picibanil and Carcinoma--Squamous-Cell

The head and neck squamous cell carcinoma microenvironments contain many immune cells and their secretory products. Many of these cells belong to the mononuclear phagocyte system. The aim of this review is to study the interactions between mononuclear phagocytes and head and neck squamous cell carcinoma tissue. The role of inflammation in tumours and the cytokine interleukin-6 will be highlighted. Future therapy strategies in the treatment of head and neck cancer might be directed towards mononuclear phagocytes and their cytokine production.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Combined Modality Therapy; Cytokines; Humans; Immunity, Innate; Inflammation Mediators; Interleukin-6; Lymphocyte Activation; Macrophages; Monocytes; Mononuclear Phagocyte System; Neoplasm Staging; Otorhinolaryngologic Neoplasms; Phagocytosis; Picibanil; Prognosis; Tumor Burden

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

We conducted a randomized controlled study of streptococcal preparation OK-432 on 120 newly identified cases of laryngeal squamous cell carcinoma who were registered at 10 participating institutions between November 1984 and October 1989. The patients were divided into two groups: those in early stages (stage I or II) and those in advanced stages (stage III or IV); these groups were further subdivided into an immunotherapy group (receiving OK-432) and a control group (who did not receive OK-432). The usefulness of OK-432 was studied using the sealed envelope method. The basic therapy for all cases was radiotherapy and, when required, surgery. As adjuvant therapy, 5Fu or derivatives were administered to all cases from the beginning of the treatment period to one year after the basic therapy, with the exception of cases in whom side effects were serious enough to contraindicate use of the drug. The target administration period was 5 years. Of the initial 120 cases, 11 cases were disqualified (3 cases of double cancer and 8 of incomplete primary therapy) and the remaining 109 were used for evaluation. The 5-year survival rate and the 5-year recurrence-free rate were 76% and 84%, respectively, in the immunized groups (both the early and advanced groups), whereas the same rates for the control groups were 78% and 75%. There was a tendency for the immunized groups to enjoy a slightly longer recurrence-free period. Over a 24-month observation period the immunized group always had higher levels of peripheral leukocytes and peripheral lymphocytes; this difference was significant for the first 21 months. Inhibition of bone marrow function is sometimes observed with radiotherapy. It is hoped that, if this inhibition can be mitigated, it will be possible to assist the compromised immune system and maintain a certain level of immune performance which will prevent recurrence and improve survival rate. In the present study we observed a tendency of the lower recurrence rate in the immunized group, and we hypothesize that OK-432 is effective in extending the recurrence-free period.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; Female; Humans; Laryngeal Neoplasms; Larynx; Male; Neoplasm Staging; Picibanil; Retrospective Studies; Survival Rate

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

The cellular immunity of peripheral blood was analyzed to evaluate the efficacy of OK-432 between 3 groups of patients with oromaxillary squamous cell cancer, which were composed of 14 patients in the pretreatment stage, 8 patients who were free from cancer more than one year after the last cancer therapy and had been continuously treated with OK-432, and 14 patients who had undertaken cancer therapy without OK-432 and were also free from cancer for at least one year. As parameters of cellular immunity, leucocyte counts, percent composition of T-cells, percent compositions of T-lymphocyte subsets (OKIal+, OKT3+, OKT4+, and OKT8+) and the ratio of OKT4+ and OKT8+, PPD skin test, and lymphocytic blastogenesis induced by PHA and Con-A, were examined. The results showed no significant difference between the patients treated with and without OK-432. Nor was there any significant difference between the pretreatment group and the posttreatment groups with and without OK-432 treatments in any of the examined immunologic parameters.

Topics: Adult; Aged; Carcinoma, Squamous Cell; CD4-Positive T-Lymphocytes; Female; Humans; Immunity, Cellular; Immunotherapy; Jaw Neoplasms; Leukocyte Count; Lymphocyte Activation; Male; Middle Aged; Mouth Neoplasms; Picibanil; T-Lymphocytes, Regulatory

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

Topics: Administration, Oral; Adolescent; Adult; Aged; Antineoplastic Agents; Carcinoma, Adenoid Cystic; Carcinoma, Squamous Cell; Clinical Trials as Topic; Drug Therapy, Combination; Female; Fluorouracil; Head and Neck Neoplasms; Humans; Male; Mouth Neoplasms; Nasopharyngeal Neoplasms; Neoplasm Metastasis; Neoplasm Recurrence, Local; Picibanil; Proteoglycans; Tegafur

Eighty-one patients with oral squamous cell carcinoma (OSCC) received oral fluoropyrimidine UFT and radiotherapy (RT) with or without an immunotherapeutic agent OK-432. Both overall survival and progression-free survival of patients who received RT + UFT + OK-432 were significantly longer than those of patients who received RT + UFT (P = .0075 and P = .0175, respectively). Clinical response was also more favorable in RT + UFT + OK-432 group than in RT + UFT group (P = .0066). Next, in vitro experiments were conducted to examine the effect of 5-fluorouracil (5-FU) and X-ray irradiation in OK-432-induced immunity. Human peripheral blood mononuclear cells stimulated with OK-432 produced helper T cell 1 (Th1)-type cytokines as well as interleukin-10 (IL-10) and transforming growth factor-β (TGF-β), which are produced by Th2 and regulatory T cells (Tregs), respectively, and are inhibitory in antitumor immunity. OK-432-induced IL-10 and TGF-β but not Th1 cytokines were significantly inhibited by 5-FU and/or X-ray. 5-FU and X-ray also inhibited the expression of mRNAs for GATA-3 and Foxp3, which are transcription factors for Th2 and Tregs, respectively, but not for T-bet, a transcription factor for Th1. In addition, 5-FU and X-ray decreased the expression of mRNAs for suppressor of cytokine signaling 1 (SOCS1) and SOCS3. Antisense oligonucleotides for SOCS1 and SOCS3 markedly reduced OK-432-induced IL-10 and TGF-β. This is the first report clearly demonstrating that OK-432-based immunotherapy significantly enhanced the therapeutic effects of chemoradiotherapy in patients with OSCC as well as elucidating the mechanism of the synergistic effect of immunochemoradiotherapy in which 5-FU and radiation enhanced OK-432-induced Th1 response mediated by the inhibition of SOCS1 and SOCS3 gene expression.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Cytokines; Dendritic Cells; Female; Fluorouracil; Gene Expression Regulation, Neoplastic; Humans; Immunotherapy; Leukocytes, Mononuclear; Male; Middle Aged; Mouth Neoplasms; Neoplasm Staging; Picibanil; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling 3 Protein; Suppressor of Cytokine Signaling Proteins; Th1 Cells; Th2 Cells; Transcription Factors

