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Biomedical subjects

N Kan

Publications and source records attributed to N Kan.

At least 37 records · Page 2Linked to original sources
PubMed1993

The therapeutic effect of OK-432-combined adoptive immunotherapy against liver metastases from gastric or colorectal cancers.

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.

Adult↗
PubMed1993

Cellular interaction against autologous tumor cells between IL-2-cultured lymphocytes and fresh peripheral blood lymphocytes in patients with breast cancer given immuno-chemotherapy.

In patients with Stage II or III breast cancer and in patients with liver metastases from breast cancer, we examined cellular interaction in the cytotoxicity against autologous tumor cells by interleukin-2(IL-2)-cultured lymphocytes (CL) and fresh peripheral blood lymphocytes (FPBL) treated with immunochemotherapy including OK-432 and cyclophosphamide. In flow cytometric analysis, CD8+CD11b+ and CD16+ cells significantly decreased after immuno-chemotherapy in both groups of patients. A protocol study in Stage II or III breast cancer patients showed suppressive activity of FPBL on the cytotoxic activity of CL in 3/9 of the non-treatment group but no suppressive activity and enhancing activity in 3/7 in the immuno-chemotherapy group. Moreover, in 19 patients with liver metastases from breast cancer treated with immuno-chemotherapy including adoptive immunotherapy, FPBL in 6/19 showed enhancing activity, and in 8/19 suppressive activity in the lysis of autologous tumor cells. In assays in vitro using autologous and allogeneic tumor cells, FPBL showed a partial specificity in cellular interaction against autologous tumor cells. CD4-depleted FPBL inhibited cytotoxicity of CL, while CD8-depleted FPBL enhanced cytotoxicity of CL in patients with liver metastases. These results suggest that immuno-chemotherapy eliminates the suppressive population in FPBL and may induce tumor regression if combined with adoptive immunotherapy using CL.

Adjuvants, Immunologic↗
PubMed1993

Bone metastasis as a prognostic factor in breast cancer patients with liver metastasis given OK-432-combined adoptive immunotherapy via the hepatic artery.

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.

Adult↗
PubMed1993

The induction of murine tumor infiltrating lymphocytes (TIL) by interleukin-2 or T cell growth factor.

Mice were injected in the foot pad with either 5 x 10(5) syngeneic plasmacytoma (MOPC104E) or fibrosarcoma cells (Meth A). Lymph nodes containing tumor cells were harvested 14 days later and cultured. In the presence of recombinant interleukin-2 (r-IL-2) predominantly tumor cells proliferated. Culture with T cell growth factor (TCGF) resulted in the growth of lymphoid cells. Concanavalin A (Con A) had only a modest effect on elimination of tumor cells in the culture. Tumor-infiltrating lymphocytes (TIL) prepared from the lymph nodes showed specific tumor-neutralizing activity when grown in the presence of TCGF. In vitro examination revealed that Meth A cells could not be lysed by TIL, while TIL from MOPC tumors showed tumor specific activity. This study may explain negative results in human trials with TIL induced by IL-2 alone.

Animals↗
PubMed1993

Interferon-gamma-producing tumor induces host tumor-specific T cell responses.

We investigated the mechanism of host immune responses against two interferon-gamma (IFN-gamma) gene-transduced tumors, plasmacytoma MOPC104E(Mu gamma) and mammary cancer SC115(K gamma), which originally had weak immunogenicity. Both IFN-gamma-producing tumor cells had reduced tumorigenicity and were rejected by syngeneic mice. The rejection was completely blocked by in vivo treatment with anti-CD8 or anti-IFN-gamma monoclonal antibodies. While anti-CD4 monoclonal antibody also blocked the rejection of SC115(K gamma), it enhanced the initial tumor growth of MOPC104E(Mu gamma). Specific protection against subsequent challenge with the respective parental tumor cells was demonstrated in mice which rejected the IFN-gamma-producing tumor cells. Cultured lymphocytes derived from immunized mouse spleens had cytotoxic T cell activity against parental tumor cells, as well as against cells that produced IFN-gamma. These findings indicate that the antitumor effects are mediated by cytotoxic T cells and, partly, by helper T cells, and that locally secreted IFN-gamma plays an important role in generating these effector cells.

Animals↗
PubMed1993

[Loco-regional immunotherapy with OK-432 and cultured autologous lymphocytes for patients with metastatic cancer].

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.

Adult↗
PubMed1993

[Transarterial immuno-chemotherapy including adoptive transfer of autologous cultured lymphocytes for stage IV breast cancer patients with locally-advanced tumor].

