picibanil and Lung-Neoplasms

Topics: Combined Modality Therapy; Humans; Immunotherapy; Immunotherapy, Adoptive; Killer Cells, Lymphokine-Activated; Lung Neoplasms; Picibanil; Pneumonectomy; Postoperative Care

Symptomatic malignant pleural effusions should be treated systemic chemotherapy in chemo-sensitive tumors such as small cell lung cancer, breast cancer, lymphoma, or ovarian cancer. In other non-chemo-sensitive malignancies including non-small cell lung cancer, water-sealed tube drainage and pleurodesis is the standard treatment of choice in most of the cases. Drugs for instillation should be blomycin or OK-432 if commercially available. Instead of the former standard drug tetracycline, doxycycline has been frequently used. As we have no randomized trials, this drug awaits phase III trials. Talc slurry has been accepted and counted as one of the standard choices in the western countries, however, it usually needs general anesthesia and adverse effects are not negligible. As we have little experience on this modality, it should not be considered as a standard treatment. Other antitumor drugs instillation, thoraco-abdominal shunting, and pleuro-pneumonectomy should be considered experimental because of the lack of randomized trials. Symptomatic pericardial malignant effusion or cardiac tamponade is an oncologic emergency. We had better to treat the patient immediately by pericardiocentesis under the cardiac echographic guidance. It should be reserved to solve in randomized trials that the best method would be pericardiocentesis alone, percutaneous continuous drainage, pericardial fenestration, or pericardio-thoraco fenestration. Instillation of drug like doxycycline, OK-432, or bleomycin, lacks phase III comparison and it should be categorized as experimental.

Topics: Antineoplastic Agents; Bleomycin; Breast Neoplasms; Carcinoma, Small Cell; Drainage; Female; Humans; Lung Neoplasms; Pericardial Effusion; Picibanil; Pleural Effusion, Malignant; Randomized Controlled Trials as Topic

The current prospective randomized study was designed to evaluate the safety and efficacy of combined intrapleural cisplatin and OK-432 (picibanil) plus hyperthermotherapy in patients with malignant pleural effusion (MPE).. A total of 358 patients with MPE due to end-stage malignancies were enrolled and randomly divided into two groups, A and B: the intrapleural combination of cisplatin and OK-432 with hyperthermotherapy (n = 179) or without hyperthermotherapy (n = 179), respectively. Mild toxicities such as nausea, vomiting or anorexia, bone marrow depression, and pyrexia were similar in both groups.. Patients in Group A (with hyperthermotherapy) showed a significantly higher overall response (93.4%) compared to those in Group B (79.8%, χ(2) = 43.11, p < .05). The median survival time for patients in Group A and Group B were 8.9 and 6.2 months, respectively (p > .05). After treatment, the quality of life scores were significantly increased in both groups as compared to prior treatment (p < .05).. In conclusion, our study suggests that combined intrapleural cisplatin and OK-432 followed by hyperthermotherapy are more effective in the control of MPE and improve patients' quality of life.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Combined Modality Therapy; Female; Humans; Hyperthermia, Induced; Lung Neoplasms; Male; Middle Aged; Picibanil; Pleural Effusion, Malignant; Prospective Studies; Quality of Life; Survival Analysis

To evaluate the efficacy and toxicity of three intrapleural therapy regimens consisting of bleomycin (BLM), OK-432 (a pulverized product of heat-killed Streptococcus pyogenes) or cisplatin plus etoposide (PE) for the management of malignant pleural effusion (MPE) in previously untreated non-small cell lung cancer. Eligible patients were randomized to the BLM arm: BLM 1mg/kg (maximum 60mg/body), the OK-432 arm: OK-432 0.2 Klinische Einheit units (KE)/kg (maximum 10KE/body), or the PE arm: cisplatin (80mg/m(2)) and etoposide (80mg/m(2)). Pleural response was evaluated every 4 weeks according to the study-specific criteria. All responders received systemic chemotherapy consisting of PE every 3-4 weeks for two or more courses. Pleural progression-free survival (PPFS) was defined as the time from randomization to the first observation of pleural progression or death due to any cause. The primary endpoint was the 4-week PPFS rate. Of 105 patients enrolled, 102 were assessed for response. The 4-week PPFS rate for the BLM arm was 68.6%, 75.8% for the OK-432 arm, and 70.6% for PE arm. Median survival time (MST) for the BLM arm was 32.1 weeks, 48.1 weeks for the OK-432 arm, and 45.7 weeks for the PE arm. However, the outcomes did not differ significantly between groups. Toxicity was tolerable in all arms except for one treatment-related death due to interstitial pneumonia induced by BLM. We will select intrapleural treatment using OK-432 in the management of MPE in NSCLC for further investigation because it had the highest 4-week PPFS rate.

Topics: Adult; Aged; Bleomycin; Carcinoma, Non-Small-Cell Lung; Cisplatin; Drug Therapy, Combination; Female; Humans; Lung Neoplasms; Male; Middle Aged; Picibanil; Pleural Effusion, Malignant; Survival Rate

To evaluate the efficacy of combined intrapleural therapy with cisplatin, an antineoplastic agent, and OK432, a sclerosing agent, in controlling malignant pleural effusions, when compared with monotherapy with either agent.. A total of 49 non-small cell lung cancer patients with malignant pleural effusion were randomly assigned to one of three groups: intrapleural cisplatin therapy (n = 17), intrapleural OK432 therapy (n = 17), or both (n = 15). They were compared in terms of success rate, duration of indwelling chest tube and adverse reactions.. Rates of pleural effusion recurrence within 180 days following cisplatin, OK432, or combination therapy were 64.7%, 52.9% and 13.3%, respectively, being significantly lower in the combination therapy group (P = 0.01). The mean duration of chest tube drainage was 8.4 days, 5.5 days and 12.9 days, respectively, being significantly longer in the combination therapy group (P < 0.001). All procedures were well tolerated.. Although chest tube drainage took longer because of the time required for multiple administration of the agents, intrapleural combination therapy with cisplatin and OK432 was more effective in controlling malignant pleural effusions due to non-small cell lung cancer than monotherapy with either agent.

Topics: Aged; Analysis of Variance; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Female; Humans; Lung Neoplasms; Male; Middle Aged; Picibanil; Pleural Effusion, Malignant; Prospective Studies; Survival Analysis

Malignant pleural effusion, a common complication seen in advanced lung cancer patients, is often treated with intrapleural administration of chemical agents. In Japan, OK-432, a biological response modifiers, which activates the cytotoxic activity of lymphocytes and boosts antitumor immunity, is among the most frequently used chemical agents. The purpose of this study was to determine, in a case-control study, whether or not the rate of lymphocytes in malignant pleural effusion (lymphocyte rate) influences the therapeutic efficacy of intrapleural OK-432.. We enrolled 20 lung cancer patients with malignant pleural effusion treated with intrapleural OK-432 who were admitted to our hospital between January 2000 and December 2004. Therapeutic efficacy was assessed from the response rate, duration of chest drainage after treatment with intrapleural OK-432, time to progression of malignant pleural effusion, and survival time.. Response rate in patients who had a high lymphocyte rate (the High lymphocyte rate group) was significantly higher than in patients who had a low lymphocyte rate (the Low lymphocyte rate group). Lymphocyte rate did not correlate with duration of chest drainage after treatment with intrapleural OK-432, time to progression of malignant pleural effusion, or survival time.. The lymphocyte rate in malignant pleural effusion influences the response rate to treatment by intrapleural OK-432. In the High lymphocyte rate group, intrapleural OK-432 for malignant pleural effusion was effective. We conclude that intrapleural OK-432 is useful for malignant pleural effusion patients with a high lymphocyte rate before treatment.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Case-Control Studies; Disease Progression; Drainage; Female; Humans; Lung Neoplasms; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Picibanil; Pleural Cavity; Pleural Effusion, Malignant; Survival Rate

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 current prospective randomized study was designed to compare the effects of intracavitary (i.c.) chemotherapy vs immunotherapy vs immunochemotherapy for malignant effusion. Between 1992 and 1995, a total of 42 patients with malignant effusion were registered, and 41 patients were eligible for statistical analysis. The primary diseases of the eligible patients included 27 gastric, four colorectal, four pancreatic, three lung, two liver and one oesophageal cancers. The patients with malignant effusion were randomly assigned into one of three i.c. therapeutic regimens: chemotherapy alone with weekly injection of anticancer agents (ACAs: cisplatin, mitomycin-C, adriamycin, etc.) (Group A, n = 13); immunotherapy alone with weekly injection of streptococcal preparation OK-432 (Group B, n = 14); or immunochemotherapy with ACAs and OK-432 (Group C, n = 14). The response of the effusion, patient survival and the kinetics of cytokines in the effusion were compared. There were no differences in the patients' backgrounds. The side-effects of the regimens included pain, anorexia, fever, leucopenia and anaemia and there were no differences in their incidence among the three groups. One patient died after cisplatin (CDDP) administration in Group A. Cytologic examination revealed that tumour cells in the effusion disappeared in 23% of Group A cases, 36% of Group B cases and 36% of Group C cases. The malignant effusion did not disappear in any of the Group A cases; however, the effusion disappeared in 29% of Group B cases and 43% of Group C cases (P = 0.03, Group A vs Group C). Furthermore, the 50% survival period was 1.6 months for Group A, 2.4 months for Group B and 3.5 months for Group C. The 6-month survival rate was 7% for Group A, 6% for Group B and 34% for Group C, and the 1-year survival rate was 0%, 0% and 17% respectively (P = 0.048, Group A vs Group C by the log-rank test). The analysis of the cytokine kinetics revealed a prominent increase in the level of interleukin-6 in the effusion in Group C. These results suggest that i.c. immunochemotherapy with OK-432 and ACAs may be more beneficial than i.c. chemotherapy alone or immunotherapy alone.

Topics: Adjuvants, Immunologic; Aged; Antineoplastic Combined Chemotherapy Protocols; Ascitic Fluid; Cisplatin; Combined Modality Therapy; Cytokines; Digestive System Neoplasms; Doxorubicin; Female; Humans; Injections, Intralesional; Lung Neoplasms; Male; Middle Aged; Mitomycin; Patient Selection; Picibanil; Pleural Effusion, Malignant; Prospective Studies

The efficacy of postoperative adjuvant chemo- and chemoimmunotherapy in non-small cell lung cancer was evaluated in a multicentric prospective randomized study. From September 1987 to June 1990, resected lung cancer patients were randomly stratified into three groups. Group A received 2 courses of chemotherapy with CDDP and VDS following operation. Group B was administered UFT daily for 1 year after 2 courses of CDDP. Group C received intrapleural administration of OK-432 after lung resection, then UFT and OK-432 once every 2 weeks for 1 year. Out of 94 cases, analyses were carried out on 87 of eligible cases. The five-year survival rate was 56.8% in stage I (43 cases), 73.3% in stage II (12 cases), 18.8% in stage IIIA (24 cases), 50% in stage IIIB (2 cases) and 33.3% in stage IV (6 cases). The five-year survival rate in group A was 32.2%, 55.2% in group B and 53.9% in group C, and no statistical difference was recognized between 3 groups. But in the cases of noncurative resection, the 5-year survival rate was significantly low in group A compared with Group B or C. Similarly, the cases with low-grade TP (<6.0 g/dl) or low response of PPD skin reaction (< 12mm) showed a significantly low 5-year survival rate only in group A. From these results, it was suspected that aggressive chemotherapy provides no benefit for postoperative lung cancer patients with advanced disease.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Chemotherapy, Adjuvant; Cisplatin; Combined Modality Therapy; Drug Combinations; Female; Humans; Japan; Lung Neoplasms; Male; Middle Aged; Picibanil; Prospective Studies; Survival Rate; Tegafur; Uracil; Vindesine

Establishment of optimal dosage of OK-432, a streptococcal preparation, was studied based on its skin test was studied. Locoregional immunotherapy using OK-432 was conducted for patients with malignant fluids. More OK-432 was administered to patients having a weaker skin reaction to OK-432 and less to those having a stronger one, corresponding to their redness diameter of skin reaction. There was a marked difference in OK-432-skin test among patients. Some patients with malignant fluids having small redness responded to the treatment after a large amount of OK-432, and others were well controlled by a smaller dosage of OK-432. It is suggested that OK-432-skin test may provide the optimal dosage for local treatment of malignant fluids.