Topics: Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Humans; Injections, Intralesional; Interferon-gamma; Male; Picibanil; Skin Neoplasms; Tumor Burden; Tumor Necrosis Factor-alpha

Toll-like receptor 4 (TLR4) plays a significant role in cancer therapy as receptors of bacteria-derived immunotherapeutic agents such as OK-432, a streptococcal immunotherapeutic agent. In addition, recent reports demonstrated that TLRs, including TLR4, are also expressed in cancer cells as well as in immunocompetent cells. It is a problem in cancer therapy that the immunoadjuvant may activate survival signals such as nuclear factor (NF)-κB or mitogen-activated protein kinases (MAPKs) in cancer cells via TLRs. In the current study, we investigated responsiveness of human head and neck cancer cell lines against TLR4 ligands, OK-PSA, an active component of OK-432, and a lipopolysaccharide (LPS). Stimulation with LPS or OK-PSA resulted in the activation of NF-κB in these cell lines expressing TLR4 and MD-2 that is a significant coreceptor for TLR4 signaling. Interestingly, OK-PSA induced cell-growth inhibition, while LPS enhanced the proliferation of the cancer cells. OK-PSA induced NF-κB activation more slowly than that induced by LPS. In addition, phosphorylation of p38 MAPK by OK-PSA was only slight compared with that by LPS. OK-PSA also induced apoptosis of the cancer cells mediated by the activation of caspase 1, 3 and 8 in a p53-independent manner. These findings strongly suggest that active components of OK-432 may elicit anti-cancer effects via enhancing host immunity as well as via directly inducing the growth inhibition and apoptosis of head and neck cancer cells through TLR4 signal.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Caspases; Humans; Lipopolysaccharides; Lymphocyte Antigen 96; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Picibanil; Salivary Gland Neoplasms; Toll-Like Receptor 4

OK-432, penicillin-killed Streptococcus pyogenes, is used in treating lymphangiomas and carcinomas. We have studied in vitro the role of mononuclear phagocytes (MNPs), including purified monocytes (MOs), in the immune response to OK-432. MIP-1alpha/beta and MCP-1 secretions were assessed in whole blood (WB), peripheral blood mononuclear cells (PBMCs) and purified MOs, after in vitro stimulation with OK-432 with or without adherence for 24 hours.. OK-432 stimulated MNPs to secrete MCP-1 and MIP-1alpha/beta in healthy individuals and in head and neck squamous cell carcinoma (HNSCC) patients, except for OK-432 stimulation of WB giving a minimal MIP-1alpha/beta response. Upon culture on low-attachment wells, a spontaneous chemokine secretion was observed, with an unchanged secretion following OK-432 stimulation. Inhibition of Syk kinase and/or PI-3 kinase did not significantly change the chemokine response to OK-432, except for MIP-1alpha production being increased upon Syk inhibitor addition and an increased MCP-1 response upon addition of both inhibitors. Adhesion may possibly involve beta1 and/or beta3 integrins, not beta2, whereas beta(1-3) integrins may act as co-stimulatory receptors for OK-432. Based on direct blockage of CD36 or CD18 by antibodies, MCP-1 production may be mediated by CD18 while MIP-1beta and MCP-1 production may occur upon binding to CD36.. Adherent human MOs produce MCP-1 and MIP-1alpha/beta upon stimulation with OK-432. CD36 modulates MIP-1beta and MCP-1 response. Thus, to some extent OK-432 acts as a substance whereby only MOs adhered to surfaces secrete MCP-1 and MIP-1alpha/beta, in part explaining why OK-432 is suited as a biological response modifying drug.

Topics: Antineoplastic Agents; Carcinoma, Squamous Cell; CD18 Antigens; CD36 Antigens; Cell Adhesion; Chemokine CCL2; Chemokine CCL3; Chemokine CCL4; Chemokines; Head and Neck Neoplasms; Humans; Immunotherapy; Intracellular Signaling Peptides and Proteins; Lymphocyte Activation; Male; Middle Aged; Monocytes; Phosphatidylinositol 3-Kinases; Phosphorylation; Picibanil; Protein Binding; Protein-Tyrosine Kinases; Signal Transduction; Streptococcus pyogenes; Syk Kinase

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

It is sometimes difficult to decide a treatment strategy for postoperative recurrence of esophageal cancer. Such recurrent esophageal cancer cases often present with extremely poor prognosis. We report a case of an 85-year-old man with a massive recurrent tumor of mediastinum 3 years after esophagectomy for squamous cell carcinoma (T3N2M0, Stage III) of the intrathoracic esophagus. The operative procedures were transhiatal esophagectomy and gastric reconstruction via posterior mediastinal route. Endoscopic local injection of OK-432 and balloon dilation was given to this patient after mediastinal recurrence. This patient lived for two years and three months after recurrence without severe side effects. Local injection of OK-432 is effective as a palliative therapy for recurrent case.

Topics: Aged, 80 and over; Carcinoma, Squamous Cell; Esophageal Neoplasms; Esophagectomy; Humans; Male; Neoplasm Staging; Picibanil; Time Factors; Tomography, X-Ray Computed

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

OK-PSA, an active component of OK-432, induces anti-tumor immunity via Toll-like receptor (TLR) 4/MD-2 complex. In the current study, we evaluated the effect of the OK-PSA on human head and neck cancer cell lines. Twelve cancer cell lines including 7 squamous cell carcinoma (SCC) cell lines and 5 salivary gland cancer (SGC) cell lines were examined. The quantitative real-time PCR analysis revealed that TLR4 mRNA was expressed in all 12 cell lines, and that MD-2 mRNA was expressed in 5 cell lines. OK-PSA stimulation resulted in the activation of NF-kappaB in the 4 SCC cell lines which express both TLR4 and MD-2 genes, and in 5 SGC cell lines which express at least TLR4 gene independently of MD-2 expression. In these OK-PSA-responsive cell lines, OK-PSA activated caspase-1, caspase-3 and caspase-8, and induced apoptosis. OK-PSA-induced apoptosis were observed even in a SGC cell line in which p53 is mutated and its function is impaired. These findings strongly suggest that OK-PSA induces apoptosis by the activation of caspases through p53-independent pathway via TLR4 signaling in head and neck cancer cells.

