picibanil and Liver-Neoplasms

The current curative treatments for hepatocellular carcinoma (HCC) do not effectively prevent tumor recurrence. Dendritic cell (DC)-based immunotherapy can be a novel strategy targeting tumor recurrence. Here, we evaluated the bioactivity and beneficial effects of DC infusion of HCC tissues following transcatheter hepatic arterial embolization (TAE). 5x10(6) of monocyte- derived DCs were administered through an arterial catheter during TAE treatment procedures in patients with hepatitis C virus-related cirrhosis and HCC. In DC preparation, peptide-stimulated DCs [HLA-DR(+)CD86(+)CD14(-)] were phenotypically immature [CD80(low)CD83(low)], while OK-432-stimulated DCs highly expressed the activation marker CD83. Following the transfer, there was no clinical or serological evidence of adverse events in any patients in addition to those due to TAE. Most interestingly, survival analysis indicated that the patients treated with OK-432-stimulated DCs prolonged the recurrence-free survivals when compared with the historical controls treated with TAE alone. Collectively, OK- 432-stimulated DC transfer to HCC tissues following TAE treatment contributes to the induction of beneficial antitumor immune responses and the prolongation of recurrence-free survivals, providing a plausible strategy to reduce the tumor recurrence rates of HCC.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Dendritic Cells; Humans; Immunotherapy; Liver Neoplasms; Picibanil

Topics: Animals; Colonic Neoplasms; Disease Models, Animal; Humans; Immunologic Surveillance; Immunotherapy; Interleukin-2; Killer Cells, Natural; Liver; Liver Neoplasms; Picibanil

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

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

We devised a new therapeutic modality for multiple hepatocellular carcinoma (HCC) consisting of transarterial immuno-embolization (TIE) using OK-432 and fibrinogen, and applied the treatment to 22 patients with advanced HCC who had been insensitive to TAE, and 21 patients who had no treatment. Nineteen patients had a high AFP level of more than 200 ng/ml. The serum AFP level decreased in 15 patients after TIE, and in 7 patients the AFP level decreased to less than 30%. Furthermore, a marked reduction in tumor size was observed in 69% after TIE. We report 61% 1-year, and 3-year survival rate for cases who had been insensitive to TAE, and 86% 2-year survival rate for those who selected TIE as the first choice. A high fever of more than 38 degrees C occurred in all cases, and hypotension less than 80 mmHg was observed in 42% patients. No deterioration of liver function and no disturbance of the coagulation-fibrinolysis system due to TIE except in one patient with liver failure after TIE.

Topics: Carcinoma, Hepatocellular; Embolization, Therapeutic; Fibrinogen; Humans; Immunotherapy; Infusions, Intra-Arterial; Liver Neoplasms; Picibanil

Immunological and histological analyses were performed on 14 patients with hepatocellular carcinoma treated by transcatheter immunoembolization (TIE) and subsequently by hepatic resection. They were compared with the cases treated by transcatheter arterial embolization (TAE). Exceptionally high plasma levels of inflammatory cytokines, such as IL-6 and IL-8, were noted 3 hours after TIE insults in the majority of the cases. On the contrary, exceptionally high levels of TNF-alpha were also observed in some cases of TIE treatment. In addition, light microscopically, the lytic necrosis of the tumor and massive infiltration of mononuclear cells were the histological characteristics of this treatment. Interestingly, the population of the infiltrates has altered after TIE treatment. It thus consisted mainly of neutrophils in early phase, subsequently of the mixture of lymphocytes, eosinophils, and plasma cells, and finally of lymphocytes. These results may suggest that certain inflammatory responses caused by TIE may play important roles in this new therapeutic modality.

Topics: Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Fibrinogen; Hepatic Artery; Humans; Interleukin-6; Interleukin-8; Liver Neoplasms; Lymphocyte Subsets; Picibanil; Tumor Necrosis Factor-alpha

We examined whether anti-cancer cells are induced in vivo in hepatocellular carcinoma (HCC) by OK-432. Ten patients with HCC were randomly divided into two groups. The group I patient (n = 5) served as the control. In group II (n = 5), OK-432 was preoperatively administered via the hepatic artery. Tumor infiltrating lymphocytes (TILs) were collected from resected tumors. Cytotoxicity of TILs against K562 cells and Raji cells was studied with phenotypic analysis by flow cytometry. Freshly isolated TILs, whether or not treated with OK-432, showed low cytotoxicity. When TILs were co-cultured with recombinant interleukin-2 (rIL-2), the cytotoxicity was significantly activated in the OK-432 treated group, whereas untreated TILs showed no activation. The natural killer (NK) activity and the lymphokine-activated killer (LAK) activity were depressed in group I after hepatic resection, but patients in group II had no depression. Our data indicate that LAK precursor cells are induced in TILs and the prevention of post-operative immune suppression is made possible by OK-432.

Topics: Carcinoma, Hepatocellular; Cytotoxicity, Immunologic; Hepatic Artery; Humans; Infusions, Intra-Arterial; Iodized Oil; Killer Cells, Lymphokine-Activated; Liver Neoplasms; Lymphocyte Subsets; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Picibanil

We investigated the question whether lymphokine-activated killer precursor (pre-LAK) cells are induced by OK-432 in vivo, in hepatocellular carcinoma (HCC). Ten patients with HCC were randomly divided into two groups. In group A (n = 5), OK-432 was pre-operatively administered via the hepatic artery. The group B patients (n = 5) served as controls. Tumor-infiltrating lymphocytes (TILs) were collected from the resected tumors. The cytotoxicity of TILs against natural killer (NK)-sensitive K562 cells and NK-insensitive Raji cells was examined by phenotypic analysis with flow cytometry. Freshly isolated TILs, whether treated with OK-432 or not, showed low cytotoxicity against both tumor cells. However, OK-432 pretreatment increased the T-lymphocyte population of TILs, particularly with interleukin-2 (IL-2) receptor positive cells. When TILs were co-cultured with recombinant interleukin-2 (rIL-2), the cytotoxicity was significantly activated in the OK-432 treated group, while untreated TILs showed no activation (P < 0.05). We postulate that pre-LAK cells are induced by OK-432 in TILs, mainly from the T-lymphocyte population. The possibility that LAK cells can be endogenously induced in HCC if OK-432 and rIL-2 are concomitantly administered needs to be considered for immunotherapy to HCC.

Topics: Adult; Aged; Carcinoma, Hepatocellular; Humans; Immunotherapy; Interleukin-2; Killer Cells, Lymphokine-Activated; Liver Neoplasms; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Picibanil; Recombinant Proteins; Stem Cells

An important objective for patients with unresectable hepatocellular carcinoma (HCC) is the development of effective chemotherapy. We administered a combination of biological response modifiers and anticancer agents to 24 patients with unresectable HCC. Each case had an implanted infuser port which was connected to a catheter placed in the hepatic artery for the intraarterial (i.a.) administration of chemotherapy. The following agents were administered to each patient: recombinant interleukin-2 (800,000 JRU/day infused i.a. continuously for 6 days/week); OK-432 (5 KE injected i.a. twice in 4 weeks and i.m. three times per week); Adriamycin (10 mg injected i.a. twice in 4 weeks); cyclophosphamide (300 mg injected i.a. twice in 4 weeks), and famotidine (40 mg/day administered orally). Objective response was assessed according to tumor size measured by computed tomography and angiography before and after treatment. We observed a complete response (CR) in 4, partial response (PR) in 3, minor response (MR) in 7, no change (NC) in 7, and progressive disease (PD) in 3. The response rate (CR+PR+MR) was 58.3%. The overall 2-year survival rate was 52%. The 2-year survival rate of the responders (CR+PR+MR) was 80%, while that of the non-responders (NC+PD) was 0%. There was a significant difference between the responders and non-responders in respect to survival rate (P < 0.05). The percentages of CD25+ cells, CD56+ cells, and Leu7-CD16+ cells and NK activity in the peripheral blood showed a significant increase following the regimen. Serum levels of tumor necrosis factor alpha TNF alpha rose after the initiation of OK-432. TNF alpha levels were higher in the responders than in the non-responders. Adverse effects included high fever (all patients) and severe transient hypotension (15 patients) that was controlled by conservative therapy. Combined immunochemotherapy administered intraarterially may be a new strategy for treating unresectable HCC.

Topics: Aged; Carcinoma, Hepatocellular; Combined Modality Therapy; Cyclophosphamide; Doxorubicin; Famotidine; Female; Humans; Immunity, Cellular; Immunotherapy; Interleukin-2; Killer Cells, Natural; Liver Neoplasms; Lymphocyte Subsets; Male; Middle Aged; Picibanil; Survival Analysis; Tumor Necrosis Factor-alpha

We conducted a randomized, controlled trial comparing 5-fluorouracil (5-FU) with or without biological response modifiers (BRMs) as a maintenance therapy for hepatocellular carcinoma (HCC) after treatment with percutaneous ethanol injection (PEI), transcatheter arterial embolization (TAE) or arterial infusion of antitumor agents (AI). A total of 58 cases of HCC were classified into 4 groups as follows: group I, PSK with 5-FU (n = 15); group II, lentinan with 5-FU (n = 15); group III, OK-432 with 5-FU (n = 12); and group IV, 5-FU alone as the control (n = 16). The mean survival time, mortality rate, time to progression, and T4/T8 ratio of lymphocytes in the peripheral blood were compared among the four groups. There was no significant difference in the background factors among the groups. In group I, the T4/T8 ratio of lymphocytes was reduced after the therapy. No significant difference was found among the groups in terms of the mean survival time, mortality rate, or time to progression. PEI for initial therapy was superior to the other therapies in terms of the mean survival time and mortality rate. These results suggest that the addition of BRM to maintenance therapy with 5-FU exerts no prognostic benefit on HCC patients treated with PEI, TAE, or AI.

Topics: Aged; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Combined Modality Therapy; Embolization, Therapeutic; Ethanol; Female; Fluorouracil; Humans; Immunologic Factors; Lentinan; Liver Neoplasms; Male; Middle Aged; Picibanil; Survival Rate

We treated 33 patients with liver metastases from breast cancer by immuno-chemotherapy including adoptive cell transfer between 1987 and 1992. In this study, we examined the change of immunological parameters in the peripheral blood lymphocytes and interleukin-2 (IL-2)-cultured lymphocytes, in primary vs. metastatic breast cancer patients and before vs. after treatment. Moreover, we examined their correlation with therapeutic response and survival after treatment. The immunological parameters used were in vitro natural killer cell activity (% lysis of K562), in vitro autologous tumor-killing activity (% lysis against autologous freshly isolated tumor cells), and proliferation of lymphocytes stimulated with IL-2 and autologous sonicated tumor extract antigen in mixed culture (IL-2-enhanced MLTR). When compared with primary breast cancer patients, patients with liver metastases showed a significant decrease in % lysis of K562 and autologous tumor cells. After treatment, the stimulation index in IL-2-enhanced MLTR increased significantly from the pretreatment level and correlated with survival after treatment. Moreover, non-specific immunological parameters (performance status, lymphocyte count, and transferred cell count and proliferation rate of cultured lymphocytes) were significantly associated with response and prognosis.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Combined Modality Therapy; Cyclophosphamide; Dose-Response Relationship, Drug; Doxorubicin; Female; Humans; Immunotherapy, Adoptive; Interleukin-2; Killer Cells, Natural; Liver Neoplasms; Lymphocyte Activation; Lymphocytes; Lymphocytes, Tumor-Infiltrating; Middle Aged; Picibanil; Prognosis

