Correlation between thyrotropin-displacing activity and human thyroid-stimulating activity by immunoglobulins from patients with Graves' disease and other thyroid disorders.

Several reports have been published on the anti-TSH receptor antibody in putative autoimmune thyroid disorders using a radioreceptor assay. We have carried out correlative studies between the ability of serum immunoglobulins to displace radiolabeled TSH from the thyroid plasma membrane receptor [TSH-displacing activity (TDA)] and that of actual stimulation of the human thyroid gland [human thyroid-stimulating activity (hTSA)] in Graves' and other thyroid diseases and in control subjects. TDA was assayed by the use of a radioligand technique, while the activation of adenylate cyclase in human thyroid slices was measured as an index of hTSA. The same immunoglobulins were employed for both assays. In this series, positive TDA and hTSA values were found in 70.4% and 81.5% of the samples in active untreated Graves' disease, respectively. Samples from normal persons and from several patients with toxic nodular goiter gave generally negative results in both assays; in a small proportion of patients with either subacute thyroiditis or Hashimoto's thyroiditis, the TDA was positive but hTSA proved to be negative. In Graves' disease (including those patients on propylthiouracil) in remission and treated with 131I, the correlation between TDA and hTSA was not significant (r = 0.309; P greater than 0.1); even when the procedures were compared in the untreated group alone, there was no significant correlation between the two activities (r = 0.309, P greater than 0.1). These studies indicate that 1) significant TDA and hTSA are observed in Graves' disease; nevertheless, the correlation between them is not significant; 2) the hTSA assay appears to be more sensitive and specific than the TDA assay; and 3) TDA may not be synonymous with thyroid stimulation.

Thyroid-stimulating hormone (TSH) binding to extrathyroidal human tissues: TSH binding to extrathyroidal human tissues: TSH and thyroid-stimulating immunoglobulin effects on adenosine 3',5'-monophosphate in testicular and adrenal tissues.

Binding of [125I]bovine TSH to human thyroid, testicular, fat, adrenal, liver, kidney, pancreas, and lung cell membranes has been studied. The first four tissues were found to have comparable high affinity constant values; the rest of the tissues lacked high affinity sites. With the exception of fat tissue, the capacities of the high affinity sites of the first four tissues were similar. Bovine TSH concentrations of 100-20,000 microIU/ml stimulated increased cAMP production in human cryopreserved testicular slices. Forty percent of the specimens of thyroid-stimulating immunoglobulin (TSI) from Graves' disease sera also increased human testicular cAMP production. In addition, bovine TSH caused a significant rise in cAMP in the whole decapsulated rat testis. Twenty-five percent of the TSI specimens tested also induced such responses. The rat adrenal gland responded with increased cAMP production to concentrations of 1,000 microU/ml bovine TSH. The physiological significance of high affinity bovine TSH and TSI binding and subsequent cAMP production in nonthyroidal tissues in not known. However, since these stimulators are present in hypothyroidism and hyperthyroidism, respectively, it is possible that the pathophysiological effects of this binding could be of some importance.

Effect of human chorionic gonadotropin on human thyroid tissue in vitro.

Thyroid stimulating substances other than TSH have been found in certain disease states associated with hyperthyroidism. The thyroid stimulator associated with the thyrotoxicosis of trophoblastic disease is uncertain; however, recent evidence suggests a role for hCG. To explore the thyroid stimulating properties of hCG further, we examined the ability of hCG to displace [1252]TSH from receptors on human thyroid membrane and to generate cyclic-AMP (c-AMP) from human thyroid slices. Human chorionic gonadotropin at a concentration of 40 IU/ml displaced labeled TSH from human thyroid membranes and, at a concentration of 69 IU/ml, hCG caused the generation of c-AMP in thyroid slices. These results suggest that hCG can bind to the TSH receptor on thyroid cells and can stimulate them to produce c-AMP at concentrations of hCG within the range that is found in trophoblastic disease.

Association of HLA-DPB1*0501 with early-onset Graves' disease in Japanese.

