A total of 747 cases of malignant neoplasms of the thyroid reported in the “Annual of the Pathological Autopsy Cases in Japan” during the past 5 years (1969-1973) were reviewed and statistically analysed.
Histological diagnosis in this series were papillary carcinoma in 323 cases (51.8%), follicular carcinoma in 143 cases (22.9%) and anaplastic carcinoma in 102 cases (16.3%). The average age of patients at autopsy was 58 years for papillary carcinoma cases, 62.4 years for follicular carcinoma cases and 61.7 years for anaplastic carcinoma cases. The incidence of metastasis to lymph nodes and to organs was 47.3% and 51.5%, respectively in cases of follicular carcinoma and 73.3% and 98.0%, respectively in cases of anaplastic carcinoma. Autopsy revealed an otherwise unnoticed thyroid cancer in 457 cases, which accounted for 61.2% of the entire autopsy cases of malignancy of this organ. A so-called multiple cancer, i.e. the concurrence of carcinomas in the thyroid gland and other organs, was seen in 239 cases (32.3%).

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After administration of the hypolipidemic agent 'dextran sulfate' to hyperlipidemic patients, the following data were acquired regardless of the thyroid function : the decrease of triglycerides, the increase of free fatty acids (FFA), the decrease of protein bound iodine, the increase of effective thyroxine ratio (ETR), the slight decrease of thyroid stimulating hormone, no significant change of thyroxine determined by radioimmunoassay (RIA-T₄), the increase of T₄ determined by competitive protein-binding analysis (CPBA-T₄) and the increase of resin triiodothyronine uptake (RT₃U) determined by Scholer's method.
Furthermore, it was recognized that the increase of CPBA-T₄ value was significantly correlative to the amount of increased FFA. Therefore, this paper was undertaken for the purpose of proving that FFA would interfere with the measurement system of commercial kits utilizing thyroxine binding proteins.
It has recently been discovered that circulating FFA is mainly combined with albumin, but that oversupplied FFA is partially combined with lipoproteins or thyroxine binding globulin (TBG), and that T₄ is displaced by FFA from the TBG-binding site and becomes free.
In hyper-free fatty acidemic serum, after the administration of dextran sulfate, it was naturally anticipated that the amount of free type of labelled T₃ must have increased in the system of saturation analysis, because FFA had already been tightly combined with the TBG site. But contrary to this expectation, the amount of separated free type of labelled T₃ decreased more than in normo-free fatty acidemic serum. This paradoxical finding was explained as the result of the surface activity-like interference of FFA with the absorption by resin strip. So it was proved that RT₃U (Scholer's method) would be raised by oversupplied FFA.
It was noticed in this study that when endogenous T₄ was extracted from serum in many commercial kits, the significant amount of FFA was also extracted by alcohol together with it. And because the extracted FFA also displaced labelled T₄ from the TBG site in the test vial, the free type of labelled T₄ increased more in the system of CPBA than when only endogenous T₄ competed with labelled T₄ from the TBG site. Thus the false elevation of CPBA-T₄ was calculated in hyper-free fatty acidemic serum. And the false elevation of ETR value in the same serum was proved as the result of the interference of FFA with the measurement system.
Because the interference of FFA in RIA-T₄ was essentially negligible, the difference between CPBA-T₄ and RIA-T₄ values was significant in hyperthyroid patients with high levels of FFA.