Topics: Ascitic Fluid; Breast Neoplasms; Chemotherapy, Cancer, Regional Perfusion; Female; Gastrointestinal Neoplasms; Humans; Immunotherapy; Injections, Intralesional; Lung Neoplasms; Male; Picibanil; Skin; Skin Tests

A prospective randomized study to evaluate the effect of adjuvant intrapleural OK-432 immunotherapy after resection of lung tumor was conducted in 93 patients with primary lung cancer. Among them, 46 patients had had intrapleural OK-432 injection, 47 had not. In the meantime, serial measurements of serum immunosuppressive acidic protein, of serum interleukin-2 receptor and of the subpopulation of the peripheral blood cells and lymphocytes were performed in all these patients. Patient characteristics in these two groups (sex, age, histological type, pathological stage, type of operation, and performance status) were compatible. The results showed that adjuvant intrapleural OK-432 injection after resection had no beneficial effect on a patient's survival time. Patients who received intrapleural OK-432, had an increase in blood leukocytes, granulocytes and monocytes and serum immunosuppressive acidic protein level. But the cell numbers of total T cells, suppressor/cytoxic cells, helper/inducer cells and natural killer cells of peripheral blood were decreased in the OK-432 positive group. Over half of the patients had transient 1- or 2-day febrile reactions after intrapleural OK-432 injection. It was concluded that neither clinical observation nor immunological monitoring of peripheral blood could demonstrate a beneficial effect from intrapleural OK-432 immunotherapy after complete resection of the tumor.

Topics: Adjuvants, Immunologic; Aged; Combined Modality Therapy; Drug Administration Routes; Female; Humans; Immunotherapy; Leukocyte Count; Leukocytes; Lung Neoplasms; Male; Middle Aged; Picibanil; Pleura; Prospective Studies

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

To evaluate the clinical efficacy of OK-432 immunotherapy, patients admitted between 1975 and 1982 were randomized into two groups: An immunochemotherapy (IM-C) group and a chemotherapy (control) group. For each group, a fixed chemotherapy was administered using a combination of three drugs. The survival rates of cases with non-small cell carcinoma were evaluated at the end of 1987. One hundred and fifty-seven cases in the IM-C group and 148 in the control group were eligible for evaluation of long-term survival rates. Statistically significant improvement of the survival rates in the IM-G group were noted in the following items: All cases, resected cases, non-resected cases, resected stage I + II cases, resected stage III cases, completely resected cases, incompletely resected cases, and cases with epidermoid carcinoma. However, in comparison of adenocarcinoma there was no significant difference between the two groups. SU-polysaccharide skin test and natural killer activity were the best immunological parameters during the OK-432 therapy. To intensify the effects of immunotherapy, a possibility of regional immunotherapy was studied following some experimental works. Regional infusion of LAK cells (induced by incubation of patient's lymphocytes with rIL-2) through bronchial artery after regional infusion of OK-432 and chemotherapeutics showed favorable effect for advanced lung cancer. Future prospect of these regional adoptive immunotherapy was discussed.

Topics: Biological Products; Humans; Immunotherapy; Interleukin-2; Killer Cells, Lymphokine-Activated; Lung Neoplasms; Picibanil; Survival Rate

A streptococcal preparation, OK-432, was employed as the adjuvant immunotherapeutic agent combined with chemotherapy in cases of lung cancer. To evaluate the clinical efficacy of OK-432, patients admitted between 1975 and 1982 were randomized into two groups: an immunochemotherapy, or immunotherapy, group and a chemotherapy, or control, group. For each case, a fixed protocol of chemotherapy was administered using a combination of three drugs. In this study, cases with small cell lung cancer were excluded, and the survival rates of cases with non-small cell lung cancer were evaluated. One hundred fifty-nine cases in the immunotherapy group and 152 cases in the control group were eligible for evaluation of long-term survival rates. When comparing the prognosis of the two groups, statistically significant improvements of the survival rate in the immunotherapy group were noted in the following categories: all cases, resected cases, nonresected cases, resected stage I + II cases, resected stage III + IV cases, completely resected cases, incompletely resected cases, and cases with epidermoid carcinoma. From the results of the present study, it is concluded that OK-432 is a potent immunopotentiative agent in the treatment of lung cancer.

Topics: Adjuvants, Immunologic; Adult; Aged; Biological Products; Carcinoma; Combined Modality Therapy; Female; Humans; Immunotherapy; Lung Neoplasms; Male; Middle Aged; Picibanil; 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

A randomized controlled study was performed to evaluate the efficacy of intrapleural and systemic administration of OK-432, streptococcus preparation, in patients with cancerous pleurisy. A total of 53 patients were accessed to the study: 29 patients for the OK-432 group and 24 patients for the control group. Intrapleural instillation of 50 mg of adriamycin and a combination chemotherapy of MFC (mitomycin C 0.08 mg/kg, 5-FU 10 mg/kg, ara-C 0.8 mg/kg iv, weekly) were administered in both groups. In the OK-432 group intrapleural instillation of 2 units of OK-432 was administered daily until disappearance of pleural effusion; thereafter, 2 to 5 units of OK-432 were administered intradermally every other day. Patients with stage III in the OK-432 group survived significantly longer than those in the control group (P less than 0.05), but there was no significance between in patients with stage IV of both treatment groups. Also patients with PPD negative skin reaction at the time of beginning of treatment in the OK-432 group survived significantly longer than those in the control group (P less than 0.001), but there was no significance between both treatment groups in patients with PPD positive skin reaction at the time of beginning of treatment. Eighteen (62%) of 29 patients treated with OK-432 had a fever, but well tolerated.

Topics: Adult; Aged; Biological Products; Clinical Trials as Topic; Female; Humans; Lung Neoplasms; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Pleural Neoplasms; Pleurisy; Random Allocation

We conducted a prospectively controlled study of adjuvant immunochemotherapy for resectable lung cancer in 37 cases of the control group, in 34 cases of levamisole group and in 40 cases of OK-432 group. No significant difference was noted in patient characteristics of age, sex, histological type, stage, cure rate, etc. The survival rates were calculated by Kaplan and Meier method. Survival curves were measured by generalized Wilcoxon test and Cox-Mantel test. When the levamisole group and the control group were compared in terms of survival rate, a significant increase of survival curves of patients treated with levamisole was observed in surgicopathological stage III + IV and relative curative operation groups (p less than 0.05). The survival rate of levamisole group was higher than that of OK-432 group in patients of surgicopathological stage III and III + IV (p less than 0.05). There was no statistically significant difference between OK-432 group and the control group, when in survival rates.

Topics: Adult; Aged; Antineoplastic Agents; Biological Products; Clinical Trials as Topic; Drug Therapy, Combination; Female; Humans; Levamisole; Lung Neoplasms; Male; Middle Aged; Picibanil

Topics: Aged; Antineoplastic Agents; Catheter Ablation; Colonic Neoplasms; Combined Modality Therapy; Female; Humans; Injections, Intralesional; Liver Neoplasms; Lung Neoplasms; Picibanil; Radio Waves; Remission, Spontaneous; Reoperation; Tomography, X-Ray Computed

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

To evaluate whether antitumor immunity is enhanced systemically by combining radiofrequency ablation (RFA) and local injection of an immunostimulant, OK-432.. Experiments were approved by the institutional animal care committee. Experimental Japanese rabbits inoculated with VX2 tumors in the lung and the auricle were randomized into four groups of eight: control (supportive care), RFA (RFA of lung tumor), OK-432 (direct injection of OK-432 into lung tumor), and combination therapy (lung RFA and direct OK-432 injection into lung tumor). All procedures were performed 1 week after implantation of VX2 tumors (week 1). In addition, a VX2 tumor rechallenge test was performed in the RFA and combination therapy groups. Survival time was evaluated by means of the Kaplan-Meier method and by using the log-rank test for intergroup comparison. Mean auricle tumor volumes were calculated every week. Specific growth rates (SGRs) were calculated and compared by using the Mann-Whitney test.. The median survival times of the control, RFA, OK-432, and combination therapy groups were 23, 36.5, 46.5, and 105 days, respectively. Survival was significantly prolonged in the combination therapy group when compared with the other three groups (P <.05). The mean auricle tumor volume decreased only in the combination therapy group. The mean auricle tumor volumes of the combination therapy group from week 1 to week 7 were 205, 339, 264, 227, 143, 127, and 115 mm(3). SGR in the combination therapy group became significantly smaller than those in the other three groups (P < .05). In the rechallenge test, the volume of all reimplanted tumors decreased.. Combining RFA with local injection of immunostimulant OK-432 may lead to indirectly activation of systemic antitumor immunity.

Topics: Animals; Catheter Ablation; Cell Line, Tumor; Combined Modality Therapy; Injections, Intralesional; Lung Neoplasms; Picibanil; Proportional Hazards Models; Rabbits; Random Allocation; Statistics, Nonparametric; Survival Rate

Hamamoto et al (1) were able to demonstrate that combination therapy of a lung tumor by using radiofrequency ablation (RFA) with local injection of an immunostimulant, OK-432, resulted in improved survival when compared with other therapies tested in a VX2 rabbit model. In addition, not only was greater tumor regression seen in a second distant ear tumor implanted prior to the therapy, but also reduced tumor growth was seen when a second tumor implantation (ie, rechallenge) was attempted. These factors strongly suggest the successful activation of systemic antitumor immunity using this approach in this specific tumor model.

Topics: Animals; Catheter Ablation; Lung Neoplasms; Picibanil

Chylothorax is a relatively rare complication of thoracic surgery. Most instances of chylothorax after pulmonary resection are diagnosed within 3 days after surgery. Hence, late-onset chylothorax is rare. A 68-year-old woman underwent right lower lobectomy and mediastinal dissection for lung cancer. After discharge, the patient developed a dry cough, and chest radiography more than 3 months after surgery revealed a right-sided pleural effusion occupying more than half of the right hemithorax, which we diagnosed as late-onset chylothorax. Treatment comprised chest drainage, subcutaneous octreotide, and pleurodesis by injecting a preparation of OK-432. Follow-up chest radiography confirmed no reaccumulation of fluid. Three months later no recurrence of pleural effusion was detected. We report a rare case of postoperative late-onset chylothorax that proved difficult to treat.

Topics: Aged; Chest Tubes; Chylothorax; Combined Modality Therapy; Drainage; Female; Humans; Lung Neoplasms; Octreotide; Parenteral Nutrition, Total; Picibanil; Pleural Effusion; Pleurodesis; Pneumonectomy; Time Factors; Treatment Outcome

A 69-year-old man was diagnosed as having syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (serum sodium: 113 mEq/L) 13 days after a right upper lobectomy due to squamous cell carcinoma of the lung (pT1N0M0, stage IA) whereas the preoperative serum sodium level was nearly normal. He had undergone pleurodesis by instillation of OK432 at 2 and 5 days after surgery for prolonged air leakage. Since other possible causes of SIADH, such as residue of lung cancer, pulmonary infections, brain disorders, or known causative drugs were ruled out, the SIADH in this patient was likely associated with pleurodesis by the use of OK-432. A review of similar cases reported suggests that it is important to be aware of the possibility of severe hyponatremia due to SIADH after chemical pleurodesis.

Topics: Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Combined Modality Therapy; Humans; Hyponatremia; Inappropriate ADH Syndrome; Lung Neoplasms; Male; Picibanil; Pleurodesis; Sodium

We evaluated the possible induction of a systemic immune response to increase anti-tumour activity by the re-implantation of destructive tumour tissue treated by liquid nitrogen in a murine osteosarcoma (LM8) model. The tumours were randomised to treatment by excision alone or by cryotreatment after excision. Tissue from the tumour was frozen in liquid nitrogen, thawed in distilled water and then re-implanted in the same animal. In addition, some mice received an immunological response modifier of OK-432 after treatment. We measured the levels of interferon-gamma and interleukin-12 cytokines and the cytotoxicity activity of splenocytes against murine LM8 osteosarcoma cells. The number of lung and the size of abdominal metastases were also measured. Re-implantation of tumour tissue after cryotreatment activated immune responses and inhibited metastatic tumour growth. OK-432 synergistically enhanced the anti-tumour effect. Our results suggest that the treatment of malignant bone tumours by reconstruction using autografts containing tumours which have been treated by liquid nitrogen may be of clinical value.