We have previously reported that the combination of mitomycin C, carboquone, 5-fluorouracil and OK-432, including the intra-arterial administration of mitomycin C and carboquone (MQ-F-OK therapy), was effective in the treatment of advanced liver cancer. The Cooperative Study Group conducted a controlled study on MQ-F-OK therapy and the combination of mitomycin C, 5-fluorouracil and doxorubicin, including the intra-arterial administration of mitomycin C and doxorubicin (FAM therapy), against advanced liver cancer. Forty patients with advanced primary or secondary liver cancer were enrolled in this study and randomized into the MQ-F-OK group and the FAM group. Seventeen of the 21 cases in the MQ-F-OK group and 16 of the 19 cases in the FAM group were eligible for response evaluation in accordance with the criteria of the Japan Society for Cancer Therapy. There was no significant difference in the patient characteristics between the two groups. Three cases in the MQ-F-OK group and two in the FAM group showed partial response. There was, however, no significant difference in the response rates and the prolongation of life between the two groups. As for the side-effects, only anemia was observed more frequently in the FAM group than in the MQ-F-OK group. In conclusion, we could not preferentially recommend either MQ-F-OK therapy or FAM therapy for advanced liver cancer. The performance status of the patient was one of the most important factors in the treatment of advanced liver cancer because patients with poor performance status showed poorer results.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carbazilquinone; Clinical Trials as Topic; Doxorubicin; Female; Fluorouracil; Humans; Liver Neoplasms; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Random Allocation

Topics: Administration, Oral; Biological Products; Carcinoma, Hepatocellular; Clinical Trials as Topic; Humans; Infusions, Intra-Arterial; Liver Neoplasms; Mitomycin; Mitomycins; Picibanil; Random Allocation; Tegafur

The effectiveness of BRM (biological response modifier) for primary liver cancer was investigated in a prospective randomized and well controlled study. The protocol consisted of 3 groups: 1) Tegafur oral administration only, 2) OK-432 i.v. plus Tegafur, and 3) PSK oral application plus Tegafur. One hundred seventy-two Japanese patients were entered. The results revealed that BRM addition was more effective than Tegafur therapy alone with regard to tumor regression and the results of clinical examinations, but that there was no difference in subjective symptoms between the use of BRM and the other regimes. As to prognosis, patients given PSK survived longer than those given Tegafur alone, but OK-432 group had the same survival rate as the other two groups as a whole. The relationship among the three groups with regard to survival time, was similar to that of their respective total efficacies. Between the three groups, there was a significant difference in the incidence of adverse effects. The difference was sustained with the occurrence of fever symptoms as a result of OK-432 stimulation, with and BRM therapy decreased the gastro-intestinal side effects in comparison with the control group.

Topics: Adult; Aged; Biological Products; Female; Humans; Liver Neoplasms; Male; Middle Aged; Neoplasm Proteins; Phytohemagglutinins; Picibanil; Prospective Studies; Proteoglycans; Random Allocation; Skin Tests; Tegafur

Radiofrequency ablation (RFA) often results in incomplete ablation for medium-to-large and irregular tumors. To solve this clinical problem, we proposed a new treatment strategy of OK-432 in combination with an anti-programmed cell death protein 1 (αPD-1) antibody for residual tumors after incomplete RFA (iRFA) of hepatocellular carcinoma (HCC).. The effect of OK-432 on immature dendritic cells (iDCs) was evaluated in vitro. A CCK-8 kit and ELISPOT were used to assess the killing effect of OK-432-induced CD8. The combined therapy of OK-432 with αPD-1 antibody induced a strong antitumor immune response, which significantly inhibited the residual tumors after iRFA of HCC. This concept may provide a new treatment strategy to increase the curative efficacy of RFA for medium-to-large and irregular HCCs.. The data of this study are available from the corresponding author on reasonable request.

Topics: Animals; Antibodies; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; Liver Neoplasms; Mice; Mice, Inbred Strains; Neoplasm, Residual; Picibanil; Radiofrequency Ablation

To investigate the efficacy of an injectable hydrogel loaded with lysed OK-432 (lyOK-432) and doxorubicin (DOX) for residual liver cancer after incomplete radiofrequency ablation (iRFA) of hepatocellular carcinoma (HCC), and explore the underlying mechanism.. The effect of OK-432 and lyOK-432 was compared in activating dendritic cells (DCs). RADA16-I (R) peptide was dissolved in a mixture of lyOK-432 (O) and DOX (D) to develop an ROD hydrogel. The characteristics of ROD hydrogel were evaluated. Tumor response and mice survival were measured after different treatments. The number of immune cells and cytokine levels were measured, and the activation of cGAS/STING/IFN-I signaling pathway in DC was evaluated both in vitro and in vivo.. LyOK-432 was more effective than OK-432 in promoting DC maturation and activating the IFN-I pathway. ROD was an injectable hydrogel for effectively loading lyOK-432 and DOX, and presented the controlled-release property. ROD treatment achieved the highest tumor necrosis rate (p < 0.001) and the longest survival time (p < 0.001) compared with the other therapies. The ROD group also displayed the highest percentages of DCs, CD4. The novel ROD peptide hydrogel induced an antitumor immunity by activating the STING pathway, which was effective for treating residual liver cancer after iRFA of HCC.

Topics: Animals; Carcinoma, Hepatocellular; CD8-Positive T-Lymphocytes; Cytokines; Doxorubicin; Hydrogels; Liver Neoplasms; Mice; Picibanil; Radiofrequency Ablation

Antitumor activities of L-MTP-PE (Liposome entrapped myuramyl tripeptide phosphatidylethanolamine) in the combination treatment with chemo- or immune-therapeutic antitumor agents against various syngeneic tumors were tested.Against Meth A fibrosarcoma solid tumor system, L-MTP-PE showed slight but statistically significant elongation of survival days against 5-FU monotherapy in spite of its non-effect on tumor growth, when combined with 5-FU. Against liver metastasis model of M5076 carcinoma, L-MTP-PE showed a tendency of elongation of survival days by its single drug treatment, however, elongation with statistical significance was observed in the combination treatment with 5-FU in comparison with control group.These data suggest that L-MTP-PE seems to elongate the survival days of the solid tumor bearing mice and the liver metastasis model basically due to its saving effect on chemotherapeutic drug-induced immunosuppression. In the combination with an immunotherapeutic agent in mice, TNF production induced by another biological response modifier OK-432 was potentiated when primed with L-MTP-PE. L-MTP-PE also potentiate the antitumor effect of OK-432 possibly through the enhanced production of TNF-α. Combination of L-MTP-PE and OK-432 is considered to be a candidate for a new treatment model for cancer.

Topics: Acetylmuramyl-Alanyl-Isoglutamine; Adjuvants, Immunologic; Animals; Drug Carriers; Fluorouracil; Immunologic Factors; Immunomodulating Agents; Liposomes; Liver Neoplasms; Mice; Phosphatidylethanolamines; 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

Preoperative transarterial immunoembolization (TIE) for hepatocellular carcinoma (HCC) is effective for preventing recurrence. We aimed to investigate the intratumoral and peritumoral M1 macrophage-induced immune response following TIE treatment.. We compared 13 patients treated with TIE between 2003 and 2009 (TIE group) and 13 patients treated with surgery alone during the same period of time at our institute (control group) using an immunohistological study with CD68 and CD163 antibodies.. No significant differences in clinicopathological characteristics, except for surgical time, were observed between the two groups. The 3-year recurrence-free survival outcome of the TIE group was quite different from that of the control group (100% vs. 38.5%, P = 0.034). In the histological investigation, lytic necrosis and coagulation necrosis of the main tumor along with the presence of multinuclear giant cells were observed in 10 of the 13 patients in the TIE group. The immunohistological study showed that not only the numbers of intratumoral CD68(+) cells, but also the numbers of intratumoral and peritumoral CD8(+) cells were significantly increased in the TIE group.. The suppression of tumor recurrence induced by preoperative TIE might be induced by intratumoral M1 macrophages that are activated by OK-432 and fibrinogen.

Topics: Aged; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Antineoplastic Agents; Carcinoma, Hepatocellular; Catheterization, Peripheral; Chemoembolization, Therapeutic; Disease-Free Survival; Female; Follow-Up Studies; Humans; Injections, Intra-Arterial; Liver; Liver Neoplasms; Macrophages; Male; Middle Aged; Picibanil; Receptors, Cell Surface; Retrospective Studies; Treatment Outcome

The mechanism of anti-tumor effect of transarterial Immuno-Embolization (TIE) using OK-432 has not been well elucidated. In this study, we aimed to investigate the tissue injury and immune response after portal venous embolization (PVE) with/without OK-432. Embolic materials (L group: lipiodol, LF group: lipiodol+fibrinogen, LO group: lipiodol+OK-432, LFO group: lipiodol+fibrinogen+OK-432) were administered via the right portal vein in Wistar rats. The histological findings in LFO group demonstrated liver damage with severe architectural changes. The concentrations of CD68(+) cells were observed in a time-dependent manner; it was significantly increased in the LO group on day 1 and in the LFO group on day 3. CD68(+)CD163(-) macrophages significantly increased in the LFO group on day 7 (P<0.05). In conclusion, PVE with fibrinogen and OK-432 markedly increased the CD68(+)CD163(-) infiltrating macrophages around the peri-portal area in the liver. This novel technique could be applied as immune-enhanced chemo-embolization of liver tumors.

Topics: Animals; Antigens, CD; Antigens, Differentiation, Myelomonocytic; Cell Movement; Embolization, Therapeutic; Fibrinogen; Liver; Liver Neoplasms; Macrophages; Male; Picibanil; Portal Vein; Rats; Rats, Wistar; Receptors, Cell Surface

To evaluate survival and distant tumor growth after radiofrequency ablation (RFA) and local OK-432 injection at a single tumor site in a rabbit model with intra- and extrahepatic VX2 tumors and to examine the effect of this combination therapy, which we termed immuno-radiofrequency ablation (immunoRFA), on systemic antitumor immunity in a rechallenge test.. Our institutional animal care committee approved all experiments. VX2 tumors were implanted to three sites: two in the liver and one in the left ear. Rabbits were randomized into four groups of seven to receive control, RFA alone, OK-432 alone, and immunoRFA treatments at a single liver tumor at 1 week after implantation. Untreated liver and ear tumor volumes were measured after the treatment. As the rechallenge test, tumors were reimplanted into the right ear of rabbits, which survived the 35 weeks and were followed up without additional treatment. Statistical significance was examined by log-rank test for survival and Student's t test for tumor volume.. Survival was significantly prolonged in the immunoRFA group compared to the other three groups (P < 0.05). Untreated liver and ear tumor sizes became significantly smaller after immunoRFA compared to controls (P < 0.05). In the rechallenge test, the reimplanted tumors regressed without further therapy compared to the ear tumors of the control group (P < 0.05).. ImmunoRFA led to improved survival and suppression of distant untreated tumor growth. Decreases in size of the distant untreated tumors and reimplanted tumors suggested that systemic antitumor immunity was enhanced by immunoRFA.

