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Biomedical subjects

O H Clark

Publications and source records attributed to O H Clark.

246 records · Page 14Linked to original sources
PubMedDate not supplied

Radioiodine-associated thyroid cancers.

Numerous investigations document that exposure to low dose external therapeutic radiation leads to the development of benign and malignant thyroid neoplasms. There is considerable controversy, however, concerning whether radioactive iodine (131I) causes thyroid cancer. The aim of this investigation was to examine our experience and that in the literature related to this problem. From 1982 to March 1993 seven of 373 patients (1.9%) with thyroid cancer who were treated by one surgeon had a history of treatment with radioactive iodine for Graves' disease and toxic nodular goiter. Sixty-five patients have previously been reported in the literature from 1957 to present. Our patients (five women, two men) ranged in age from 26 to 80 years (mean 57 years). The interval between the exposure to the internal radiation and development of cancer ranged from 3 to 29 years (mean 11.4 years), and the mean age at the time of 131I treatment was 45 years (18-76 years). The therapeutic dose of 131I was 5 to 100 mCi (mean 25.3 mCi) in our patients. Two of our patients received 131I twice. The age of patients reported in the literature at the time of 131I treatment ranged from 7 to 74 years (mean 48 years). The mean therapeutic dose of 131I was 20.6 mCi (1.25-180.0 mCi) and the latent period was documented for a mean 8.7 years (0.25-28.0 years) in these patients. Three of 29 patients in the literature received 131I twice. Fine-needle aspiration cytology of thyroid nodules was positive for cancer in six of our patients (86%).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenocarcinoma, Follicular↗
PubMedDate not supplied

Epidermal growth factor receptors and adenylate cyclase activity in human thyroid tissues.

Thyroid stimulating hormone (TSH) and epidermal growth factor (EGF) are growth factors for some thyroid cells in cultures. We have previously found more EGF receptors in neoplastic human thyroid tissues than in normal thyroid tissues. We have also found a higher TSH-stimulated adenylate cyclase (AC) activity in neoplastic human thyroid tissues than in normal thyroid tissues. To clarify the relationship between the effect of EGF and TSH on thyroid tissue, we measured the binding of EGF and TSH and the basal, TSH-stimulated and forskolin-stimulated adenylate cyclase activity in 49 normal, hyperplastic and neoplastic human thyroid tissues (5 normal, 2 Hashimoto thyroiditis, 5 Graves' disease, 14 multinodular goiters, 9 follicular adenomas, 5 follicular carcinomas, 8 papillary carcinomas, and 1 undifferentiated carcinoma). Specific binding of EGF and TSH were measured by radioreceptor assays using competitive inhibition of radio-labeled ligand by unlabeled ligand. Basal, maximally (300 mU/ml) TSH-stimulated, and maximally (100 mM) forskolin-stimulated adenylate cyclase activities were also measured in the same membrane particulate fractions from the thyroid tissues. We found: neoplastic thyroid tissues bind more labeled EGF than nonneoplastic thyroid tissues; follicular adenomas and carcinomas have higher EGF binding than other thyroid tissues; a weak but significant correlation between specific EGF binding and specific TSH binding, and between specific EGF binding and TSH-stimulated adenylate cyclase activity of the thyroid membrane preparations. These findings are consistent with the hypothesis that TSH stimulates an increase in thyroid EGF receptors by increasing intracellular cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗
PubMedDate not supplied

Effect of somatostatin on adenylate cyclase activity in normal and neoplastic thyroid tissue.

Thyroid stimulating hormone (TSH) and other substances increase adenylate cyclase (AC) activity and growth of normal and neoplastic thyroid tissue. Factors that inhibit cAMP may provide targeted therapy to tumors dependent on cAMP for growth. Somatostatin has been reported to inhibit the growth of gastrinomas and carcinoid tumors. We therefore studied the effects of somatostatin on basal, TSH, pertussis toxin, and forskolin stimulated adenylate cyclase activity in normal and neoplastic thyroid tissue from 19 patients. Adenylate cyclase (AC) activity was determined by the conversion of alpha 32P-ATP to 32P-cAMP in pmoles/mg protein/30 minutes in an 8000 x g particulate fraction rich in thyroid plasma membranes. TSH (300 mU/ml) and forskolin (100 mM) (a diterpine that directly stimulates the catalytic unit of AC) increased AC activity in normal and neoplastic thyroid tissue. The AC stimulation was greater in the neoplasms (p less than 0.01). Somatostatin (5 x 10(-6)M) decreased basal and TSH stimulated AC activity below basal levels in both normal and neoplastic thyroid tissue (including papillary, follicular, and medullary carcinomas). The inhibition of AC by somatostatin was greater in neoplastic tissue (p less than 0.025). Pertussis toxin (which blocks the inhibitory guanyl nucleotide regulatory protein) was able to partially reverse the effect of somatostatin. Somatostatin partially inhibited forskolin stimulated AC activity. Somatostatin inhibits basal and TSH stimulated AC activity in both normal and neoplastic human thyroid tissue, with a greater effect on neoplasms. These studies establish that somatostatin blocks a major regulator of thyroid growth and provides the rationale for the use of somatostatin analogs in the treatment of thyroid cancers.

