Biomedical subjects
Publications and source records attributed to Y Tokuda.
The first case of blue-rubber-bleb nevus syndrome treated with CAPD in Japan was presented. As operation for A-V fistula construction could not be performed due to the skin lesions, she was obliged to have CAPD treatment. She has been visiting our hospital for regular check-ups.
The effect of oral administration of lentinan (LTN), a biological response modifier, in the control of systemic immune function was studied in 6-week old male Wistar-Imamichi SPF rats. In the LTN group, 1 mg LTN dissolved in 1 ml physiological saline was administration forcibly into the stomach twice weekly. Physiological saline alone was administered in a similar fashion to the control group. Blood samples were obtained prior to and after four and eight weeks of administration. White blood cells and lymphocyte counts were obtained and lymphocyte subsets were measured using monoclonal antibodies W3/13, W3/25 and 0 X 8 (Sera-Lab), and a laser flow cytometry system (Orthospectrum III, Orthodiagnostic System). The T cell ratio, helper/inducer T (Th) cell ratio, and suppressor/cytotoxic T (Ts) cell ratio were measured. The peripheral white blood cell count and lymphocyte count were not significantly different between the control and LTN groups. After four weeks of LTN administration, however, the LTN group showed a significantly higher T cell ratio, Th cell ratio and Th/Ts cell ratio than did the control group, and the Ts cell ratio was significantly lower. In the groups undergoing administration for eight weeks, no difference was noted in the lymphocyte subsets between the two groups. Oral administration of LTN apparently modulates the systemic immune function through T cell stimulation, especially Th cells, but continued administration may induce a tolerance to the effect of LTN.
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In order to evaluate the possible utility of autologous bone marrow transplantation (ABMT), eighteen cancer patients were treated with high-dose combination chemotherapy supported by ABMT. We investigated CFU-GM/kg infused as well as bone marrow nucleated cells/kg to predict for hematopoietic recovery. Although hematopoietic recovery was not related to the nucleated cell number of the transfused bone marrow, CFU-GM infused related significantly to neutrophil recovery to 500/mm3 (correlation coefficient, r = -0.73, p less than 0.001) and platelet recovery to 50,000/mm3 (r = -0.69, p less than 0.001). Furthermore, a significant relationship of CFU-GM infused to the period of neutropenia below 500/mm3 was observed (r = -0.67, p less than 0.001). Taken together, CFU-GM dose can predict for neutrophil and platelet recovery, suggesting that ABMT can shorten the period of bone marrow suppression following high-dose chemotherapy.
It is a matter of debate whether the amplification of c-erbB-2 oncogene or production of the oncoprotein in breast cancers correlate with the presence of lymph node metastasis and with a poor prognosis. This study was aimed at elucidating the immunohistochemical localization of oncogene products which are related to cell growth, c-erbB-2 product, epidermal growth factor receptor (EGFR), c-myc protein and estrogen receptor (ER), in benign and malignant lesions of the breast. Fresh frozen sections of 25 breast cancers and 11 fibroadenomas from Japanese women were studied by indirect immunoperoxidase method with proper fixation. C-erbB-2 product and EGFR were localized on the cell membrane whereas c-myc protein and ER were observed in the nuclei. Immunohistochemical expression of oncogene products and ER were not only observed in the mammary carcinomas but also in the fibroadenomas. However immunoreactivities of EGFR and ER were more frequently seen in the fibroadenomas (p less than 0.05). In breast cancers, the incidence of immunoreactivity for c-erbB-2 was higher in the cases with lymph node metastasis than cases without nodal metastasis (p less than 0.05) and there was reciprocal correlation between the expressions of EGFR and ER (p less than 0.05). Regarding the size of the primary tumour, there was no statistically significant correlation with the expressions of c-erbB-2, EGFR, c-myc or ER. Histological grade correlated only with the expression of ER (p less than 0.05).