Topics: Abdominal Neoplasms; Animals; Antineoplastic Agents; Bone and Bones; Bone Neoplasms; Cryopreservation; Female; Interferon-gamma; Interleukin-12; Lung Neoplasms; Mice; Mice, Inbred C3H; Nitrogen; Osteosarcoma; Picibanil; Random Allocation; Replantation

We herein describe the case of a 20-year-old woman who was diagnosed as having tuberous sclerosis complex (TSC) at the age of 10 years. The patient had a history of right pneumothorax at the age of 19. This time, a right pneumothorax recurrence was detected, and video-assisted thoracoscopic surgery (VATS) was performed. In the intraoperative findings, an infinitesimal lung cyst was detected on the lung lobe, and partial resection was performed. Pathologically, antibody-positive smooth muscle cells of the human melanoma block (HMB)-45 had grown and been diagnosed as pulmonary lymphangioleiomyomatosis (LAM). About half a year later, left pneumothorax occurred, and VATS was performed again. Pathologically, antibody-positive smooth muscle cells of HMB-45 were not detected. Occasionally, TSC is known to cause LAM complications, but in some cases it is difficult to make an accurate pathological diagnosis. Making a pathological diagnosis based on the VATS findings and taking a sufficient amount of tissue specimen are considered useful for making the diagnosis.

Topics: Adult; Antigens, Neoplasm; Antineoplastic Agents; Female; Humans; Incidental Findings; Lung Neoplasms; Lymphangioleiomyomatosis; Melanoma-Specific Antigens; Myocytes, Smooth Muscle; Neoplasm Proteins; Picibanil; Pneumothorax; Receptors, Estrogen; Receptors, Progesterone; Thoracic Surgery, Video-Assisted; Treatment Outcome; Tuberous Sclerosis

The patient was a 40-year-old woman who was admitted to our hospital because of severe cough and dyspnea due to multiple lung metastases from breast cancer, who had undergone Auchincloss operation for right breast cancer about five years earlier. While systemic chemotherapy (CAF) was started after admission,she presented with cardiac tamponade. A cardiac echogram revealed marked retention of pericardial effusion. Pericardiocentesis was carried out, and the cytology of the effusion showed class V, resulting in the diagnosis of carcinomatous cardiac tamponade due to breast cancer. She was treated with intrapericardial chemotherapy using OK-432 and mitomycin C (MMC), and has not suffered from pericardial effusion after the intrapericardial chemotherapy. Intrapericardial chemotherapy using OK-432 and MMC may be very useful for malignant pericardial effusion.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Carcinoma, Ductal, Breast; Cardiac Tamponade; Drug Administration Schedule; Female; Humans; Lung Neoplasms; Mitomycin; Pericardial Effusion; Pericardiocentesis; Picibanil; Quality of Life

We report a case of cerebral arterial air embolism that was followed by a brain computed tomographic scan and magnetic resonance imaging during the first week after onset. A 73-year-old man was admitted for treatment of pleural dissemination that was a recurrence after right lower bilectomy for advanced lung cancer. Thirty minutes after an anti-drug administration through the chest drainage tube, he lost consciousness shortly after coughing. A bubble in the inferior sagittal sinus was observed on the day of the stroke, which then disappeared within 24 hours. It seems that the anti-cancer agent evoked inflammation at the visceral pleura and the subject inhaled massive air flow into the systemic circulation.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Brain Edema; Brain Ischemia; Bronchial Fistula; Carcinoma, Squamous Cell; Cerebral Infarction; Chest Tubes; Cisplatin; Coma; Combined Modality Therapy; Cough; Disease Progression; Embolism, Air; Fatal Outcome; Fistula; Hemiplegia; Humans; Injections; Intracranial Embolism; Lung Neoplasms; Lymph Node Excision; Male; Picibanil; Pleura; Pleural Cavity; Pleural Effusion, Malignant; Pneumonectomy; Postoperative Complications; Pulmonary Veins

A 42-year-old man had swelling in the right side of the neck, cough and chest pain. On admission, an abnormal shadow was detected in the right upper lung field and squamous cell carcinoma of the lung with superior vena cava (SVC) syndrome was diagnosed. Concurrent radiotherapy and systemic chemotherapy consisting of cisplatin and vinorelbine induced a partial response. At 15 months after diagnosis, he was re-admitted because of bilateral pleural effusion and facial edema due to relapse of SVC syndrome. Examination of the milky right pleural effusion revealed chylothorax (959mg/dl of beta-lipoprotein and 675mg/dl of triglyceride). The right effusion was finally controlled by pleurodesis with OK-432. Non-traumatic chylothorax is a rare complication of lung cancer.

Topics: Adult; Antineoplastic Agents; Carcinoma, Squamous Cell; Chylothorax; Fatal Outcome; Humans; Lung Neoplasms; Male; Picibanil; Pleurodesis; Superior Vena Cava Syndrome; Treatment Outcome

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

Malignant pleural effusion is typical of complications in advanced lung cancer patients, most of whom complain of dyspnea. The standard treatment for symptomatic pleural effusion is intrapleural administration of a chemical agent. In Japan, OK-432, a streptococcal preparation, and cisplatin (CDDP) have been among the most frequently used chemical agents. There have been very few reports on the efficacy of chemical agents for malignant pleural effusion. We compared therapeutic efficacy and toxicity of intrapleural OK-432 with CDDP in a case-control study. The subjects consisted of 32 lung cancer patients with malignant pleural effusion who were admitted to our hospital between January 2000 and June 2004. The therapeutic efficacy was assessed from duration of chest drainage after intrapleural administration, response rate, time to progression of malignant pleural effusion, and survival time. No statistically significant difference was observed for therapeutic efficacy. Although the OK-432-treated group had only grade 1 fever, chest pain, nausea, the CDDP-treated group had a grade 2 increase in creatinine and grade 3 nausea. Intrapleural OK-432 seemed to be better tolerated in the treatment of malignant pleural effusion than intrapleural CDDP.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Case-Control Studies; Cisplatin; Disease Progression; Drainage; Female; Humans; Lung Neoplasms; Male; Middle Aged; Picibanil; Pleural Cavity; Pleural Effusion, Malignant

Malignant pleural effusion develops frequently in patients with advanced lung cancer. Chemical pleurodesis is the most effective palliative treatment for these patients. The efficacy of pleurodesis using both OK-432, a preparation of Streptococcus pyogenes, and doxorubicin for 20 patients with cytology-proven malignant pleural effusion associated with lung cancer was evaluated. After complete removal of pleural effusion, OK-432 and 30 mg of doxorubicin were injected via an inserted chest tube. Treatment was terminated when the volume of daily drainage reached <200 mL. If the daily volume remained >200 mL, an additional OK-432 was administered every 3 days. In total, 16 patients (80%) revealed a complete response, two patients (10%) revealed a partial response, and no response was seen in two patients. Eighteen patients with complete or partial responses did not show subsequent reaccumulation of pleural effusion after pleurodesis. The chest tube remained in place for an average of 6.4 days, draining a mean of 2,854 mL. The main side-effects were fever and pain that were easily treated with nonsteroidal anti-inflammatory drugs. Pleurodesis using both OK-432 and doxorubicin showed high efficacy for controlling malignant pleural effusions caused by lung cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Doxorubicin; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Injections, Intralesional; Lung Neoplasms; Male; Middle Aged; Picibanil; Pleural Effusion, Malignant; Pleurodesis; Prospective Studies; Remission Induction; Risk Assessment; Tomography, X-Ray Computed; Treatment Outcome

We evaluated the efficacy of pleurodesis using OK-432 (Picibanil) for the treatment of pneumothorax associated with pulmonary lymphangioleiomyomatosis (LAM). Seven episodes of pneumothorax in five patients with LAM were treated with pleurodesis using OK-432. First, all patients underwent tube thoracostomy drainage. After drainage, 5 or 10 KE of OK-432 was administered via the tube. If incomplete lung expansion or a continuous air leak occurred, an additional 5 KE of OK-432 was administered. Of the five patients, two developed pneumothorax for the first time and three had a history of previous pneumothorax. The mean total dose of OK-432 administered was 13.6 KE, and the mean period of tube drainage was 11 days. The only recurrence of ipsilateral pneumothorax after OK-432 pleurodesis was observed seven years and eight months later in association with chronic respiratory failure in one patient. This patient was successfully treated with repeated pleurodesis using OK-432 during mechanical ventilation, and no recurrence has developed in the eight years since then. The main side effects of the procedure with OK-432 were fever and chest pain, which were well controlled by non-steroidal anti-inflammatory drugs. The study concluded that pleurodesis with OK-432 was an effective and safe treatment for intractable and recurrent pneumothorax associated with LAM.

Topics: Adult; Female; Humans; Lung Neoplasms; Lymphangioleiomyomatosis; Middle Aged; Picibanil; Pleurodesis; Pneumothorax; Recurrence; Retrospective Studies; Treatment Outcome

We reviewed our experience with iatrogenic chylothorax after pulmonary resections for lung cancer to evaluate our treatment strategy and to identify factors that predict the need for reoperation.. From July 1992 through February 2000, a total of 1110 patients underwent pulmonary resection (at least lobectomy) and systematic mediastinal lymph node dissection for lung cancer at our division. Twenty-seven patients (2.4%) had postoperative chylothorax develop. We initially treated 26 of these patients conservatively with complete oral intake cessation and total parenteral nutrition, and these patients constituted the subjects in this study.. There were 21 men and 5 women with a median age of 62 years (range 44 to 80 years). The initial procedures were pneumonectomy in 2 cases, bilobectomy in 1 case, and lobectomy in 23 cases. Twenty-one patients (81%) had the condition cured with conservative treatment. These patients resumed a normal diet at a median of 8 days after chylothorax diagnosis (range 4-35 days). The remaining 5 patients (19%) underwent reoperation at a median of 14 days after diagnosis (range 5-35 days). Chest tube drainage of less than 500 mL during the first 24 hours after complete oral intake cessation and total parenteral nutrition predicted a cure with conservative treatment.. Although most cases of chylothorax after pulmonary resection with systematic mediastinal lymph node dissection can be cured with a conservative strategy, early surgical intervention may be indicated if chest tube drainage is more than 500 mL during the first 24 hours after complete oral intake cessation and total parenteral nutrition.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Chylothorax; Female; Humans; Japan; Lung Neoplasms; Lymph Node Excision; Male; Middle Aged; Parenteral Nutrition, Total; Picibanil; Postoperative Complications; Predictive Value of Tests; Reoperation; Treatment Outcome

A lipoteichoic acid-related molecule (OK-PSA) isolated from OK-432, a penicillin-killed Streptococcus pyogenes, is a potent inducer of Th1 cytokines, and elicits anti-cancer effect in tumor-bearing mice. Toll-like receptor (TLR) 4 is a member of the recently identified toll-like receptor family of proteins that has been implicated in lipopolysaccharide-induced cell signaling. In the present study, we have examined the role of TLR4 for OK-PSA-induced Th1-cytokine production and anti-tumor effect by using C3H/HeJ mice in which TLR4 function is impaired. Although OK-PSA strikingly induced Th1 cytokines [interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-2, IL-12 and IL-18] in the splenocytes derived from control animals (C3H/HeN), OK-PSA did not induce the cytokines in the splenocytes from C3H/HeJ. Furthermore, C3H/HeJ-derived splenocytes acquired the responsiveness to OK-PSA stimulation by overexpression of TLR4 gene. Finally, OK-PSA administration significantly inhibited the tumor growth and lung metastasis of syngeneic squamous cell carcinoma cells in C3H/HeN; however, no effect of OK-PSA was observed in C3H/HeJ. These findings strongly suggest that TLR4 signaling is involved in regulating OK-PSA-induced anti-cancer immunity.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cell Line; Culture Media; Drosophila Proteins; Lipopolysaccharides; Lung Neoplasms; Membrane Glycoproteins; Mice; Mice, Inbred C3H; Mice, Knockout; Mutation; Penicillins; Picibanil; Receptors, Cell Surface; Spleen; Streptococcus pyogenes; Teichoic Acids; Toll-Like Receptor 4; Toll-Like Receptors; Transfection; Tumor Cells, Cultured

