humans; Interferon Type I; Killer Cells, Natural; Lung Neoplasms; Male; Middle Aged; Picibanil; Pleural Effusion; T-Lymphocytes, Regulatory

Pleural effusions and sera of two patients with lung cancer were tested after intrapleural injection of OK-432 as an anticancer drug for IFN-alpha activity by biological assay and for IFN-alpha as an antigen by radioimmunoassay. The titers by radioimmunoassay were fairly consistent with those by biological assay, but were usually higher. In Case 1, IFN-alpha was observed fairly early after administration of OK-432 and only in pleural effusions. In Case 2, induction of IFN-alpha at low level was observed late after the first administration of OK-432 both in the pleural effusion and serum and was detected only by radioimmunoassay.

Topics: Adenocarcinoma; Aged; Biological Products; Carcinoma, Small Cell; Drug Therapy, Combination; Female; Humans; Injections; Interferon Type I; Lung Neoplasms; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Pleura; Pleural Effusion

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

Lymphocytes from peripheral blood (PBL) and from pleural effusions (PEL) of cancer patients were tested for cytotoxicity against tumor cells freshly isolated from carcinomatous pleural effusion of the same patient. Significant lysis of autologous tumor cells was recorded for 4 of 28 PBL samples and for 5 of 28 PEL cases when investigated in a 4-hour 51Cr release assay. In vitro treatment of lymphocytes for 20 hours with the streptococcal preparation OK432 resulted in an induction or augmentation of cytotoxicity against autologous tumor cells in 21 of 28 PBL and PEL specimens. OK432-induced cytotoxicity required active cell metabolism, RNA and protein syntheses, but not DNA synthesis of lymphocytes. Supernatants of OK432-stimulated lymphocytes, and interferon and interleukin 2 failed to induce autologous tumor killing. Nylon wool-nonadherent lymphocytes were involved in both spontaneous and OK432-induced lysis of fresh autologous tumor cells. OK432-activated lymphocytes from normal donors and cancer patients caused lysis of fresh allogeneic tumor cells and also K562 cells.

Topics: Adenocarcinoma; Adult; Aged; Biological Products; Cytotoxicity, Immunologic; Dactinomycin; Female; Humans; Killer Cells, Natural; Leukemia; Lung Neoplasms; Lymphocyte Activation; Lymphocytes; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Pleural Effusion

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

Topics: Adenocarcinoma; Biological Products; Female; Humans; Melanoma; Ovarian Neoplasms; Picibanil

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

Carboquone (CQ) was administered to 20 patients with ovarian cancer as a main drug in the multiple chemotherapy. Picibanil and Futraful (FT-207) were medicated simultaneously. CQ was given 3 mg each, 2 times a week, up to total 30 mg intravenously or intraperitoneally. 1) The effect of CQ was evaluated in 6 cases. The response was good in 2 cases, fair in 3, and poor in 1. In the other 3 cases after surgery long-lasting remission suggested the effectiveness of this drug. 2) When compared with 43 cases of control group(historical control), apparent higher survival rate was observed until 3 years in this group. 3) Side effects were noted in 89% of the patients. In 5 patients CQ treatment was discontinued because of severe complications. These complications were more pronounced when it was administered intraperitoneally or combined with radiation.

Topics: Adenocarcinoma; Adenocarcinoma, Mucinous; Adult; Aged; Azirines; Carbazilquinone; Cystadenocarcinoma; Drug Evaluation; Drug Therapy, Combination; Endometriosis; Female; Humans; Middle Aged; Ovarian Neoplasms; Picibanil; Tegafur

Intraperitoneal injections of OK-432, originated from Group A streptococcus pyogens of human origin, were administered to 77 patients with ascites caused by cancer of the digestive tract. Complete disappearance of effusion was observed in 43 cases, its reduction in five out of 77. They received cytologic examination of ascites daily before and after OK-432 injection. One of these patients, a 77-year-old man with carcinomatous peritonitis due to gastric cancer, showed an interesting phenomenon after OK-432 injection. All adenocarcinoma cells in his ascites disappeared at least with 36 hours after OK-432 injection with increasing number of intraperitoneal neutrophils. In addition, neutrophils collected from his ascites or peripheral blood showed cytostatic effect on his ascites-derived tumor cells in vitro. His neutrophil-depleted intraperitoneal cells, however, had no significant effect on DNA synthesis of his tumor cells in vitro. OK-432 itself had no significant effect on DNA synthesis of his tumor cells in vitro. This report describes a patient in whom OK-432-induced neutrophils may play an important role in his tumor cell destruction in ascites.

Topics: Adenocarcinoma; Aged; Ascites; Ascitic Fluid; Biological Products; Cytotoxicity, Immunologic; DNA, Neoplasm; Gastrointestinal Neoplasms; Humans; Male; Neutrophils; Picibanil

Topics: Adenocarcinoma; Antibiotics, Antineoplastic; Biological Products; Carcinoma, Squamous Cell; Humans; Lung Neoplasms; Picibanil; Proteoglycans; Radiotherapy Dosage

Topics: Adenocarcinoma; Aged; Drug Therapy, Combination; Hexestrol; Humans; Male; Middle Aged; Mitomycins; Picibanil; Prostatic 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