The generation of lymphokine-activated killer (LAK) activity and the proliferative response to human recombinant interleukin-2 (IL-2) were significantly reduced by the presence of human recombinant leukocyte interferon (IFN alpha) in cultures of human peripheral blood mononuclear cells (PBMC). Mature natural killer (NK) cells can be depleted from PBMC with the toxic lysosomotropic agent L-leucine methyl ester. The generation of cytotoxic cells from lymphocytes depleted in leucine methyl ester was also inhibited by indicating that the IFN-alpha effect is not limited to mature cytotoxic NK cells. Depletion of adherent cells from PBMC did not affect the suppression of LAK induction by IFN-alpha. Surface marker analyses of Tac antigen and transferrin receptor (TfR) showed that the presence of IFN alpha throughout the culture period significantly suppressed the typical increase in IL-2-induced Tac- and TfR-positive cells. In contrast, IFN alpha treatment before and after IL-2 culture enhanced LAK cytotoxic activity. Therefore, combinations of these biological response modifiers for clinical use should take into account the dual effect of IFN alpha on key features of the IL-2 response.
We performed basic studies on a new high-yield culture system (concentrate rotary tissue-culture system) for application to adoptive immunotherapy with lymphokine-activated killer (LAK) cells. Using this system, we demonstrated that up to 2 x 10(7) peripheral blood mononuclear cells/ml could be cultured in interleukin-2 with a sufficient recovery rate and cytotoxicity in short-term cultures (6 days). This system can also be used to proliferate LAK cells to four times the initial cell number with sufficient cytotoxicity for 14 days of culture. Thus, this system allows activation of sufficient numbers of cells to conduct clinical trials on humans.
In an assay for thyroid-stimulating antibodies, in which FRTL-5 thyroid cells were incubated with crude immunoglobulin (Ig) fractions precipitated from serum with 15% polyethylene glycol, significant increase in cAMP production was elicited by the samples from 25 (35.7%) out of 70 pregnant women. The highest value was 529.5%. There was a close correlation between thyroid stimulating activities and serum hCG concentrations (r = 0.708, P less than 0.001). When 125I-hCG was added to serum from pregnant women, about 20% of the radioactivity was incorporated into the Ig fractions. hCG preparations within a range of concentrations of 30-300 IU/m elicited 2.3-16.5 times increase in cAMP in a dose-dependent manner. Nine pregnant women with serum TSH concentrations less than the lower limit of the normal range (less than 0.25 mU/l) displayed significantly higher values for both thyroid stimulating activities and serum hCG concentrations (P less than 0.001, respectively) compared with those who had normal TSH levels in serum. These data suggest that hCG or its variant may stimulate the thyroid sufficiently to suppress secretion of TSH from the pituitary in some pregnant women.
Two patients had unusual squamous cell carcinoma (SCC) arising in a burn scar. The SCCs rapidly recurred and metastasized after radical operation, and the patients died of disseminated metastases. Histopathologically, the SCC was poorly differentiated and consisted of acantholytic round cells that diffusely proliferated into the deep dermis. However, small, solid nests composed of squamoid cells were focally observed. Immunohistochemical studies revealed that the acantholytic round neoplastic cells expressed not only keratin but also vimentin, and the coexpression was substantiated with double immunostaining. Vimentin-positive SCC composed of acantholytic round neoplastic cells may be a highly malignant subset of cutaneous SCC.
Twenty-five patients older than 50 years with atopic dermatitis (AD) diagnosed by the criteria of Tokyo Medical College were investigated on the basis of clinical course and features, IgE RIST, skin reactions, IgE RAST score to several antigens, and IgG4 levels in order to clarify the character of senile AD. The results were compared with the data from younger patients. It was found that the senile type AD showed various type of eczematous lesions whose onset was in the fourth decade of life, and higher IgE RIST and IgG4 levels than healthy people, but lower than younger AD patients. Immediate skin reactions to dermatophagoides and house dust were highly positive in the senile group like the younger group, while the reaction to spices was more highly positive (43%) than in younger persons. Clinically the recognition of the existence of senile type AD and the introduction of antiallergic therapy for severe eczema of old persons are important.
The correlation of variation in serum IgE and IgE-RAST in 364 cases of patients with atopic dermatitis (AD) aged 4 months to 78 years was analysed by comparison with the scatter diagram and fifth dimension regression curve representing the serum IgE and IgE-RAST scores of mite, egg white, milk, soybean, wheat and rice. The antigens indicating a high IgE-RAST score varied according to age. They were egg white and milk in infancy and mite from one to fifteen years of age. Rice and wheat came later. A high value of serum IgE with AD was seen to depend on the production of specific mite IgE antibody and to be influenced by each specific IgE antibody production, which varied according to age. It seemed that egg white and milk were initiators of AD and mite acted as a promotor. Rice and wheat were accelerators in patients with adult type AD. It was confirmed that, for AD patients of all ages, improvement of the environmental antigens and diet therapy was necessary.