Topics: Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Head and Neck Neoplasms; Humans; Lymphocyte Antigen 96; NF-kappa B; Picibanil; Polymerase Chain Reaction; Toll-Like Receptor 4

This study investigated the combined effect of photodynamic therapy (PDT) using high power laser irradiation (HPL), which generates both a hyperthermic and a photodynamic effect, and OK-432 on NR-S1 mouse squamous cell carcinoma. The photosensitizer (haematoporphyrin oligomers 20 mg/kg BW) was injected to the mice intraperitoneally 48 h before laser irradiation. OK-432 was injected into the tumour 3 h prior to laser irradiation. The experimental protocols consisted of HPL-PDT with or without OK-432, low power laser PDT with or without OK-432, HPL alone and OK-432 alone, and a control group. The tumour necrotic area was determined, and tumour sizes were measured 3, 7 and 10 days after each protocol. The anti-tumour effect of HPL-PDT was enhanced by preadministration with OK-432. Treatment with OK-432 alone or hyperthermic HPL irradiation presented little anti-tumour effect. HPL-PDT in combination with OK-432 topically administered 3 h before photo-irradiation is considered to be a promising therapeutic modality.

Topics: Animals; Antineoplastic Agents; Carcinoma, Squamous Cell; Combined Modality Therapy; Hyperthermia, Induced; Male; Mice; Mice, Inbred C3H; Necrosis; Photochemotherapy; Picibanil

Priming with tumor antigens is one of the most important strategies in cancer immunotherapy. To enhance tumor antigenicity, OK-432, a streptococcal preparation, was coupled to squamous cell carcinoma (KLN-205) by means of a 0.2% glutaraldehyde method. The purpose of this study was to investigate whether OK-432-conjugated tumor vaccines could induce tumor-specific immunity. Our originally developed mouse tongue cancer model was used throughout this work for the analysis of antitumor effects. Prepared OK-432-conjugated KLN-205 vaccines were immunized 3 times to DBA/2 mice. The results showed that the KLN-205 vaccines induced cytolytic activity and strongly suppressed both KLN-205 tumor incidence and growth, and survival of the mice was improved. Moreover, the histological results showed that a greater number of lymphocytes had infiltrated around tumor cells by 24 hours after tumor inoculation in the vaccine group. These results suggest that immunizations with KLN-205 vaccines increase the antitumor effects against tongue cancer.

Topics: Animals; Antigens, Neoplasm; Antineoplastic Agents; Cancer Vaccines; Carcinoma, Squamous Cell; Disease Models, Animal; Female; Immunization; Lymphocytes; Mice; Mice, Inbred DBA; Picibanil; Survival Rate; Tongue Neoplasms; Vaccines, Conjugate

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

The measurement of the intra-tumoral level of thymidylate synthetase (TS), and dihydropyrimidine dehydrogenase (DPD), may be useful in predicting tumor sensitivity to 5-fluorouracil (5-FU). In this study, we examined the mRNA levels of DPD and TS in 28 oral squamous cell carcinomas (SCC), and 22 salivary gland tumors by semi-quantitative reverse transcription polymerase chain reaction. Then we examined the correlation of the responsiveness of the patients with oral SCC to 5-FU with the intra-tumoral levels of DPD and TS mRNA. All specimens were obtained at the biopsy before treatment, and then the patients were treated by oral administration of a 5-FU compound (UFT), the irradiation of cobalt-60 (upto 60 Gy) and injection of an immuno-potentiator (OK-432). Intra-tumoral levels of DPD mRNA in the patients who showed CR (complete response) and PR (partial response) were significantly lower than those in the patients who showed NC (no change). However, intra-tumoral levels of DPD mRNA did not correlate with the local recurrence of the tumor during the observation period after initial treatment with or without surgical resection of the residual tumors. On the other hand, TS mRNA levels in the tumors did not correlate with any clinico-pathological parameters. These observations suggest that intra-tumoral levels of DPD mRNA may predict the tumor response to 5-FU-based chemo-immuno-radiation therapy in the patients with oral SCC.

Topics: Antimetabolites, Antineoplastic; Biopsy; Carcinoma, Squamous Cell; Cobalt Radioisotopes; Combined Modality Therapy; Dihydrouracil Dehydrogenase (NADP); DNA Primers; Drug Resistance, Neoplasm; Fluorouracil; Humans; Immunotherapy; Oxidoreductases; Picibanil; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Salivary Gland Neoplasms; Thymidylate Synthase; Tumor Cells, Cultured

Biological response modifier antitumor effects are enhanced by the activation of the host defense mechanisms. We have investigated the antitumor effect of photodynamic therapy (PDT) and/or local administration of a biological response modifier, the streptococcal preparation OK-432, on transplanted NR-S1 mouse squamous cell carcinoma. Hematoporphyrin oligomers (20 mg/kg body weight) were used to photosensitize PDT. A pulsed Nd:YAG dye laser, tuned at 630 nm, was used as the light source. The laser power was 15 mJ cm(-2) pulse(-1), and the irradiation time was 40 min. The photosensitizer was injected intraperitoneally 48 h before laser irradiation. Where used, OK-432 was injected into the tumor either 3 h prior to PDT or immediately afterwards. The antitumor effects were evaluated 48 h after each protocol by (a) estimating the area of tumor necrosis (%) in hematoxylin/eosin-stained specimens, and (b) bromodeoxyuridine immunohistochemistry. Furthermore, the tumor sizes were evaluated 3, 7 and 10 days after each protocol, and the survival time after each protocol was evaluated as well. The antitumor effect of PDT was enhanced by administration of OK-432 3 h before PDT, whereas the administration of OK-432 immediately after PDT did not potentiate a PDT antitumor effect. Treatment with OK-432 alone had little effect on tumors. Photodynamic therapy in combination with local administration of OK-432 3 h before PDT is considered to be a useful treatment modality.

