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Biomedical subjects

O H Clark

Publications and source records attributed to O H Clark.

At least 109 records · Page 6Linked to original sources
PubMed1995

Epidermal growth factor (EGF)- and transforming growth factor alpha-stimulated invasion and growth of follicular thyroid cancer cells can be blocked by antagonism to the EGF receptor and tyrosine kinase in vitro.

We have shown recently that epidermal growth factor (EGF) enhanced invasion and growth of differentiated thyroid cancer cells in vitro and in vivo. The present study analyzed the effects of transforming growth factor alpha (TGF-alpha) on invasion and growth of a follicular thyroid cancer cell line (FTC133) and whether blocking the EGF receptor by a monoclonal antibody (Mab528) or blocking the tyrosine kinase of the receptor by genistein abolished the EGF- and TFG-alpha-mediated effects. Growth and invasion (penetration of 8-microns pore polycarbonate membranes coated with Matrigel) were determined by the dimethylthiazol-diphenyltetrazolium bromide assay. Epidermal growth factor (10 ng/l) stimulated invasion of FTC133 by 42% and TGF-alpha (10 ng/l) stimulated invasion of FTC133 by 27% (p < 0.02). Both growth factors also enhanced growth by 62% (EGF) and 30% (TGF-alpha) (p < 0.003). Epidermal growth factor receptor antibodies (1 microgram/ml) abolished EGF-mediated stimulation of invasion and growth completely and that of TGF-alpha by 93%. At 100 ng/ml genistein reversed EGF and TGF-alpha stimulation, and at 1 microgram/ml it inhibited invasion (27%) and growth (40%) of unstimulated FTC133 (p < 0.02). We conclude that TGF-alpha stimulates invasion and growth of follicular thyroid cancer by binding to the EGF receptors, that EGF- and TGF-alpha-mediated effects can be blocked by antagonism to the EGF receptor and to tyrosine kinase, and that genistein not only neutralized EGF and TGF-alpha effects but also inhibited invasion and growth of unstimulated FTC133.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1995

Primary hyperparathyroidism in patients who have received radiation therapy and in patients who have not received radiation therapy.

BACKGROUND: Primary hyperparathyroidism (HPT) occurs more frequently in persons who have been exposed to low-dose therapeutic radiation. Little information is available concerning whether or not the clinical, metabolic, and pathologic manifestations, as well as outcome, differ in these patients when compared with patients with sporadic HPT. STUDY DESIGN: Records from 438 unselected patients with primary HPT, who were treated from 1982 to 1993 were retrospectively analyzed. All patients prospectively received a standard questionnaire preoperatively and postoperatively concerning clinical manifestations and a history of radiation exposure. Forty-nine patients had a history of radiation exposure (rHPT), whereas 389 did not have sporadic HPT (sHPT). RESULTS: There was no difference in gender (36 women and 13 men versus 289 women and 100 men) or age (mean of 52 +/- 12 versus 57 +/- 16 years) in patients with rHPT or sHPT. Fatigue, neuropsychiatric disorders, memory loss, nocturia, and polyurea were more common in patients with sHPT (p < 0.05), whereas pain in joints was more common in patients with rHPT (63 versus 52 percent; p < 0.001). Serum calcium levels were similar (11.1 +/- 0.8 versus 11.2 +/- 0.8 mg per dL), but serum parathyroid hormone levels were higher in rHPT (448 +/- 14 percent of upper limit of normal versus 371 +/- 12 percent upper limit of normal). The parathyroid pathology was similar in the two groups (single adenoma 74 versus 72 percent, hyperplasia 14 versus 16 percent, and double adenoma 12 versus 12 percent in rHPT versus sHPT, respectively). Thyroid pathology was more common in the rHPT group (multinodular goiter 27 versus 7 percent and papillary thyroid carcinoma 14 versus 0.3 percent). Seven (1.8 percent) of patients not receiving radiation therapy treated by us had persistent HPT, but no patients receiving or not receiving radiation therapy had recurrent HPT during the follow-up period (six years). CONCLUSIONS: Patients who have HPT after radiation treatment have more thyroid neoplasms but are otherwise quite similar to other patients with primary hyperparathyroidism.