It is not clear whether postoperative inflammation affects the prognosis of malignant disease.. We retrospectively reviewed the patients with non-small-cell lung cancer who underwent a complete resection at the National Kyushu Cancer Center from 1989 to 1996. For the treatment of prolonged air leakage after a pulmonary lobectomy, 25 patients received an intrapleural injection of OK-432, a lyophilized preparation of the heat- and penicillin-treated Su-strain of the Streptococcus pyogenes group A3. All patients were males who were older than 50 years of age. As a control, we selected 164 male patients who were older than 50 years of age and not given OK-432 during the same period.. The administration of OK-432 in most patients was performed on the 4th day after the operation. Pleural drainage could be terminated in a mean of 5.5 days after the intrapleural administration of OK-432. In the control group, the serum C-reactive protein (CRP) level reached a peak on day 4 after the operation and returned to almost a normal level on day 14 after the operation. In the OK-432 group, the peak CRP level, which was significantly higher than that in the control group, was observed on day 7 after the operation and the elevated CRP level was maintained until 28 days after the operation. The mean level of CRP in the OK-432 group was significantly higher than that in the control on days 7, 14, and 28 after the operation. No significant difference was observed in the disease-free survivals between the two groups.. Based on the above findings, postoperative prolonged inflammation does not seem to affect the progression of subclinically residual tumor cells.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Disease-Free Survival; Humans; Inflammation; Injections; Lung Neoplasms; Male; Middle Aged; Picibanil; Postoperative Period; Prognosis; Retrospective Studies

After the establishment of transplantation law, the right pulmonary transplantation was done from the brain dead donor for the first time in Japan at the attached hospital of Institute of Development, Aging and Cancer, Tohoku University on March 29, 2000. The woman in 30's had been deteriorated from progressive lymphangiomyomatosis since 1984. She was waiting for the right lung transplantation in the related hospital of the Institute Hospital since May, 1999. A brain dead donor appeared in Tokyo. After receiving the information from Japan Organ Transplant Network, we immediately started for Tokyo in order to procure the lung. We carried the right lung by Shinkansen. The lung of the donor was transplanted to the patient under the partial extracorporeal circulation on March 29, 2000. The total operating time was 6 hours and 7 minutes: 5 hours and 20 minutes for total ischemic period of the lung and 2 hours and 7 minutes for using extracorporeal circulation. The total amount of bleeding during the operation was 3,695 ml. Postoperative course of the transplanted patient was fair except chylothorax in the operated side, which was successfully controlled by intrathoracic infusion with OK-432. The transplanted patient was discharged from the hospital after 75 days postoperatively.

Topics: Adult; Brain Death; Chylothorax; Female; Humans; Japan; Lung Neoplasms; Lung Transplantation; Lymphangioleiomyomatosis; Picibanil; Postoperative Complications; Tissue Donors; Treatment Outcome

Eleven patients with massive effusion due to pleuritis carcinomatosa were treated by tube drainage, followed by instillation of OK-432 and minocycline for pleurodesis. Pleural immunological and chemical reactions of adhesion were strongly induced by the use of these adhesive agents. As a result, pleural effusion was diminished in all patients without recurrence, allowing the drainage tubes to be successfully removed. As severe adverse effects following this course of therapy, high fever was observed in all patients, and acute renal failure in one. Blood chemical data from the patients revealed an increase in the number of granulocytes with a high level of interleukin-6 one day after instillation. These findings suggested that the symptoms of general inflammation were induced by local pleural inflammation. The median survival period was 253.7 days for 5 patients who were sufficiently fit to be discharged from our hospital. This was better than the historical average for the patients with uncontrolled pleural effusion. In conclusion, it was possible to control malignant pleural effusion and achieve longer survival periods through the optimal management of tube drainage and instillation of adhesion-inducing agents.

Topics: Aged; Aged, 80 and over; Anti-Bacterial Agents; Antineoplastic Agents; Drug Therapy, Combination; Female; Humans; Lung Neoplasms; Male; Middle Aged; Minocycline; Picibanil; Pleura; Pleural Effusion, Malignant

A 66-year-old man was admitted to our hospital because of bloody sputum. Chest computed tomographic scans disclosed a right hilar tumor. A tumor in the right upper-lobe bronchus was detected by fiberoptic bronchoscopy. Microscopic examination disclosed moderately differentiated squamous cell carcinoma. The patient was treated with irradiation and combination chemotherapy. Thereafter, right chylous pleural effusion developed and continued to accumulate. Pleurodesis was induced by the intrathoracic injection of OK-432 at 15 KE per dose. Lung cancer with nontraumatic chylothorax is rare. In our patient, pleurodesis with OK-432 was an effective treatment.

Topics: Aged; Carcinoma, Squamous Cell; Chylothorax; Combined Modality Therapy; Humans; Lung Neoplasms; Male; Picibanil; Pleurodesis; Treatment Outcome

Prolonged air leak with dead space after lobectomy was successfully treated with autoblood plus OK432 pleurodesis in 10 patients. We tried this method for the purpose of (1) reduction of dead space and (2) effective chemical sclerosis. This easy method was associated with acceptable side effects and should be considered as an option for the treatment of prolonged air leak after lobectomy, especially with dead space.

Topics: Blood; Combined Modality Therapy; Drainage; Humans; Lung Neoplasms; Picibanil; Pleurodesis; Pneumonectomy; Postoperative Complications; Sclerosing Solutions

We here report a case presenting with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH) after having been treated for pleurodesis with OK-432, which is a lyophilized preparation of an attenuated strain of Streptococcus pyogenes. The patient, who had undergone a subtotal esophagectomy 4 years previously, was referred to our department after the diagnosis of a metastatic lung tumor. A right lower lobectomy of the lung was performed, and prolonged air leakage from a pulmonary fistula thereafter developed because of the dissection of severe pleural adhesion. OK-432 (5 klinische einheiten) was administered to the pleural cavity 3 times. On the 13th postoperative day, the patient began to complain of general fatigue and nausea. SIADH was diagnosed based on laboratory findings such as hyponatremia, serum hypo-osmolality and a high excretion of sodium in the urine. A restriction of the fluid intake with a sodium supplement resulted in the return to a normal serum level within 2 weeks. We therefore concluded that the intrapleural instillation of OK-432 had apparently caused SIADH in this case, because no other causes could be found.

Topics: Antineoplastic Agents; Esophageal Neoplasms; Female; Follow-Up Studies; Humans; Inappropriate ADH Syndrome; Lung Diseases; Lung Neoplasms; Middle Aged; Picibanil; Pleural Diseases; Pleurodesis; Pneumonectomy; Respiratory Tract Fistula; Tissue Adhesions; Treatment Outcome

We examined the effect of OK-432 on induction of cytotoxic T lymphocytes (CTL) directed against autologous tumor cells (ATC) and lymphokine-activated killer (LAK) cells from mononuclear cells separated from regional lymph node cells (RLMNCs) of 49 lung cancer patients. We also examined the phenotypic changes of RLMNCs during incubation with or without OK-432. Significant CTL activity and LAK activity against ATC developed from RLMNCs after stimulation with OK-432 or IL-2. Sequential treatment with OK-432 plus IL-2 or IL-2 plus OK-432 also developed significant CTL activity and LAK activity from RLMNCs. The CTL activity produced by OK-432 alone was as high as the CTL activity developed by IL-2 alone, OK-432 plus IL-2, or IL-2 plus OK-432. There was no significant difference in the CTL activities achieved by these four treatments. The proportion of CD25+ cells in RLMNCs after incubation with OK-432 was twice that before incubation. Although OK-432 increased IL-2 receptor expression on RLMNCs, it showed no synergistic effect with IL-2 in developing CTL and LAK activity. After incubation with OK-432, the proportion of HLA-DR + cells was also increased significantly. Moreover, the proportions of HLA-ABC+ and HLA-DR+ (class I and class II major histocompatibility complex antigens) cells in ATC were significantly larger than in Daudi cells. OK-432 alone could develop CTL activity against ATC from the RLMNCs of lung cancer patients that was as high as that developed by IL-2 alone or by sequential treatment with OK-432 plus IL-2 or IL-2 plus OK-432. The CTL developed from the RLMNCs of lung cancer patients may recognize class I and/or II antigens on the surface of ATC. These results indicated that treatment with OK-432 might be therapeutically useful for lung cancer patients as a CTL inducer rather than a LAK inducer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Female; HLA-DR Antigens; Humans; Immunotherapy, Adoptive; Intercellular Adhesion Molecule-1; Interleukin-2; Killer Cells, Lymphokine-Activated; Lung Neoplasms; Lymph Nodes; Male; Middle Aged; Phenotype; Picibanil; T-Lymphocytes, Cytotoxic

We investigated whether the combination treatment of 15 cGy total body irradiation (TBI) and a streptococcal preparation, OK-432, synergistically suppresses spontaneous lung metastasis and augments phytohemagglutinin (PHA) and concanavalin A (Con A) responses of splenocytes in WHT/Ht mice. TBI with 15 cGy was carried out 20 days after subcutaneous injection of squamous cell carcinoma cells into a hind leg. Lung colony number was counted 40 days after tumor injection. For PHA and Con A responses, mice were killed 4 hr after 15 cGy TBI. The combination treatment of 15 cGy TBI and OK-432 was most effective when OK-432 was administered 2 days before 15 cGy TBI. The combination treatment decreased the lung colony number to 29.9% of the control number. OK-432 slightly increased the PHA and Con A responses, and 15 cGy TBI did not increase them. However, when these two were combined, the PHA and Con A responses were significantly increased to 393% and 278% of the control levels, respectively. It was suggested that TBI and OK-432 acted synergistically in suppressing the lung metastasis and mitogenic response of splenocytes.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Cells, Cultured; Combined Modality Therapy; Disease Models, Animal; Dose-Response Relationship, Radiation; Female; Growth Substances; Lung Neoplasms; Mice; Mice, Inbred Strains; Picibanil; Radiation Dosage; Spleen; Whole-Body Irradiation

We investigated the efficacy of the streptococcal preparation OK-432 as an adjuvant for in vivo priming in induction of sensitized cells for adoptive immunotherapy of the poorly immunogenic B16-BL6 (BL6) melanoma. C57BL/6 (B6) mice were immunized subcutaneously (s.c.) with 3 x 10(6) viable BL6 tumor cells admixed with various doses of OK-432 ranging from 1 to 100 micrograms in the foot-pad. Draining popliteal lymph nodes (LNs) were harvested 7 days after immunization and LN cells were further sensitized with irradiated tumor cells in the presence of 60-300 IU/ml of IL-2 for 11 days. These in vitro sensitized (IVS) cells (2 x 10(6)) were transferred intravenously (i.v.) to B6 mice bearing 4-day pulmonary metastases established by i.v. injection of 2-4 x 10(5) viable BL6 cells. The mice were also received intraperitoneally (i.p.) 4 x 10(4) IU/day of IL-2 for 4 days after adoptive transfer. Transfer of IVS cells from mice immunized by s.c. injection of tumor cells admixed with 10 micrograms of OK-432 significantly reduced the numbers of BL6 pulmonary metastases compared with that of control IVS' cells without the administration of OK-432 (P = 0.003). These effective IVS cells also significantly prolonged the survival of treated animals (P = 0.003). Functional IVS cells required in vitro stimulation with tumor cells. However, addition of OK-432 in the vaccine resulted in no enhancement of in vitro cytotoxicity and no characteristic change of phenotype of IVS cells. These results suggest that in vivo priming of OK-432 facilitates the sensitization of tumor-reactive T-cells. The procedure of in vivo priming with OK-432 may be beneficial in the adoptive immunotherapy of melanoma.

Topics: Animals; Female; Immunization; Immunotherapy, Adoptive; Lung Neoplasms; Lymphoid Tissue; Melanoma, Experimental; Mice; Mice, Inbred C57BL; Phenotype; Picibanil; T-Lymphocytes; Tumor Cells, Cultured

Eight patients who developed interstitial pneumonia after surgery for primary lung cancer were reviewed to investigate its causes and the key points in treatment. These patients accounted for 1.8% of 633 operated lung cancer patients at our institution over the last 9 years. Risk factors such as bilateral recurrent laryngeal nerve palsy, preoperative chemoradiotherapy, and extensive mediastinal involvement were present in all of them. Pneumonia developed on the nonoperated side in all patients between the 2nd and 45th postoperative day (mean: 18 days). In most of the patients, faint reticular shadows initially appeared in the lower lobe of the nonoperated lung, rapidly spread to the upper lobe, and finally affected the whole lung. Among these eight patients, the initial five patients died because steroids were only administered after the pneumonia had become widespread, whereas the last three patients received early steroid therapy and were saved. The findings that 1) this pneumonia originated from the lower lobe of the nonoperated lung where blood flow is highest postoperatively, 2) the eosinophil count increased just before the onset of pneumonia, and 3) early steroid therapy and immunosuppressive therapy were effective suggest that an allergic or autoimmune mechanism may play some role in its development. When characteristic reticular shadows appear in the lower lobe on the nonoperated side in a lung cancer patient, even if not associated with any symptoms, an early diagnosis of interstitial pneumonia and initiation of steroid therapy is mandatory to ensure survival.