To investigate the association between HLA antigens and Graves' disease among Japanese, serologic typing and DPB1 genotyping using the PCR-RFLP method have been performed. HLA alleles of 106 patients with Graves' disease were determined, and the frequency of HLA-B46 was found to be significantly increased. Furthermore, the frequencies of HLA antigens were compared between two age groups: early-onset and late-onset patients (under and over 20 years, respectively). It was found that the frequency of DPB1*0501 (88.9%) was significantly increased (pc < 0.004) in the early-onset group as compared with the healthy controls (55.0%) but not in the late-onset group (60.7%). On the other hand, a significant increase of HLA-B46 was observed in the late-onset patients (pc < 0.0004). These results suggest that the genetic background of Japanese patients with early-onset Graves' disease is different from late-onset patients. Namely, the HLA-DP allele (DPB1*0501) and the HLA-B allele (B46) are primarily involved in the pathogenesis of early-onset and late-onset Graves' disease in Japanese, respectively.

The relationship between multiple intrathyroidal involvement in papillary thyroid carcinoma and chronic non-specific thyroiditis.

The relationship between multiple intrathyroidal involvement (MII) and chronic non-specific thyroiditis (CT) was investigated in 69 papillary thyroid carcinoma patients who received a subtotal or total thyroidectomy. The overall incidence of MII in patients with CT and the incidence of MII in the affected lobe of the patients with CT were significantly higher than that without CT (P = 0.0012 and 0.0425, respectively). Because Hashimoto's thyroiditis is believed not to carry the increased risk of associated thyroid malignancy, the high incidence of MII in the affected lobe in the case with CT is postulated to be caused by intraglandular metastases.

Clinical evaluation of upper mediastinal dissection for differentiated thyroid carcinoma.

BACKGROUND: An extensive upper mediastinal dissection in advanced differentiated thyroid carcinoma is occasionally required. This investigation was undertaken to clarify the indications for mediastinal lymph node dissection and the route of upper mediastinal metastases. METHODS: Twenty-one patients with differentiated thyroid cancer, who underwent their first radical operations with mediastinal dissection through a partial midline sternotomy, were enrolled in this study. Of 21 patients, 10 (48%) were found to have mediastinal lymph node metastases. RESULTS: The tumor size in the group with metastatic disease was much bigger than that in the group without metastatic disease. Histologic type and age were similar between the two groups. The extent of cervical lymph node metastases was more significant in the group with metastatic disease; in particular, all 10 patients showed more than two metastatic nodes along the internal jugular vein of the tumor-free side. CONCLUSIONS: This study indicates that metastases to the internal jugular chain on the side contralateral to the primary tumor would be an extremely important factor for indication of extensive upper mediastinal lymph node dissection after median partial sternotomy in patients with differentiated thyroid carcinoma.

Frequent natural killer cell abnormality in children in an area highly contaminated by the Chernobyl accident.

Since January 1991, we have been performing thyroid surveys and hematologic and immunologic screening on children in Chechersk, Belarus, a city situated in one of the areas most seriously contaminated with high levels of radionuclides after the Chernobyl accident. Ten children selected from 713 children because of goiter did not show a decrease in humoral immunity or in the number and function of T cells. By contrast, natural killer (NK) cell activity against K562 cells was depressed in 4 of these 10 children. The clinical and laboratory findings indicated that previously reported diseases with NK cell dysfunction could be excluded. A comparative analysis of NK cell activity in children from areas with and without high 137Cs levels revealed a high frequency of abnormal NK cell activity only in children from the area contaminated by radioactive fallout. In addition, there was no correlation between NK cell activity and NK cell number as percentage in the children from the area with high 137Cs levels. Neither activity nor number of NK cells was correlated with the body content of 137Cs. Thus, the frequent abnormality of NK cell function may not have been due to actual internal exposure to the long-lived radionuclide.

Suppressive effect of ulinastatin on plasma fibronectin depression after cardiac surgery.

Plasma fibronectin, an opsonic glycoprotein, is known to modulate the reticuloendothelial phagocytic clearance of nonbacterial and, possibly, bacterial particulates. The decreased plasma fibronectin levels seen after cardiac surgery have been considered to derive mainly from opsonic consumption. In the present study, we demonstrated that the administration of ulinastatin, a human urinary trypsin inhibitor, to patients after cardiac surgery not only inhibited the postoperative depression of plasma fibronectin levels, but also maintained the plasma fibronectin level within the normal range. This effect apparently resulted from the inhibitory activity of ulinastatin on the proteolytic enzymes released after operation. This result suggests that the decreased plasma fibronectin level noted after cardiac surgery may derive mostly from excessive proteolytic enzymes. Our observation also indicates that the prophylactic administration of ulinastatin to patients undergoing major operations will result in a favorably functional reticuloendothelial phagocytic system.

