Efficacy and Safety of High-Dose Mizoribine Combined With Cyclosporine, Basiliximab, and Corticosteroids in Renal Transplantation: A Japanese Multicenter Study.

Mizoribine (MZR) is an immunosuppressive agent that exhibits a less potent immunosuppressive effect at doses up to 3 mg/kg/d. We investigated whether high-dose MZR is effective and safe for renal transplant patients in conjunction with cyclosporine (CsA), basiliximab, and corticosteroids. Ninety Japanese renal transplant patients were administered MZR (6 mg/kg/d), CsA (7 mg/kg/d), prednisolone (maintenance dose, 10 mg/d), and basiliximab (20 mg/body). They were compared with a control group of 81 renal transplant patients who received mycophenolate mofetil (MMF; 1500 mg/d), CsA, prednisolone, and basiliximab. The 2-year patient and graft survival rates were 98.9% and 97.8% in the MZR group and 98.8% and 97.5% in the MMF group, respectively. The rejection rate within 2 years after transplantation was 21.1% in the MZR group and 16.0% in the MMF group; the difference was nonsignificant. None of the MZR group developed cytomegalovirus (CMV) disease, whereas 12.3% of the MMF group contracted CMV (P < .0001). CMV viremia developed in 28.9% of the MZR group vs 46.9% of the MMF group (P < .0001); their peak antigen levels were 20.4 ± 44.1 and 252.8 ± 527.0 (P < .01). Furthermore, the incidence of gastrointestinal disorder, hyperlipidemia, and blood disorder was significantly lower in the MZR group than in the MMF group. The combination of high-dose MZR with CsA, basiliximab, and corticosteroids not only provides satisfactory immunosuppression but is also associated with a low incidence of CMV infection and gastrointestinal and blood disorders.

Factors influencing the paradoxical effect of transfusions on kidney transplants.

Cadaver donor graft survival data obtained between 1970 and 1980 show that transfused patients had statistically significant improvements in transplant survival rates for each of the 11 years, as compared with untransfused patients. Patients with many transfusions could be successfully grafted at any time following their last transfusion, whereas those with few transfusions had varying success rates at different intervals following their last transfusion. Even one transfusion produced a statistically significant improvement (52 +/- 3% one-year graft survival) as compared with no transfusion (41 +/- 1%) and survival rates increased up to 14 transfusions (75 +/- 7%). Subsequent transfusions did not appear to be more beneficial, although there is a possibility that patients who receive a larger number of transfusions are medically different from those who receive fewer transfusions. Most important, patients who had cytotoxic antibodies following transfusions had a higher transplant survival rate than did untransfused patients with no antibodies. Thus cytotoxic antibodies per se are not harmful to transplants. Patients with cytotoxins are not automatically at a higher risk and are not "sensitized" in the conventional sense. They are only unable to accept grafts from certain donors.

Association of anti-F(ab')2 antibodies with higher kidney transplant survival rates.

When the pretransplant sera of cadaver donor transplant patients were divided into 132 with anti-F(ab')2 (Fab) antibodies and 121 without anti-Fab antibodies, those patients with the antibodies had a 2-year graft survival rate of 59.7 +/- 4.6% (+/- SE) as compared with 34.0 +/- 5.0 % (+/- SE) for those without antibodies (P less than 0.001). This difference was greater when the patients were further classified by whether they had antibodies reactive to B lymphocytes in the cold. Patients with anti-Fab antibodies and B-cold antibodies had a 2-year graft survival of 81.3 +/- 9.8% as compared with 15.7 +/- 7.9% for patients without anti-Fab antibodies and with B-cold antibodies. We suggest that these anti-immunoglobulin antibodies may function in some immunoregulatory role. The number of transfusions was not directly related to the frequency of occurrence of these antibodies.

Endoscopic injection sclerotherapy for esophageal variceal hemorrhage in a patient with idiopathic myelofibrosis.