Topics: Aged; Humans; Lung Diseases, Interstitial; Lung Neoplasms; Male; Middle Aged; Picibanil; Postoperative Complications; Risk Factors

We investigated the changes in cellular components and neutrophil chemotactic factors in pleural fluid from 19 lung cancer patients who received intrapleural injection of OK-432 to treat malignant pleurisy. Not only neutrophil chemotactic activity (NCA) but also neutrophil count and percentage were increased significantly at 6 hours after OK-432 injection. The neutrophil count was significantly correlated with NCA level. The levels of C5a and IL-8 in pleural fluid were increased significantly after OK-432 injection. The increased IL-8 level was associated with a increase of both NCA and neutrophil count. OK-432 treatment also induced a marked increase of IL-1 beta and IL-6 in pleural fluid. Thus, intrapleural injection of OK-432 induced production of neutrophil chemotactic factors (IL-8 and C5a) and cytokines (IL-1 beta and IL-6), which eventually attracted neutrophils into the pleural space. These observations suggest that neutrophil migration mediated by these factors and cytokines may contribute to the sclerosing effects of OK-432 treatment.

Topics: Adult; Aged; Chemotactic Factors; Complement C5a; Female; Humans; Interleukin-1; Interleukin-6; Interleukin-8; Leukocyte Count; Lung Neoplasms; Male; Middle Aged; Neutrophils; Picibanil; Pleural Effusion, Malignant

An 80-year-old woman with angiosarcoma of the scalp was treated with radiation and interleukin 2. The patient experienced dyspnea one month later because of pulmonary metastases, and underwent video-assisted thoracoscopic surgery for a right pneumothorax. Right hemopneumothorax recurred 3 weeks after the surgery and left hemopneumothorax occurred 4 months later. Both were successfully treated with intrapleural OK432 and drainage. As of March 1995 the patient had been alive and well for one year since the right pneumothorax developed.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Female; Hemangiosarcoma; Hemopneumothorax; Humans; Lung Neoplasms; Picibanil; Pleura; Skin Neoplasms

We report here a case of hepatocellular carcinoma (HCC) with multiple lung metastases, which were disappeared by treatment of OK-432. The patient was a 65-year-old man and was diagnosed in 1986 with a small (17 x 11 mm) HCC in the anterior-superior segment of the liver. A part of the right hepatic lobe including the tumor was surgically removed, and transarterial injections of adriamycin (10 mg/week) and subcutaneous injections of OK-432 (10 KE/week) were given. Two and a half years later, recurrence of HCC in the liver and its invasion to vena cava inferior (IVC) were found. OK-432 administration was then stopped and percutaneous ethanol injection therapy (PEIT) was performed 10 times. Six months later, the PEIT was effective and the liver tumor with IVC invasion diminished. However, multiple lung metastases were visible on roentgenograms of the chest, and serum alphafetoprotein (AFP) concentration increased to 50,000 ng/ml. The OK-432 treatment resumed. After 6 months of OK-432 treatment, the multiple lung metastases were disappeared and the serum AFP level decreased to 100 ng/ml. At present, the patient is surviving without any sign of recurrence in either the liver or the lung. The clinical course of this case suggests that OK-432 might have effectively treated lung metastases of HCC, although the exact mechanisms are at present unclear.

Topics: Aged; alpha-Fetoproteins; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Lung Neoplasms; Male; Picibanil

Metastases from breast or gastrointestinal cancers have been treated loco-regionally with immunotherapy using OK-432 and cultured autologous lymphocytes since 1983. Response rate for patients with liver, lung, or pleural metastases from breast cancer was 57%, 53%, 90%, respectively, and for those with liver metastases from gastric or colo-rectal cancer was 31% or 29%. Survival of the patients with liver, pleural metastases from breast cancer, or with peritoneal seeding from gastric cancer was prolonged when compared with historical controls. Immunotherapy was one of significant prognostic factor to prolong the survival in patients with pleural effusion from breast cancer, with Stage IV breast cancer, or with peritoneal seeding from gastric cancer. Moreover, concomitant regression of non-treated metastatic sites after the response of treated disease was often observed especially in breast cancer patients with both liver and bone metastases or with Stage IV disease. Thus, loco-regional immunotherapy can show a systemic beneficial effect.

Topics: Adult; Aged; Breast Neoplasms; Gastrointestinal Neoplasms; Humans; Immunotherapy, Adoptive; Killer Cells, Lymphokine-Activated; Liver Neoplasms; Lung Neoplasms; Middle Aged; Picibanil; Pleural Neoplasms; Tumor Cells, Cultured

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

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

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

A 61-year-old woman was admitted to our hospital because of hoarseness and abnormal shadow on chest X-ray. We diagnosed this patient as large cell carcinoma of the right upper lobe of the lung; T3N3M1 Stage IV. She was treated with OK-432, CDDP and CQ. On the 6th day after 2nd cycle chemotherapy, she was confused, and we diagnosed her as a case of hyperosmolar nonketotic coma (HNC) on the 7th day. Unfortunately, she died on the 8th day, after 20 hours of treatment for HNC. She suffered from chronic dehydration due to trouble with left recurrent nerve palsy. Although continuous intravenous hyperalimentation was used, she had severe HNC. HNC might be one complication in chemotherapy for patients with malignancy.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carbazilquinone; Carcinoma, Non-Small-Cell Lung; Cisplatin; Female; Humans; Hyperglycemic Hyperosmolar Nonketotic Coma; Infusions, Intravenous; Lung Neoplasms; Middle Aged; Parenteral Nutrition, Total; Picibanil

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

A total of 12 patients with advanced renal cell carcinoma received interferon alpha (3 million units intramuscularly 6 times weekly) and OK-432 (5 KE (Klinische Einheit) intramuscularly twice weekly). Metastatic lesions appeared before operation in six patients and after operation in six patients. Among them 5 patients had received interferon therapy and this combination therapy was started after the judgment of progressive disease for interferon therapy. Eleven pulmonary and 5 bone metastases were evaluable. The median duration of the combination therapy was 89.3 weeks. There were 4 partial responses and no complete responses among the 12 patients, giving a response rate of 33.3%. The median duration of response was 25 months, with a range of 6 to 54 months. Responses were seen predominantly in patients in whom metastases appeared after operation (3 of 4 responders). However, regarding the individual organs, two complete and 2 partial responses were observed among 11 pulmonary metastases and 2 partial responses among 5 bone metastases. The survival period after discovery of the metastasis was 10 to 67 months and the 5-year survival rate was 70.5%. Almost all patients had fever and induration at the injection site. Other side effects included leukopenia, anorexia, and depression. This combination therapy is thought to be effective against bone or other organs metastasis resistant to interferon alone.

Topics: Aged; Bone Neoplasms; Carcinoma, Renal Cell; Female; Humans; Immunotherapy; Injections, Intramuscular; Interferon-alpha; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Picibanil

We established a method of in vitro immunization of human lymphocytes against human cancer cells and efficiently obtained human-human hybridomas producing cancer-specific antibodies using the in vitro immunized lymphocytes. Human lymphocytes were cocultured with human lung cancer cell line A549 for four days in medium containing various immunoactive reagents. In vitro immunization was effectively caused by the addition of OK-432 or muramyl peptides, IL-2, and IL-6, to the coculture of A549 cells and lymphocytes. Although specific antibodies of both IgM and IgG classes were produced by this method, the ratio of IgG to IgM was greater than or equal to 2. The efficiencies of in vitro immunization fluctuated about threefold in lymphocytes derived from several donors. The in vitro immunized lymphocytes were fused with human fusion partner A4H12 cells. Hybridomas producing specific antibodies reactive to A549 cells were efficiently obtained by sequential cell fusion. The efficiency of acquisition of hybridomas producing specific antibodies with the in vitro immunized lymphocytes was about 10-fold higher than that with lymphocytes spontaneously immunized in bodies of lung cancer patients.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Antibodies, Monoclonal; Cell Fusion; Enzyme-Linked Immunosorbent Assay; Humans; Hybridomas; Immunization, Passive; Immunoenzyme Techniques; In Vitro Techniques; Interleukin-2; Lipopolysaccharides; Lung Neoplasms; Lymphocytes; Picibanil; Pokeweed Mitogens

A 66-year-old woman was hospitalized in a state of shock with rupture of hepatocellular carcinoma and multiple pulmonary metastasis. Her bleeding was successfully controlled by emergency transcatheter arterial embolization with Lipiodol (Lp-TAE). Treatments with UFT, OK-432 and two additional Lp-TAE caused the disappearance of pulmonary metastasis with AFP levels decreased and natural killer cell activity increased. The patient died one and a half years after the emergency Lp-TAE. The disappearance of pulmonary metastatic lesions seemed to be caused by improvement of the patient's immunity, which related to the regression of primary tumor after Lp-TAE. It was suggested that Lp-TAE is worth undertaking even in rupture of hepatocellular carcinoma with remote metastatic lesions.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Doxorubicin; Female; Hepatic Artery; Humans; Iodized Oil; Liver Neoplasms; Lung Neoplasms; Mitomycin; Picibanil; Prognosis; Remission Induction; Rupture, Spontaneous; Tegafur; Uracil

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

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

A case of hepatic and splenic metastases of lung cancer infused with LAK cells and anticancer drugs from hepatic artery with total implantable port (Port-A-Cath: Pharmacia, Incorp.) was reported. A 56-year-old male was admitted to our hospital because of general fatigue, jaundice, pleural effusion and elevation of transaminase caused by hepatic and splenic metastases of lung carcinoid. Abdominal ultrasonography revealed 6 hepatic metastatic foci 10-35 mm in diameter and splenic metastases. The patient received 5 courses of MMC infusion, CPA (2 courses) and epirubicin, CDDP (3 courses), and 5 courses of LAK cells (total 1.4 x 10(10)) with IL-2 and OK-432. Eight months after initiation of treatment, jaundice and pleural effusion disappeared, transaminase returned to the normal level and the condition of the patient improved. Although the response of hepatic metastases to the treatment was NC, the size of a splenic metastasis decreased from 35 x 55 mm to 24 x 35 mm (PR).

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoid Tumor; Combined Modality Therapy; Drug Administration Schedule; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Interleukin-2; Killer Cells, Lymphokine-Activated; Liver Neoplasms; Lung Neoplasms; Male; Middle Aged; Picibanil; Splenic Neoplasms

In order to evaluate the significance as a parameter for monitoring immunological status and for predicting therapeutic effect and prognosis, Su-PS skin test was performed in 68 cases of primary lung cancer treated with chemotherapy and administration of OK-432. In 16 of 68 cases, lymphocyte subsets of peripheral blood using Leu monoclonal antibodies were analyzed to investigate the immunological status. Su-PS skin test was performed at the time of before treatment, 1 week after administration of OK-432, 4 weeks after chemotherapy and intervals during treatment. The reactions to Su-PS skin test in these patients were divided into 3 groups according to the maximum size during the treatment as follows; less than 20 mm, 20 mm to 50 mm and over 50 mm. As compared with the reaction to Su-PS skin test and the survival, there was a significant difference between each group. The analysis of the lymphocyte subsets also indicated that immunological status tended to be activated more in strong responders to the Su-PS skin test than in weak responders. Therefore, Su-PS skin test is considered to be an useful immunological parameter of cancer patients under treatment.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Combined Modality Therapy; Female; Humans; Leukocyte Count; Lung Neoplasms; Lymphocytes; Male; Middle Aged; Picibanil; Polysaccharides, Bacterial; Predictive Value of Tests; Prognosis; Remission Induction; Skin Tests; Streptococcus pyogenes

We have studied the immunological status of patients treated with streptococcal preparation OK-432. Two KE of OK-432 was injected intramuscularly once every week for more than three years unless the patients died. The natural killer (NK) activity in those patients who underwent curative surgery for lung cancer and had no sign of recurrence was significantly increased (P less than 0.01) during the OK-432 treatment. However, the NK activity in the patients who had persistent disease (non-resected cases, incompletely resected cases or recurrent cases) was not significantly increased in comparison with that before the immunotherapy. Also, in the cases with no clinical symptoms of recurrence, both the lymphoblastogenetic reactions to the mitogens and the IL-2 production were significantly enhanced (P less than 0.01) during the administration of OK-432. Reactions in the SU-PS (polysaccharide taken from the cell-wall fraction of the Streptococcus pyogenes SU strain and containing 7.2% of protein) skin-test appeared to significantly correlate with the immunological status of the patients under OK-432 therapy, but the PHA and PPD skin reactions showed no definitive enhancement. The survival rate of the patients whose SU-PS skin tests were positive during the OK-432 immunotherapy was significantly higher (P less than 0.01) than that of the patients with negative reactions.