Adolescent↗
PubMed1994

Localization procedures in patients with persistent or recurrent hyperparathyroidism.

OBJECTIVE: To determine the accuracy of noninvasive and invasive localization studies in patients with persistent or recurrent hyperparathyroidism (HPT). DESIGN AND SETTING: Reoperations based on patients who were treated surgically for recurrent or persistent HPT at the University of California-San Francisco Hospitals from 1982 to 1993. PATIENTS: This study evaluated 174 localization studies performed in 152 patients before reoperation (110 women and 42 men). MAIN OUTCOME MEASURES: The accuracy of localization studies, including ultrasonography, thallous chloride T1 201-technetium Tc 99m pertechnetate scanning, technetium Tc 99m sestamibi scanning, magnetic resonance imaging, computed tomography, and selective venous catheterization, were evaluated, as were the results of parathyroid reoperations. RESULTS: A total of 174 consecutive reoperations were performed in 152 patients with HPT (persistent, 113; recurrent, 39; mean age, 54 years; range, 21 to 88 years). One hundred thirty-three patients had primary HPT, 15 had secondary HPT, and four had tertiary HPT. Overall, 141 (93%) became normocalcemic, two (1%) became hypocalcemic, and nine (6%) remained hypercalcemic. Abnormal parathyroid glands at reoperation were situated in a normal location in 77 cases (44%), in the mediastinum in 37 cases (22%), in a deep cervical location in 34 cases (19%), or in an intrathyroidal location in 14 cases (8%), or were undescended in four cases (2%); supernumerary glands were found in 26 cases (15%). Some patients had more than one remaining abnormal gland. Selective venous catheterization with a parathyroid hormone assay was done in cases in which the results of noninvasive localization studies were equivocal or negative, and it frequently converted an equivocal result of a localization study to a definitely positive result. There were no complications from the localization studies. At reoperation, permanent hypoparathyroidism that required parathyroid autotransplantation of cryopreserved tissue developed in two patients and two patients had recurrent laryngeal nerve palsies. CONCLUSION: We currently recommend using ultrasonography and technetium Tc99m sestamibi scanning and magnetic resonance imaging for patients with recurrent or persistent HPT. Selective venous catheterization with a parathyroid hormone assay is done selectively. Localization tests decrease morbidity and improve overall results in these patients.

Adult↗
PubMed1994

Aberrations of growth factor control in metastatic follicular thyroid cancer in vitro.

The aggressiveness of follicular thyroid cancer (FTC) varies widely, and metastasis is the primary cause of death. Uncontrolled proliferation of cancer cells may be associated with loss of growth factor control. We investigated the effects of stimulating (epidermal growth factor [EGF]; thyreotropin [TSH] in low concentrations) and inhibiting growth factors (transforming growth factor beta 1 [TGF beta 1]; TSH in high concentrations) on invasion and growth of FTC cell lines from the thyroid tumor (FTC133) and from the lymph node (FTC236) and lung (FTC238) metastases of the same patient. Invasion-penetration through an 8 microns pore membrane, covered by Matrigel (basement membrane)-and growth were measured using the MTT-method. EGF (10 ng/ml) and TSH in low concentrations (1 mU/ml) stimulated invasion and growth of all FTC cell lines, but the amplitude of stimulation differed significantly. The parental cell line FTC133 was considerably more responsive to growth factor stimulation than the metastatic clones. Invasion of FTC133 was enhanced by 42% (EGF; p < 0.02) and 21% (TSH; p < 0.01), invasion of FTC236 by 8% (EGF; p < 0.02) and 8% (TSH; p < 0.01), and invasion of FTC238 by 9% (EGF; p < 0.02) and 8% (TSH; p < 0.01). Conversely, invasion and growth of FTC133 were significantly more inhibited by TGF beta 1 (10 ng/ml) and supraphysiologic concentrations of TSH (100 mU/ml) than the cell lines from the lymph node and lung metastases. At day 7, invasion of FTC133 was inhibited by 32% (TGF beta 1; p < 0.02) and 21% (TSH; p < 0.01), invasion of FTC236 by 18% (TGF beta 1; p < 0.02) and 11% (TSH; p < 0.01), and invasion of FTC238 by 16% (TGF beta 1; p < 0.02) and 12% (TSH; p < 0.01). Moreover, we analyzed growth factor independence in minimally supplemented or unsupplemented medium. Growth, but no invasion was evident when cells were cultured completely unsupplemented over 7 days. These results suggest that metastatic FTCs may have developed by escaping from the normal control of TSH and other growth factors.