One hundred seventy-three patients were treated 256 times with chemotherapy supported by autologous bone marrow transplantation during the past 9 years. The two most commonly used protocols were (cyclophosphamide 1,600-2,400 mg/m2 + adriamycin 80 mg/m2 + ACNU 3 mg/kg) and (cyclophosphamide 1,600-2,400 mg/m2 + adriamycin 100 mg/m2 + CDDP 100-150 mg/m2). Among 115 patients in the therapeutic setting in which two courses were usually given, 75 were evaluable and the overall response rate was 42.7% with 12.0% CR rate. Breast and pediatric groups responded well; the response rate in breast cancer was 67.9% with 21.4% CR rate. Two patients with breast cancer who had multiple distant metastases and 2 pediatric patients are now alive with NED after 5 years of the treatment and seem to have been cured. The results in adjuvant settings have also been quite promising, e.g., 79.4% 5-year survival probability among breast patients mainly in stage III. Although drops of blood cell counts to the nadirs (WBC counts: less than 100-300) could not be prevented, the periods of myelosuppression appeared to have been effectively shortened so that the patients could be safely managed with intensified general supportive measures. Platelet counts are usually less affected, but the recovery is slower than for WBC counts. There were 13 patients who died within 10 weeks of the initiation of the treatment. Two of them succumbed to sepsis, and progressive disease was the cause of death in 8 patients whose terminal phases were undoubtedly affected by some infectious problems. We have shown that there are inverse relationships between infused numbers of CFU-GM and marrow recovery judged by the duration of neutropenia and the time required for neutrophils to recover over 500. Our recent laboratory experiments testing CFU-E, BFU-E and CFU-Mk in addition to MNC counts and CFU-GM showed that vulnerabilities of marrow progenitors seem to differ from cell lineage to cell lineage. This must therefore be taken into careful consideration in pursuing marrow transplantation.
We developed a high-yield culture system, consisting of a culture bag on a rotator. The culture bag has two compartments, an inner compartment separated from an outer compartment by a semipermeable membrane. Cells in an appropriate culture medium are placed in the inner compartment, and medium without serum is placed in the outer compartment. The bag is rotated at an angle of 45 degrees between 0.5 and 5 rpm in a 37 degrees C incubator. The medium is changed in the outer compartment at intervals when needed. The outer compartment acts as the feeder as well as allows catabolites to diffuse through the culture. In addition, since the system is a closed-system, sterile conditions can easily be maintained. Using this system, we demonstrated that up to 20 X 10(6) cells/ml of PBMC could be cultured in IL-2 with sufficient recovery rate and cytotoxicity.
We investigated on antibodies to human T cell leukemia virus type I (anti HTLV-I) in 101 patients with primary glomerulonephritis in Kagoshima prefecture, an endemic area of HTLV-I in Japan. The positive rate in patients with primary glomerulonephritis was 17.8%, which was not significantly higher than in healthy residents 4741 persons of 11.9% in the same area. Classified by renal biopsy findings, the positive rate in patients with membranous nephropathy was 21.4% (9/42), minimal change nephrotic syndrome 14.3% (2/14), IgA nephropathy 15.4% (2/26), and others 15.8% (3/19) respectively, which were not significantly differed from that in healthy residents. Positivity of aged patients (60 years or over) in membranous nephropathy on the contrary was significantly higher than that in healthy residents (p less than 0.01). Further study is required to clarify the relationship between HTLV-I infection and glomerulonephritis.
Inhibitors of erythropoiesis found in the blood of uremic patients have been implicated as some of the causes of anemia in chronic renal failure. As a treatment to remove the inhibitors, continuous ambulatory peritoneal dialysis (CAPD) is thought to be more effective than hemodialysis. Some researchers have reported that CAPD has improved anemic state in hemodialysis patients. However, there have been some cases of severe anemia seen in CAPD patients. To access the effect of the CAPD, we have performed serial examination on hemoglobin (Hb) and hematocrit (Ht) in 5 uremic patients under CAPD treatment. Hb levels in 4 and Ht in 3 of 5 patients have been known to be increased. One patient was shown to have no increment on the levels of Hb and Ht. On the other hand, further investigation has been down to access the effect of the recombinant human erythropoietin (r-HuEPO: Chugai pharmaceutical) on anemic patients, in whom no effect was noticed by treatment of CAPD. One severe anemic patient, who had been undergoing the treatment of CAPD for two years, was given r-HuEPO intravenously. The patient showed the increment on the levels of Hb and Ht, and the decreases on the levels of serum iron and ferritin. However, the patient has developed hypertension. In conclusion, CAPD was known to be not always effective for the increment of Hb and Ht, while r-HuEPO was very effective for the improvement of severe anemia in CAPD patients which enabls them to lead better social life for them.