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To investigate the role of peripheral blood lymphocytes in thyroid auto-immunity, the in vitro responsiveness to allogeneic lymphocytes (MLC) or phytomitogens was examined in the lymphocytes from patients with Hashimoto's thyroiditis.
The MLC responses of 16 patients were compared with those of age- and sex-matched normal controls. All possible combinations between lymphocytes from the patients and controls were mixed in both one-way and two-way MLC. From the results of one-way MLC, the stimulatory capacity and responding capacity of lymphocytes from the patients and controls were calculated respectively as follows :
Nm→ N : 4,829 ± 3,257 (M ± SD, cpm) (1)
Hm → N : 4,735 ± 3,029 (2)
Nm→H : 3,716 ± 2,401 (3)
To the same allogeneic stimulation of Nm (mitomycin-treated stimulating lymphocytes from controls), lymphocytes from the patients (H) exhibited a lower response (P>0.05) than did those from the controls (compare (1) with (3)).
Phytomitogen-response was simultaneously studied for residual cells of MLC. Lymphocytes from the patients showed a significantly decreased (P<0.01) response to phytohemagglutinin-p and concanavalin A in comparison with the response of normal lymphocytes.
From these results, it was suggested that cell-mediated immunity in vivo was impaired in Hashimoto's thyroiditis

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Steroid hormone biosynthesis by human ovarian follicles in vitro over a period of follicular maturation and ovulation was studied in the light of follicle morphology. The largest follicle was isolated from each of the five ovaries removed at various stages in the follicular phase of the menstrual cycle from patients who were undergoing surgery for carcinoma of the uterus. Slices of each follicle tissue were incubated with 50μCi of acetate-1-¹⁴C in Hanks's solution for 3 hours at 37°C under the gas phase of 95% oxygen and 5% carbon dioxide. A portion of the follicle was subjected to histological examination. Incorporation of radioactive acetate into pregnenolone, 17α-hydroxypregnenolone, progesterone, 17α-hydroxyprogesterone, dehydroepiandrosterone, androstenedione, testosterone, estrone and estradiol-17β were assessed by a reverse isotope dilution technique with recrystallization to constant specific activity.
Although a minimum amount of incorporation of radioactive acetate into progestogens and estrogens was identified, androstenedione was the only major product in a less matured follicle which had a moderate proliferation granulosa cells and a relatively small thecal cell.
On the other hand, the predominant incorporation into estrone and estradiol-17β with a concomitant slight increase in the incorporation into progestogens was observed in a mature follicle as judged by its histology with marked proliferation of granulosa cells and regularly arranged nuclei in the elongated basal granulosa cells.
Progesterone and 17α-hydroxyprogesterone were the major steroidal products in the two preovulatory follicles. These were characterized by granulosa cells tending to be ovoidal in shape with a relatively abundant cytoplasm, a slight swelling of the thecal cells and hyperemia in the thecal layer, although these morphological features differed from each other to a considerable degree.
In the follicle just prior to rupture, as evidenced histologically by the indistinguishable border between granulosa and thecal layer, and the contracted thecal cells sparsely scattered in surrounding hemorrhage, only progesterone preserved a relatively high production. On the other hand, 17a-hydroxyprogesterone showed a distinct decrease, and the production of androgens and estrogens were severely interrupted in this follicle.
The role of the granulosa and thecal cells is discussed in relation to the above described changes in steroidogenesis.