Topics: Animals; Antineoplastic Agents; Catheter Ablation; Combined Modality Therapy; Disease Models, Animal; Ear Neoplasms; Female; Follow-Up Studies; Liver; Liver Neoplasms; Picibanil; Rabbits; Survival Analysis; Treatment Outcome

Despite curative locoregional treatments for hepatocellular carcinoma (HCC), tumour recurrence rates remain high. The current study was designed to assess the safety and bioactivity of infusion of dendritic cells (DCs) stimulated with OK432, a streptococcus-derived anti-cancer immunotherapeutic agent, into tumour tissues following transcatheter hepatic arterial embolization (TAE) treatment in patients with HCC. DCs were derived from peripheral blood monocytes of patients with hepatitis C virus-related cirrhosis and HCC in the presence of interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor and stimulated with 0·1 KE/ml OK432 for 2 days. Thirteen patients were administered with 5 × 10⁶ of DCs through arterial catheter during the procedures of TAE treatment on day 7. The immunomodulatory effects and clinical responses were evaluated in comparison with a group of 22 historical controls treated with TAE but without DC transfer. OK432 stimulation of immature DCs promoted their maturation towards cells with activated phenotypes, high expression of a homing receptor, fairly well-preserved phagocytic capacity, greatly enhanced cytokine production and effective tumoricidal activity. Administration of OK432-stimulated DCs to patients was found to be feasible and safe. Kaplan-Meier analysis revealed prolonged recurrence-free survival of patients treated in this manner compared with the historical controls (P = 0·046, log-rank test). The bioactivity of the transferred DCs was reflected in higher serum concentrations of the cytokines IL-9, IL-15 and tumour necrosis factor-α and the chemokines CCL4 and CCL11. Collectively, this study suggests that a DC-based, active immunotherapeutic strategy in combination with locoregional treatments exerts beneficial anti-tumour effects against liver cancer.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Hepatocellular; Combined Modality Therapy; Cytokines; Dendritic Cells; Disease-Free Survival; Embolization, Therapeutic; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Hepatitis C; Humans; Immunotherapy, Active; Interleukin-4; Liver Neoplasms; Male; Middle Aged; Monocytes; Neoplasm Recurrence, Local; Picibanil; Radiography

A patient with malignant melanoma of the oral cavity who lived for a long period despite developing liver metastasis is presented. An 81-year-old female was referred to our hospital because of a pigmented tumor of the lower gingiva. Under the clinical diagnosis of malignant melanoma, she underwent bilateral functional neck dissection and marginal mandiblectomy. Histological diagnosis of the operation material was malignant melanoma with regional lymph node metastasis. In spite of loco-regional control, liver metastasis developed at 7 months after the surgery. She then underwent combination chemotherapies with dimethyl triazeno imidazole carboxamide (DTIC), nimustine hydrochloride (ACNU) and vincristin (DAV therapy), or cisplatin, DTIC, ACNU and tamoxifen (DAC-tam), but no marked response was obtained. Considering the advanced age of the patient, immunotherapy with a biological response modifier, OK432, alone was started. After administration of OK432, the metastatic tumor gradually decreased, and she is alive without any clinical symptoms of tumor at 46 months after the detection of liver metastasis, although it is still present on ultrasonic and CT examinations.

Topics: Aged, 80 and over; Antineoplastic Agents; Female; Humans; Liver Neoplasms; Lymphatic Metastasis; Melanoma; Mouth Neoplasms; Picibanil; Treatment Outcome

Suppressor of cytokine signaling 1 (SOCS1) plays a critical role in antitumor immunity. Down-regulating SOCS1 in antigen-presenting dendritic cells (DCs) could enhance antigen-specific antitumor immunity. This study was to investigate the antigen-specific antitumor effect and mechanism of DCs with siRNA-mediated inhibition of SOCS1, stimulated by OK-432 and pulsed with hepatocellular carcinoma cell line HepG2 antigens.. The expression of SOCS1 in immature DCs was down-regulated by RNA interference (RNAi). DCs were pulsed with lysate of HepG2 cells and stimulated with OK-432. The morphology of DCs was observed under converted phase microscopy. Phenotypic changes in cells after stimulation were characterized by flow cytometry (FCM). The Alamar Blue assay was adopted to evaluate the activation and proliferation of autologous lymphocytes induced by mature DCs. The cytotoxicity of cytotoxic T lymphocytes (CTLs) elicited by modified DCs to HepG2, EC109 and K562 cells was tested by the lactate dehydrogenase (LDH) assay.. Cells displaying a typical morphology and phenotypic properties of mature DCs were obtained successfully. The expression of SOCS1 in DCs was down-regulated by SOCS1 RNAi. Mature DCs showed high expressions of CD80, CD83, CD86, and HLA-DR. Pulsing of DCs with lysate of HepG2 had no influence on the phenotypic properties of DCs. Down-regulating SOCS1 expression enhanced the maturation of DCs. The modified DC tumor vaccine stimulated the proliferation of autologous lymphocytes effectively, and the proliferation rate of T cells was (110.7+/-22.2)%. After being activated by modified DCs, TCLs exerted a specific and effective killing effect on HepG2 cells, but not on EC109 and K562 cells.. Mature DCs could induce antigen-specific antitumor immunity against hepatocellular carcinoma after silencing of SOCS1 by siRNA, stimulation by OK-432 and pulsing of DCs with HepG2 cell antigens.

Topics: Antineoplastic Agents; Cancer Vaccines; Carcinoma, Hepatocellular; Cell Line, Tumor; Cytotoxicity, Immunologic; Dendritic Cells; Humans; Liver Neoplasms; Lymphocyte Activation; Picibanil; RNA, Small Interfering; Suppressor of Cytokine Signaling 1 Protein; Suppressor of Cytokine Signaling Proteins; T-Lymphocytes, Cytotoxic

Patients with metastatic breast cancer to the liver are generally considered to have a poor prognosis. The purpose of this study was to identify factors contributing to long term survival in 11 patients who were 35 76 years old at the time of diagnosis with liver metastasis, and survived for 5 years. No patients were treated with a standard systemic chemotherapy alone. All of the 11 patients received OK 432 combined adoptive immunotherapy (OK-AIT), 5 underwent hepatectomy as an additional local therapy, and 2 were additionally treated by hepatic arterial infusion chemotherapy. The liver was the primary and secondary sites of metastasis in 8 and 3 of the 11 patients, respectively. In all of the 128 patients given OK-AIT at 5 years after diagnosis, the 5-year survival rates with primary and secondary liver metastases were 11.8. and 5%, respectively. Hormone receptors (HR) were undetermined in 4 patients, positive in 6, and negative in 1 patient, who was also positive for HER2. To determine the relationships among the prognosis of the liver metastasis, AIT indications, HR, and HER2, we analyzed our 139 liver metastasis patients encountered in 2001 and onwards. Fifty-one patients with primary liver metastasis had a median survival time (MST) of 31 months, and a 5-year survival rate of 25%, indicating an improved prognosis. In particular, a MST of 50 months (n=18) in HR (+), HER2 (-) patients was in sharp contrast to the poor prognosis (a MST of 6 months, n=2) in HR (-) HER2 (-) patients. HER2 (+) patients had a MST of 27 months (n=31). Eighty-eight patients with secondary liver metastasis had a MST of only 11 months and a 5-year survival of only 6%; however, the MST in these patients showed the same tendency as in the primary liver metastasis patients: ER (+) HER2 (-) >HER2 (+) >HR (-) HER2 (-) (17, 13, and 4 months, respectively). The response rates of OK-AIT in the primary and secondary liver metastasis patients were 52 and 34%, respectively, showing no significant difference. However, there was a significant difference in the response rate between the HR (+) and HR (-) patients, at 52 and 12%, respectively (p=0.0041). Of the patients in the past, 18 with primary liver metastasis underwent hepatectomy in combination with OK-AIT. Of these 18 patients, 5 had concurrent metastases to other sites, but achieved a 5-year survival rate of 56%, suggesting that it is incorrect to conclude that patients with liver metastasis have generally a poor prognosis. Key

Topics: Adult; Aged; Breast Neoplasms; Female; Follow-Up Studies; Hepatectomy; Humans; Immunotherapy, Adoptive; Liver Neoplasms; Middle Aged; Picibanil; Prognosis; Receptor, ErbB-2; Receptors, Steroid; Survival Rate

The treatment of massive osteolysis with lymphangioma and/or hemangioma (Gorham-Stout syndrome) has been controversial. The authors report on a patient with multiple massive osteolyses and extensive lymph-hemangiomatosis whose lesions were reduced by interferon alfa therapy. A 2-year-old girl had complained of left chylothorax. Thoracoscopy showed an increase in small lymphatic vessels in the chest wall. The chylothorax was improved by coagulation of the lymphatic vessels. Later, multiple massive osteolyses appeared in the left 11th and 12th ribs, the TH10-L3 vertebrae, and the right femur. There were also hemangiomas in the liver and spleen, a tumor lesion in the left lower chest wall, and hemangiomatous change on the skin surface of the left back. The left lung had only a minimal air content. After OK-432 was injected into the femur and chest wall lesions, the femur lesion disappeared. Then, as right chylothorax appeared, OK-432 was injected into the right pulmonary cavity. The chylothorax disappeared, but pericardial effusion appeared. After steroid pulse therapy, pericardial effusion disappeared. During these treatments, the 7th to 10th ribs disappeared from the x-ray and scoliosis developed. One month later, a cloudy fluid collection in the right lung was found on computed tomography. Interferon alfa and steroid pulse therapy were started. Interferon alfa (1,500,000 units) was subcutaneously administered daily for 2 months and was gradually reduced and maintained at 1,500,000 unit/wk. Steroids were also reduced and maintained at 5 mg/d of predonine. Later, the progress of osteolysis and the extension of lymph-hemangiomatosis stopped. Ten months later, hemangioma in the back disappeared, and the 7th to 10th ribs, which had disappeared, reappeared. The interferon alfa therapy was stopped 14 months after it was administered. The patient's condition has been stable for 10 months since then. At this time, computed tomography shows regression of the hemangiomatous lesion in the back. The authors clinically diagnosed the patient as having Gorham-Stout syndrome with extension of lymph-hemangiomatosis. Interferon alfa with or without steroid therapy should be a choice for patients with extension lesions.

Topics: Adrenal Cortex Hormones; Angiogenesis Inhibitors; Antineoplastic Agents; Child, Preschool; Chylothorax; Drug Therapy, Combination; Female; Femur; Hemangioma; Humans; Interferon-alpha; Liver Neoplasms; Lymphangioma; Neoplasms, Multiple Primary; Osteolysis, Essential; Picibanil; Pleural Effusion; Pulmonary Atelectasis; Remission Induction; Ribs; Scoliosis; Skin Neoplasms; Spine; Splenic Neoplasms; Syndrome; Thoracic Neoplasms

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

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

We report a 51-year-old man with a ruptured hepatocellular carcinoma (HCC). He was admitted to the hospital with abdominal pain and distension. Imaging studies revealed massive ascites, liver cirrhosis, and a 3-cm tumor at the inferior edge of the medial segment of the liver, with adhesions to the greater omentum. Abdominal paracentesis showed bloody ascites, and the patient was diagnosed with a ruptured HCC. OK-432, an immunomodulatory agent prepared from an attenuated strain of Streptococcus pyogenes, was injected (10 KE) into the peritoneal cavity four times within 1 week; the massive ascites disappeared, and the serum alpha-fetoprotein (AFP) level decreased to within the normal limits. Afterwards, he underwent a curative operation for HCC. His postoperative course was uneventful and he was discharged from the hospital on the twenty-second postoperative day. He had shown no evidence of recurrence or metastases at the time he died of hepatic failure related to alcohol abuse 9 months after the operation.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Humans; Injections, Intraperitoneal; Liver Neoplasms; Male; Middle Aged; Picibanil; Rupture, Spontaneous

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

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

Recurrence of hepatocellular carcinoma (HCC) is frequent, even after apparently curative resection. Preoperative transcatheter arterial chemoembolization (TAE) does not improve disease-free survival after hepatic resection. We previously reported the potential usefulness of transarterial immunoembolization (TIE), a newly developed arterial embolization technique using OK-432 and fibrinogen, as preoperative treatment. In this study, we further investigated the effect of TIE by histologic examination of the resected specimens and compared it with conventional TAE in a prospective nonrandomized manner. Thirty-nine patients underwent TIE (n = 17) or TAE (n = 22) before curative hepatectomy for HCC. Transarterial immunoembolization was performed according to the standard protocol using OK-432, fibrinogen, and thrombin. Histologic changes in cancerous and noncancerous liver tissues were examined at different stages after TIE. Histologic grading of cancer cell injury according to the modified Shimosato criteria (Grades 0-IV, in increasing order of severity of cell injury) and postoperative disease-free survival were compared between the two groups. Based on the results of histopathology, TAE was more effective than TIE against the main tumor. In contrast, TIE was significantly more effective than TAE against extracapsular invasion and intrahepatic metastasis. Disease-free survival after hepatectomy tended to be better in patients pretreated with TIE than TAE. Postoperative tumor recurrences in the TIE group (n = 4) occurred in the nontreatment regions, whereas tumor recurrences in TAE group developed mostly (8 of 11 patients) in treated liver regions. Based on results of histologic examination, TIE seems to be more effective than conventional TAE against extracapsular invasion and intrahepatic metastasis. Data for disease-free survival and recurrence site suggest TIE may be a useful preoperative treatment.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Catheterization; Disease-Free Survival; Embolization, Therapeutic; Female; Fibrinogen; Hepatectomy; Hepatic Artery; Humans; Liver; Liver Neoplasms; Male; Middle Aged; Neoadjuvant Therapy; Neoplasm Recurrence, Local; Picibanil; Preoperative Care; Prognosis; Thrombin; Time Factors