Topics: Animals; Antineoplastic Agents; Bromodeoxyuridine; Carcinoma, Squamous Cell; Combined Modality Therapy; Immunohistochemistry; Male; Mice; Mice, Inbred C3H; Necrosis; Neoplasm Transplantation; Neutrophils; Photochemotherapy; Picibanil; Time Factors; Treatment Outcome; Tumor Cells, Cultured

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

Hyperthermia is being investigated as a cancer treatment. Many of its basic mechanisms, particularly those related to cell killing, are still poorly understood. We used a transplanted squamous cell carcinoma cell line to investigate the therapeutic effect of hyperthermia. In particular, we examined the effect of OK-432 (biological response modifier) on hyperthermia-induced apoptosis. In the hyperthermia only group the most extensive necrosis occurred on day 3 (70.3%), and the apoptosis index also was highest on that day (69.3). These results suggest that the induction of apoptosis is closely related to the cell death caused by hyperthermia. The percent of necrosis was significantly higher in the groups given hyperthermia and combined OK-432 and hyperthermia treatment than in the OK-432 group (p < 0.05). The apoptosis index was significantly lower in the combined OK-432 and hyperthermia treatment group than in the hyperthermia only group, indicative that the antitumor effect of combined hyperthermia and OK-432 therapy is not ascribable to the induction of apoptosis.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Squamous Cell; Combined Modality Therapy; Hyperthermia, Induced; Male; Mice; Mice, Inbred C3H; Necrosis; Picibanil

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

The multi-cytokine inducer OK-432 is a pulverized preparation of the low-virulence SU strain of Streptococcus pyogenes of human origin. A reduction of the tumour mass in the OK-432-injected areas was observed in 11 out of 13 patients with metastatic and/or recurrent head and neck cancer. Complete response (CR), partial response (PR) and minor response (MR) were noted in six, three and two cases respectively. OK-432 local administration therapy could create a new strategy for cancer therapy.

Topics: Adult; Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Female; Head and Neck Neoplasms; Humans; Immunologic Factors; Injections, Intralesional; Male; Middle Aged; Neoplasm Recurrence, Local; Picibanil; Treatment Outcome

A well-known metastic model of human oral cancer employs 9,10-dimethyl-1,2-benzanthracene (DMBA) to induce hamster cheek-pouch carcinoma. Streptococcal immunopotentiator OK432 was studied here for its inhibitory effect on lymph-node metastasis in that model. The intraperitoneal administration of OK432, after excision of cheek-pouch tumours induced by DMBA, resulted in a marked reduction in the incidence of cervical lymph-node metastasis to 7%, a significant decrease beneath the rates observed for control animals not receiving OK432 (40%). OK432 also caused an increased in serum levels of tumour necrosis factor-alpha and interleukin-6 in tumor-bearing hamsters. These results suggest that the immune response may play an important part in the antimetastatic effects of OK432.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Adjuvants, Immunologic; Animals; Antineoplastic Agents; Carcinogens; Carcinoma, Squamous Cell; Cheek; Cricetinae; Disease Models, Animal; Humans; Injections, Intraperitoneal; Interleukin-6; Lymphatic Metastasis; Male; Mesocricetus; Mouth Neoplasms; Picibanil; Tumor Necrosis Factor-alpha

To investigate the histological effect of intranodal injection of the streptococcal preparation OK-432, we performed intranodal injection in 4 patients with cervical lymph node (CLN) metastases of malignant head and neck tumors (squamous cell carcinoma (SCC) of the oropharynx, SCC of the parotid gland, malignant lymphoma, and rhabdomyosarcoma of the nasal cavity). An initial dose of 5 klinische Einheit (KE) and a maintenance dose of 10 KE of OK-432 were administered into each metastatic or residually involved CLN twice a week. The total dose of OK-432 ranged from 105 KE to 395 KE and the number of administrations ranged from 11 to 40. Post treatment histological examination of excised tissue specimens revealed no tumor cells; there was only fibrosis and inflammatory cell infiltration. These findings suggest that intranodal injection of OK-432 can be utilized for treatment of relatively small CLN metastases of malignant head and neck tumors.

Topics: Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Head and Neck Neoplasms; Humans; Lymphoma; Male; Middle Aged; Neoplasm Metastasis; Picibanil; Retrospective Studies; Rhabdomyosarcoma

A patient with neck lymph node metastasis from squamous carcinoma of the uterine cervix was treated by immunotherapy and neo-adjuvant intraarterial infusion chemotherapy (OK-432 ic, etoposide 25 mg/body x 7 days po, CDDP 100 mg/m2/5 hr iA, CPM 200 mg/body iv, THP 50 mg/m2/2 hr iA). Three courses of the neo-adjuvant chemotherapy were given. After the first course, the neck metastatic tumor appeared remarkably small. After the second, the neck tumor disappeared and the uterine tumor appeared small and to have good movement. Hysterectomy was performed one month after. Each tissue platina concentration (microgram/cm3) is 9.12 uterus cervix, 10.9 uterus corporis, 8.17 fallopian tube, 14.0 ovarium, 1.47-0.88 pelvic lymph node. This patient was treated with irradiation after operation, and is presently in a state of cytological complete remission. Now she continues maintenance immunochemotherapy with UFT and OK-432 with a home doctor.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Drug Administration Schedule; Etoposide; Female; Humans; Hysterectomy; Immunotherapy; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Lymph Node Excision; Picibanil; Remission Induction; Tegafur; Uracil; Uterine Cervical Neoplasms