Adenylate Cyclase Toxin↗
PubMedDate not supplied

Mutational activation of RAS and GSP oncogenes in differentiated thyroid cancer and their biological implications.

Activating mutations of ras-genes (Kirsten-ras, Harvey-ras, N-ras) and genes encoding for the alpha subunit of G-proteins (Gs, Gi2, Gi3, Go, Gz) were assessed in 32 differentiated thyroid cancer (DTC) tissues from German (n = 22) and American (n = 10) patients. Gs-protein (GSP) and/or ras mutations were found in 69% of all tissues with a heterogeneous distribution pattern. An increased prevalence could be demonstrated in metastatic (8 of 9 mutation positive) when compared to localized disease (13 of 23 mutation positive) (p less than 0.001) and in patients greater than 50 years of age (16 of 18 mutation positive), when compared to younger patients (6 of 14 mutation positive) (p less than 0.001). No activating mutations were found on H-ras and K-ras genes nor on genes encoding for the alpha subunits of Gi2, Gi3, Go, and Gz. Differentiated thyroid cancer tissue from German patients revealed a higher prevalence for GSP mutations (73%) than did DTC from American patients (20%) (p less than 0.001). We demonstrated a high frequency of ras and GSP mutations in DTC and suggest that these mutations may contribute to our basic understanding of this disease and might initiate a new search for more rational and individualized therapeutic approaches in patients with DTC.

Base Sequence↗
PubMedDate not supplied

Unilateral neck exploration for primary hyperparathyroidism: analysis of a controversy using a mathematical model.

Most endocrine surgeons explore both sides of the neck and identify all parathyroid glands when operating on patients with primary hyperparathyroidism. Others, however, advocate the unilateral approach, i.e., if an adenoma and a normal gland are identified, the contralateral side is not explored. We analyzed the strategy of the unilateral approach using a mathematical model to determine the variables that influence the probability of missing a tumor on the unexplored side of the neck. Assuming the frequency of single adenoma is 80%, hyperplasia 14%, double adenomas 4%, triple adenomas 1%, and carcinoma 1%, and the probability of missing a tumor on the explored side is 5%, we found that: 1. Only 41% of the patients treated by the unilateral approach undergo unilateral exploration. This is increased to 62% when a localization study with a sensitivity of 80% is used pre-operatively. 2. The probability of missing a tumor on the unexplored side of the neck parallels the prevalence of multiple adenomas. Half of the patients with triple adenomas and two-thirds of the patients with double adenomas will have a missed tumor when treated by the unilateral approach. 3. Patients who undergo unilateral exploration have an additional 7% to 8% probability of missing a tumor that would have been found if bilateral exploration is performed. This risk is lowered to 2% by a pre-operative localization study that is 80% sensitive. 4. A prospective study will require 684 patients, randomized to the unilateral or bilateral approach, to have an 80% statistical power (alpha = 0.05, beta = 0.20) of detecting a difference between a 5% and a 10% risk of missing a tumor.

Adenoma↗
PubMedDate not supplied

Invasion by cultured human follicular thyroid cancer correlates with increased beta 1 integrins and production of proteases.

A recognized model of tumor invasion requires cells to adhere to epithelial basement membrane and extracellular matrix components triggering release of proteases thus allowing cancer cells to invade the substrate. This adhesion is mediated by beta 1 integrins, a family of receptors to substrates such as collagen, laminin, and fibronectin. In order to study tumor invasion in follicular thyroid cancer (FTC), we used cell lines derived from a single patient's FTC primary tumor (FTC-133), neck lymph node metastases (FTC-236), and lung metastases (FTC-238). In vitro invasion as determined by the ability of the tumor cells to penetrate Matrigel was assessed by scanning electron microscopy. FTC-133 did not invade, FTC-236 was moderately invasive, and FTC-238 was highly invasive. Immunoprecipation with a monoclonal antibody to beta 1 integrin subunits and SDS-PAGE showed increased synthesis and flow cytometry showed increased expression of this subunit in FTC-236 and FTC-238 compared to FTC-133. Proteolytic activity was assessed by gelatin zymography. FTC-238 cell extract and conditioned media exhibited a more complex array of proteases consistent with activated type I collagenase and stromelysin compared to the less invasive clones, however 72 and 92 kd gelatinases consistent with type IV collagenases were present in the conditioned media from all three lines. In conclusion, in vitro invasion parallels in vivo metastasis by the source cells in the FTC-133/236/238 cell-lines. The ability to invade basement membrane preparation correlates with increased synthesis and expression of beta 1 integrins and activation of tumor proteases.