OK-432 is a biological response modifier used in Japan to augment host immunity and is known to increase the host antitumour response. By using liposomes, which are vesicles made from phospholipids that have a structure resembling the cell membrane, we encapsulated OK-432.. Encapsulated OK-432 was injected into the tail veins of mice, and its effect was compared with that of unencapsulated OK-432 given intravenously. In mice that received either form of OK-432, both the number of natural killer (NK) and intermediate T cell receptor (intTCR) cells (intrahepatic T cells generated by extrathymic differentiation) increased markedly in the liver, with the peak level occurring 3 days after administration. Both forms of OK-432 also increased cytotoxic activity against Yac-1 cells. The increase in numbers of cells and in cytotoxic activity in the liver persisted for longer in mice that received encapsulated OK-432 than in animals that received unencapsulated OK-432.. Because it has been shown that both NK and intTCR cells play an important role in tumour immunity, an increase in the number of such cells can be considered likely to have an increased antitumour effect. Encapsulated OK-432 elicited liver-specific augmentation of cytotoxic activity and the effect was more persistent than that produced by OK-432 given in the conventional form; therefore, it may be useful for the treatment of tumours, particularly those arising in the liver.

Topics: Animals; Antineoplastic Agents; Cells, Cultured; Drug Carriers; Killer Cells, Natural; Liposomes; Liver; Liver Neoplasms; Mice; Phenotype; Picibanil; Receptors, Antigen, T-Cell; Streptococcus pyogenes

Epithelioid haemangioendothelioma is an unusual type of endothelium-derived vascular tumour of borderline malignancy, which has high variability in clinical presentations, depending on the primary site of involvement. We report on a 20-year-old woman who presented with progressive abdominal fullness for 6 months. Multiple lung and liver nodules with pleural effusion and profuse ascites were found. The diagnosis of epithelioid haemangioendothelioma was made after wedge biopsy of the liver. The ascites was intractable and refractory to strong diuretic therapy and repeated paracentesis. Therefore, six courses of intraperitoneal injection of OK-432 were administered. The ascites subsided to a minimal amount after treatment and the patient remained symptom-free for approximately 8 months. The ascites recurred later and another three courses of intraperitoneal injection of OK-432 were administered. The ascites disappeared again. The patient has remained symptom-free since the end of the second period of treatment.

Topics: Adult; Antineoplastic Agents; Ascites; Female; Hemangioendothelioma, Epithelioid; Humans; Injections, Intraperitoneal; Liver Neoplasms; Palliative Care; Picibanil

Surgical resection, transcatheter arterial embolization (TAE) and percutaneous ethanol injection therapy (PEIT) are effective for hepatocellular carcinoma (HCC), but the recurrence rate is high. We have devised a new therapy of transarterial immuno-embolization (TIE) with OK-432, fibrinogen and thrombin, and 2 cases are reported. Case 1: A 78-year-old Japanese male with HCC (diameter, 4 cm in subsegment 5) received TIE. The tumor size was markedly decreased, and the patient survived for more than 3 years without recurrence. Case 2: A 61-year-old Japanese male with HCC (diameter, 4.5 cm in segment 5) received hepatic subsegmentectomy following TIE. Histological examination of resected specimens following TIE showed massive infiltration of mononuclear cells in the main tumor. Tumor recurrence had developed three times thereafter, but was effectively treated by TIE. TIE may be an effective therapy for HCC.

Topics: Aged; Carcinoma, Hepatocellular; Embolization, Therapeutic; Fibrinogen; Hepatic Artery; Humans; Immunotherapy; Iodized Oil; Liver Neoplasms; Male; Middle Aged; Picibanil; Thrombin

The effects of OK-432 and/or MMC on host immunity were studied in patients with advanced colorectal cancer. OK-432 was administered to the portal vein, and MMC was dispersed into the peritoneal cavity for prevention of liver metastasis. In the MMC group, NK activity was significantly reduced at 7 days postoperatively, while such a reduction was not seen in the OK and OK + MMC groups. The administration of OK-432 decreased the postoperative proportion of suppressor T cells in the lymphocyte subsets more than that of MMC group. Our results strongly suggest that intraoperative administration of BRM to the patients with advanced colorectal cancer can significantly prevent postoperative immunosuppression.

Topics: Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Humans; Immunity, Cellular; Immunologic Factors; Immunotherapy; Infusions, Parenteral; Killer Cells, Natural; Liver Neoplasms; Lymphocyte Subsets; Mitomycin; Picibanil

The antitumor effects of immunotherapy using streptococcal preparations (OK-432), recombinant granulocyte-colony-stimulating factor (rG-CSF) and recombinant interleukin-2 (rIL-2) were examined for human hepatocellular carcinoma (HCC). Following subcutaneous injection of OK-432 (2 KE) and rG-CSF (50-60 microg), low-dose intratumoral administration of OK-432 (3-12 KE) was performed. Thereafter, 2 x 10(5) JRU of rIL-2 was subcutaneously injected. This therapeutic regimen was repeated twice. Serum alpha-fetoprotein levels were markedly decreased in three of seven patients with HCC by this treatment. Post-therapeutic histological examination revealed that trabecular cords or pseudoglandular arrangements of tumor cells were completely disordered in all cases and that extensive infiltration of lymphocytes into the tumor stroma was present in five cases. The number of CD4- and CD57-positive cells among tumor-infiltrating lymphocytes after immunotherapy was significantly higher than that in patients without immunotherapy (P <0.01). These findings suggest that even a small intratumoral injection of OK-432 can induce extensive infiltration of helper/inducer and natural killer cells into the tumor stroma when combined with subcutaneous injection of OK-432, rG-CSF and rIL-2 and that these cells might play important roles in tumor cytotoxicity.

Topics: Aged; alpha-Fetoproteins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Drug Administration Schedule; Female; Granulocyte Colony-Stimulating Factor; Humans; Immunohistochemistry; Immunotherapy; Interleukin-2; Leukocyte Count; Liver Neoplasms; Male; Middle Aged; Neutrophils; Picibanil; Recombinant Proteins

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

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

The role of biological response modifiers (BRM) in locoregional therapy for liver metastases of colorectal cancer was studied clinically and experimentally. Seven patients with numerous metastases to both lobes of liver were given intraarterial administration of BRM in combination with anticancer drugs. A partial response was observed in 1 patient. The response rate was 14.3%. Alternatively, intraarterial administration of both OK-432 and IL-2 into the rabbit with liver metastases of VX-2 tumors could bring about the infiltration of cytotoxic T lymphocytes around the tumors, followed by a significant decrease of the metastatic nodules. In addition, the same anti-tumor effect was observed when PSK was administered intraperitoneally into the BALB/c mouse with liver metastases of colon 26 tumors. Moreover, the therapeutic effect of water in oil type emulsion encapsulating both OK-432 and IL-2 was greater than that of the solution of BRM in BALB/c mouse with liver metastases of colon 26 tumors. These results indicated that BRM could be one of the promising agents in locoregional therapy against liver metastases of colorectal cancer.

Topics: Adult; Aged; Animals; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Colorectal Neoplasms; Doxorubicin; Female; Fluorouracil; Hepatic Artery; Humans; Infusions, Intra-Arterial; Interleukin-2; Leucovorin; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Mice; Middle Aged; Picibanil; Rabbits

We performed the locoregional injection of OK-432/fibrinogen/thrombin to unresectable hepatic tumors metastasized from colorectal cancers, which were hardly controlled by arterial infusion chemotherapy. CEA was markedly decreased following this treatment, although abdominal CT did not show a significant reduction of tumor mass. This immuno-injection therapy may be a choice of treatment for metastatic liver tumors, refractory to treatment by conventional chemotherapy.

Topics: Antineoplastic Agents; Carcinoembryonic Antigen; Colorectal Neoplasms; Drug Administration Schedule; Drug Therapy, Combination; Female; Fibrinogen; Humans; Injections, Intralesional; Liver Neoplasms; Male; Middle Aged; Picibanil; Thrombin

We have previously demonstrated that administration of killed streptococcal preparation (OK432), a biological modifier, increased the number of asialo GM1-positive cells in the liver, enhanced NK activity of hepatic mononuclear cells, and reduced the number of hepatic metastases of colon 38 adenocarcinoma that were inoculated into the superior mesenteric vein of C57BL/6 strain mice. In the present study, to clarify the role of the spleen in immune surveillance of the liver, the effect of splenectomy on hepatic metastasis of colon carcinoma and on hepatic NK activity has been examined. The number of hepatic metastasis increased in the splenectomized mice, compared with that in sham-operated mice. Administration of OK432 increased the number of asialo GM1-positive cells in the liver and enhanced NK activity of hepatic mononuclear cells in both groups, but NK activity of hepatic mononuclear cells in the splenectomized mice was less than that of the sham-operated mice. An enhanced NK activity of these cells was abolished by treatment with anti-asialo-GM1 antibody plus complement in vitro. Interleukin-2 mRNA expression was increased in the spleen 2 hr after OK432 administration and persisted until 8 hr, but was scarcely noted in the liver. On the other hand, NK activity of hepatic mononuclear cells in the asialo GM1-positive cell-depleted (previous administration of antiserum against asialo GM1) mice was enhanced after OK432 administration in the sham operated and splenectomized mice, but an enhanced NK activity in these mice was only partially or not at all abolished by treatment with anti-asialo GM1 antibody plus complement in vitro, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Colonic Neoplasms; G(M1) Ganglioside; Interleukin-2; Killer Cells, Natural; Liver; Liver Neoplasms; Male; Mice; Mice, Inbred C57BL; Picibanil; RNA, Messenger; Spleen; Splenectomy

The antitumor activity of combination therapy with traditional Chinese medicines and OK432 (Streptococcus pyogenes) for cancer patients was investigated. Excellent antitumor activity of this treatment was achieved in one patient with hepatocellular carcinoma. The present report describes the clinical course of this patient and examines the contribution of production of tumor necrosis factor (TNF) and interferon-gamma (IFN). Endogenous production of TNF could be observed after drip intravenous injection of OK 432 in the serum of patients treated by previous oral administration of traditional Chinese medicines. The serum levels of IFN were very low and remained at almost undetectable levels under these conditions. The selective use of immunostimulants such as traditional Chinese medicines may be of value in combination with other therapies such as drip infusion of OK 432, in the treatment of advanced cancer or of aged patients because of the low toxicity. One patient out of 12 revealed a partial response as assessed by the antitumor activity. However, with this treatment, patients did become free from pain and a good performance status was supported.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Drugs, Chinese Herbal; Female; Humans; Interferon-gamma; Interleukin-1; Liver Neoplasms; Lymphocyte Count; Male; Picibanil; T-Lymphocyte Subsets; Tumor Necrosis Factor-alpha

An experimental model for hepatic metastasis with a transplantation route of free-pedicled subcutaneous-embedded spleen was established in BALB/c mice. Colon-26 tumor cells to produce hepatic metastasis were inoculated into the spleen and the influence of surgical stress by means of a 20-min exposure of the abdominal cavity on the incidence of hepatic metastasis was examined. Hepatic metastasis was more promoted by the surgical stress in order when it was given on the same day, the 7th day and the 3rd day of the inoculation. Administration, without surgical stress, of ASGM 1, a specific inhibitor of the natural killer activity, also facilitated the hepatic disease. Administration of OK-432 prior to the surgical stress or ASGM 1 was at least partly effective for prevention of the hepatic metastasis and prolonged the survival of the inoculated mice. Preoperative immunotherapy utilizing OK-432 might be a possible means to prevent hepatic metastasis triggered in colorectal surgery for cancer.