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Described here is a patient, suffering from both primary aldosteronism and a primary double cancer of the thyroid and rectum, who died of meningo-encephalitis due to Listeria monocytogenes.
The patient, a 57-year-old man, was admitted to Tenri hospital in January, 1977, for analysis of hoarseness and a solitary nodule in the thyroid. Physical examination revealed a well-nourished man with a left-sided solitary nodule in the thyroid associated with the enlargement of neighboring lymph nodes and recurrent nerve involvement. The thyroid scintigram, obtained 24 hours after ¹³¹I administration, demonstrated less activity in the nodule than in the adjacent thyroid tissue, showing the nonfunctioning nodule. Thyroxine, triiodothyronine and TSH concentrations in serum were almost within normal limits. Thus, he was diagnosed as having thyroid cancer, and the removal of the nodule and of the enlarged lymph nodes was performed in February, 1977. The histological diagnosis was pappillo-follicular adenocarcinoma of the thyroid. The metastasis to lymph nodes was also found.
In addition to the thyroid cancer, it was noted that his blood pressure was 160-192/ 60-120 mm.Hg, and the serum potassium concentrations were under 3 mEq./L. in repeated determinations. The renal potassium clearance rate was 44.9 ml./min. (normal range : 10-30 ml./min.) on loading of Na₂S₂O₃, indicating an excess loss of potassium through urinary excretion. The distinct elevations of the supine plasma aldosterone concentration (PAC, 55 ng/100 ml.) and urinary aldosterone excretion (24 μg/day), which were determined by radioimmunoassay, were found on ordinary sodium intake (120 mEq./day). On the other hand, the supine plasma renin activity (PRA), determined by radioimmunoassay, was below the limit of detection on ordinary sodium intake. When sodium intake was restricted (10 mEq./day), the plasma potassium level increased to the low-normal range, while the increment of PRA was negligible, even when an upright position was sustained for 2 hours and furosemide was injected simultaneously. Moreover, the serum potassium level also increased to a low-normal range after the administration of spironolactone, but glucocorticoid administration had no effect on the diminished potassium level in plasma and on hypertension. Plasma cortisol concentrations were 17.5 μg/100 ml. at 9 : 00 AM and 9.5 μg/100 ml. at 5 : 00 PM. Urinary 17 OHCS and 17 KS excretion were within normal limits. Thus, the results were consistent with the clinical diagnosis of primary aldosteronism.
During further evaluation of the primary aldosteronism, the patient suffered from headache, nausea and vomiting associated with high fever, and rapidly lapsed into a coma. Lumbar puncture revealed cloudy fluid under an initial pressure equivalent to 350 mm. of water. The fluid contained 313 white cells per cubic millimeter, showing mainly neutrophils. The smear and culture showed gram-positive rods, suggesting Listeria monocytogenes. Although antibiotic therapy was promptly instituted, he died 14 days after the onset of his illness.
Autopsy was performed about 6 hours after death. A yellow tumor (1.4 × 1.2 × 0.7 cm in size and 0.5 g in wet weight) was found in the right adrenal gland. Rare mitotic figures and no pleomorphism on light microscopic examination sustained the diagnosis of adrenal adenoma. There was residual thyroid cancer in the right lobe of the thyroid. Moreover, a small tumor (about 1 cm. in diameter) was found in the rectum, and the histological diagnosis was adenocarcinoma, which was apparently different from that of the thyroid histologically, indicating a primary double cancer of the thyroid and rectum. There were several microabscesses in the basal ganglia and the mid-brain and histiocyte included gram-positive rods found in the abscess.

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Pancreatic islet cell tumors were induced in 37 of 44 male Wistar rats (84%), surviving 9 to 14 months after treatment, not only by various doses of streptozotocin alone, but also by the combined administration of streptozotocin with nicotinamide or picolinamide.
A single i.v. injection of 30, 40, 50 and 65 mg/kg body weight of streptozotocin alone produced adenomas of pancreatic islet cells in 8 out of 9 (89%), 6 out of 7 (86%), 2 out of 4 (50%) and 1 out of 2 rats (50%), respectively. The neoplasms were seen in all of the 8 rats given a single, 65 mg/kg body weight, i.v. injection of streptozotocin, preceded (15 min) by a single, 250 mg/kg body weight, i.p. injection of picolinamide. Among the 14 rats given a single, 500 mg/kg body weight, i.p. injection of nicotinamide, 15 min before a single i.v. injection of 65 mg/kg body weight of streptozotocin, 13 rats (93%) developed pancreatic islet cell adenomas.
Renal tumors were seen in only 3 rats treated with streptozotocin and nicotinamide. Each of them had islet cell tumors of the pancreas. None of the rats used in this study developed hepatic tumors.
Plasma insulin levels rose markedly following the glucose load in most of the rats with islet cell tumors, irrespective of the kind of treatment schedules, as compared to the response of the controls, whereas 4 out of 34 rats with islet cell tumors showed no insulin response to the glucose load and hyperglycemia.
The present study demonstrates that streptozotocin, even in a dose of 30 mg/kg body weight, has an exceedingly marked tumorigenic action on the rat endocrine pancreas, while it has slight effect on kidneys and little on livers. Observations on the physiologic responses of the rats with islet cell tumors indicate that the induced tumors could be classified into two groups on the basis of their insulin responses to glucose load : 'high insulin responding tumor' and 'low insulin responding tumor'.