A 74-year-old female with idiopathic myelofibrosis (IMF) was admitted to our hospital because of massive hematemesis and melena. Immediate upper gastrointestinal endoscopy revealed an intermittent spurting hemorrhage from extensive esophageal varices. Endoscopic injection sclerotherapy (EIS) was carried out and the bleeding ceased. After five courses of EIS, all the esophageal varices were eradicated. About 15 months later, the patient died, due to a cerebral hemorrhage, without further variceal bleeding. A postmortem examination was carried out and the portal hypertension was considered to be due not only to extramedullary hematopoiesis in the sinusoids, but also to increased splenic blood flow. We are confident that EIS is an effective therapeutic procedure for patients with IMF showing esophageal variceal hemorrhage. EIS should be the preferred choice of treatment for esophageal varices in patients with IMF, since it is less invasive than splenectomy.

Association of anti-Fab and anti-IgG antibodies with high kidney transplant survival.

Pretransplant sera from 371 first cadaver and 58 second cadaver kidney transplant patients were examined for the presence of anti-Fab and antiimmunoglobulin antibodies. The 1-year graft survival rate for 109 patients with anti-Fab antibodies was 59 +/- 5% as compared with 47 +/- 5% for 106 patients without anti-Fab antibodies (p less than 0.05). Among patients with more than five transfusions, those with anti-Fab antibodies had a survival rate of 81 +/- 8% as compared with 53 +/- 9% for patients with no anti-Fab antibodies (p less than 0.01). Among 74 patients with anti-IgG antibodies, the 1-year graft survival rate was 63 +/- 6% as compared with 56 +/- 3% for 270 patients without anti-IgG antibodies (p = N.S.). After more than five transfusions, the graft survival rate was 83 +/- 1% for those with anti-IgG and 68 +/- 6% for those without IgG (p = N.S.). There was no correlation between the presence of anti-Fab and anti-IgG antibody and the number of transfusions. We conclude that anti-Fab antibodies and possibly anti-IgG antibodies have an enhancing effect on graft survival.

The beneficial effect of tamoxifen therapy in patients with resected adenocarcinoma of the pancreas.

BACKGROUND/AIMS: Hormone therapy by tamoxifen was performed on patients with adenocarcinoma of the pancreas and the effect of tamoxifen on their survival rate was evaluated in patients with resected pancreatic adenocarcinoma (n = 65). MATERIAL AND METHODS: Tamoxifen was administered once daily (at 20 mg) in addition to immunochemotherapy (Tegaful, Mitomycin, Krestin or OK-432). RESULTS: A remarkably beneficial effect of tamoxifen was found when compared with non-tamoxifen group (p < 0.01). When the location of the pancreatic carcinoma was considered, the survival rate of the tamoxifen group with adenocarcinoma in the head and in also the body/tail of the pancreas revealed the same statistically significant difference (p < 0.01) individually. Regarding curability by surgery, the beneficial effect of tamoxifen was observed even in the survival rate of patients who had received noncurative surgery. Furthermore, the remarkable effect of tamoxifen was revealed in the male group, whose one-year survival rate for resected carcinoma in the head of the pancreas was 85.6% (n = 16) as when compared to 19.1% of non-tamoxifen group (n = 15) and also in the female group whose one-year survival rate was 53.8% (n = 1.3) compared with 21.4% of non-tamoxifen group (n = 7) (p < 0.01). CONCLUSION: With these data, we can see that the adjuvant therapy of tamoxifen in carcinoma of the pancreas confers a significant benefit to those patients who have received a surgical resection and reduction in the volume of the carcinoma in the pancreas.

Eradication of syngeneic tumor (Meth A fibrosarcoma) from mice by adoptive immunotherapy of immunized spleen cells induced by Corynebacterium parvum-pyridine extract residue.