Adenocarcinoma, Follicular↗
PubMed1994

Octreotide therapy in advanced thyroid cancer.

Octreotide is a long-acting somatostatin analog that inhibits cell growth and hormone secretion. It has been successfully used in the management of a variety of endocrine tumors (i.e., acromegaly, carcinoid tumors, gastrinomas). In vitro, octreotide suppresses adenylate cyclase activity, DNA synthesis, and cell growth in cultured thyroid cell lines. Previous studies examining the use of octreotide in the treatment of medullary thyroid cancers, in vivo, report symptomatic improvement from tumor-related hormonal hypersecretion; however, octreotide's ability to suppress tumor growth was limited. In the present study, we examine the efficacy of long-term octreotide administration in six subjects with metastatic thyroid carcinoma, including Hurthle cell (one subject), medullary (one subject) and papillary or mixed papillary/follicular cancer (four subjects). All of the subjects had documented recurrences of their thyroid tumors despite appropriate therapy, and were considered to be untreatable by conventional therapeutic modalities (i.e., radioiodine or surgery). Subjects were monitored while receiving relatively high doses (4 mg daily) octreotide subcutaneously for up to 12 months. Octreotide therapy was very well tolerated; mild gastrointestinal symptoms persisted throughout treatment in one subject. Octreotide did not significantly decrease tumor markers (e.g., thyroglobulin, calcitonin, carcinoembryonic antigen). The carcinomas progressed during treatment, as evidenced by an increase in the size and/or number of metastatic lesions. In summary, in this small series subcutaneous octreotide administration did not appear to be efficacious in the management of advanced thyroid cancers.

Aged↗
PubMed1994

Management of patients with differentiated thyroid cancer who have positive serum thyroglobulin levels and negative radioiodine scans.

Most current evidence suggests that patients with papillary or follicular thyroid cancer after total thyroidectomy who are Tg positive (Tg > or = 10 ng/mL) and radioactive iodine scan negative warrant treatment with 100 mCi of 131I with a follow up scan and Tg determination. If isolated focal metastatic deposits are present they should be resected before treatment with radioiodine. Although some physicians might recommend radioiodine treatment only for high risk patients, we would recommend it for all patients with elevated serum Tg levels that increase after TSH stimulation, or until further information becomes available to support a different approach.

Combined Modality Therapy↗
PubMed1994

A virilized patient with congenital hemihypertrophy.

An 18 year old woman with congenital hemihypertrophy of her left side, presented with the rapid onset of virilism, hypertension and a cushingoid appearance. A computed tomographic examination revealed adrenal and hepatic masses. Adrenocortical carcinoma was confirmed by surgical pathology. Hemihypertrophy is linked to a variety of benign and malignant disorders that usually appear during childhood. These disorders include adrenocortical carcinoma and hepatoblastoma. We bring this case to clinical attention to increase awareness that adult patients with congenital hemihypertrophy are still at a significant risk of developing neoplasms.

Adolescent↗
PubMed1994

Desensitization of adenylate cyclase in Chinese hamster ovary cells transfected with human thyroid-stimulating hormone receptor.