Topics: Humans; Hypersensitivity, Delayed; Immunity, Cellular; Immunotherapy; Interleukin-2; Killer Cells, Natural; Lung Neoplasms; Lymphocyte Activation; Picibanil; Skin Tests

This study was carried out to determine the effect of local irradiation of the NFSa tumors on the incidence of lung metastases. The spontaneous lung metastases were found in those animals whose tumors had grown in size bigger than 10 mm in diameter. The incidence of metastases and the number of lung nodules were increased in those animals of irradiated group when compared to those of control group with the same size. This is probably because the irradiation of tumors resulted some retardation in their growth and thus, the irradiated tumors took a longer time to reach a given size than those unirradiated control tumors. The incidence of spontaneous lung metastases was significantly reduced by subcutaneous administration of OK-432 (2.5KE/mouse) locally into the surroundings of the tumor immediately after irradiation. The administration of OK-432 after the metastasis development was no longer effective. Both of intraperitoneal and subcutaneous administrations of OK-432 into opposite side of unirradiated thigh showed no suppression of metastasis. These results suggest that an appropriate immunostimulation combined with radiotherapy may be important for the suppression of tumor metastases.

Topics: Animals; Combined Modality Therapy; Fibrosarcoma; Lung Neoplasms; Male; Mice; Mice, Inbred C3H; Picibanil

The marrow granulocyte reserve (MGR) of patients with lung cancer have been estimated by measuring the maximum neutrophil increment after administration of hydrocortisone. The MGR was found to have decreased in four of 19 untreated patients, but the reason for this decrement was not clear. Further, there were no differences in the MGR between the cell types or cancer stages. The MGR in patients 70 years old or older tended to be decreased. After chemotherapy or radiation therapy, the MGR depressed significantly. However, on administration of OK 432, the MGR significantly increased in two patients who had received radiation therapy and whose MGR had been deficient initially.

Topics: Adult; Age Factors; Aged; Antineoplastic Agents; Bone Marrow; Female; Granulocytes; Humans; Hydrocortisone; Leukocyte Count; Lung Neoplasms; Male; Middle Aged; Neutropenia; Neutrophils; Picibanil; Radiation Injuries; Radiotherapy

The authors have investigated the effect of OK-432 on the spontaneous metastasis from a murine fibrosarcoma, either an NFSA or a SANH, that had been transplanted into the right thigh of C3H mice. When the NFSA or the SANH tumors grew to 7 mm in diameter, they were irradiated with a single dose of 30 Gy and 20 Gy, respectively. A local administration of OK-432 (2.5 KE) around each of the tumors was initiated immediately after irradiation and continued twice a week. It was found that regrowth in both tumors was not modified by the OK-432, though the mean number of metastatic lung nodules per mouse from either tumor was significantly decreased. The incidence of a lung metastasis also was reduced by the OK-432 but not significantly. Further, mice that had received a SANH tumor transplant developed a lymph node metastasis in the abdominal cavity that was depressed by the OK-432.

Topics: alpha 1-Antichymotrypsin; Animals; Biological Products; Combined Modality Therapy; Fibrosarcoma; Lung Neoplasms; Lymphatic Metastasis; Male; Mice; Mice, Inbred C3H; Picibanil; Radiotherapy Dosage

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Cisplatin; Cytotoxicity, Immunologic; Humans; Killer Cells, Natural; Lung Neoplasms; Nimustine; Picibanil; Vindesine

Interleukin-1 (IL-1) inducing activity of a streptococcal preparation OK-432 and its fractions by monocytes were investigated in patients with lung cancer and healthy subjects. The results showed that cell free extracts and cell wall fractions of OK-432 were the strong IL-1 inducing fractions. IL-1 activity released by OK-432-stimulated monocytes of patients with lung cancer fell within normal range. OK-432 stimulated intracellular IL-1 synthesis as well as extracellular release by monocytes. These results, therefore, suggested that OK-432 immunotherapy in patients with malignant diseases might be effective by increasing IL-1 production of monocytes.

Topics: Aged; Biological Products; Cells, Cultured; Female; Humans; Interleukin-1; Lung Neoplasms; Male; Middle Aged; Monocytes; Neoplasm Staging; Picibanil; Streptococcus pyogenes

Experimental studies were performed to clarify the mechanism of facilitation of tumor metastasis to the lung by operative stress, using an experimental model in which 5-week old female Sprague-Dawley (SD) rats were inoculated with a low antigenic and easily metastasizable tumor, MRMT-1. In particular, relevance of adrenocortical hormones to the facilitation of tumor metastasis was examined. Furthermore preventive effects of preoperative administration of a nonspecific immunopotentiator, OK-432, were examined. Number of metastatic nodules was increased significantly by operative stress and the increase was proportionate to severity of the stress. The facilitation of metastasis by operative stress was significantly inhibited by preoperative OK-432 administration. In adrenalectomized rats, no such facilitation of metastasis by operative stress was observed. After administration of 2.5 to 20mg of hydrocortisone, number of metastatic nodules increased dose-dependently. The increase in metastatic nodules by administration of 5mg of hydrocortisone was inhibited by preoperative OK-432 administration. Thus it was concluded that facilitation of tumor metastasis by operative stress was proportionate to severity of the stress, and one of its essential causative factors was the stress-induced adrenocortical hypersecretion, which suppressed immunity of the host. Administration of OK-432 was effective for counteracting the stress-induced facilitation of metastasis.

Topics: Adrenal Cortex Hormones; Animals; Biological Products; Female; Lung Neoplasms; Neoplasms, Experimental; Picibanil; Rats; Rats, Inbred Strains; Specific Pathogen-Free Organisms; Stress, Physiological; Surgical Procedures, Operative

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Humans; Interferon-gamma; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Picibanil; Remission Induction

Murine RCT(+) sarcoma cells were sorted using a fluorescence-activated cell sorter with regard to the expression of H-2 antigens and then an increased H-2-expressing subclone was established, and named RCT(+)H-2+. The experimental metastasis of RCT(+) cells was compared with that of RCT(+)H-2+ cells by counting pulmonary colonies on the 21st day after i.v. inoculation of tumor cells (5-10 x 10(4)/mouse). When mice were inoculated with RCT(+) cells, mean numbers of pulmonary colonies were 2.1(range 0-6), 2.8(range 0-7) using 5 x 10(4) and 1 x 10(5) cells, respectively. On the other hand, in the mice inoculated with RCT(+)H-2+ cells, figures obtained were 7.0(range 4-16), 31.9(range 13-79), using 5 x 10(4) and 1 x 10(5) cells, respectively. The survival rate of RCT(+)H-2+ cells was higher than that of RCT(+) cells, when this was assayed in the early stage after i.v. injection of 51Cr-labeled cells (1 x 10(5) cells/mouse). In addition, RCT(+)H-2+ cells were more resistant than RCT(+) cells to lysis mediated by natural killer cells. These data suggest that an increase in metastatic ability was paralleled by an increase in the H-2 antigen expression and a decrease in sensitivity to the natural killer cells.

Topics: Animals; Antigens, Neoplasm; Cytotoxicity, Immunologic; H-2 Antigens; Histocompatibility Antigens; Killer Cells, Natural; Lung Neoplasms; Male; Mice; Mice, Inbred C3H; Picibanil; Sarcoma, Experimental; Spleen

Enough amounts of tumor necrosis factor (TNF) in mice serum for the therapy were observed by treatment with 100 units of recombinant human TNF-alpha (rHuTNF-alpha) followed by administration of OK-432 (a streptococcal preparation). Optimal time interval between rTNF and OK-432 to produce endogenous TNF was 3 h, and priming activity of rTNF persisted for at least 10 h. The same effect was observed using novel human recombinant TNF-SAM2 (rHuTNF-SAM2) developed by our group. Production of endogenous TNF using rTNF-alpha or rTNF-SAM2 as a priming reagent was almost equal among various mice strains. Induced TNF in mice serum was completely neutralized by anti-MuTNF antiserum, but not by anti-HuTNF monoclonal antibody. rMuTNF could also induce the priming state; however, the dose-response kinetics of the priming effect to produce endogenous TNF was different between rHuTNFs and rMuTNF-alpha, suggesting species specificity among rTNFs used. The therapeutic effect against Meth A and MH134 tumors in mice treated by rHuTNFs in combination with OK-432 was superior to that by single administration of either OK-432 or rHuTNFs or by successive administrations of OK-432. Especially, the antitumor effect against MH134 hepatoma was superior to that of any other treatment using known biological response modifiers so far experienced. These results suggest that such combination antitumor therapy as rTNF together with OK-432 should be applicable to cancer patients.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fibrosarcoma; Liver Neoplasms, Experimental; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Inbred Strains; Neoplasms, Experimental; Picibanil; Recombinant Proteins; Tumor Necrosis Factor-alpha

Topics: Animals; Biological Products; Fibrosarcoma; Lung Neoplasms; Mice; Mice, Inbred C3H; Neoplasm Transplantation; Picibanil; Thigh

Topics: Adjuvants, Immunologic; Administration, Oral; Animals; Biological Products; Emulsions; Killer Cells, Natural; Lung Neoplasms; Male; Mice; Picibanil; Sarcoma, Experimental; Triglycerides

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

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

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

Immunological competence plays an important role in response of patients to radiation therapy and dose of radiation required for tumor control depends also on the immunocompetence of the individual patient. Radiation therapy (even localized irradiation) can, however, cause lymphopenia and induce an immunodeficient state. This may facilitate growth of residual tumor cells or metastatic foci, this negating benefits of the therapy. A brief overview of damage to T and B lymphocytes as well as macrophages and natural killer (NK) cells by radiation therapy was presented. The restoration and potentiation of the immunological competence of the patients by biological response modifiers (BRM) such as OK432 (a bacterial preparation), recombinant interferon (rIFN-gamma) and recombinant interleukin-2 (rIL-2) with or without lymphokine activated killer (LAK) cells, were discussed.

Topics: B-Lymphocytes; Humans; Interferon-gamma; Interleukin-2; Killer Cells, Natural; Lung Neoplasms; Macrophages; Picibanil; Radiation Tolerance; Radiotherapy Dosage; T-Lymphocytes; T-Lymphocytes, Regulatory

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

In the course of administration of an immunopotentiator, streptococcal agent OK-432, a patient with lung cancer was found to have severe anemia and a strongly positive antiglobulin test. In the absence of the drug, eluates from the patient's erythrocytes reacted strongly by the indirect antiglobulin test with a panel of washed Group O erythrocyte samples. The eluated antibody was composed of monoclonal IgG1-lambda. Upon discontinuing the drug the patient's hemoglobin level increased slowly with concomitant normalization of the reticulocyte count. Although very rare, drug-induced immune hemolytic anemia should be included in the list of adverse effects of immunopotentiators. This is the first reported case of immune hemolytic anemia associated with OK-432.