Eradication of immunologically-syngeneic tumors was achieved by adoptive chemotherapy using effector cells induced by Corynebacterium parvum-Pyridine Extract Residue (CP-PER). A mixture of 2 X 10(6) Meth A cells and 0.1 mg CP-PER was subcutaneously inoculated into the back of donor BALB/c mice, with the result that their spleen cells showed an antitumor effect 10 to 13 days after the inoculation. These cells were used as immune cells. Recipient mice were inoculated with 1 X 10(6) Meth A cells, and 2 days later were administered cyclophosphamide. On the following day, 1 X 10(8) immune cells were adoptively transferred into the recipient mice. As a result, the tumor began to regress 7 to 12 days after the adoptive transfer. An immuno-histochemical study of the donors' spleens and the recipients' regressing tumors revealed that the ratio of L3T4+ T cells to Lyt-2+ T cells in the donors' spleens was increased and that the infiltrating cells in the recipients' tumors were mainly composed of L3T4+ T cells. This confirmed that the transfer of L3T4+ T cells led to the infiltration of L3T4+ T cells into the recipients' tumors, causing their eradication.

Establishment of a new myeloid cell line with i(17q) as the sole chromosomal anomaly from the bone marrow of a patient with myelodysplastic syndrome.

A new myeloid cell line, MTO-94, was established from the bone marrow of a patient with myelodysplastic syndrome (MDS). MTO-94 cells matured in culture medium without the addition of growth factors, and yielded neutrophils with pseudo-Pelger Huët anomaly or hypersegmentation until 6 months. Ten months after the start of cell cultivation, MTO-94 consisted of myeloblasts. Surface phenotypes were as follows: CD7 90.3%, CD13 99.6%, CD33 75.6%, HLA-DR 96.3% and CD34 0.9%. The karyotype was 46, XY i(17q). The proliferation of MTO-94 cells was enhanced by rhIL-3, G-CSF, rhGM-CSF and rhSCF but not by rhIL-6 and erythropoietin. MTO-94 cells with i(17q) might be useful in the study of biological aspects of not only MDS, but also hematological malignancies with i(17q) as the sole chromosomal anomaly.

Possible induction by blood transfusion of immunological tolerance against growth of transplanted tumors in mice.

That blood transfusions aid kidney graft survival is well known. Our data show that blood transfusions, except for the red blood cell component, promote growth of transplanted tumors in mice. These clinical and experimental observations suggest that blood transfusions may induce some immunological tolerance.

Beneficial effect of donor-specific blood transfusions (DST) on living-related kidney allograft survival.

The survival rate of 19 patients who underwent living-related kidney transplantation after donor-specific blood transfusions (DST) was compared with that of 32 historical controls receiving transplants without DST. The graft survival rate of the DST group was 82% after two and three years. The graft survival rate of the DST group was significantly better than the 53% rate after two years obtained with the 32 historical controls (p less than 0.05). We tested sera from 16 DST-treated recipients to study the beneficial effect of DST on kidney allograft survival using the mixed lymphocyte culture (MLC) serum inhibition test. The results demonstrated that MLC inhibitory factors were induced in the serum of the recipient after completion of DST. This inhibition of MLC was observed by treatment of responder lymphocytes with serum obtained three weeks after DST plus rabbit complement. The inhibitory effect was also specific for responder cells in anti-donor MLC. Regarding the correlation with rejection episodes, these MLC inhibitory factors were often observed in the non-rejection group (p less than 0.05). The data suggest that such factors may be anti-idiotypic antibodies and be associated with prolonged graft survival.

Establishment of a new cell line (MTT-95) showing basophilic differentiation from the bone marrow of a patient with acute myelogenous leukemia (M7).