Topics: Animals; Antibodies; Antineoplastic Agents; Colonic Neoplasms; Cytotoxicity, Immunologic; Disease Models, Animal; G(M1) Ganglioside; Killer Cells, Natural; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Neoplastic Cells, Circulating; Picibanil; Stress, Physiological; Surgical Procedures, Operative

Two cases of hepatic metastasis of colorectal cancer were treated effectively by intrahepatic-arterial infusion immunotherapy using OK-432 (2 KE/week or 2 weeks), recombinant IL-2 (35 x 10(4) JRU or 40 x 10(4) JRU/week or 2 weeks), MMC (4 mg/week or 2 weeks) and 5-FU (250 mg/day during admission, 250 mg/week or 2 weeks during outpatient treatment). The levels of CEA were decreased from 17.2 ng/ml to 2.4 ng/ml after 8 weeks in the first case (50 y. o. male) and from 521 ng/ml to 66 ng/ml after 8 weeks in the second case (36 y. o. female), respectively. Abdominal CT revealed a partial response for 11 months in the first case and 6.5 months in the second case.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Colorectal Neoplasms; Drug Administration Schedule; Female; Fluorouracil; Humans; Immunotherapy; Infusions, Intra-Arterial; Interleukin-2; Liver Neoplasms; Male; Middle Aged; Mitomycin; Picibanil; Recombinant Proteins

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

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

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

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

The prognosis of patients with multiple hepatocellular carcinoma (HCC) remains disappointing. In this study, we devised a new therapeutic modality for HCC consisting of transarterial immunoembolization (TIE) using OK-432 and fibrinogen and then analyzed the preliminary results. In the first series, we applied the treatment to 19 patients with advanced HCC who had proved to be insensitive to several previous conventional treatments. In all, 14 patients (74%) with unresected HCC have currently survived for between 2 and 16 months after TIE. The remaining 5 patients died at 17, 14, 8, 7, and 4 months after TIE. The serum levels of tumor markers decreased in all of the patients, and a marked reduction in tumor size was observed in six patients after TIE. A high fever occurred in all cases, and abdominal pain and loss of appetite were also observed after TIE. However, deterioration of liver function was negligible. After confirmation of the safety of this method, we started a second study series in which this TIE treatment was selected as the first choice. Six patients have been treated to date. All patients in this group underwent hepatic resection at 6-48 days following TIE. Histological examination of the resected specimens following TIE showed massive infiltration of mononuclear cells around tumor cell nests and lytic necrosis as well as coagulation necrosis of the main tumor and the intrahepatic metastases. In conclusion, our results indicate that TIE may be a safe and promising therapy for patients with HCC.

Topics: Adult; Aged; Biomarkers, Tumor; Carcinoma, Hepatocellular; Embolization, Therapeutic; Female; Fibrinogen; Humans; Immunotherapy; Injections, Intra-Arterial; Liver Neoplasms; Male; Middle Aged; Picibanil; Prognosis

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

The outcome in 31 patients with liver metastases from breast cancer given OK-432-combined adoptive immunotherapy via the hepatic artery was analyzed. Patients received intraarterial OK-432, a streptococcal preparation, followed by the transfer of autologous lymphocytes cultured with autologous tumor extract and interleukin-2 for 9-13 days. Liver lesions were evaluable in 11 of the 12 patients with bone metastasis (group A) and in 16 of the 19 patients without bone metastasis (group B). Complete response (CR) in the liver was attained in 8 patients in group A, but in only 1 in group B (p < 0.01). In group A, radiological features of all metastatic foci of bone improved after CR in the liver. Moreover, the median survival time (MST) of group A (20 months) was longer (p = 0.06) than that of group B patients with extra-hepatic metastasis (n = 12; MST = 6 months), while group B patients with liver metastasis alone (n = 7) showed a MST similar to that of group A. Thus, loco-regional immunotherapy via the hepatic artery was found to be useful in controlling both liver and bone metastasis from breast cancer. Moreover, in breast cancer patients with liver metastasis, bone metastasis appears to be a prognostic factor associated with good response to this immunotherapy.

Topics: Adult; Bone Neoplasms; Breast Neoplasms; Combined Modality Therapy; Female; Hepatic Artery; Humans; Immunotherapy, Adoptive; Injections, Intra-Arterial; Interleukin-2; Killer Cells, Lymphokine-Activated; Liver Neoplasms; Lymphocyte Activation; Lymphocytes; Middle Aged; Outcome Assessment, Health Care; Picibanil; Prognosis; Retrospective Studies

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

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

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

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

The efficacy of transarterial immuno-embolization therapy (TIE) was examined in six operable patients with hepatocellular carcinoma (HCC). We administered OK-432, fibrinogen (30 mg/ml) and thrombin (1 U/ml) through a catheter which was inserted into the tumor-feeding artery. In all patients with a high level of tumor markers (AFP and PIVKA-II), the level decreased promptly to less than the pretreatment level after TIE therapy. The therapy has not caused any serious side effects. No disturbance of the coagulation-fibrinolysis system due to TIE was observed in any patient. Histological examination of resected specimens following TIE showed massive infiltration of mononuclear cells around tumor cell nests, and lytic necrosis as well as coagulation necrosis of the main tumor and the intrahepatic metastases. Our results indicate that TIE may be an effective and promising modality for HCC patients.

Topics: Aged; Carcinoma, Hepatocellular; Chemoembolization, Therapeutic; Combined Modality Therapy; Female; Fibrinogen; Humans; Iodized Oil; Liver Neoplasms; Male; Middle Aged; Picibanil; Thrombin

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

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

Human neutrophil-mediated oxidative processes against a human hepatoma cell line, HCC-M, was visualized at the cellular level by using a silicon-intensified target camera and subsequently processing with a computer-assisted digital-imaging processor. Neutrophils were activated by a streptococcal preparation, OK-432. A hydroperoxide-sensitive tracer, dichlorofluorescein diacetate, was loaded in HCC-M and temporal and spatial changes of lipid peroxides in this cell after addition of stimulated neutrophils were analyzed. The luminol-dependent chemiluminescence activity of neutrophils was significantly enhanced and continued for at least 2 hr by stimulation with OK-432, and its activity was shown to be accumulated at the site where a neutrophil attached with HCC-M. The intensity of dichlorofluorescein fluorescence in HCC-M rapidly increased after adding stimulated neutrophils, and their reaction was significantly attenuated by superoxide dismutase. The number of non-viable cells was increased as the dichlorofluorescein fluorescence increase. It is suggested that oxidative stress may play an important role in neutrophil-mediated tumor-cell damage.

Topics: Carcinoma, Hepatocellular; Fluoresceins; Humans; Liver Neoplasms; Luminescent Measurements; Neutrophils; Oxidation-Reduction; Picibanil; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

The efficacy of transarterial immuno-embolization therapy (TIE) was investigated in 7 patients with multiple hepatocellular carcinoma (HCC). We administered OK-432 (10 KE), fibrinogen (30 mg/ml) and thrombin (1 U/ml) as a new treatment for HCC with intrahepatic metastasis. In all patients with a high level of AFP, the AFP level decreased promptly less than the pretreatment level after TIE therapy. High fever in all cases, epigastralgia in 6 cases and appetite loss in 3 cases were observed after TIE therapy. Our results indicate that this therapy may be a safe and effective method in HCC patients with intrahepatic metastasis.

Topics: Administration, Oral; Aged; Carcinoma, Hepatocellular; Embolization, Therapeutic; Fibrinogen; Fluorouracil; Hepatic Artery; Humans; Immunotherapy; Iodized Oil; Liver Neoplasms; Male; Middle Aged; Picibanil; Thrombin

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

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

Topics: Chemoembolization, Therapeutic; Hepatic Artery; Humans; Infusions, Intra-Arterial; Liver; Liver Cirrhosis; Liver Neoplasms; Mitomycin; Picibanil

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

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

Two surgical procedures were required to make experimental model of liver metastasis (SC42-DS). In this paper, the protective effects of OK432 against liver metastasis were examined experimentally, as a immunotherapeutic agent under perioperative condition. In 5 combinations of administration, OK432 showed some different effects on liver metastasis, however, in general, simultaneous intrasplenic injection of OK432 reduced liver metastasis. From this result, the efficacy of intraoperative OK432 via portal vein was speculated.

Topics: Animals; Drug Administration Schedule; Immunization; Liver Neoplasms; Male; Mice; Picibanil

Intrasplenic administration of 1 x 10(6) C-1300 murine neuroblastoma cells induced spleen tumor in 78.6% of mice and liver metastasis in 64.3%. When mice were pretreated with carrageenan, an antimacrophage agent, the incidence of spleen and liver tumors in this system was lower, possibly due to the rebound increase in macrophage activity following the disappearance of the carrageenan effect. Continuous daily intraabdominal injection of 1 KE of OK-432 streptococcus preparation markedly reduced the appearance of liver metastasis (P less than 0.01), whereas the spleen mass was not reduced to such an extent. However, the survival rate of the OK-432-treated group did not differ greatly from that of the nontreated group. These results demonstrate the usefulness of the model of liver metastasis induced by intrasplenic administration of tumor cells and the effectiveness of OK-432 against liver metastasis formation.

Topics: Animals; Carrageenan; Immunity, Cellular; Immunotherapy; Liver Neoplasms; Macrophages; Male; Mice; Mice, Inbred A; Neoplasm Metastasis; Neuroblastoma; Picibanil; Spleen; Survival Analysis

In the early period following radical hepatectomy for hepatoma, recurrences in the remaining liver are frequently found. In regenerating liver, implantation and growth of tumour cells released into the portal system during surgical treatment might be promoted. We examined the relationship between liver regeneration and the formation of metastases following hepatic resection. Intraportal injections of rat ascites containing hepatoma AH130 cells at a concentration of 1 x 10(5) cells 0.2 ml-1 were made at various periods following two thirds liver resection in rats. Tumour cell injections immediately at 24 h after surgery resulted in an increased number of hepatic metastases compared with control animals. Tumour cell injections 2 weeks after hepatectomy, however, had no significant difference in effect compared with control rats. In contrast, tumour cells injected immediately after removal of half of the caudate lobe resulted in the same number of metastases as control animals. These results demonstrate that the number of artificially induced hepatic metastases was increased during an initial period of active liver regeneration and was proportional to the volume of hepatectomy. The effect of 5-fluorouracil (5FU) or mitomycin C (MMC) as inhibitors of hepatic regeneration on liver metastasis after hepatectomy was studied. The administration of 5FU (20 mg kg-1) or MMC (0.2 mg kg-1) immediately, 24 and 48 h after hepatectomy resulted in a marked reduction in metastatic lesions. The administration of 5FU caused delays in weight gain and decreases in the wet weight of remaining liver, while MMC had no effect on either. Accordingly, results of 5FU administration may be due to inhibitory effects on liver regeneration whilst that of MMC administration may be due to cytocidal antitumour effect. The effect of OK-432 as an immunoactivator on the implantation and growth of tumour cells in regenerating liver was also studied. Pretreatment with OK-432, 0.5 mg intraperitoneally on 7 consecutive days, had no effect on hepatic metastases. The pathophysiology of liver regeneration may enhance hematogenous hepatic metastasis and release of tumour cells during surgical manipulation may represent an important cause of recurrence following hepatic resection.