Topics: Aged; Anemia, Hemolytic; Antibodies, Monoclonal; Biological Products; Blood Grouping and Crossmatching; Carcinoma, Small Cell; Haptoglobins; Hemoglobins; Humans; L-Lactate Dehydrogenase; Lung Neoplasms; Male; Picibanil; Serologic Tests

A rare case of metastatic renal cell carcinoma which represented complete remission by chemotherapy and surgical treatment is presented. A 59-year-old female was admitted to our hospital because of general fatigue, weight loss and appetite loss. The diagnosis of right renal tumor metastasized to both lungs and extending into the inferior vena cava was made by radiographic findings. Because of very poor general condition the first choice of treatment was chemotherapy with cisdichlorodiamine platinum, adriamycin, cyclophosphamide, 1-(2-tetrahydrofuryl)-5-fluorouracil) (UFT), and OK432. Five months after the beginning of chemotherapy both lung coin lesions disappeared completely, and radical nephrectomy including venacavotomy and tumor thrombectomy was performed. At present, 6 months after the radical nephrectomy, she is free from the disease and complete remission has been obtained by oral administration of 400 mg/day UFT and 5.0 KE OK432 intracutaneous injection every week.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Humans; Kidney Neoplasms; Lung Neoplasms; Middle Aged; Nephrectomy; Picibanil; Remission Induction; Tegafur; Thrombosis; Uracil; Vena Cava, Inferior

Skin testing with intradermally injected Su-Polysaccharide (extracted from Su strain Streptococcus bacteria) was performed in 41 cases of lung cancer. Su-polysaccharide skin test results were correlated, to some extent, with the patient's age, clinical stage and performance status and showed a similar trend to the simultaneously performed PPD skin test. These results suggested the potential usefulness of Su-Polysaccharide skin test results as one of the parameters of immunological status of patients with lung cancer. It was also demonstrated that skin reaction to Su-Polysaccharide was increased specifically after OK-432 immunotherapy and was well correlated with the prognosis of the disease. The Su-Polysaccharide skin test was thus considered to be a useful parameter for monitoring the immune response to OK-432 immunotherapy in lung cancer and also one of the parameters of prognostic value.

Topics: Adult; Aged; Aged, 80 and over; Biological Products; Female; Humans; Lung Neoplasms; Male; Middle Aged; Picibanil; Polysaccharides, Bacterial; Skin Tests; Streptococcus pyogenes; Tuberculin Test

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

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

Twenty patients with lung cancer were treated with a streptococcal preparation, OK-432 in addition to various other treatments, and we evaluated the effect of OK-432 in comparison with an equivalent number of patients without OK-432. With regard to advanced-stage patients, the median survival time of those treated with OK-432 was longer than that of patients without OK-432. Patients whose PPD or SU-PS skin reactions were positive had a longer survival time than those giving a negative reaction. OK-432 significantly increased the reactions for both PPD and SU-PS. On the other hand, OK-432 did not have any significant effect in increasing the numbers of peripheral lymphocytes and T-cell subsets. Furthermore, there were no effects on tumor markers, such as CEA, beta 2-microglobulin and ferritin. However, OK-432 had a remarkable effect in decreasing immunosuppressive acidic protein.

Topics: Adult; Aged; Biological Products; Female; Humans; Immunity, Cellular; Killer Cells, Natural; Lung Neoplasms; Male; Middle Aged; Neoplasm Proteins; Picibanil; T-Lymphocytes; Tuberculin Test

Topics: Adjuvants, Immunologic; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Combined Modality Therapy; Female; Humans; Lung Neoplasms; Male; Middle Aged; Picibanil; Postoperative Period; Prognosis; Proteoglycans

The strong tumor-selective cytocidal action of tumor necrosis factor (TNF) has been observed in vitro and in vivo. Sato et al. have reported that it was possible to induce a primed state of TNF triggering by injection of purified protein derivative (PPD) even a long time after BCG sensitization, suggesting that this treatment could be applied to human patients. In the present study, we achieved a partial response of a metastatic lesion in a patient with renal cancer by the induction of endogenous TNF by PPD and OK-432 (a streptococcal preparation). This study suggested the possible application of this therapy to also patients with malignant tumor which are highly resistant to any conventional antitumor therapy.

Topics: Biological Products; Carcinoma, Renal Cell; Glycoproteins; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Picibanil; Tuberculin; Tumor Necrosis Factor-alpha

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

Almost all cases with metastatic lung tumor have no symptoms and their metastatic lesions of the lung are detected on X-ray films. The shapes of the shadows are so different that many kinds of examination are made. Among them, the radiographic examination is the most common and useful. It is important to make a diagnosis of metastatic lung tumor in the early stage in order to select effective treatment. In forty patients in whom metastatic lung tumors were removed in our institute hospital, the 5-year survival rate is as good as that of primary lung cancer. Ten of these patients survived for over 5 years after surgical treatment for metastatic lesions. The number of lesions and the type of lung resection did not relate to the prognosis. The thoracotomy is an effective therapeutic method for operable patients with metastatic lung tumor.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Doxorubicin; Humans; Lung Neoplasms; Picibanil; Pneumonectomy; Prognosis; Radiotherapy Dosage; Tomography, X-Ray Computed; Vindesine

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

OK-432, a streptococcal preparation, is known to have strong BRM functions and is expected to produce clinical improvement and prolongation of survival in treated cancer patients. In order to clarify the immunopharmacological mechanisms involved with its clinical effectiveness, intrapleural injection of OK-432 was attempted in patients with malignant pleural effusion due to metastasis from lung cancer. About 70-80% of patients thus treated showed clinical improvements with reduction or disappearance of effusion and effusion tumor cells within a week after the therapy. The clinical response was accompanied by an abrogation or reduction of suppressor macrophages and a stimulatory increase of effective cytotoxic cells resulting in an increase of NK and ATK activity. These in vivo effects observed in the OK-432-treated patients were reproducible in vitro by incubating normal or effusion lymphocytes with tumor-associated macrophages. OK-432 was also shown to reduce the locomotor inhibitory activity of macrophages toward LGL, and to augment the production of various sorts of cytokines, such as IL-1 and MCF by macrophages and IL-2 and NKCF by lymphocytes, all of them being exerted upon activation of the anti-tumor immunological mechanism.

Topics: Biological Products; Cytotoxicity, Immunologic; Humans; Interleukin-1; Interleukin-2; Killer Cells, Natural; Killer Factors, Yeast; Lung Neoplasms; Lymphocytes; Macrophages; Picibanil; Proteins; T-Lymphocytes, Cytotoxic

Renal cell carcinoma (RCC) is one of the most insensitive urologic tumors to either radiotherapy or anticancer chemotherapy. Recently, effectiveness of interferon (IFN) against RCC has been reported. However, because this effect is somewhat limited, a new modality of treatment is needed. We herein report our experience with IFN and OK-432, a streptococcal preparation for patients with advanced RCC. Twenty patients aged from 26 years to 75 years, with an average age of 52.3 years, were entered into this study. Intramuscular injection of human lymphoblastoid interferon (HLBI) at a dose of 3 X 10(6) units was given daily for between 4 and 76 weeks. Treatment with OK-432 then followed HLBI, unless the patient achieved CR or the status of the patient seriously deteriorated during the initial treatment with HLBI. OK-432 was given to 12 patients at a dose of 5KE (Klinische Einheit) 2 days a week for between 10 and 64 weeks. Effectiveness of HLBI therapy was 20% (CR 1 case, MR 3 cases, NC 11 cases, PD 5 cases). With adjuvant OK-432 therapy for patients whose disease proved to be resistant to HLBI, effectiveness was 25% (CR 1 case, MR 2 cases, NC 6 cases, PD 3 cases). The results obtained indicated that OK-432 following IFN is a potentially active antitumor regimen in patients with advanced RCC.

Topics: Adult; Aged; Biological Products; Carcinoma, Renal Cell; Drug Therapy, Combination; Humans; Interferon Type I; Kidney Neoplasms; Lung Neoplasms; Male; Middle Aged; Picibanil

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

Topics: Adult; Aged; Aged, 80 and over; Animals; Biological Products; Female; Humans; Lung Neoplasms; Male; Middle Aged; Picibanil; Rabbits

Topics: Aged; Aged, 80 and over; Biological Products; Female; Glycoproteins; Growth Inhibitors; Humans; Lung Neoplasms; Male; Middle Aged; Picibanil; Pleural Effusion; Pleurisy; Tumor Necrosis Factor-alpha

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

Topics: Animals; Biological Products; Glycoproteins; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Mice; Middle Aged; Nephrectomy; Picibanil; Tuberculin; Tumor Necrosis Factor-alpha

Topics: Antineoplastic Combined Chemotherapy Protocols; Biological Products; Carcinoma, Renal Cell; Humans; Kidney Neoplasms; Lung Neoplasms; Male; Medroxyprogesterone; Medroxyprogesterone Acetate; Middle Aged; Picibanil

Active and adoptive immunotherapy as an adjunct to surgical treatment in non-small cell lung cancers was analysed, based on the results of our TF experiences and a literature review, and its significance was discussed.

Topics: Adjuvants, Immunologic; BCG Vaccine; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Combined Modality Therapy; Humans; Levamisole; Lung Neoplasms; Picibanil; Pneumonectomy; Postoperative Care

In vivo animal studies support the concept that monocytes and macrophages are important in the immune surveillance of oncogenesis and that in vitro activated murine macrophages are cytocidal for tumour cells. In this study, the tumour cell cytotoxic activity of human peripheral blood monocytes was examined by measuring the inhibition of 3H-thymidine uptake in the human cancer cell line, established in our laboratory from human squamous cell lung cancer. The monocytes from 8 of the 31 lung cancer patients (26%) showed a percentage growth inhibition of less than 69.8%, which exceeded the 95% confidence limits of the percentage growth inhibition observed with healthy control monocytes. On the other hand, among the 16 sarcoidosis and the 8 tuberculosis cases no value was below 69.8%. However, there was no significant difference between the growth inhibition and the clinical stages or histological type. When OK-432, a Streptococcal agent, was administered in vivo to patients with lung cancer, an elevation of the growth inhibition was observed in 7 out of 8 patients. It was confirmed that the tumour cell cytostatic activity of the monocyte is suppressed in patients with lung cancer, and these monocyte deficits hinder the inhibition of tumour growth and metastasis.

Topics: Cell Division; Cells, Cultured; Humans; Immunity, Cellular; Lung Neoplasms; Monocytes; Picibanil

Several types of combination therapy, including OK432, cyclophosphamide (CY), and/or lentinan plus bacterial lipopolysaccharide (LPS), reported to have strong antitumor activity against some tumors, were only slightly effective on Lewis lung carcinoma (LC) in C57BL/6 mice. Combination therapy by intralesional injection of OK432 followed by intraperitoneal administration of CY, lentinan and LPS caused almost complete regression of intradermal solid-type LC. Maximal antitumor activity was observed when lentinan and LPS were administered later than CY. Mice in which LC had regressed due to this combination therapy showed an antitumor delayed hypersensitivity reaction (measured by the footpad test), but they were not resistant to rechallenge with LC. These results provide a new model for combination therapy against weakly immunogenic tumors.

Topics: Animals; Biological Products; Combined Modality Therapy; Cyclophosphamide; Hypersensitivity, Delayed; Immunotherapy; Lentinan; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Picibanil; Polysaccharides, Bacterial

Topics: Biological Products; Humans; Infusions, Parenteral; Injections, Intramuscular; Lung Neoplasms; Monocytes; Muramidase; Neutrophils; Picibanil

The effect of treatment with bacterial preparations on blood flow in normal and malignant tissues was investigated, clinically and experimentally. The time course of the local effect of the preparations was recorded by Laser Doppler Velocimetry (LDV) via a probe on the surface of normal and malignant tissues directly over the injection site. Experimentally, no definite enhancement of blood flow with OK-432, a streptococcal preparation, was observed in nude mice. Clinically, intradermal administration of OK-432 or tuberculin (PPD) resulted in an approximate 11-or 4-fold increase in blood flow, respectively. The injection of OK-432 into malignant tissues, such as dermal cancer and breast cancer with direct extension to the skin, resulted in an approximate 3.5-fold increase. The results suggested that bacterial preparations can act as an adjuvant to enhance drug delivery to tumor tissue in cancer chemotherapy, and that the enhancement of blood supply is induced by immune response.

Topics: Adult; Aged; Animals; Biological Products; Blood Volume; Breast Neoplasms; Esophageal Neoplasms; Female; Humans; Lidocaine; Lung Neoplasms; Male; Mice; Mice, Nude; Microcirculation; Middle Aged; Picibanil; Regional Blood Flow; Skin; Skin Neoplasms

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

The application of a heat pad in the hyperthermia treatment of malignant skin tumors was examined. The temperature on the skin surface, and at a depth of 1 mm and 2 mm became 42C, 41C and 40C respectively, and was maintained for 4 hours. Two patients were treated with the heat pad alone, four were treated in combination with radiotherapy and one patient each with Pepleomycin injection and Bleomycin ointment. Irrespective of the above methods used, the heat pad was effective.