Desensitization or decreased response to the same (homologous) or other stimuli (heterologous) is a well known process. Homologous desensitization to TSH has been demonstrated in normal thyroid tissue. Chinese hamster ovary cells (CHO) transfected with normal human TSH receptor (hTSHR) DNA, in contrast, have been reported not to desensitize. The purpose of our investigation was to determine whether CHO cells transfected with hTSHR desensitize in response to TSH and postreceptor stimulation. CHO cells were stably transfected with plasmid DNA containing hTSHR; nontransfected CHO cells served as the control. TSH (10 mU/ml), 5'-beta,gamma-imido-triphosphate [Gpp(NH)p; 0.1 mM], sodium fluoride (NaF; 10 mM), forskolin (10 microM), and (Bu)2cAMP (100 microM) were used to determine whether homologous or postreceptor heterologous desensitization of adenylate cyclase activity occurred in CHO-transfected cells. Intracellular cAMP accumulation was determined by RIA. Cells were incubated with TSH (to stimulate TSH receptor), Gpp(NH)p, NaF (to stimulate G-protein), forskolin (to stimulate adenylate cyclase activity), and (Bu)2cAMP (nonmetabolized cAMP analog). A second incubation was carried out with TSH (10 mU/ml). Maximal desensitization to either TSH or postreceptor stimulation was observed at 2 h. When transfected CHO cells were preexposed to TSH (10 mU/ml) for 4 h, even the smallest dose of TSH (0.001 mU/ml) caused desensitization. All substances that increased the intracellular cAMP concentration, such as TSH, Gpp(NH)p, NaF, forskolin, and (Bu)2cAMP, caused desensitization. The decrease in the cAMP response to TSH added in the second incubation was 63% less than the initial response to TSH or to postreceptor stimulation (P = 0.0001). In conclusion, desensitization of hTSHR-transfected CHO cells occurs in response to both receptor and postreceptor stimulation that increase cAMP levels. Because hTSHR transfected CHO cells desensitize, no specific thyroid factor(s) other than increased levels of cAMP is required.

Adenylyl Cyclases↗
PubMed1994

Epidermal growth factor enhances proliferation, migration, and invasion of follicular and papillary thyroid cancer in vitro and in vivo.

The prognosis of patients with follicular (FTC) and papillary (PTC) thyroid cancer depends on age and the size and extent of the tumor. Differentiated thyroid cancers bind more epidermal growth factor (EGF) than normal thyroid tissue, but the role of EGF in the proliferation and invasion of thyroid cancer is unknown. We investigated the effects of EGF on growth, migration, and invasion in a follicular thyroid cancer that metastasized to cervical lymph nodes and the lung (FTC 133, primary; FTC 236, lymph node; and FTC 238, lung metastasis) and in a papillary thyroid cancer (PTC-UC3). As measured by the formazan method (dimethylthiazol-diphenyltetrazolium bromide), EGF caused a dose- and time-dependent increase in the growth of FTC 133 and PTC-UC3 by 25%, but its stimulatory effect on growth of the metastatic FTC subclones was smaller (FTC 236, 14%; FTC 238, 8%; P < 0.001). EGF also enhanced the ability of all cell lines to migrate (through 8-microns pore membranes without Matrigel) or invade (membranes with Matrigel). Migration of FTC 133 was enhanced from 86% migrated tumor cells to 95% after 72 h (P < 0.02). Again, stimulation by EGF was lower in FTC 236 and FTC 238. EGF increased migration in PTC-UC3 from 49% to 58%. EGF stimulated invasion of FTC 133 from 17.5% to 24.9%. In the absence of EGF, FTC 238 was the most invasive tumor, but, again, the EGF stimulatory effect was less pronounced than in the primary tumor. EGF stimulated the invasion of PTC-UC3 from 10.9% to 14.3% (P < 0.03). EGF also stimulated the growth of thyroid cancer xenografts in nude mice. Although all FTC cell lines were 100% tumorigenic in nude mice, PTC-UC3 was less tumorigenic. However, after sc inoculation of EGF-pretreated tumor cells, 7 of 10 animals developed tumors (mean size, 2.3 cm3) compared to 2 of 10 animals (mean size, 1.4 cm3) in the control group (P < 0.02). In summary, EGF stimulates the growth and invasion of differentiated thyroid cancer cells in culture and in nude mice. Escape from growth factor control, such as in FTC 236 and FTC 238, may be an important step in the development of metastatic thyroid cancer.