Immuno-chemotherapy via a catheter in the subclavian artery using sequential treatment with OK-432, chemotherapeutic agents (ADM, 5-FU), and cultured autologous lymphocytes, was performed for 9 Stage IV breast cancer patients with locally-advanced primary tumor. Tumor reduction of more than 50% was observed in 8 patients including 4 whose breast tumors had disappeared. Among 11 evaluable distant metastatic lesions, 7 (1 pleural effusion, 2 lung, 2 liver, 2 bone metastases) regressed after local immunotherapy of breast or additional regional immunotherapy (1 lung, 1 liver, 1 pleural effusion). Median survival time to date is 56 months. Five patients are currently alive, although 3 of them did not undergo mastectomy. Local immuno-chemotherapy may be useful because (a) toxicity is limited, (b) low doses of anti-cancer agents during the therapy (median dose of ADM, 60 mg) do not limit subsequent systemic chemotherapy, and (c) distant metastases often regress concomitantly with the primary lesions.

Adult↗
PubMed1992

Metabolic bone disease following gastrectomy: assessment by dual energy X-ray absorptiometry.

Although disorders in bone metabolism have long been recognized as typical sequelae of gastrectomy, there has until now been no reliable method of providing precise assessment of bone mass, resulting in a variation of reported incidence. In this study, metabolic bone disease was evaluated in a well characterized population: 34 men 2-5 years after gastrectomy; 11 men 6-10 years after gastrectomy; eight men 2-5 years after colonic resection; and 115 healthy men. The age range was 50-69 years. An innovative reliable method of dual energy X-ray absorptiometry was used which allows quantitative assessment of bone mineral content. Measurement of lumbar spine bone mineral density revealed that the mean(s.e.m.) bone mineral density in patients who had had a gastrectomy (2-5 years 0.84(0.03) g/cm2, 6-10 years 0.85(0.05) g/cm2) was significantly lower than that of patients who had undergone colonic resection (0.96(0.04) g/cm2) or healthy men (0.96(0.03) g/cm2). This study demonstrates that a high incidence of bone atrophy is induced at the relatively early period of 2-5 years after gastrectomy.

Absorptiometry, Photon↗
PubMed1992

Factors influencing the response and survival of patients with liver metastases from breast cancer receiving OK-432-combined adoptive immunotherapy.

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.

Breast Neoplasms↗
PubMed1992

Therapeutic and life-prolonging effect of intrapleural injection with a streptococcal preparation, OK-432, and IL2-cultured effusion lymphocytes to breast cancer patients with malignant pleural effusion.

We developed a local AIT using PEL cultured with TCGF combined with preadministration of OK-432. Twenty-six patients of breast cancer with pleural effusion have been treated with this therapy since 1983. PEL expanded and tumor cells collapsed by day 9 in culture with TCGF. Cultured PEL possessed significantly higher cytotoxic activity against autologous tumor cells than PBL cultured in the same condition (p less than 0.05), but there was no difference between their cytotoxic activities against K562. The proliferation rate of PEL obtained after intrapleural administration of OK-432 was higher than that obtained before OK-432 (p less than 0.01). Moreover, the cytotoxic activities against both autologous tumor and K562 of cultured PEL obtained after OK-432 administration was significantly (p less than 0.05) higher than those cultured PEL obtained before. Cultured PEL (1 x 10(8)-6 x 10(9)) were transferred into the pleural cavity after the intrapleural administration of OK-432 (1-5 KE). The volume of pleural effusion increased temporarily after the administration of OK-432 but significantly (p less than 0.01) decreased after AIT. Tumor cells disappeared cytologically in 22 patients at the last puncture of pleural effusion. Pleural effusion disappeared completely in 19 of 26 patients and decreased by more than 50% in volume in 6 patients. Performance status improved in 22 patients. The response rate for OK-432-combined AIT in the present study was 96%. The survival period of the patients treated by OK-432-combined AIT in this trial was significantly (p less than 0.002) prolonged compared to that of the patients receiving chemotherapy alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

[Augmentation of therapeutic effect of adoptive immunotherapy through a synergy between transferred killer cells and host's fresh lymphocytes].

Among several approaches to augment the therapeutic effect of adoptive immunotherapy, we focused the antitumor synergy between transferred killer cells and host's fresh lymphocytes. Immunotherapy models using murine tumors or clinical experiments revealed that preadministration of immunostimulator such as OK-432, followed by chemotherapeutic agents such as cyclophosphamide, can induce host's non-cytotoxic fresh lymphocytes that act synergistically with cultured killer cells against autologous tumor cells. Immuno-chemo-lymphocytotherapy (a sequential treatment with OK-432, chemotherapy and adoptive immunotherapy) is useful to treat the patients with advanced cancer even if the number of transferred lymphocytes is limited.

Animals↗
PubMed1992

[Intrapleural treatment of breast cancer patients with pleural effusions: an analysis of 13 institutes in Kyoto and Shiga Prefectures. Kyoto and Shiga Breast Cancer Study Group].