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This study was designed to investigate the pituitary responsiveness of normal, regularly menstruating women to [Des-Gly¹⁰-NH₂, Pro⁹-ethylamide] -LH-RH, the first superpotent analog of LH-RH. Also in this study, the LH-RH/FSH-RH activity of [Des-Gly¹⁰-NH₂, Pro⁹-ethylamide] -LH-RH was compared with that of synthetic LH-RH in the follicular phase, and the half-life value of the analog in the blood was calculated.
[Des-Gly¹⁰-NH₂, Pro⁹-ethylamide] -LH-RH was given subcutaneously in a dose of 100μg to 17 women during different phases of the menstrual cycle. Five subjects were studied in the follicular phase (days 5, -6); 7 subjects were studied in the preovulatory phase (1-3 days before the expected date of ovulation); and the remaining 5 subjects were studied in the luteal phase (5-6 days after the BBT elevation). Five other subjects were given 100μg of synthetic LH-RH subcutaneously in the follicular phase (days 5-6) for a comparison. Blood samples were obtained under a prearranged schedule before and after the injection. The plasma levels of LH, FSH, estradiol-17β and progesterone were determined by radioimmunoassay. The gonadotropin response during the 6-hr period after the injection was assessed for Student's t-test and significant correlation with basal gonadal steroid levels using Pearson's correlation coefficient.
Unexpected changes in the gonadotropin response were observed in 2 subjects studied during the preovulatory phase : the plasma level of LH in these 2 subjects continued to increase gradually after the injection and reached its peak 48 and 120 hours later, and the peak levels of LH were 295 and 313 mIU/ml, respectively. The response pattern of FSH was almost similar to that of LH. Such a large amount of gonadotropin release could have been due to the action of the endogenous LH-RH at midcycle as well as the depot effect of the analog. The plasma level of estradiol-17β in these 2 subjects also increased slowly after the injection and reached its peak 24 hours before their respective LH peaks, and then decreased abruptly on the following day. These 2 subjects were excluded from the following statistical analyses.
The LH response to 100μg of the analog was significantly greater in both the preovulatory phase and the luteal phase than in the follicular phase (P<0.01 and P<0.05, respectively). There was no significant difference in the LH response between the preovulatory and luteal phases. The plasma level of LH reached its peak 2-3 hours after the subcutaneous injection of the analog in most of the subjects. The peak levels of LH (mean ± SE) were 101.4 ± 17.2 mIU/ml in the follicular phase, 280.3 ± 31.1 mIU/ml in the preovulatory phase, and 172.6 ± 31.3 mIU/ml in the luteal phase. The mean plasma levels of LH 6 hours after the injection in the follicular and luteal phases were still significantly elevated (P<0.02 and P<0.05, respectively), and they were 4.3 and 7.8 times the preinjection levels, respectively. There was no significant difference in the FSH response to the analog between the three different phases. The plasma level of FSH reached its peak 2-4 hours after the subcutaneous injection of the analog in most of the subjects. The peak levels of FSH (mean ± SE) were 22.4 ± 3.6 mIU/ml in the follicular phase, 57.8 ± 17.7 mIU/ml in the preovulatory phase, and 20.9 ± 4.0 mIU/ml in the luteal phase. The mean plasma levels of FSH 6 hours after the injection in the follicular and luteal phases were still significantly elevated (P<0.01 and P<0.05, respectively), and they were 2.4 and 2.9 times the preinjection levels, respectively.

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