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

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

Combination therapy consisting of radiation and local administration of OK-432 was administered to 73 patients with esophageal cancer without distant metastases. Seventy patients were examined. The average age was 71 years. There were 60 males and 10 females. The mean tumor length was 7.0 cm.. One mg of OK-432 was administered endoscopically to and around the cancerous lesion at the beginning of radiotherapy and a second dose of 0.5 mg of OK-432 was given in the same manner 2 weeks later. X-ray irradiation was given at a daily dose of 1.6-1.8 Gy, five fractions a week. The average total dose was 61.1 Gy.. Complete responses were obtained in 49 of the 70 patients (70.0%), and partial responses (PR) in the remaining 21. The 5-year cause-specific survival rate of the 70 patients was 33.1%. The 5-year survival rate of the 49 patients with CR was 44.9%, and there were no patients with PR who survived more than 2 years. The 5-year survival rate of the 13 patients with T1 (UICC, 1987) was 79.6%, of the 24 patients with T2/3 41.1%, and of the 33 patients with T4 11.6%. The 5-year survival rates of the 18 patients with tumors less than 5 cm in length and the 40 patients with tumors 5 to 10 cm were 59.9 and 37.9%, respectively. In the patients with tumors more than 10 cm in length, the 4-year survival rate was 14.6%. Sixty-nine of the 70 patients were discharged in good condition and were able to take food orally.. This combination therapy may contribute not only to the survival rate, but also to patients' quality of life.

Topics: Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Combined Modality Therapy; Esophageal Neoplasms; Female; Follow-Up Studies; Humans; Injections, Intralesional; Male; Middle Aged; Neoplasm Recurrence, Local; Picibanil; Pilot Projects; Radiotherapy Dosage; Remission Induction; Survival Rate

The influence of OK-432, a streptococcal preparation, on human polymorphonuclear leukocytes (PMN) was examined. OK-432 increased O2- generation was also observed when PMN were cultured with 10(-2)KE/ml OK-432 for 1 h and then stimulated with phorbol myristate acetate or formyl-metionyl-leucil-phenylalanine (FMLP). In addition, PMN O2- generation was promoted by culture supernatants of peripheral blood mononuclear cells (PBMC) incubated with 10(-3) or 10(-2) KE/ml OK-432. Furthermore, OK-432 (10(-3)-10(-2) KE/ml) enhanced the chemiluminescence of FMLP- and PMA-stimulated PMN. However, nitroblue tetrazolium reduction and myeloperoxidase activity were only minimally enhanced. Not only the candidacidal activity of PMN but also antibody-dependent cell-mediated cytotoxicity against Candida and Raji cells were enhanced in correspondence with the increased generation of reactive oxygen species. Culture of PMN or PBMC for 24 h with OK-432 resulted in a concentration-dependent increase in the substantial production of interleukin-1 beta, interleukin-6 and tumor necrosis factor-alpha. OK-432 also enhanced granulocyte-macrophage colony stimulating factor and gamma-interferon generation by leukocytes in a dose-dependent manner. Our research indicates that OK-432 enhances PMN function directly as well as via the promotion of cytokine production, and suggests that these effects of OK-432 could be beneficial in immunosuppressed patients.

Topics: Candida albicans; Carcinoma, Squamous Cell; Combined Modality Therapy; Cytokines; Cytotoxicity, Immunologic; Humans; In Vitro Techniques; Leukocytes, Mononuclear; Luminescent Measurements; Mouth Neoplasms; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Nitroblue Tetrazolium; Phagocytosis; Picibanil; Superoxides; Tetradecanoylphorbol Acetate

Two cases with osteolytic bone metastases from cervical cancer and esophageal cancer treated by local therapy were reported. The first case is a 53-year-old female with bone metastases of left ischium developed 1 year after hysterectomy. She was treated by intratumor injection of sizofiran (SPG) 20 mg/w and radiation therapy. After 4 weeks, ischias pain decreased and bone lesion showed remarkable calcification (PR) 8th months later. The second case is a 58-year-old male with bone metastases of the left tibia and fibula developed 1 year after surgery. He was treated by intratumor injection of SPG 20 mg/w x 4 and OK-432 1.0 KE/w x 8 after radiation therapy. After 4 weeks, pain and swelling of left leg decreased and bone lesions showed remarkable calcification (PR) three months later. We suggest that intratumor injection of SPG and OK-432 with radiation therapy was effective for osteolytic bone metastases.

Topics: Adult; Bone Neoplasms; Carcinoma, Squamous Cell; Combined Modality Therapy; Esophageal Neoplasms; Female; Humans; Injections, Intralesional; Male; Middle Aged; Picibanil; Radiotherapy Dosage; Sizofiran; Uterine Cervical Neoplasms

Both cell-mediated and cytokine-mediated antitumor activities were induced in peripheral blood mononuclear cells (PBMC) in short-term culture with streptococcal preparation, OK-432. Kinetic analysis of OK-432-activated killer activity (OKAK) showed that it reached a plateau level much faster (by 48 h of culture) than that detected in PBMC stimulated with recombinant interleukin 2 (rIL-2) (lymphokine-activated killer: LAK). We also found that the tumor growth inhibitory factor (TGIF) activity was produced in the culture supernatant (CSN) of the OK-432-activated PBMC (OK-MC) and the activity synchronously increased with augmentation of OKAK activity. The TGIF activity was rarely found in the CSN of rIL-2-stimulated PBMC. The TGIF activity detected in CSN of OK-MC was further characterized as derived from a cytokine different from interferon gamma (IFN gamma), tumor necrosis factor (TNF), or lymphotoxin (LT) by a neutralization test using monoclonal antibodies to these cytokines. These 48-h-cultured-OK-MC were adoptively transferred (adoptive immunotherapy: AIT) into 19 head and neck cancer patients either alone or in combination with chemotherapy and/or radiation therapy, and their therapeutic effects were examined. AIT was performed by intra-arterial or intratumoral administration of OK-MC. There were no significant side effects observed in this treatment. In these patients, approximately 1-10 x 10(7) cells were transferred into the tumor burden. Of the 19 patients, 17 had primary cancer, and in 6 (6/17;35%) of them complete remission (CR) of the tumor was obtained. Partial remission (PR) was attained in 9 of the 17 patients (9/17; 53%), giving the overall response rate of 88%.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Cytokines; Female; Growth Inhibitors; Head and Neck Neoplasms; Humans; Immunoenzyme Techniques; Immunotherapy, Adoptive; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Lymphokines; Male; Middle Aged; Picibanil; Remission Induction; Tumor Cells, Cultured