Significance of values of thyrotropin binding inhibitor immunoglobulins and appearance of intrathyroidal lymphocytes at subtotal thyroidectomy for Graves' disease.

This study was undertaken to investigate whether thyrotropin binding inhibitor immunoglobulins (TBII) values at and after subtotal thyroidectomy correlated with the outcome or the histologic grade applied to the appearance of intrathyroidal lymphocytes at the time of surgical treatment. In addition, the main reason for the study was to determine whether or not it was possible to predict the outcome after the operation by the data obtained. There was no relation between the TBII results and the grade of the appearance of intrathyroidal lymphocytes at the time of operation or the TBII postoperative results (whether positive or negative) and the final outcome. However, it was of interest that patients with a recurrence of hyperthyroidism had the TBII values of more than 50 percent at the time of surgical treatment, and also manifested continuously positive TBII values after the operation. They also had moderate grades of lymphocytic infiltration and lymph follicle formation in the surgical specimen. It seemed impossible to predict the outcome of each instance in accordance with TBII values and the grade of the appearance of intrathyroidal lymphocytes at the time of the operation. However, it might be possible to predict at least the recurrence of hyperthyroidism by the consideration of changes of TBII values postoperatively.

Thyroid abnormalities among children in the contaminated area related to the Chernobyl accident.

Gradual increases of various radiation-related diseases including thyroid cancer following the Chernobyl accident have been recently reported. We have carried out systematic thyroid surveys in school children aged 10-15 years in the highly contaminated area and compared the results with a similar survey in a nonaffected neighboring area as a control. Systematic examinations of the thyroid gland were performed in 888 schoolchildren (408 males and 480 females) in the districts of Chechelsk city with 5 to over 40 Ci/km2 of radiation level for 137Cs. In the control area (Bobruisk city), 521 children with the same age range (229 males and 292 females) were examined. Thyroid surveys were carried out as follows: palpation, ultrasonography, blood examinations of thyroid function, and measurements of daily urinary excretion of iodine. Certain thyroid abnormalities were observed in the high radioactive fallout area more frequently than in the control region. In particular, the prevalence of multiple micronodular lesions in diffuse goiter in the contaminated area was significantly higher than in the control area. However, endemic goiter due to iodine deficiency was present in both districts. The environment factor of iodine deficiency might have resulted in the early occurrence of ultrasonographic thyroid abnormalities attributed to radioactive contamination.

Immunohistochemical studies on local antitumor effects of streptococcal immunopotentiator, OK-432, in human solid malignant tumors.

Immunocytochemical techniques were used to clarify the local inhibitory effects of a streptococcal immunopotentiator, OK-432, against solid malignant tumor growth. Natural killer (NK) cells and fibronectin were chosen as immunostaining markers to demonstrate the antitumor effects. Immunocytochemical staining was performed by the avidin-biotin-peroxidase complex method. These investigations demonstrated that (1) local administration of OK-432 seems to promote a marked induction of NK cells and fibroblasts around or entering into the cancerous lesions and (2) the cancer cell-killing effect of NK cells and the fibronectin-enriched stromal reaction augmented by the injection of OK-432 suggest at least the possibility of protection against neoplastic growth with invasion and the spread of distant or nodal metastases of solid carcinomas.

Lower esophageal sphincter pressure after subtotal gastrectomy and postoperative reflux esophagitis.

Although reflux esophagitis after subtotal gastrectomy has been noticed by surgeons, the mechanism of its development is obscure. This study was undertaken with the aim of clarifying the role of the lower esophageal sphincter in the development of this abnormality. Manometric studies were carried out on 42 patients with gastric cancer, and on 19 with cholelithiasis. The lower esophageal sphincter pressure was measured using a catheter tip pressure transducer and a rapid pull-through technique, and the results presented as the mean of three measurements. The technical error of this experiment was estimated to be within 2 mmHg by a study of the cholecystectomy patients. After gastrectomy, the lower esophageal pressure decreased in 17 patients, increased in 4 and remained unchanged in 21. A more pronounced decrease in the lower esophageal sphincter pressure was found after Billroth II. Clinical evaluation of the 42 patients revealed symptoms of postgastrectomy regurgitation in 10. Preoperatively, these 10 had lower values of the lower esophageal sphincter pressure followed by a more marked postoperative decrease, as compared with the patients with no regurgitation symptoms. Oral administration of a test meal revealed regurgitation after subtotal gastrectomy. This study suggests that a low value of the pre-operative lower esophageal sphincter pressure, a marked decrease in the pressure after gastrectomy, and Billroth II anastomosis, may be factors that predispose to regurgitation.