Adenocarcinoma, Follicular↗
PubMed1994

Transforming growth factor-beta 1 is a negative regulator for differentiated thyroid cancer: studies of growth, migration, invasion, and adhesion of cultured follicular and papillary thyroid cancer cell lines.

Invasion and metastasis may be caused by the escape of tumor cells from the negative control of growth factors. We analyzed the effects of transforming growth factor-beta 1 (TGF beta 1) on growth, migration, invasion, and adhesion in three follicular thyroid cancer cell lines (FTC133, primary; FTC236, lymph node metastasis; FTC238, lung metastasis) from one patient and in a papillary line (PTC-UC3). Cell growth was measured by dimethylthiazol-diphenyltetrazolium bromide assays, and migration (basal or epidermal growth factor stimulated) was determined by the ability of cells to penetrate 8-microns pore membranes that were covered with Matrigel for invasion assays. Moreover, we studied tumor cell adhesion to collagen type IV, fibronectin, and laminin. TGF beta 1 inhibited growth in FTC (FTC133, by 31%; FTC236, 15%; FTC238, 17%; P < 0.008), but not in PTC. Migration was inhibited in all cell lines. TGF beta 1 inhibited epidermal growth factor-stimulated migration of FTC133 by 43% vs. 29% without epidermal growth factor (P < 0.03). TGF beta 1 also inhibited invasion (FTC133, 32%; FTC236, 18%; FTC238, 16%; PTC-UC3, 32%; P < 0.02). All cell lines adhered preferably to collagen type IV and fibronectin. TGF beta 1 enhanced adhesion. Again, these effects were less pronounced in the FTC metastases. In conclusion, TGF beta 1 inhibits the growth, migration, and invasion of thyroid cancer cells in vitro. It enhances adhesion to components of the extracellular matrix. Metastatic thyroid tumors may be less responsive to the negative regulation of TGF beta 1.

Adenocarcinoma, Follicular↗
PubMed1994

The role of total thyroidectomy in the management of differentiated thyroid cancer.

The extent of surgical resection required in the optimal management of differentiated (papillary and follicular) thyroid carcinoma remains controversial. Arguments in favor of total thyroidectomy include the adequate treatment of tumor multifocality, reduction in local recurrence rates and anaplastic transformation, and creating a suitable environment for radioactive iodine scanning and treatment of metastases. The benefits of this procedure have to be weighed against the potential but minimal morbidity.

Adenocarcinoma, Follicular↗
PubMed1994

[Growth and invasion in differentiated thyroid carcinoma. Function of different growth factors].

Aggressiveness of follicular (FTC) and papillary thyroid cancer (PTC) varies widely. Tumorigenesis is associated with an imbalance of growth-promoting and growth-constraining factors. We investigated the effects of thyrotropin (TSH), epidermal growth factor (EGF) and transforming growth factor beta 1 (TGF-beta 1) on invasion and growth of 3 FTC- and 2 PTC-cell lines. Invasion (penetration through an 8 microns pore membrane, covered by Matrigel) and growth were measured using the MTT-method. EGF (10 ng/ml) and TSH in low concentrations (1 mU/ml) stimulated invasion and growth of FTC and PTC, whereas TGF-beta 1 (10 ng/ml) and TSH in high concentrations (100 mU/ml) were inhibiting. The parental cell line FTC133 was considerably more responsive to all growth factors than the metastatic clones. Invasion of FTC133 was enhanced by 42% (EGF) and 21% (TSH), invasion of FTC236 by 8% (EGF and TSH). Conversely, invasion of FTC133 was inhibited by 32% (TGF-beta 1) and 21% (TSH), invasion of FTC236 by 18% (TGF-beta 1) and 11% (TSH). TSH, EGF and TGF-beta 1 have an important impact on differentiated thyroid cancer cells and metastases may have developed by escaping from the normal control of growth factors.

Adenocarcinoma, Follicular↗