According to the effect of preoperative chemotherapy for tongue cancer, if the operation method is modified, the modality of treatment for tongue cancer will contribute to preserve the tongue in terms of function and aesthetics as well as improve the quality of life. A clinicopathologic study on 81 patients with tongue cancer was conducted to elucidate the relationship between clinical and histological effects of preoperative chemotherapy with a single agent and multiple-drug regimens, in order to determine the safe surgical margins in the resection of squamous cell carcinoma of the tongue. Fifty patients were treated with bleomycin alone, sixteen with bleomycin and methotrexate and another fifteen with bleomycin, OK-432 and cisplatin. Multiple-drug regimens resulted in greater response rates than the single agent, but there was not always agreement in the relationship between the tumor regression rate and the histological effects of chemotherapy. The histological effects, including the residual aspects of the tumor cell population, were associated with the grade of histological malignancy according to the mode of tumor cell invasion, mitotic index of tumor cell, the tumor differentiation, the degree of stromal lymphocyte infiltration and cellular atypism. These data indicate that special consideration should be also given to the degree of histological malignancy for biopsied specimen, in addition to the tumor regression rate, in determining safe surgical margins and in the modality of treatment of tongue cancer.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Chemotherapy, Adjuvant; Cisplatin; Drug Administration Schedule; Female; Humans; Male; Middle Aged; Picibanil; Preoperative Care; Tongue Neoplasms

We attempted intra-arterial infusion chemotherapy using a reservoir system in recurrent cervical lymph nodes after surgery for esophageal cancer, and obtained favorable results. Intra-arterial infusion chemotherapy (75 mg of cisplatin and 5 mg of peplomycin) was performed using a reservoir system connected with a catheter inserted into the left subclavian artery, because recurrent lymph nodes developed in the left supraclavicular fossa. The therapy was effective for 6 months and the quality of life was improved without side effects.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Drug Administration Schedule; Esophageal Neoplasms; Fluorouracil; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Lymph Nodes; Lymphatic Metastasis; Male; Middle Aged; Neck; Peplomycin; Picibanil; Postoperative Period

The intimate correlation between marked lymphocyte infiltration in the cancer tissue and the superior clinical prognosis has been reported in human cancers. Sizofiran (SPG), a polysaccharide consisting of beta-1,3-D-glucopyranosyl linkage with beta-1,6-D-glucopyranosyl branches, or OK-432, a heat- and penicillin-treated, lyophilized preparation of the Su strain of Streptococcus pyogenes of human origin, was administered intratumorally to nine patients with advanced uterine cervical carcinoma before radical hysterectomy to assess their immunological modulating properties to tumor-infiltrating lymphocyte subpopulations immunohistochemically. The degree of infiltration of CD3- and CD5-positive cells increased moderately or markedly in the stroma surrounding the lesion in both SPG group and OK-432 group, as well as that of CD4- and CD8-positive cells, from that before administration. The density of infiltration of CD3-positive, CD4-positive, and CD8-positive cells in the lesion increased slightly or moderately in both groups after administration. As for CD16-positive cell infiltration, both SPG and OK-432 increased its degree in the stroma lining the lesion while SPG alone augmented its degree in the lesion. This augmentation of lymphocyte infiltration in situ induced by intratumoral administration of SPG and OK-432 is expected to lead to a favorable prognosis of patients with cervical cancer.

Topics: Adult; Aged; Antigens, CD; Antigens, Differentiation; Antigens, Differentiation, T-Lymphocyte; Carcinoma, Squamous Cell; CD3 Complex; CD4 Antigens; CD5 Antigens; CD8 Antigens; Female; Humans; Immunity; Immunohistochemistry; Lymphocyte Subsets; Middle Aged; Picibanil; Receptors, Antigen, T-Cell; Receptors, Fc; Receptors, IgG; Sizofiran; Uterine Cervical Neoplasms

Local administration of OK-432, a biological response modifier, was combined with radiation in 30 patients with esophageal cancer as a pilot study. Complete response was obtained in 22 of 30 patients (73.3%); and partial response was obtained in the remaining eight cases (26.7%). Complete response was obtained in all eight patients with a tumor less than 5 cm in length. In the group with tumors 5-10 cm in length, complete response was obtained in 11 of 14 cases (78.6%); and partial response was obtained in 3 of 14 cases. In the group with a tumor length of more than 10 cm, complete response was obtained in 3 of 8 cases (37.5%); and partial response was obtained in 5 of 8 cases. One-year, 2-year, and 3-year survival rates of the 30 patients, including four patients who died of other diseases, were 67.9%, 40.8% and 29.0%, respectively. This new combination therapy may contribute not only to local control, but also to survival.

Topics: Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Combined Modality Therapy; Esophageal Neoplasms; Female; Humans; Male; Middle Aged; Picibanil; Pilot Projects; Radiation-Sensitizing Agents; Survival Rate

A patient with metastatic liver tumor from esophageal cancer having an anomaly of the hepatic artery was treated by regional immunochemotherapy using two infuserports, which were implanted transfemoral to the right and the left hepatic artery, respectively. The schedule of this therapy was as follows: CDDP (30 mg/m2) on day 1 and 8, 5-FU (1,000 mg/m2) on day 1, 2, 8, 9, 15 and 22, and OK-432 (1 KE/body) on day 3-6, 10-13 and 16-20 were administered via the hepatic artery; and OK-432 (5 KE/body) was also injected intramuscularly three times a week. After the first course of this therapy was performed via the left hepatic artery, metastatic foci in the left lobe regressed, while those in the right lobe progressed markedly. Thereafter, the second course was performed via the right hepatic artery, and then the third course was via both right and left hepatic artery. Following these trials, metastatic foci of the right and the left lobes showed remarkable regression. These results suggest that the effect of immunochemotherapy is closely related with the local concentration of anti-cancer agents.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Esophageal Neoplasms; Fluorouracil; Hepatic Artery; Humans; Infusion Pumps; Infusions, Intra-Arterial; Injections, Intramuscular; Liver Neoplasms; Male; Middle Aged; Picibanil; Tegafur; Uracil

A streptococcal preparation, Sapylin, was employed for 27 cases of oral squamous cancer without treatment that was injected into normal submucosa or sub-skin around the tumor. The recent clinical efficacy is as follows: 3 cases specially effective, 10 cases marked effective, 6 cases effective and 8 cases not effective. Effective percent 70%. A delayed SK-SD skin reaction were found to enhance, but NK activity and T-Rosette were not. A middle grade fever was present as a side effect of this preparation. The result suggested Sapylin that may be a useful to biological response modifier (BRM) agent for oral squamous cancer.