Therapeutic efficacy of the angiogenesis inhibitor O-(chloroacetyl-carbamoyl) fumagillol (TNP-470; AGM-1470) for human anaplastic thyroid carcinoma in nude mice.

TNP-470 (AGM-1470), a synthetic analog of fumagillin (6-chloroacetyl-carbamoyloxy-4-(1,2-epoxy-1,5-dimethyl- 4-hexenyl)-5-methoxy-1-oxaspiro [2,5] octane 1, has been reported to reduce the supply of nutrients to experimental tumors by inhibiting angiogenesis. In this study, we investigated anti-tumor activity of TNP-470 against human thyroid anaplastic carcinoma with a view to developing a new treatment for this thyroid tumor. A transplantable tumor was established from thyroid anaplastic carcinoma of a 78-year-old woman, as a xenograft in nude mice (BALB/c, nu/nu, male). This transplantable tumor, with chromosomal abnormality was shown to be non-functional in excretory hormones and to preserve morphological characteristics of the original anaplastic tumor tissue. TNP-470 was given at a dose of 50 mg/kg b.w. to nude mice transplanted with human thyroid anaplastic carcinoma by different routes of administration: intratumoral, peritumoral, subcutaneous and intraperitoneal. Intratumoral and peritumoral administration were effective, and especially the TNP-470 administered by the former route completely inhibited tumor growth. Immunohistochemical analysis using anti-factor VIII antibody revealed the density of microvessels to be significantly decreased by local administration of TNP-470 (intratumoral administration, 7.8 +/- 2.9/mm2, control, 27.0 +/- 6.3/mm2; peritumoral administration, 9.7 +/- 2.6/mm2, control, 21.1 +/- 5.1/mm2). Our findings suggested the possibility of clinical application of TNP-470 to control the growth of human anaplastic thyroid carcinoma.

Thyroid carcinoma associated with hot nodule diagnosed by ultrasonography.

A patient with thyroid carcinoma showing a hot nodule on radioiodine scintigraphy was examined by ultrasonography and was revealed to have occult carcinoma co-existing with adenomatous goiter. Ultrasonography should be performed to establish the diagnosis even if radioiodine scintigraphy reveals a hot nodule, as should fine-needle aspiration biopsy.

[Combination neoadjuvant therapy with continuous intra-arterial CDDP infusion and radiotherapy for locally advanced breast cancer].

Neoadjuvant therapy combined with intra-arterial continuous infusion of CDDP and external radiation was evaluated in a patient with locally advanced breast cancer. Although only MR was observed on the primary tumor, PR was found in several metastatic lymph nodes and daughter nodules. All tumor markers elevated before treatment decreased to normal ranges only by this therapy, and histological damage was also recognized remarkably with a high concentration of free Pt (8.89 micrograms/g) in cancer tissues. Since no severe side effects appeared during the present therapy, extended radical mastectomy with wide skin resection could be performed following additional intra-arterial chemotherapy using 5-FU, epi-ADM and MMC. From this experience, it was suggested that CDDP was an useful drug in the chemotherapy for breast cancer.

[Medical images; the clinical significance of the medical images of thyroid cancer].

Supplementary diagnosing methods for thyroid cancer were discussed, with particular reference to medical images. Although palpation is, of course, essential in the examination of nodules, we have also used soft X-rays and I-123 scintigraphy, as well as Tl-201 scintigraphy, ultrasonography and aspiration biopsy. In addition, various diagnosing methods have been employed to determine the degree of invasion in advanced cancer patients, such as CT scan for observing invasion of the surrounding tissues, naso-tracheoscopy for invasion of the trachea and a flow meter for vascular tracts. When the tumor size is under 2 cm, we use soft X-rays, ultrasonography and sometimes try additional aspiration biopsy. When the tumor is smaller, aspiration biopsy is employed with ultrasonography. For tumors larger than 2 cm, we use soft-X-rays, I-123 scintigraphy and ultrasonography. Tl-201 scintigraphy is employed to determine operative indication, following which aspiration biopsy and CT scan are performed. CT scan, tracheofiberscopy and doppler flow studies are carried out for advanced cancer cases to determine the degree of invasion of carcinomas.