Topics: Animals; Fluorouracil; Liver; Liver Neoplasms; Liver Neoplasms, Experimental; Liver Regeneration; Mitomycin; Neoplasm Metastasis; Picibanil; Rats; Rats, Inbred Strains

The response and survival of 26 patients with liver metastases from breast cancer, who received OK-432-combined adoptive immunotherapy from 1984 to 1990, were evaluated. OK-432-combined adoptive immunotherapy was comprised sequential treatment via the hepatic artery with a streptococcal preparation, OK-432 (1-5 KE), and adoptive transfer of lymphocytes expanded in T-cell growth factor and sonicated tumor extract antigen. Seventeen (65%) patients responded to the therapy. The median survival time of all patients after treatment was 13 months (range, 2-63 months). Of the 20 prognostic factors analyzed, performance status (PS) alone was related to response (P less than 0.01). The response rate of the patients with a PS of 0-2 was 83% but only 25% in those with a PS of 3 or 4. In univariate analysis, 11 factors significantly influenced the survival: tumor response; size of primary tumor; menopausal status; PS; serum bilirubin, albumin, lactate dehydrogenase and glutamate-oxalate transaminase (aspartate aminotransferase); the extent of liver involvement; and the number and the proliferation rate of transferred lymphocytes. The MST was 22.8 months for the responders versus 2.8 months for the nonresponders (P less than 0.01). In multivariate analysis, the most important factor associated with survival was the tumor response, as well as PS, liver involvement, lactate dehydrogenase and albumin. These results suggest that OK-432-combined adoptive immunotherapy can be considered a candidate for a randomised control study and these factors should be used for stratification.

Topics: Breast Neoplasms; Combined Modality Therapy; Female; Humans; Immunotherapy, Adoptive; Infusions, Intra-Arterial; Liver Neoplasms; Neoplasm Recurrence, Local; Picibanil; Prognosis; Survival Analysis

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

To increase antitumor effects of transcatheter arterial embolization therapy (TAE) for hepatocellular carcinoma (HCC), immunochemo-embolization therapy via hepatic artery was performed with a mixture of doxorubicin and iodized oil (LPD) following a mixture of gamma-IFN, OK-432 and gelatin sponge, and then a mixture of actinomycin D and gelatin sponge. Three patients with HCC were treated by this procedure. One patient had tumor thrombus in inferior vena cava (IVC). The serum alpha fetoprotein (AFP) levels before this procedure ranged from 66 ng/ml to 8,360 ng/ml. Following this procedure, the serum AFP levels began to decrease for 1-3 months, then increased for 3-6 months, and again suddenly decreased under 10 ng/ml in two cases after initial procedure. The serum AFP levels of two cases revealed under 10 ng/ml for 9-18 months. CT after 2 weeks to 3 months of this procedure showed a low-density area around LPD-uptaking tumor and after 1-8 months decreased tumor in size with diminishing of the low-density area. Therapy for the main tumor of one case with tumor thrombus of IVC proved to be effective, but it was not effective for tumor thrombus of IVC. The reasons that the serum AFP level increased after decreasing for 1-3 months and then fell below 10 ng/ml following this procedure, may be some kinds of immunological antitumor effects produced by endogenous cytokines.

Topics: Aged; alpha-Fetoproteins; Carcinoma, Hepatocellular; Dactinomycin; Doxorubicin; Female; Humans; Interferon-gamma; Iodized Oil; Liver Neoplasms; Male; Middle Aged; Picibanil; Tomography, X-Ray Computed

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

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

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

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

It has been generally agreed that the prognosis of widely spreaded "surgically unresectable" metastatic liver tumor originated from breast cancer is very poor. We reported here the result of clinical efficacy of sequential immunotherapy with intra-tumoral injection of large dose OK-432, after oral administration of cyclophosphamide during 7-10 days, and continuous perfusion of purified human recombinant interleukin-2 (rIL-2) from hepatic artery for the breast cancer patients with unresectable metastatic liver tumors. In all of 3 cases, metastatic liver tumor revealed overwhelming tumor reduction more than 50% of preoperative total tumor burden evaluated by computed tomography. Only 1 day after operation, large doses of OK-432 was injected intratumorally, both activity of Natural Killer (NK) cells and lymphokine activated killer (LAK) cells in peripheral blood lymphocytes were 5-20 folds augmented in all clinical trials. Serum tumor markers, i.e., Carcinoembryonic Antigen (CEA) and CA15-3, were rapidly decreased in all cases, respectively. Our clinical data indicate that intratumoral injection of large dose OK-432 and continuous administration of rIL-2 via hepatic artery, pretreated with cyclophosphamide, were clinically effective immunotherapy for reduction of metastatic liver tumor.

Topics: Administration, Oral; Adult; Animals; Breast Neoplasms; Cyclophosphamide; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Injections, Intralesional; Interleukin-2; Killer Cells, Lymphokine-Activated; Killer Cells, Natural; Liver Neoplasms; Liver Neoplasms, Experimental; Mice; Mice, Inbred C3H; Middle Aged; Picibanil; Recombinant Proteins; Remission Induction

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

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

OK-432 and etoposide were administered intravenously to a patient with liver metastasis of ovarian cancer. OK-432 induced IFN-gamma and TNF. SuPS and PPD skin reaction became positive after the therapy. The size of metastatic lesions was reduced significantly (partial response). It is suggested that the combination therapy of OK-432 and etoposide may be effective to the liver metastasis of ovarian cancer.

Topics: Adult; Carcinoma, Hepatocellular; Etoposide; Female; Humans; Injections, Intravenous; Liver Neoplasms; Ovarian Neoplasms; Picibanil

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

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

Hepatic resection of metastatic colorectal carcinoma offers a chance for long term survival and is being performed with increasing frequency. The aim of this study is to reduce the re relapse in the residual liver after curative hepatectomy. Nineteen patients with hepatic metastases from colorectal carcinoma who underwent hepatic resection plus hepatic artery infusion therapy using an implantable port (HR-HAI) were analyzed. As hepatic resection, lobectomies were performed in 6 patients, segmentectomies in 8 patients and wedge resection in 5 patients. As chemotherapeutic agents, adriamycin in 8 patients, mitomycin C in 7 patients and OK-432 in 4 patients were used. The drugs were administered through hepatic artery via a port every one month for one year at the out patient clinic. Eight out of 19 patients had no complication by HR-HAI therapy, but 3 patients had catheter obstruction within one year, 4 had gastrointestinal discomfort, 3 fever up and 1 liver tissue necrosis. The serious hepatotoxicity such as sclerosing cholangitis was not observed. Re-relapses were appeared in 15 patients and the sites were the residual liver in 10 patients, and 5 in the other organs. The 3-year survival rate of 19 treated patients was 40.0% higher than 33.3% of 52 patients undergone hepatic resection alone, but the difference was not statistically significant.

Topics: Antineoplastic Agents; Colorectal Neoplasms; Combined Modality Therapy; Doxorubicin; Female; Hepatectomy; Hepatic Artery; Humans; Infusion Pumps, Implantable; Infusions, Intra-Arterial; Liver Neoplasms; Middle Aged; Mitomycin; Mitomycins; Picibanil; Survival Rate

Unresectable hepatocellular carcinoma (HCC) has a poor prognosis and little sensitivity to anticancer agents. We planned a combination immunotherapy, associating with rIL-2 continuous injection. Combination immunotherapy consists of 5 different biological response modifiers (BRM), i.e., rIL-2, OK-432, adriamycin (ADR), cyclophosphamide (Cy), and famotidine (Fa). rIL-2, OK-432 and ADR were administered from implantable infuser port connecting to a catheter which was injected into the hepatic artery via the gastroduodenal artery under laparotomy. OK-432, Cy, and Fa were also administered systemically. From 1988 to 1990, seven patients with unresectable HCC and two patients who underwent curative resection were treated by this therapy. The objective responses were evaluated by CT and angiography. This combination immunotherapy produced 3 cases of complete response and 2 of minor response. Immunological monitoring of lymphocyte subsets and NK activity of peripheral blood mononuclear cells was also performed. NK activity was significantly augmented and the percentage of Leu 7(-) NCD 16(+) cells increased during this therapy. Serious toxicity, but transient high fever and hypotension, was not observed during this therapy. All of these patients left the hospital within two weeks and returned to their previous job or similar life activity. These results suggest that this combination immunotherapy is worth performing in further clinical trials for hepatocellular carcinoma.

Topics: Antineoplastic Combined Chemotherapy Protocols; Biological Products; Carcinoma, Hepatocellular; Cyclophosphamide; Doxorubicin; Famotidine; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Injections, Intramuscular; Interleukin-2; Liver Neoplasms; Male; Middle Aged; Picibanil; Quality of Life; Remission Induction

Antitumor effect of TNF has been demonstrated to be increased with some kinds of anticancer agents. We reported antitumor effect of hepatic endogenous TNF induced with gamma-IFN and OK-432 for hepatocellular carcinoma (HCC). To increase antitumor effect of transcatheter arterial embolization (TAE), hepatic arterial chemoembolization was performed with a mixture of gamma-IFN, OK-432 and gelatin sponge following a mixture of Doxorubicin and iodized oil (LPO) on the first time. Serum alpha-fetoprotein decreased from 18,903 ng/ml to 470 ng/ml but elevated three months after these procedures. Following the above procedure, hepatic arterial embolization with a mixture of gelatin sponge and Actinomycin D as an inhibitor of RNA was given the second time. Serum alpha-fetoprotein decreased under 5 ng/ml and computed tomography revealed decreased tumor size and low density area following this second procedure. Hepatic arterial chemoembolization with a mixture of hepatic induction of endogenous TNF and anticancer agents may well be beneficial for survival of patient with HCC.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Carcinoma, Hepatocellular; Dactinomycin; Delayed-Action Preparations; Doxorubicin; Drug Administration Schedule; Embolization, Therapeutic; Gelatin Sponge, Absorbable; Hepatic Artery; Humans; Infusions, Intra-Arterial; Interferon-gamma; Iodized Oil; Liver Neoplasms; Male; Picibanil; Tumor Necrosis Factor-alpha

Intratumor injection of OK-432, a biological response modifier, in the treatment of small HCC was studied in 7 inoperable patients. After evaluation with ultrasound (US), computed tomography (CT), angiography and US-guided biopsy, implantation of a steel coil in the tumor, intratumor injection was performed under US guidance. After completion of the treatment, liver biopsy and image studies were again done to evaluate the extent of tumor necrosis. One patient was alive and well without recurrence 19 months after treatment. Four had recurrent tumors at different site of the liver 4 months, 9 months, 9 months and 8 months later. Two died of progressive malignancy 3 months and 8 months later. In the 6 patients with elevated serum alpha-fetoprotein (AFP) levels, 4 had decreased AFP after treatment, and the 2 mortalities had steadily increased AFP. The most common side effects are fever and chills. Transient abdominal pain with elevated transaminase activities, cough with hemoptysis, and vomiting were seen in 1 case each. After treatment, the biopsy specimens showed total necrosis of HCC. Although the T4/T8 ratio of peripheral blood was increased as compared with that before treatment in 4 cases, peritumoral cytotoxic T lymphocyte and monocyte infiltration were seen in one specimen only, and another 7 examined specimens showed negative staining with monoclonal antibodies of T cells. We conclude that intratumor injection of OK-432 is an alternative treatment for small HCC in inoperable cases. The effectiveness may be due to the direct tumoricidal mechanism of OK-432.