Topics: Biological Products; Carcinoma, Squamous Cell; Female; Humans; Immunologic Factors; Immunotherapy, Active; Injections, Subcutaneous; Male; Middle Aged; Mouth Neoplasms; Picibanil

A secondary metastasis after surgery was uncovered in 12 out of 73 cases of oral squamous cancer. The clinical and histological characteristic tendencies of the metastasis of these 12 cases were the tongue as the tumor site (11/12), and an aggressive invasion in the tumor-host borderline with 2 of Gr, 3, 5 of Gr. 4C and 5 of Gr. 4D, according to the grading of Yamamoto and Kohama (1982). The control of these metastases was not easy because of their multiple and extra-nodal spread. Tumor-free survival occurred in 4 out of 11 (36.3%). Therefore, in some situations, a prophylactic neck dissection would seem to be recommended.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Bleomycin; Carcinoma, Squamous Cell; Cisplatin; Female; Humans; Lymphatic Metastasis; Male; Methotrexate; Middle Aged; Mouth; Mouth Neoplasms; Neck Dissection; Neoplasm Invasiveness; Picibanil; Postoperative Period; Tongue Neoplasms

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

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

Factors influencing the depression of natural killer (NK) activity and its prevention were studied in 57 esophageal cancer patients. NK activity off peripheral blood mononuclear cells was measured by a 51Cr-release assay against K-562 target cells. NK activity in esophageal cancer patients was significantly lower than that in healthy individuals and tended to be lower compared with those in stomach and colon cancer patients. The depression of NK activity was significantly correlated with the reduction of serum albumin level, creatinine height index of nutritional assessment. The activity was also suppressed in proportion to the size of cancer and its staging. Both preoperative radiation and surgery markedly depressed NK activity. Postoperative depression recovered to the Preoperative level 4 weeks after operation. These results indicated that malnutrition, cancer bearing and therapeutic stress were associated with the depression of NK activity. As the preventive measures against such depression of NK activity, avoidance of preoperative radiation and better selection for two-stage operation enhanced recovery of the depressed NK activity. Furthermore, the preoperative administration of OK-432, as n immuno-activator, could be effective to minimize a decrease of NK activity related to radiation and surgery, and to accelerate its recovery to the level before treatment.

Topics: Adjuvants, Immunologic; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Cytotoxicity, Immunologic; Esophageal Neoplasms; Female; Humans; Killer Cells, Natural; Male; Middle Aged; Neoplasm Staging; Nutrition Disorders; Picibanil; Risk Factors

A newly developed treatment method of local administration of OK-432 bronchoscopically combined with irradiation was applied to a patient with carcinoma of the Trachea complaining dyspnea and dysphagia. The tumor showed extra-wall growth. Dyspnea was improved in a week and the tumor disappeared after the treatment. A patient became to take food orally and could discharge in well condition.

Topics: Biological Products; Carcinoma, Squamous Cell; Combined Modality Therapy; Humans; Injections; Male; Middle Aged; Picibanil; Remission Induction; Tracheal Neoplasms

Prognosis on evaluable 86 patients with primary bladder tumor seen during the 10 years up to 1985 was evaluated in relation to treatment mode and tumor stage. The majority of patients underwent multimodal therapies including surgery, chemotherapy and immunotherapy with picibanil (OK432). Transurethral resection of the tumor was performed as an initial surgical treatment in 49 patients, 9 of whom ultimately underwent total cystectomy. After leaving hospital, these patients were kept on immunotherapy with OK432 and topical chemotherapy with bladder instillation of mitomycin C or adriamycin (ADM) with or without systemic administration of Tegefur as long as possible. The overall actual 5-year survival rate for the patients treated by initial transurethral resection was 80%. Recurrence rate for these 49 patients was 35%. Total cystectomy with urinary diversion was performed in 37 patients who had been placed postoperatively on systemic administration of Tegafur and immunotherapy with OK 432 as long as possible. The overall actual 5-year survival rate for the patients treated with total cystectomy was 54%. The patients with pT2 and lower stage tumor had an actual 5 year survival rate of 72%, while the patients with pT3 and higher stage tumors had a survival of 10%. The high recurrence rate in the patients with superficial tumor and the low actual survival rate of the patients with pT3 and higher stage remain a problem in the treatment of bladder tumor. In recent trials, bacillus Calmette-Gúerin instillation therapy has been initiated to lower the recurrence rate in superficial tumor and we have had a satisfactory 4-year result.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Combined Modality Therapy; Doxorubicin; Female; Fluorouracil; Humans; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Prognosis; Tegafur; Uracil; Urinary Bladder Neoplasms

Topics: Aged; Biological Products; Carcinoma, Squamous Cell; Female; Humans; Picibanil; Uterine Cervical Neoplasms

Topics: Aged; Aged, 80 and over; Biological Products; Carcinoma, Squamous Cell; Combined Modality Therapy; Esophageal Neoplasms; Evaluation Studies as Topic; Female; Humans; Male; Picibanil; Pilot Projects; Radiotherapy Dosage; Remission Induction

A 38-year-old female suffering from chronic respiratory symptoms due to lung cancer occupying the left main bronchus was treated by frequent intratumoral injections of OK-432. The immune-modifying therapy was performed as follows; 0.2 KE of OK-432 was injected intracutaneously once a week, then the dose was gradually increased to 3.0 KE once a week. Following immunization, intratumoral injection was done under endoscopy at a dose of 3.0 KE every two weeks. Three months later, the tumor showed remarkable regression, and clinical symptoms were diminished. In conclusion, intratumoral injection of OK-432 was considered to be very beneficial in lung cancer.