The purpose of these studies was to compare local and systemic human lymphokine activated killer (LAK) and natural killer (NK) cytotoxicity and to determine its modulation by the systemic administration of recombinant interleukin-2 (rIL-2). After preoperative systemic rIL-2, we extracted tumor infiltrating lymphocytes (TIL) and peripheral blood lymphocytes (PBL) from patients with pulmonary tumors and compared pre- and posttreatment spontaneous NK activity and their response to in vitro rIL-2. Spontaneous TIL NK activity was increased in patients receiving 15,000 units/kg rIL-2 preoperatively [6.6 lytic units (LU)] compared to those receiving 1,000-10,000 units/kg (0.8 LU) or no rIL-2 (1.4 LU). After 3 days incubation with 1,000 units/ml rIL-2, TIL NK cytotoxic activity was increased in patients receiving 15,000 units/kg rIL-2 (65.4 LU) compared to those receiving 1,000-10,000 units/kg (6.0 LU) or no treatment (24.9 LU). Spontaneous TIL LAK activity was low overall (1.1 LU) with the exception of two patients receiving 15,000 units/kg who had 3.1 and 3.7 LU spontaneously. TIL LAK precursor activity was only slightly increased in patients receiving 1,000-10,000 units/kg rIL-2, whereas those receiving 15,000 units/kg rIL-2 had an average of 22.8 LU. Systemic rIL-2 also increased spontaneous PBL NK activity. Reincubation of PBL obtained at time of surgery or 3 days after discontinuing systemic rIL-2 resulted in significant increases in cytotoxic response to in vitro rIL-2 compared to pre-IL-2 in vitro responses. Systemic rIL-2 had no effect on spontaneous PBL LAK activity. Thus, the immunosuppressive tumor environment can be partially reversed with 15,000 units/kg systemic rIL-2. Higher doses of systemic rIL-2 also increased spontaneous PBL NK activity at time of surgery and 3 days after discontinuing rIL-2. Both TIL and PBL inducible cytotoxicity were boosted in vitro following higher doses of systemic rIL-2.
Thyroid imaging using TI-201 was useful to visualize the normal thyroid tissue, which was not visualized by conventional imaging using I-123 or Tc-99m, in three patients with toxic nodular goiter.
Thyroid stimulating antibodies (TSAb) and TSH-binding inhibitor immunoglobulins (TBII) were assessed in 30 patients with euthyroid Graves' disease. TSAb were detected in 24 cases (80.0%), the incidence being not significantly different from that in hyperthyroid Graves' disease (29/30, 97.6%). On the other hand, the incidence of TBII in patients with euthyroid Graves' disease (12/30, 40.0%) was significantly lower than that in patients with hyperthyroid Graves' disease (30/30, 100.0%). The mean TSAb and TBII activities in the euthyroid patients were significantly lower than in the hyperthyroid patients (P less than 0.005 and P less than 0.001, respectively). Both TBII and, more closely, TSAb activities correlated with T3-nonsuppressibility and inhibition of serum TSH response to TRH stimulation. The findings supported the stimulation in vivo of the thyroid by these antibodies. Both antithyroglobulin and antimicrosomal antibody titres in euthyroid Graves' disease were significantly lower than in hyperthyroid Graves' disease (P less than 0.05, P less than 0.01, respectively). Goitre size was significantly smaller (P less than 0.001), and 99mTc thyroid uptake was significantly lower (P less than 0.001) in the euthyroid than in the hyperthyroid group. Thus, the reduced mass of thyroid tissues responding to the stimulators was considered to be one of the factors responsible for the euthyroidism despite the presence of TSAb. The high incidence of TSAb and relatively low incidence of TBII in euthyroid Graves' disease indicate that the presence of TSAb does not necessarily lead to hyperthyroidism and that the development of overt thyrotoxicosis may require augmentation of both TSAb and TBII.