A new myeloid cell line, MTT-95, was established from the bone marrow of a patient with acute myelogenous leukemia (AML, M7). MTT-95 cells differentiate into mature basophilic cells in culture medium with no chemical component or cytokine. Surface phenotypes were as follows: CD11b 79.3%, CD13 92.4%, CD33 99.8%, CD34 87.9%, CD41a 77.6% and HLA-DR 0.3%. MTT-95 cells were strongly positive for glycoprotein IIb/IIIa by immunohistochemical staining and revealed metachromatic granules. MTT-95 cells seem to possess characteristics of both megakaryocytes and basophils. These findings suggest that MTT-95 cells are basophil progenitors. MTT-95 cells might be useful in the study not only of the biological aspects of basophils, but also of the diversities of AML (M7).

Effects of streptococcal preparation OK-432 on cytokine induction in spleen and tumour tissues of mice bearing MH-134 tumour cells.

Streptococcal preparation OK-432 is a bacterial immunopotentiator extensively used in Japan for adjuvant cancer therapy. Using C3H/He mice bearing MH-134 tumour cells, cytokine inductions of tumour necrosis factor-alpha, interleukin 1 beta, interleukin 6 and interferon-gamma were determined in spleen and tumour tissues by reverse transcriptase-polymerase chain reaction analysis. No significant induction of cytokine mRNA was observed after subcutaneous administration of OK-432 (OK-432, s.c.) or after intratumoural injection of IFN-gamma (IFN-gamma, i.t.), compared with controls, either in spleen or tumour tissues. In contrast, subcutaneous administration of OK-432 followed by intratumoural OK-432 injection (OK-432, s.c. + i.t.) was found to induce some cytokine mRNAs significantly. The mRNA levels of tumour necrosis factor alpha and interferon-gamma in spleen tissue and those of interleukin 1 beta and interferon-gamma in tumour tissues were significantly elevated in mice with OK-432, s.c. + i.t. treatment compared with controls. These results suggest that treatment with OK-432, s.c. + i.t. effectively induced splenic antitumour immunity as well as local immunity against tumour cells.

[Serum superoxide dismutase (SOD) activity in diabetes mellitus].

The serum superoxide dismutase (s-SOD) activities in patients with diabetes mellitus (DM) were assayed in order to evaluate its usefulness for monitoring of DM and also evaluate the relation between s-SOD activities and microangiopathies (nephropathy, neuropathy and retinopathy). As results followings were obtained; 1) s-SOD activities in DM patients were significantly higher than those in healthy controls (12.56 +/- 7.73 vs 10.51 +/- 1.69, p < 0.01). 2) There was no relations between s-SOD activities and FBS-, fructosamine- and HbA1-levels, respectively. 3) Among DM patients s-SOD activities were significantly higher in patients with microangiopathy than those in patients without microangiopathy (14.18 +/- 11.00 vs 11.24 +/- 3.13, p < 0.01). 4) Among DM patients with microangiopathy higher s-SOD activities tended to be observed in patients with triopathy such as nephropathy, neuropathy and retinopathy than in those with one or two microangiopathic complications. 5) Among DM patients with nephropathy the correlation was present between s-SOD activities and levels of creatinine. These results suggest that the assay of s-SOD activity is not useful for the monitoring of DM, however, it is suggested that the high s-SOD activity reflects the microangiopathic complications, particularly nephropathy.

[Ultramicroassay of red cell group using Terasaki-plate].

In order to simplify the testing-method of blood groups (ABO, Rh, MN, Ss, P, I, Lewis, Duffy, Kidd and Diego) and the assay of glycosyl transferases activity, we have developed a new method using Terasaki plate (T-plate method), and examined its usefulness in the routine examination. As results followings were obtained: 1) The sensitivity of T-plate method was equal or superior than that of the common method using test-tube. 2) Samples used for T-plate method were smaller in volume compared with those for the common tube test method. 3) The percent of coincidence between T-plate method and tube test method was 100% for ABO, Rh, MN, Ss, P, I, Duffy, Kidd and Diego grouping. They were 98% for Lewis(a) and 96% for Lewis(b) grouping, respectively. These results indicate the superiority of T-plate method than the common method using test-tubes in respects of smaller volume of samples, lower price and handling of a large amount of samples.