[Intra-arterial infusion chemotherapy of locally advanced and recurrent breast cancer].

A total of 15 cases of advanced and recurrent breast cancer of more than 3-year duration were subjected to continuous intra-arterial infusion in our department, and its therapeutic effect and the judgement were examined. Using subclavian artery and internal thoracic artery for the primary cases and the latter artery for the recurrent cases for infusion, continuous administration of 5-FU and one-shot injection of ADM and MMC were performed twice a week. 99mTc-angiography was effective for the identification of arterio-controlled areas. Under the judgement criteria for therapeutic effects according to the breast cancer handling agreement, CR, PR, NC and PD were noted in 1, 8, 5 and 1 cases, respectively, with a 60% rate of effectiveness. Judgement of effects by 201Tl-chloride scintigraphy showed some correlation with the histological judgement, with its apparent effectiveness. Examination of the remote results revealed 3-year survival rate of 83.3% and 3-year healthy survival rate of 66.7% for the primary cases. Two of the 3 recurrent cases died at 2 and 11 post-infusional months, respectively, but 1 showing CR is still alive 4 years and 10 months, post infusionally.

[Local immunotherapy of breast cancer: a case of advanced breast cancer improved by combined local injection therapy with OK-432 and rIL-2].

An effective immunotherapy for breast cancer has yet to be established. We have recently experienced an inoperable case of advanced breast cancer due to mental disorder. Combined local injection therapy with OK-432 and rIL-2 was performed in addition to non-surgical multi-disciplinary treatment, with obvious therapeutic effects. The case is a 67-year-old female, who had a 5.0 x 4.7 cm tumor in the area A of the left mammary gland. Aspiration cytologic examination revealed class V breast cancer. Besides systemic chemotherapy, local injection therapy with OK-432 2.0 KE on day 1 and rIL-2 500 U on day 3 was performed. Upon starting local injection therapy, a rapid reduction was noted in the tumor diameter (reduction rate, 75.5%). Tumor makers of CEA, CA 15-3 also showed obvious diminution. Although the dose and interval of administration remain to be further examined, the combined local injection therapy with OK-432 and rIL-2 was suggested to be an effective local immunotherapy for breast cancer.

[Ultrasonography in the diagnosis of malignant lymphoma of the thyroid].

Malignant lymphoma of the thyroid was rare condition and it was difficult to make a diagnosis of malignant lymphoma preoperatively. Both ultrasonographic appearance and diagnostic significance of ultrasonography in malignant lymphoma of the thyroid were investigated in this study. Ultrasonography of 10 patients with malignant lymphoma of the thyroid was analyzed. Only 3 cases of 10 were diagnosed as malignant lymphoma by ultrasonography. Five cases were misdiagnosed as thyroid carcinoma, 1 as adenomatous goiter accompanied by cystic degeneration and 1 as chronic thyroiditis. Nine cases were nodular type i.e. limited extremely hypoechoic mass as contrasted with surrounding thyroid tissue, occupying asymmetrically in the thyroid gland. One case was diffuse type i.e. diffused hypoechoic area without surrounding residual thyroid tissue. The tumor size of the 2 cases in which no accumulation was observed in the 67Ga scintigram was 2 cm or less. By ultrasonography of these 2 cases, one case was diagnosed as malignant lymphoma and the other as thyroid carcinoma. Ultrasonography can be regarded to be very significant method as a screening test to make a diagnosis of malignant tumor for nodular type, especially small sized malignant lymphoma of the thyroid.

[Clinical evaluation of operative procedure for differentiated carcinoma of isthmus of the thyroid].

We studied 19 patients who had undergone operation for differentiated carcinoma of isthmus of the thyroid in Shinshu University Hospital from 1967 to 1986. Regarding the operations, total thyroidectomy was performed in 6 cases, subtotal thyroidectomy in 8 cases, lobectomy in one case and isthmectomy in 4 cases. In 12 cases, lymph node dissection was carried out. Among these 12 cases, 6 cases (50%) had evidence of metastasis. Intraglandular metastasis was found in 3 cases. There were no relationship between tumor size and nodal metastasis. From these results, we do not think that total thyroidectomy is indicated in the case of differentiated carcinoma of isthmus of the thyroid. In conclusion, subtotal thyroidectomy with bilateral modified radical neck dissection is sufficient as the operative procedure for differentiated carcinoma of isthmus of the thyroid.