Sixty-seven breast cancer patients with malignant pleural effusions underwent their first thoracentesis between 1980 and 1990 at 13 institutes in Kyoto and Shiga Prefectures. They received various intracavitary treatments including OK-432 and cultured effusion lymphocytes (n = 29, group A), OK-432 alone (n = 12), chemotherapeutic agents alone (n = 9), OK-432 and chemotherapy (n = 16) or other (n = 1, lentinan and tetracycline) therapy. Response rate and median survival time were 90%, 12 months for group A, respectively and 40% and 3 months for other treatments (group B, n = 38), resulting in significant differences. Multivariate analysis using Cox's proportional hazard model showed that the immunotherapy using cultured lymphocytes was the most important factor prolonging survival among several significant prognostic factors such as concomitant liver metastasis, disease-free period and laterality of effusion.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Problems in the definition and treatment of early gastric cancer.

Radical operation with extensive dissection of lymph nodes (R1, 48 patients; R2, 196 patients; R3, one patient) was performed in 245 out of 247 patients with early gastric cancer. The 5-year survival rate was only 73.2 per cent in the 34 patients with lymph node metastases (31.8 per cent). Analysis of factors influencing recurrence revealed that not only lymph node metastases but also the depth of cancer invasion could affect prognosis in early gastric cancer. This study suggests that radical operation with complete dissection of the first and second group of lymph nodes (R2 resection) is a safe and appropriate treatment even for early gastric cancer. We propose that the definition of early gastric cancer be modified to 'carcinoma with invasion confined to the mucosa or submucosa and without evidence of lymph node metastases'.

Female↗
PubMed1991

A murine plasmacytoma MOPC 104E resistant to cyclophosphamide is resistant to immunotherapy.

A murine plasmacytoma MOPC 104E (MOPC) is highly sensitive to chemotherapeutic agents such as cyclophosphamide and mitomycin C as well as to immunotherapy (OK-432-combined adoptive immunotherapy using interleukin-2-cultured killer cells). In the present study, we prepared cyclophosphamide-resistant MOPC cells (MOPC-CPA/R) by serial in vivo passage of tumor cells following cyclophosphamide treatment. The in vivo sensitivity of MOPC-CPA/R to mitomycin C or to immunotherapy (OK-432-combined adoptive immunotherapy) was significantly decreased compared to the parent MOPC. In vitro experiments showed that MOPC-CPA/R were more resistant (five-fold) to lysis by cultured immune spleen cells than MOPC. Inhibition of the lytic activity of cultured immune spleen cells against MOPC was significantly increased (P less than 0.05) by the addition of unlabeled MOPC compared to unlabeled MOPC-CPA/R. These results suggest that MOPC-CPA/R express weaker antigenicity than MOPC. However, the transfer of immune spleen cells cultured with tumor extract derived from MOPC-CPA/R significantly prolonged the survival of MOPC-CPA/R-inoculated mice. Thus, by repeated cyclophosphamide treatment, tumor cells with low-antigenicity were selected. These tumor cells had lower sensitivity to another chemotherapeutic agent and immunotherapy. Such an immunological response may play an important role in cancer therapy.

Animals↗
PubMed1990

Effect of heat treatment on tumor cells and antitumor effector cells.

We examined the effects of heat treatment on tumor cells and antitumor effector cells in order to investigate the combined effects of hyperthermia and immunotherapy including adoptive immunotherapy. Plasmacytoma MOPC104E syngeneic to BALB/c mice was used as the tumor cell line, while fresh spleen cells immunized to MOPC104E (IM-FSC) and interleukin-2-cultured lymphocytes induced in vitro from IM-FSC (CL) were used as the effector cells. Tumor cells or effector cells were heat-treated in a water bath at 42 degrees C for 30 or 60 min. Tumor cells heat-treated at 42 degrees C for 30 min grew temporarily and then regressed in the tumor transfer test, whereas untreated tumor cells showed no regression under any conditions. Furthermore, fresh spleen cells of mice inoculated with heat-treated tumor cells from regressed tumors showed marked tumor-neutralizing activity. The antitumor effects of CL were markedly inhibited by heat treatment according to the results of the tumor-neutralizing test and the 51Cr release assay, whereas heat treatment had little influence on the antitumor activity of IM-FSC. However, the neutralizing activity of effectors and the killing activity of CL against heat-treated tumor cells were both markedly augmented, since the susceptibility of the tumor cells to the antitumor effector cells was augmented by heat treatment. These results suggest that heat treatment of tumor cells augments the antitumor effects of IM-FSC and CL, hence we speculate that hyperthermia augments the effects of immunotherapy including adoptive immunotherapy.

Animals↗
PubMed1990

[Adoptive immunotherapy against peritoneal metastases from stomach cancer--application of regional lymph node lymphocytes].

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

Adult↗
PubMed1990

The therapeutic effect of OK-432-combined adoptive immunotherapy against liver metastases from breast cancer.

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.

Adult↗