[Changes in ketone body ratio and levels of pyruvate and lactate in arterial blood of patients with hepatocellular carcinoma after transcatheter arterial embolization].

The ketone body ratio (acetoacetate/3-hydroxybutyrate:KBR) and levels of pyruvate and lactate in arterial blood of patients with hepatocellular carcinoma (HCC) were examined. KBRs and levels of pyruvate and lactate in patients with HCC were similar to those in patients without liver diseases (1.57 +/- 0.88, 0.84 +/- 0.32, 11.4 +/- 4.5 vs 1.80 +/- 0.9, 0.89 +/- 0.48, 10.8 +/- 6.2). However, pyruvate to lactate ratios were significantly lower in HCC patients (7.45 +/- 1.57 vs 8.62 +/- 2.15, p less than 0.05). Among the HCC patients the levels of pyruvate and lactate were significantly higher in patients with liver cirrhosis (LC) than those in patients without LC. The sequential changes of KBRs and levels of pyruvate and lactate were examined before and after transcatheter arterial embolization (TAE). Although KBRs were transiently decreased immediately after TAE, they were at higher levels from the 3rd to 21st day in comparison with those before TAE. The levels of pyruvate and lactate showed no significant changes immediately after TAE. However, they followed a course similar to that of KBRs after TAE. Lower KBRs and higher levels of pyruvate and lactate tended to be observed in HCC patients with LC after TAE than in those without LC. This suggests a decrease of intrahepatic blood flow probably due to histological reconstruction. These results suggest that the presence of LC is one of the most important factors influencing the functional reserve of liver in HCC patients. In HCC patients without LC, the recovery from the overload of TAE may operate at mitochondrial levels at least the 3rd day after TAE.

[The evaluation of weekly hepatic arterial infusion of high-dose 5-FU for liver metastases from colorectal cancer].

A study was conducted on weekly infusion of high-dose 5-FU through the hepatic artery for liver metastases from colorectal cancer. In the evaluation of 38 cases, no CR and 16 PR were to control the extrahepatic metastases is a subject for forthcoming study.

[Chemotherapy with low-dose CDDP and continuous 5-FU for the treatment of advanced gastric cancers].

INTRODUCTION: 5-fluorouracil (5-FU) has been widely used for the treatment of gastrointestinal cancers. On the basis of recent findings, low-dose Cisplatin (CDDP) and continuous venous infusion of 5-FU have shown additive or synergistic antitumor effects in experimental models. We evaluated clinical effects of low-dose CDDP and 5-FU (low-dose FP therapy) in patients with advanced gastric cancers. PATIENTS AND METHODS: In December 1993 and June 1998, 52 patients with advanced gastric cancer were entered in this study. Patients were considered eligible if they had a bidimensionally measurable tumor. 5-FU (160 mg/m2/day) was continuously infused over 24 hours using an implantable port, and CDDP (3 mg/m2/day) was infused for half an hour. The administration schedule consisted of 5-FU for 7 consecutive days and CDDP for 5 days followed by a 2-day rest every four weeks according to response and tolerance. RESULTS: Low-dose FP therapy was given 44 patients (85%). The response rate was 65.9% and median survival time was 249 days. The responder group showed good survival compared with the non-responder group. The regimen was tolerable, and the most common toxicity was anorexia (40.3%). Three patients suffered from grade 3 anorexia, leukopenia and mucositis. On the other hand, renal dysfunction occurred in 50% (two of four patients administered over 1,000 mg CDDP). These results raise the possibility that the dose-limiting factor of low-dose FP therapy may account for the total dosage of CDDP. CONCLUSION: Low-dose FP therapy promises to be effective in the clinical management of advanced gastric cancer.

[Preliminary clinical evaluation of low-dose CDDP and continuous 5-FU therapy for advanced gallbladder cancer].