Topics: Aged; Carcinoma, Hepatocellular; Female; Humans; Injections, Intralesional; Leukocytes, Mononuclear; Liver Neoplasms; Lymphocyte Subsets; Male; Middle Aged; Picibanil; T-Lymphocytes, Cytotoxic

Lymphokine-activated killer (LAK) activity of peripheral blood mononuclear cells (PBMC) from 33 patients with hepatocellular carcinoma was significantly decreased compared with that of healthy volunteers. There was less LAK activity in PBMC from patients with larger tumours (5 cm or more in diameter) than in patients with smaller tumours (under 5 cm in diameter). In 8 out of 20 patients with larger tumours there was none or little LAK activity. Flow cytometry revealed that the percentage of Leu11b+ cells in PBMC was lower in patients than in normal volunteers, and was lowest in patients with larger tumours. 10 patients with hepatocellular carcinoma were treated with intratumoral injection of OK432. LAK activity was enhanced after treatment in 7 cases, and the percentage of Leu11b+ cells was increased. Enhancement of LAK activity in response to OK432 was more significant in patients with smaller rather than larger tumours. Of the 7 high LAK responders, 4 showed 50-100% tumour regression at 6-9 weeks after injection.

Topics: Carcinoma, Hepatocellular; Cytotoxicity, Immunologic; Female; Flow Cytometry; Humans; Killer Cells, Lymphokine-Activated; Leukocyte Count; Liver Neoplasms; Male; Middle Aged; Picibanil

We studied the therapeutic effect of OK-432 combined with adoptive immunotherapy in 19 cases of liver metastases from breast cancer. Of the 14 patients who received intraarterial OK-432 injection and transfer of cultured lymphocytes, 9 responded to this therapy, whereas no patients responded to intravenous administration. The minimum cell number for a therapeutic response was 8 x 10(8) cells. Metastatic lesions other than those in the liver regressed after therapy in 4 patients. The serum carcinoembryonic antigen level paralleled the therapeutic effect. There were no severe side-effects accompanying this therapy. These results indicate that intraarterial adoptive immunotherapy combined with OK-432 is effective as a new therapeutic approach against liver metastases from breast cancer.

Topics: Adult; Aged; Biological Products; Breast Neoplasms; Carcinoembryonic Antigen; Cytotoxicity, Immunologic; Female; Humans; Immunization, Passive; Killer Cells, Lymphokine-Activated; Liver Neoplasms; Lymphocytes; Middle Aged; Picibanil; Radiography

For prophylactic therapy to inhibit hepatic metastatic recurrence after surgical treatment of gastro-intestinal carcinomas, the effects of OK-432, a biological response modifier (BRM), were examined with inoculation of tumor cells and administration of OK-432 via portal vein. Experiments with the inhibition of liver metastasis were performed as follows. The animals were divided into five groups. Group 1: 1.0 KE of OK-432 was given intraportally 5 minutes after injection of 5.0 X 10(6) tumor cells per rat via the portal vein. Group 2: Non-medicated group, only 5.0 X 10(6) tumor cells per rat were injected into portal vein, as the control for group 1. Group 3: 0.5 KE of OK-432 and 2.5 X 10(6) tumor cells per rat were used. Group 4: 1.0 KE of OK-432 and 2.5 X 10(6) tumor cells were used. Group 5: Non-medicated group, injected with 2.5 X 10(6) tumor cells as the control group for groups 3 and 4. Colonies of metastases in the liver of each group were examined by autopsy on the 30th day after treatment. Metastases were observed in 75% of group 1, 100% of group 2, 58.8% of group 3, 64.3% of group 4 and in 90% of group 5. For the investigation of the mechanisms to inhibit these liver metastases, 51Cr labeled AH60C tumor cells were injected into the portal vein, and the remained of radioactivity in rat liver was examined. The result showed that OK-432 injected into the portal vein did not directly kill the lodging tumor cells. To prove the morphological evidence of inhibition of hepatic metastasis, the changes of tumor cells were microscopically observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Biological Products; Gastrointestinal Neoplasms; Injections, Intravenous; Liver Neoplasms; Male; Picibanil; Portal Vein; Rats

OK-432 purified from streptococcal preparations was administrated via either hepatic artery or peripheral vein to the patients with primary liver cancer to prevent the decrease of immunopotency in the peri-operative periods. In "OK-432 administration" group, the immunological parameters such Su-PS skin reactions, number of lymphocytes, NK activity, and Leu 11 positive cells of peripheral blood showed more increased levels than those in "untreated" group. Histologically, the resected specimens showed varying degrees of lymphocyte infiltration throughout the cancerous tissue in five out of nine patients who received OK-432 via hepatic artery. In patients received OK-432 via the hepatic artery which was feeding cancer lesion, there were formation of lymph follicles in the cancerous tissues and destruction of the cancer nests by infiltrating lymphocytes. Together with the immunological and histological findings, the intraarterial administration of OK-432 seemed to be useful as a multidisciplinary treatment.

Topics: Adult; Aged; Biological Products; Combined Modality Therapy; Hepatic Artery; Humans; Infusions, Intra-Arterial; Killer Cells, Natural; Liver; Liver Neoplasms; Lymphocytes; Middle Aged; Picibanil; Postoperative Care; Preoperative Care

Antitumor effect and reduction of tumor size by some cytokines as Biological Response Modifier have been demonstrated by various studies. Endogenous tumor necrosis factor is produced from macrophage. To increase the antitumor effect of transcatheter arterial embolization (TAE) in hepatocellular carcinoma (HCC), we treated 7 HCC patients with endogenous tumor necrosis factor (ETNF) which was induced by hepatic arterial injection of gamma-IFN (1.0-3.0 X 10(6) IU) as priming agent and OK-432 (2-5 KE) as triggering agent. TAE was performed with Lipiodol, ADM and gelatin sponge on 3-10 days after the induction of ETNF. TNF activity was detected in 2 cases and suspected to depend on the dose of gamma-IFN and OK-432. Serum alpha-Fetoprotein levels after the injection of ETNF began to decrease from 3-30 days in 5 patients and remained unchanged in 2 cases. Serum alpha-Fetoprotein levels after TAE with the induction of ETNF were decreased 1-5 months in 5 cases. Reduced size and low-density area on CT scan in 3 advanced cases after these procedures were no different from those of HCC patients treated with TAE alone. In one of two inoperable cases with a single mass lesion in the liver, CT scan after one more added TAE following these procedures showed a low-density area around the Lipiodol uptaking tumor, indicating obstruction of the peripheral portal vein. CT scan of another case revealed low density around Lipiodol in the tumor, which showed complete necrotic change. In all cases, middle-grade fever and hypotension were seen transiently, but these subsided by symptomatic treatment. The antitumor effect of TAE in HCC might be enhanced with ETNF induced by hepatic arterial injection of a low dose of gamma-INF and OK-432.

Topics: Aged; alpha-Fetoproteins; Carcinoma, Hepatocellular; Combined Modality Therapy; Doxorubicin; Embolization, Therapeutic; Female; Hepatic Artery; Humans; Infusions, Intra-Arterial; Interferon-gamma; Liver Neoplasms; Male; Middle Aged; Picibanil; Tumor Necrosis Factor-alpha

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

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

The relationship between nonspecific cytotoxic activity of spleen cells and the resistance against the graft challenge of a human hepatoma cell line (HCC-M) was investigated in nude mice. Two administrations of an immunopotentiator, OK-432 or human interleukin-2, prior to the subcutaneous inoculation of HCC-M cells, which was performed 24 h after the last administration, significantly inhibited the tumor development in terms of rate of tumor take and tumor size. This effect was abrogated by simultaneous administration of an anti-asialo GM1 (ASGM1) antiserum. There was a significant inverse correlation between tumor volume and spleen cell cytotoxicity which was determined at the time of HCC-M cell inoculation against a YAC-1 or HCC-M target. Spleen cell cytotoxicity enhanced by these immunopotentiators could not completely be abolished by in vitro treatment with ASGM1 and complement. This result suggests that effector cells of the enhanced cytotoxicity consist of heterogeneous cells including both ASGM1+ natural killer cells and other nonselective cytotoxic cells. These results suggest that nonspecific cytotoxic cells play crucial roles in the resistance against tumor cell challenge and that the total level of cytotoxic activity of these cells at the time of tumor cell challenge is a key factor which determines tumor development.

Topics: Animals; Biological Products; Carcinoma, Hepatocellular; Cell Line; Cytotoxicity, Immunologic; Female; Graft Rejection; Humans; Interleukin-2; Liver Neoplasms; Male; Mice; Mice, Nude; Neoplasm Transplantation; Picibanil; Spleen

In order to evaluate the combination therapy for liver and bile tract cancer, the effects of anticancer drugs and hyperthermia were observed using cultured human cancer cell lines. In the case of gall bladder cancer cell line (NOZ), combination of adriamycin and hyperthermia showed more effective inhibition for cell proliferation than MMC + hyperthermia and 5-FU + hyperthermia. Hepatocellular carcinoma cell line (JHH-4) showed remarkable inhibition of cell growth and secretion of albumin by combination treatment of adriamycin and hyperthermia. Morphologically, JHH-4 cells were enlarged and the nucleus was also enlarged with combination adriamycin and hyperthermia by phase contrast microscopy. Cytoskeleton of JHH-4 cells became irregular and intercellular borderline was unclear by plasma polymerization replica method (PPRM). The effects of BRM (OK-432 and TNF) on HCC cell lines was also investigated. OK-432 directly inhibited proliferation of JHH-4 cells. We observed internalization of OK-432 by JHH-4 cells with TEM and 16-mm movie. TNF showed various effects on human HCC cell lines. Proliferation of two cell lines was inhibited, and one tended to be enhanced after the addition of TNF to the medium. Hyperthermia influenced the effects of TNF to HCC cell lines. We think that this paper is a very significant study for improving the therapy for hepato-biliary cancers.

Topics: Antineoplastic Agents; Carcinoma, Hepatocellular; Cell Line; Combined Modality Therapy; Doxorubicin; Fluorouracil; Gallbladder Neoplasms; Humans; Hyperthermia, Induced; In Vitro Techniques; Liver Neoplasms; Mitomycin; Mitomycins; Picibanil; Tumor Necrosis Factor-alpha

Hepatic resection is generally considered to be superior to any other therapeutic procedures for hepatocellular carcinoma (H.C.C.). However, the resectability of the patients who have HCC. with liver cirrhosis is still low, and surgery is appropriate in only a minority of patients. Although some successful reports of intra-arterial chemotherapy for HCC. have been documented, most of the therapeutic effects are transient and the survival rate is not satisfactory. This report is of a rare case, that of a long-term survivor with HCC treated by intra-arterial chemotherapy and immunotherapy. A 66-year-old man, with a 10-year history of liver cirrhosis was admitted to The Center for Adult Diseases, Osaka, after detection of a tumor in the right lobe on US. On admission, serum AFP was within normal range, HBs-Ag was negative, and ICG-R 15 was 20.8%. On hepatic angiogram, a hypervascular tumor (6 cm in size) was recognized in the middle of the right lobe. He was assessed as unresectable because of insufficient reserve capacity, and the catheterization of the hepatic artery for intra-arterial chemotherapy and the injection 35 KE of OK-432 into the tumor were carried out under laparotomy. After the procedure, the patient was treated by intra-arterial infusion of doxorubicin (ADR) at a total dose of 150 mg and 5-FU in total dose of 25 g, with a hypodermic injection of OK-432 at a total dose of 161 KE. Hepatic angiography, carried out one year after the procedure, disclosed no foci in the liver. The duration of complete remission continued more than 5 years. The patient eventually died of intrahepatic recurrence, but he lived for 7 years and 3 months after the catheterization.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biological Products; Carcinoma, Hepatocellular; Combined Modality Therapy; Doxorubicin; Fluorouracil; Humans; Infusions, Intra-Arterial; Injections; Injections, Intradermal; Liver Neoplasms; Male; Picibanil; Remission Induction

We studied the effect of OK-432 combined AIT in 24 cases of liver metastases of breast cancer. Eleven of the 16 patients (69%) who received intraarterial transfer responded to this therapy. On the other hand, no patients responded to intravenous or intraportal transfer. The minimum cell number for a therapeutic response was 10(9) cells. Four patients had abscopal effects after therapy. The serum CEA level paralleled the therapeutic effects. There were no severe side effects accompanying this therapy. These results indicate that intra-arterial OK-432 combined AIT should be the first choice therapy against liver metastases of breast cancer.