Topics: Adult; Biological Products; Bronchial Neoplasms; Bronchoscopy; Carcinoma, Squamous Cell; Female; Humans; Picibanil; Remission Induction

Topics: Aged; Biological Products; Bleomycin; Carcinoma, Squamous Cell; Combined Modality Therapy; Female; Humans; Instillation, Drug; Mitomycin; Mitomycins; Picibanil; Vulvar Neoplasms

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

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

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

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

A 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

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

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

Thermotherapy combined with tegafur (FT-207) and Picibanil was performed in 13 patients with cancer of the urinary bladder. The thermotherapy was performed using a closed circulation type of thermotherapeutic apparatus manufactured for this experiment, by way of a 3-way catheter. The flow rate of the perfusate was 150 ml/min at a constant temperature of 43 degrees C. The temperature was monitored at the inlet and outlet catheter of the urethral meatus. The thermotherapy was performed for a 6-hour period once a week. A tegafur 3000-mg suppository was given 2 hours before the thermotherapy, and Picibanil was added to the perfusate at the time of thermotherapy. No anesthesia was used. Complete disappearance of the tumor was observed in 1 case. The concentrations of tegafur in the serum, tumor and bladder wall were measured simultaneously. The levels obtained at two hours after rectal administration of the tegafur 3000-mg suppository were 19.420 mcg/ml for FT-207 and 0.025 mcg/ml for 5-FU in the serum, 13.170 mcg/g for FT-207 and 0.140 mcg/g for 5-FU in the bladder tumor, and 20.447 mcg/g for FT-207 and 0.252 mcg/g for 5-FU in the bladder wall. Eruption was observed in 1 case. No other side effects were noted.

Topics: Adult; Aged; Biological Products; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Female; Fluorouracil; Humans; Hyperthermia, Induced; Male; Middle Aged; Picibanil; Suppositories; Tegafur; Urinary Bladder; Urinary Bladder Neoplasms

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

The streptococcal preparation OK-432 was used by intradermal administration as an immunotherapy in 18 patients with oral cancer, and the sera from patients during OK-432 treatment were serially assayed for interferon (IFN) activity by the plaque-reduction method with vesicular stomatitis virus in FL cells derived from human amniotic membrane. The type of serum IFN was characterized by acid-treatment and neutralization test with anti-IFN-alpha and anti-IFN-beta antisera. IFN-gamma was expressed for its titer as the residual IFN activity after neutralization with both antisera. An intradermal injection of OK-432 transiently induced IFN activity and 3 patterns in the type and level of the produced IFN were observed. Although most of the patients induced IFN-gamma and acid-stable IFN or only IFN-gamma, 2 patients seemed to be unresponsive to OK-432. When we examined the relationship between natural killer (NK) activity and IFN titer, a sharply declined NK activity was found immediately post OK-432 administration, and then NK activity stayed around the pretreatment level. Most of the tested patients' induced IFN-gamma, preceding the step toward the gradual increase in NK activity, decreased with OK-432. However, even in the patients showing no IFN induction with OK-432, a significant decrease of NK activity occurred.

Topics: Aged; Biological Products; Carcinoma, Squamous Cell; Female; Humans; Immunotherapy; Injections, Intradermal; Interferons; Killer Cells, Natural; Male; Middle Aged; Mouth Neoplasms; Picibanil; Vesicular stomatitis Indiana virus

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

During the period from October 1972 to January 1983, 462 patients with squamous cell carcinoma of the esophagus were admitted to Toranomon Hospital. Those patients with carcinoma of the hypopharynx, cervical esophagus, or cardia extending to the esophagus were excluded from the study. Resection and reconstruction were carried out in 295 patients with a resectability rate of 63.9 percent and an operative mortality rate of 1.7 percent. The 5 year survival rate for 101 patients who had resection with minimum 5 year follow-up was 34.7 percent. Although the ultimate outcome is largely influenced by the tumor type representing malignancy, it is worthwhile to make all efforts to resect the tumor with a negative surgical margin and to resect concomitant lesions if there are any. Surgeons should not be discouraged by the length or size of a tumor. The extent of positive lymph node is closely related to long-term results. However, systemic lymph node dissection should be carried out because 5 year survival can then be expected, even when positive nodes are dissected from various areas.

Topics: Carcinoma, Squamous Cell; Combined Modality Therapy; Esophageal Neoplasms; Esophagoplasty; Humans; Lymph Node Excision; Lymphatic Metastasis; Picibanil

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

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

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

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

Eighty-eight cases of urinary bladder tumor were treated in our Department from 1976 to 1978. The effect of so-called immunopotentiators (OK-432, Levamisole and PSK) was studied in 23 patients. The following results were obtained. Pretreatment intracutaneous response to PHA was significantly lower in the high stage and high grade group than in the low stage and low grade group (P less than 0.025). However, there was no correlation between the effect of immunotherapy and PHA skin reaction. Of the immunoglobulins, only IgM was significantly lower in the high grade group than in the low grade group (P less than 0.025). The one-year survival rate for the patients in the high stage group was higher receiving immunotherapy than those not treated. This suggests that immunotherapy may be useful for prolonging the survival time of patients with advanced bladder carcinoma.

Topics: Adjuvants, Immunologic; Aged; Antibiotics, Antineoplastic; Biological Products; Carcinoma, Squamous Cell; Carcinoma, Transitional Cell; Female; Humans; Levamisole; Male; Middle Aged; Phytohemagglutinins; Picibanil; Prognosis; Proteoglycans; Skin Tests; Urinary Bladder Neoplasms

We have been interested in direct activity of OK-432 on cancer lesion and applied a combined therapy of perifocal administration of OK-432 with radiation for 2 cases as a new trial. Following results were obtained. Histological efficacy as Ef3 at resected specimen was observed in one case and complete regression of cancer lesion was confirmed by X-ray, fiber scope and biopsy after combined therapy of perifocal administration of 10 KE of OK-432 with radiation of 2400 rad in total.

Topics: Aged; Biological Products; Carcinoma, Squamous Cell; Esophageal Neoplasms; Humans; Male; Picibanil

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

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

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