Adenocarcinoma↗
PubMedDate not supplied

Primary hyperparathyroidism in younger and older patients: symptoms and outcome of surgery.

Two-hundred and fifty patients undergoing initial exploration for primary hyperparathyroidism were analyzed for differences in clinical presentation, biochemical status, pathology, and outcome of surgery. In patients less than 60 years of age (younger patients, n = 119) the most common preoperative symptoms and signs were fatigue (40.3%), bone pain (33.6%), renal stones (31.0%), hypertension (27.7%), and psychiatric illness (27.7%). In patients greater than or equal to 60 years of age (older patients, n = 131) the most frequent symptoms and signs were hypertension (46.6%), fatigue (35.1%), bone pain (30.5%), muscle weakness (28.2%), and joint pain (22.9%). Renal stones were 2.6 times more common (p less than 0.001, chi 2) in younger patients and hypertension 1.7 times more common (p less than 0.05, chi 2) in older patients. There was no significant difference in the preoperative and postoperative laboratory values typically associated with primary hyperparathyroidism. Double adenomas were more common in older (9.2%) than in younger patients (2.5%, p less than 0.05, chi 2). Surgical cure was obtained in 98.8% of patients, and after parathyroidectomy 83% of the younger and 82% of the older patients experienced substantial relief of pre-operative symptoms. Specific questioning revealed most patients to be symptomatic and older patients appear to receive the same clinical and metabolic benefits from parathyroidectomy as younger patients.

Adolescent↗
PubMedDate not supplied

Persistent or recurrent primary hyperparathyroidism.

More than 95% of patients with Primary Hyperparathyroidism (PHPT) are treated successfully at the initial operation when the operation is done by an experienced surgeon, but the success rate is considerably lower when done by an unexperienced surgeon. The approach to patients with persistent and recurrent PHPT is to confirm the diagnosis and to use precise localization procedures done by expert radiologists. Reexploration after one or more previously failed parathyroid operations is unfortunately associated with a higher morbidity and a lower success rate. Improved pre- and intraoperative testing during the last decade has improved the results of reoperation and allowed more focused approaches. Preoperatively, we recommend a combination of sestamibi scanning, ultrasound, and MRI scanning. Highly selective venous sampling for iPTH is recommended for patients with recurrent or persistent PHPT when the non-invasive studies are negative, equivocal, or discordant. Several factors such as age of the patient, severity of symptoms, comorbidity, and the results of localization studies, should all be considered in the management of these patients although we believe that reoperation is indicated for most of these patients. Today successful reoperations can be done in more than 90% of patients with a relatively low morbidity rate.

Algorithms↗
PubMedDate not supplied

Immunoperoxidase confirmation of parathyroid origin of ultrasound-guided fine needle aspirates of the parathyroid glands.

It may be difficult to differentiate between cells of parathyroid and thyroid origin in ultrasound-guided fine needle aspirations of the neck region, even in patients with a clinical history of hyperparathyroidism. A parathyroid hormone antibody was used in an immunohistochemical system to confirm a parathyroid origin in fine needle aspirate smears from nine patients with hyperparathyroidism. Immunoperoxidase positivity for parathyroid hormone confirmed a parathyroid origin in six of nine cases and was strongly suggestive, although equivocal, in the remaining three cases. Technical problems included nonuniform staining and background staining.

Adenoma↗
PubMedDate not supplied

[Persistent and recurrent primary hyperparathyroidism].

Aim of this study is to evaluate clinical, radiological and therapeutic aspects of patients who have persistent or recurrent primary hyperparathyroidism. First, it is essential to reconfirm the diagnosis. Then, the previous operative and pathology reports must be reviewed. In these patients, it is important to use preoperative localization studies. When the results of the various localization tests were combined, the site of the elusive remaining parathyroid tumor could be identified in more than 80%, enabling a focused surgical approach which not only saves time, but also improves the success rate and decreases morbidity. Cryopreservation and autotransplantation are commonly used.

Adenoma↗