Topics: Biological Products; Breast Neoplasms; Female; Humans; Immunization, Passive; Killer Cells, Natural; Liver Neoplasms; Lymphokines; Picibanil

Topics: Animals; Biological Products; Carboxymethylcellulose Sodium; Carcinoma, Hepatocellular; Catheterization; Dextrans; Drug Combinations; Embolization, Therapeutic; Gelatin Sponge, Absorbable; Hepatic Artery; Humans; Iodamide; Iodized Oil; Iron; Liver Neoplasms; Liver Neoplasms, Experimental; Male; Middle Aged; Picibanil; Rabbits

In order to prevent endotoxemia after hepatectomy in cirrhotic patients, we administered OK-432 before and after hepatectomy to activate the reticuloendothelial function and studied its effect on postoperative endotoxemia. In the cirrhotic group without OK-432 administration (7 patients), the value of endotoxin increased significantly after hepatectomy, compared to the cirrhotic group which received OK-432 administration (5 patients) and the non-cirrhotic group (12 patients), and the endotoxin level was still higher than the preoperative value even on the 14th day. On the other hand, the cirrhotic group with OK-432 administration and the non-cirrhotic group showed minimal increases of endotoxin levels at the first day, which returned to the preoperative values at the third day. Base on these findings, it is suggested that activation of the reticuloendothelial function bears substantial significance as one of the therapeutic modalities for prevention of endotoxemia after hepatectomy in cirrhotic patients.

Topics: Biological Products; Carcinoma, Hepatocellular; Endotoxins; Hepatectomy; Humans; Liver Cirrhosis; Liver Neoplasms; Mononuclear Phagocyte System; Picibanil; Postoperative Complications

Interferon-gamma (IFN-gamma) was induced from a human peripheral mononuclear fraction by incubation with a streptococcal preparation stabilized with penicillin G (OK432). This IFN-gamma-producing activity was significantly reduced in patients with chronic hepatitis and hepatocellular carcinoma. In patients with liver cirrhosis it was also reduced but not significantly. Serum hepatitis B virus DNA and skin tests for the purified protein derivative of tuberculin, phytohemagglutinin-P and a polysaccharide fraction prepared from streptococcus pyogenes Su strain were determined to have no significant relation to this IFN-gamma-producing activity. Although the addition of interleukin 2 (IL-2) to the culture medium enhanced the IFN-gamma-producing activity, there was no difference in this enhancement between normal control and chronic hepatitis. Therefore reduction of the IFN-gamma-producing activity observed in chronic hepatitis seems to be caused by a decreased number of IFN-gamma-producing activity cells or hypofunction of these cells or both. Since HBeAg became negative in patients whose IFN-gamma-producing activity was increased by the administration of the immunopotentiator OK432 or IFN-beta, the IFN-producing system in the patients with B type hepatitis may contribute to the elimination of HBV. Adenine arabinoside suppressed IFN-gamma-producing activity both in vivo and in vitro.

Topics: Adult; Carcinoma, Hepatocellular; Female; Hepatitis; Humans; In Vitro Techniques; Interferon-gamma; Leukocytes; Liver Cirrhosis; Liver Diseases; Liver Neoplasms; Male; Middle Aged; Picibanil

Natural killer (NK) activity in the peripheral blood of patients with chronic liver disease was measured using 51Cr labeled K562 cells as target cells. NK activity was elevated but not significantly in patients with chronic hepatitis compared with healthy controls and significantly lower in the patients with hepatocellular carcinoma. The activity decreased in the order of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Although the level of NK activity in patients with chronic hepatitis did not correlate with the level of alanine aminotransferase (ALT), it tended to be elevated in association with elevation of ALT in patients treated with OK432, interferon-beta, glycyrrhizin or adenine arabinoside. In chronic liver disease, phytohemagglutinin (PHA) skin test showed a positive correlation with NK activity. In all patients who were treated with the immunopotentiator, OK432, and whose HBeAg became negative, NK activity was elevated during the treatment. These results suggest that the NK activity in peripheral blood may be related to hepatocytic injury even if this is not the effector mechanism of the injury.

Topics: Adult; Carcinoma, Hepatocellular; Chronic Disease; Cytotoxicity, Immunologic; Female; Glycyrrhetinic Acid; Glycyrrhizic Acid; Hepatitis B; Humans; Interferon Type I; Killer Cells, Natural; Liver; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Picibanil; Radioimmunoassay; Skin Tests; Vidarabine

Twenty-one patients with nonresectable hepatocellular carcinoma (HCC) received intraarterial infusion chemotherapy of Adriamycin (Adria Laboratories, Columbus, Ohio) via an indwelling catheter in the hepatic artery. Additional intratumoral injection therapy of OK-432 (50 KE) was administered to ten of these 21 patients. Nine of the ten patients showed a remarkable decrease in lymphocyte count on the first day after therapy. In all of the patients with a decreased lymphocyte count, computed tomograms (CTs) demonstrated evidence of necrosis associated with a rapid decrease in alpha fetoprotein (alpha-FP). Blastogenesis of lymphocytes in peripheral blood induced by phytohemagglutinin (PHA) increased by 3.99 +/- 1.9 (mean +/- SE) times 4 weeks after therapy. On the basis of these results, we concluded that intratumoral injection therapy of OK-432 apparently produced initiation of necrosis in HCC by cell-damaging activity as well as by improvement of cell-mediated immunity.

Topics: alpha-Fetoproteins; B-Lymphocytes; Biological Products; Carcinoma, Hepatocellular; Doxorubicin; Hepatectomy; Hepatic Artery; Humans; Immunotherapy; Leukocyte Count; Liver Neoplasms; Lymphocyte Activation; Picibanil; T-Lymphocytes; Tomography, X-Ray Computed

Topics: Adult; Biological Products; Carcinoma, Hepatocellular; Doxorubicin; Embolization, Therapeutic; Female; Humans; Injections, Intra-Arterial; Iodized Oil; Liver Neoplasms; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil

The studied patient (70 years old, male) had primary hepatoma with rupture of the liver. We resected his left lobe partially and were able to save him. Since a residual tumor was found after surgery, we injected a total of 30 mg of MMC into the SCA 3 times. Under continuous administration of OK-432, the patient survived for 3 years and 6 months in remission. Because the tumor grew gradually, we started a multi-drug immunotherapy (OK-432 5 KE/2 W/intradermal, PSK/3.0 g/day/P.O., SPG/20 mg/2 W/I. M.) which we have advocated. In 6 months the tumor regressed to 1/3 of its original size. The patient is currently in good condition 4 years and 7 months after the operation. This case demonstrated the superiority of multi-drug immunotherapy over single-drug immunotherapy.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Male; Mitomycin; Mitomycins; Picibanil; Prognosis; Proteoglycans; Sizofiran

Ten patients with hepatocellular carcinoma (HCC) received intra-tumoral injection of OK-432 (6 patients), 99.5% ethanol (2 patients) or both (2 patients). Under ultrasonographic control, a PTC needle (22 G) was inserted percutaneously into the tumor and OK-432, which was prepared with a solution of Su-strain Streptococcus pyogenes A3, or 99.5% ethanol was injected. Patients were injected with OK-432 repeatedly at one-to two-week intervals (up to 5 times) for a total duration of 5 to 15 weeks. The degree of skin test reaction for Streptococcus pyogenes was increased in all patients after the treatment. Over 40% tumor regression was noted in 6 out of 9 patients who received intra-tumoral injection of OK-432. Complete regression was noted in one patient. Before treatment, Interleukin-2 (IL-2) and lymphokine-activated killer (LAK) cell activity in peripheral blood lymphocytes decreased in HCC patients. Two of 6 patients showed markedly increased activity of LAK-cells one week after treatment with OK-432. One other patient had moderately increased LAK-cell activity after treatment with OK-432. No increase in LAK-cell activity was seen in 3 patients who received intra-tumoral injection of ethanol. An especially increased response of LAK-cell activity was seen in patients with small-sized HCC (diameter below 5 cm).

Topics: Administration, Topical; Aged; Biological Products; Carcinoma, Hepatocellular; Ethanol; Female; Humans; Interleukin-2; Liver Neoplasms; Lymphocyte Activation; Male; Middle Aged; Picibanil; Skin Tests; T-Lymphocytes

Topics: Biological Products; Carcinoma, Hepatocellular; Humans; Killer Cells, Natural; Liver Neoplasms; Lymphokines; 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

Topics: Aged; Biological Products; Embolization, Therapeutic; Female; Humans; Liver Neoplasms; Lymphocytes; Picibanil

1-Hexylcarbamoyl-5-fluorouracil (HCFU) was orally administered at doses of 300-600 mg daily for 7-360 days to 27 inoperable cirrhotics with hepatocellular carcinoma. They were simultaneously treated with transcatheter arterial embolization (TAE), and mitomycin C (MMC) injected into the hepatic artery and/or subcutaneous injection of OK-432. Efficient treatment according to the Koyama and Saito (PR and MR) and Karnofsky classification (I -A and I -B) was obtained in 40.7 and 29.6%, respectively, of all the patients; 81.8 and 54.5%, respectively, in the patients treated with TAE and intraarterial MMC injection and 25.0 and 12.5%, respectively, in those given MMC therapy. However, the total doses of HCFU administered (3-216 g) were not related to either efficient or inefficient treatment. Survival rate obtained 1 year following diagnosis of HCC was much better in the patients treated with TAE and/or MMC therapy (greater than 70%) than in those without these treatments (20%). TAE intervals in HCC patients given repeated TAE and intrahepatic MMC injection were slightly prolonged by oral administration of HCFU (more than 12 g). The results suggest that HCFU might be effective for prevention of HCC recurrence following TAE.

Topics: Administration, Oral; Aged; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Embolization, Therapeutic; Female; Fluorouracil; Hepatic Artery; Humans; Liver Cirrhosis; Liver Neoplasms; Male; Middle Aged; Mitomycin; Mitomycins; Picibanil; Prognosis

Topics: Adult; Aged; Biological Products; Carcinoma, Hepatocellular; Contrast Media; Female; Humans; Injections; Liver Neoplasms; Male; Middle Aged; Picibanil; Punctures; Ultrasonography

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

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

Topics: Biological Products; Carcinoma, Hepatocellular; Humans; Injections; Liver Neoplasms; Picibanil

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

A low-molecular-weight fraction (M.W. approximately 700) that specifically impairs the induction of type II interferon in mice by purified protein derivative of tuberculin or OK-432 was isolated from the cell-free ascitic fluid of mice bearing Ehrlich ascites carcinoma. Purification was achieved by ultrafiltration and gel filtration. The inhibitory activity of the isolated fraction was 10 times greater than that of the unfractionated starting material in the impairment of type II interferon induction. The significant inhibition was observed even when 0.2 ml of the 10,000-fold dilution of the fraction, which was previously adjusted to 0.25 A unit at 290 nm absorption, was once treated i.p. in normal mice 48 hr before challenge of type II interferon inducers. This fraction was stable to heating at 56 degrees for 60 min. The active component, however, did not affect the in vivo induction of type I interferon by polyriboinosinic-polyribocytidylic acid or tilorone-HCl. In parallel experiments, an identical low-molecular-weight fraction that impairs the type II interferon induction in mice was isolated from the ascitic fluids of rats bearing AH-100B ascites tumor and from a human hepatoma case with advanced cancer metastatic to the peritoneal cavity. However, nontumorous ascitic fluids obtained from adjuvant-stimulated mice and a human liver cirrhosis case did not contain any such inhibitory activity.

Topics: Animals; Ascitic Fluid; Carcinoma, Ehrlich Tumor; Carcinoma, Hepatocellular; Chromatography, Gel; Humans; Interferon Inducers; Liver Neoplasms; Mice; Picibanil; Ultrafiltration