Topics: Adult; Aged; Bleomycin; Breast Neoplasms; Combined Modality Therapy; Female; Hot Temperature; Humans; Lung Neoplasms; Male; Middle Aged; Ointments; Peplomycin; Picibanil; Skin Neoplasms; Skin Temperature

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

There is significant evidence that the macrophage plays a critical role in the host's defense against neoplasia. Tumor-necrosis factor was recognized by Carswell et al. during a study of the antitumor activity of serum from mice infected with BCG and subsequently injected with endotoxin. The same procedure was applied to rabbits in order to obtain serum containing tumor-necrosis factor (TNF). Sera from these mice and rabbits contained a factor that induced hemorrhagic necrosis of certain mouse sarcomas in vivo and had cytotoxic effects on mouse and human tumor cells in vitro. Sera from mice and rabbits singly treated with BCG or endotoxin did not have these properties. Other agents such as C. parvum, OK-432, lentinan or zymosan, that cause hyperplasia of reticuloendothelial system and increase sensitivity to endotoxin lethality, could substitute for BCG in priming for TNF release. However, the use of P. acnes as a priming agent was the most effective and lipopolysaccharide from gram-negative bacteria appeared to be unique in its ability to elicit TNF release. TNF is a protein with a molecular weight, ranging from 40,000 to 60,000 that has both tumor necrotizing activity in vitro and tumor killing activity in vitro. It is relatively stable to heating at up 70 degrees C. This result indicated that both in vitro and in vitro activities of mouse and rabbit TNF are a property of one and the same molecule. TNF is thought to be produced by macrophage and is distinguished from the other know macrophage products in serum containing TNF. TNF is cytotoxic to several but not all tumor cell lines. Its most interesting feature is that it reportedly dose not affect any non-transformed cell types, implying that it somehow recognizes transformed cells.

Topics: Animals; Cytotoxicity, Immunologic; Female; Glycoproteins; Growth Inhibitors; Humans; Lung Neoplasms; Macrophages; Melanoma; Mice; Mice, Inbred BALB C; Mice, Nude; Molecular Weight; Mycobacterium bovis; Neoplasms, Experimental; Picibanil; Rabbits; Sarcoma, Experimental; Tumor Necrosis Factor-alpha

Large granular lymphocytes (LGL) showing Leu 7 and weak E rosettes were separated from two metastatic tumors of lung cancer. Weak cytotoxic activity of these cells was recognized against autochthonous tumors, but never against K-562 cells. After OK-432 therapy, this cytotoxicity was not enhanced, but antibody dependent cell-mediated cytotoxicity (ADCC) of peripheral blood mononuclear cells of the patient was induced against metastatic tumors. These signs may suggest that specific immunotherapy should be available for these cancers.

Topics: Antibody-Dependent Cell Cytotoxicity; Carcinoid Tumor; Female; Humans; Killer Cells, Natural; Lung Neoplasms; Lymphatic Metastasis; Middle Aged; Picibanil

Skin metastasis of malignant melanoma has been difficult to control by chemoimmunotherapy. We report a case of melanoma with marked reduction of multiple skin and lung metastasis and an improved cell-mediated immunity using combined DAV (DTIC, ACNU, Vincristine) and OK-432 chemoimmunotherapy in association with doses of indomethacin administered over a long period (250 mg/day, 6 months) to relieve the cancerous pain.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Dacarbazine; Humans; Indomethacin; Lung Neoplasms; Male; Melanoma; Nimustine; Nitrosourea Compounds; Pain, Intractable; Picibanil; Skin Neoplasms; Suppositories; Vincristine

A streptococcal preparation, OK-432 was employed as the adjuvant immunotherapeutic agent for lung cancer. To evaluate the clinical efficacy of the OK-432, patients admitted between 1975 and 1979 were randomized into two groups: (1) an immunochemotherapy group and (2) a chemotherapy, or control, group. For evaluation of long-term survival, there were 108 cases in the immunochemotherapy group and 103 cases in the chemotherapy group. When comparing the prognosis of the two groups, the survival rate was statistically higher in the immunochemotherapy group than the control group. The resected cases in Stages I and II showed better prognosis with immunochemotherapy than the cases in the same stages treated with chemotherapy alone. Among the resected cases in the more advanced stages, mostly Stage III and a few cases in the Stage IV, the cases treated with immunochemotherapy also showed more favorable prognosis than the cases treated with chemotherapy alone. In terms of the cell type of the lung cancer, the cases with epidermoid carcinoma in Stages I and II showed significantly better prognosis with immunotherapeutics than the control group. The cases with positive reaction to the streptococcal polysaccharide skin test apparently showed better prognosis than those with negative reaction.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Female; Humans; Lung Neoplasms; Male; Methotrexate; Middle Aged; Picibanil; Probability; Random Allocation; Vincristine

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

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

The immune responses of patients with lung cancer undergoing therapeutic irradiation were evaluated. Absolute lymphocyte counts, PPD skin test, PHA skin test and in vitro lymphocyte transformation test with PHA were performed on each patient before and after 40 Gy irradiation. The values of these parameters were depressed as the increment of the irradiated dose, OK-432 and PS-K administration combined with radiotherapy suppressed the depression of the PHA skin test reactivity and in vitro lymphocyte transformation with PHA. Adding to the effect on immune response of the whole body, the local radiation effect on immunological reaction of tumor tissue was also evaluated.

Topics: Cell Division; Cell Survival; Combined Modality Therapy; Fibroblasts; Humans; Immunity, Cellular; Lung Neoplasms; Lymphocyte Activation; Lymphocytes; Picibanil; Prognosis; Proteoglycans; Radiotherapy Dosage; Skin Tests; Tuberculin Test

Successive transplantations of metastatic secondary tumors of a 3-methylcholanthrene-induced sarcoma in (C57BL/Ka X C3H/He)F1 male and female syngeneic mice resulted in the establishment of two unique tumor cell lines with enhanced metastatic potential. Moreover, each line showed distinct and selective propensities for the mode of metastasis. The 1101Pn tumor line, obtained by successive transplantations of metastatic pulmonary nodules, metastasized to many visceral organs via the bloodstream. Another tumor line, 1101Ln, selected by repeated transplantations of lymph node metastases, metastasized to almost all lymph nodes and to the lungs. When the metastatic pulmonary tumor of mice bearing 1101Ln was subcutaneously implanted on the backs of syngeneic mice, the tumor grew locally and eventually metastasized via the lymphatics, with systemic involvement of the lymph nodes. This finding is an indication that the intrinsic properties of tumor cells that form pulmonary metastases in 1101Ln tumor-bearing mice are distinct from those in 1101Pn tumor-bearing mice in terms of metastatic mode. The 1101Pn and 1101Ln tumor lines were nonimmunogenic or less immunogenic than the 505 tumor (the parental, nonselected tumor line). The growth and metastatic action of 505 tumors were enhanced by 400 R whole-body X-radiation, but no such effect was seen with 1101Pn tumors. Pretreatment of mice with OK-432, an immunopotentiator, retarded the growth and metastasis of 505 tumors but exerted little or no effect on 1101Pn tumors. The experimental results suggest that a tumor is composed of a heterogeneous cell population with respect to metastatic potential, metastatic mode, and tumor immunogenicity and that some intrinsic properties of the tumor cell have a primary role in the determination of the mode of cancer metastasis.

Topics: Animals; Cell Line; Female; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Male; Methylcholanthrene; Mice; Mice, Inbred C57BL; Neoplasm Transplantation; Picibanil; Sarcoma, Experimental; Time Factors; Whole-Body Irradiation

Topics: Adenoma; Adjuvants, Immunologic; Biological Products; Carcinoma, Squamous Cell; Humans; Lung Neoplasms; Picibanil; Proteoglycans

To investigate the mechanism of tumor growth enhancement induced by operative stress in rats, laparo-thoracotomy was performed on day 2 after tumor cell inoculation associated with administrations of various kinds of immunopotentiators. OK-432 (Streptococcal preparation), PS-K (extract from mycelium of Coriolus Versicolor), Lentinan (extract from Lentinus Edodus) and C. parvum were administered intravenously or intraperitoneally in the fractionated form prior to or after inoculation. In general, administration of each immunopotentiator, except for Lentinan, resulted in a recovery from the reduction in survival days after laparo-thoracotomy. In particular, OK-432 administration prior to inoculation showed a significant improvement.

Topics: Adjuvants, Immunologic; Animals; Lung Neoplasms; Male; Neoplasm Transplantation; Neoplasms, Experimental; Picibanil; Rats; Stress, Physiological; Thoracic Surgery

Influences of operative stress on nonspecific cell-mediated immunity and on liability to tumor metastasis and preventive effects thereon of a nonspecific immunopotentiator OK-432 were examined. Syngeneic female SD rats were inoculated SC with 200 mg of a transplantable mammary carcinoma MRMT-1 at the dorsal flank. After 2 weeks the tumor was surgically excised simply or combined with 30-min laparotomy. It was revealed by follow-up examination that the laparotomy stress significantly increased incidence of postoperative lung metastasis. It was found that PHA-induced blastogenesis of peripheral lymphocytes was markedly reduced in the early period following laparotomy. Preoperative or post-operative (especially the former) administration of OK-432 was effective for preventing both the postlaparotomy facilitation of lung metastasis and the postlaparotomy reduction in PHA lymphoblastogenesis.

Topics: Animals; Bacterial Vaccines; Biological Products; Female; Immunity, Cellular; Immunotherapy; Laparotomy; Lung Neoplasms; Lymphocyte Activation; Lymphocytes; Mammary Neoplasms, Experimental; Neoplasm Transplantation; Phytohemagglutinins; Picibanil; Rats; Rats, Inbred Strains; Stress, Physiological; Time Factors

Topics: Adult; Aged; Biological Products; Female; Humans; Lung Neoplasms; Male; Middle Aged; Picibanil

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

The combination of 1 KE/day of OK-432 (everyday) and 10 mg/day of Carboquone (once a week) had been administered for three weeks to 18 cases of the patients with unresectable lung cancer. The response rate was 50% in the patients whose diameters of tumors could be measured. These results might be provided by the fact that the large dose administration of Carboquone became possible with simultaneous administration of OK-432, which might have an activating effect of bone marrow function; consequently, original properties of alkylating agent could be utilized in this therapy. Leukopenia, (leukocyte counts: less than 3,000) was observed in 10 out of 18 cases (55.6%) at one week after administration of the drugs, and in all but one case leukopenia was recovered after 4 weeks of the administration. No other severe side effects were observed.

Topics: Aged; Azirines; Biological Products; Carbazilquinone; Female; Humans; Leukocytes; Lung Neoplasms; Male; Middle Aged; Picibanil

Topics: Adjuvants, Immunologic; Adult; Aged; Carcinoma, Squamous Cell; Female; Humans; Lung Neoplasms; Male; Middle Aged; Picibanil; Proteoglycans

Topics: Adjuvants, Immunologic; Adult; Aged; Female; Humans; Lung Neoplasms; Male; Middle Aged; Picibanil

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

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

Topics: Biological Products; Humans; Immunotherapy; Lung Neoplasms; Lymphocyte Activation; Picibanil

Topics: Adult; Aged; Female; Humans; Immunotherapy; Lung Neoplasms; Lymphocyte Activation; Male; Middle Aged; Picibanil; Tuberculin Test

Topics: Biological Products; Breast Neoplasms; Esophageal Neoplasms; Female; Humans; Lung Neoplasms; Male; Mouth Neoplasms; Neoplasms; Pharyngeal Neoplasms; Picibanil; Radiotherapy Dosage

Immunocompetency was assessed before and after the operation in 40 patients with lung cancer by skin reaction against tuberculin (PPD) and dinitrochlorobenzene (DNCB), lymphocyte response to PHA, proportion of T-cells, macrophage migration inhibition test (MIT) and the presence of blocking factor. MIT was positive in 27 per cent and blocking factor was positive in 42 per cent. Immune response paralleled the clinical stage of the lesion. In curative resection cases, the immune response rose postoperatively, but declined in non-resectable or recurrent cases. The influence of postoperative radiation therapy, cancer chemotherapy and host mediated agents on the patients was observed. The feasibility of adjuvant specific immunotherapy is discussed.

Topics: Aged; Animals; Cell Migration Inhibition; Female; Fluorouracil; Humans; Immunotherapy; Lung Neoplasms; Lymphocytes; Male; Mice; Mice, Nude; Middle Aged; Phytohemagglutinins; Picibanil; Tuberculin Test

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