5-fluorouracil (5-FU) has been widely used for the treatment of gastrointestinal cancers. Low-dose cisplatin (CDDP) and continuous venous infusion of 5-FU have recently shown additive or synergistic antitumor effects in experimental models. In this study, we evaluated the clinical effects of low-dose CDDP and 5-FU (low-dose FP therapy) in patients with advanced gallbladder cancer. From December, 1993 to June, 1998, 13 patients with advanced gallbladder cancer were treated with low-dose FP therapy. Patients were eligible for this study if they had a bidimensionally measurable tumor. 5-FU (160 mg/m2/day) was continuously infused over 24 hours using an implantable port, and CDDP (3 mg/m2/day) was infused for one hour. The administration schedule consisted of 5-FU for 7 consecutive days and CDDP for 5 days followed by a 2-day rest, each for four weeks according to response and tolerance. Low-dose FP therapy was given to 12 patients (92.3%). The response rate was 66.7% and the median survival time was 151 days. The regimen was tolerable, with the most common toxicity being nausea (38.5%). There were no severe side effects except for one patient who suffered from grade 3 nausea. We conclude that low-dose FP therapy may be useful as a palliative chemotherapy for cases of advanced gallbladder cancer.

[Low-dose CDDP and continuous 5-FU treatment of advanced gastric cancer with peritoneal dissemination: a case with long disease-free survival].

The patient was diagnosed to have gastric cancer (T3 N3 M0 P3, Stage IV b). We conducted LcFP therapy. CDDP, 7 mg/m2/day, day 1-5 i.v. drip for 2 hours, and 5-FU, 170 mg/m2/day, day 1-7, i.v. continuously for 24 hours. After 3 courses (one course: 4 LcFPs followed by one rest week), down staging (T3 N2 M0 P1. Stage IV a) and improvement of performance status were obtained, and then surgical resection was undertaken. After operation one course of LcFP therapy served as adjuvant chemotherapy. The patient has survived over one year and 8 months to date in a tumor-free condition. LcFP therapy promises to be useful in the clinical management of advanced gastric cancer.

[Ambulatory and domiciliary cancer chemotherapy with forearm implant catheter system and low-dose CDDP + 5-FU therapy].

Shortening the period of hospitalizations and improving QOL attracting a great deal of attention in the field of medicine recently. Therefore, ambulatory and domiciliary treatment has become more important. This is not an exception in cancer therapy; the conversion from hospital treatment to ambulatory and domiciliary treatment is promoted. However, there is the danger of a lowered QOL as a resistant side effect, when the conventional cancer chemotherapy in the hospital is used as the ambulatory and domiciliary treatment. Recently, low-dose CDDP + 5-FU therapy (LFP therapy) that applies biochemical modulation has been developed for advanced gastrointestinal cancers. This therapy is thought to have a good antitumor effect and slight side effects, so it can be widely used. However, this therapy needs the continuous injection of 5-FU, so the hospital treatment was necessary, and ambulatory treatment was difficult with the usual administration method. Thus, we implanted a forearm central venous catheter system (forearm IVH reservoir), through which we can administer medication safely and conveniently without limiting the patient activity. LFP therapy was attempted in ambulatory and domiciliary treatment. Low-dose FP therapy consisted of 5-FU (160 mg/m2/day every day by continuous infusion) and cisplatin (3 mg/m2/day in 100 ml of normal saline by infusion over 30 minutes on days 1-5/W). Patients were treated for 4 consecutive weeks with a subsequent one-week rest period. The overall response rate was 52.1%. Grade 3 toxicity was observed in 5% of patients. An advantage was that in the ambulatory and domiciliary cancer chemotherapy the hematotoxicity was slight, and LFP therapy could be continued safely. In addition, it was also possible to attempt the improvement in QOL with the forearm IVH reservoir system. LFP therapy using the forearm IVH reservoir system may develop as a standard method of ambulatory and domiciliary cancer chemotherapy in the future.