Correlation of CT findings with clinical evaluations in 261 patients with symptomatic bronchiectasis.

OBJECTIVE: In a multicenter study, we evaluated the relationships between the extent and severity of bronchiectasis on CT and clinical symptoms, spirometric abnormality, and sputum characteristics. SUBJECTS AND METHODS: The study population included 261 patients with symptomatic, physiologically significant bronchiectasis, who were enrolled in another study evaluating the clinical efficacy of deoxyribonudease in treatment of bronchiectasis. Patients with cystic fibrosis, allergic bronchopulmonary aspergillosis, and fungal or mycobacterial infection were excluded. In addition to high-resolution CT scanning, all patients underwent clinical evaluation, spirometry, and sputum culture. CT features scored by consensus of two observers included the extent of bronchiectasis, type of bronchiectasis (cylindric, varicose, or cystic), extent of mucoid impaction, and degree of bronchial wall thickening. RESULTS: Scores for the severity and extent of bronchiectasis correlated with the forced expiratory volume in 1 sec (FEV1) (r = -.362, p < .0001) and with the forced vital capacity (FVC) (r = -.362, p < .0001). Scores for bronchial wall thickening correlated with the FEV1 (r = -.367, p < .0001) and FVC (r = -.239, p < .001). Patients with cystic bronchiectasis were significantly more likely to grow Pseudomonas from their sputa and to have purulent sputa than were patients with cylindric or varicose bronchiectasis. Patients with cystic bronchiectasis had significantly lower FEV1 and FVC values than did patients with cylindric or varicose bronchiectasis. CONCLUSION: In this patient population, we found weak but significant correlations between the degree of morphologic abnormality on CT and the extent of physiologic impairment. Cystic bronchiectasis was associated with sputum purulence and with the growth of Pseudomonas. CT classification of the type of bronchiectasis may be useful as an index of severity of disease.

Epidermal growth factor receptors in normal and neoplastic thyroid tissue.

Epidermal growth factor (EGF) stimulates DNA synthesis and proliferation of thyroid cells in culture and may have an important role in the regulation of normal and neoplastic thyroid cell growth. We therefore studied paired normal and neoplastic thyroid tissue from eight patients for the presence of EGF receptors using a radioreceptor assay. 125I EGF binds to a particulate membrane fraction from both normal and neoplastic thyroid tissue with high affinity (dissociation constant ranged from 0.5 to 16.7 nmol/L). The binding is saturable, and maximal binding is achieved within 40 minutes at 37 degrees C and pH 7.5. This EGF binding is specific since it is competitively inhibited by unlabeled EGF but not by other hormones (thyrotropin, insulin, glucagon, and transferrin). The binding of EGF to thyroid neoplasms is higher than the binding to normal thyroid tissue (p less than 0.05). Thyroid tumors with a poorer prognosis appear to have higher EGF binding compared with adjacent normal thyroid tissue than have tumors with a better prognosis. EGF may have a role in the regulation of normal and neoplastic thyroid cell growth. Characterization of EGF receptors may help predict the clinical course of patients with malignant thyroid neoplasms.

Thyrotropin receptor-adenylate cyclase system in Hurthle cell neoplasms.

Hurthle cell neoplasms are though to arise from the follicular cells of the thyroid gland, although some studies suggest that they originate from the parafollicular cells. We studied tissue from five patients (three men and two women, aged 33-72 yr) with Hurthle cell neoplasms (four adenomas and one carcinoma) to determine whether Hurthle cell neoplasms have an intact TSH receptor-adenylate cyclase (AC) system and, if so, whether it differs in benign and malignant Hurthle cell and neoplasms. Binding of [125I]bovine (b) TSH and an AC response to TSH occurred in all four Hurthle cell adenomas. In three of these tumors, there was good binding and a relatively good correlation between the concentration of bTSH producing half-maximal inhibition of [125I]bTSH binding (4.8 mU/ml) and the TSH concentration causing half-maximal stimulation of AC (2.2 mU/ml). There was also a 2- to 5-fold increase in AC activity in response to bTSH (300 mU/ml), a value comparable to that which occurs in follicular thyroid neoplasms and differentiated thyroid cancers. In the fourth Hurthle cell adenoma, however, binding was low, the apparent Kd (170 mU/ml) and Km (20 mU/ml) were high, and there was only a 1.4-fold increase in AC activity in response to bTSH (300 mU/ml). In the one metastatic Hurthle cell carcinoma, there was no high affinity TSH binding or AC response to TSH. Thus, Hurthle cell neoplasms are of follicular cell origin, since benign Hurthle cell tumors have an intact TSH receptor-AC system. Malignant Hurthle cell neoplasms, like undifferentiated and medullary thyroid cancer, lack a functional TSH receptor.

Thyrotropin regulation of adenylate cyclase activity in human thyroid neoplasms.

Thyrotropin (TSH), stimulators of guanyl nucleotide regulatory protein, (sodium fluoride and guanyl-5'-yl-imido-diphosphate [Gpp(NH)p]) and a stimulator of the catalytic unit of adenylate cyclase (AC) (forskolin) were used to probe the TSH receptor-guanyl nucleotide regulatory protein-cyclase unit in normal and neoplastic thyroid tissue from 17 patients. Eleven of these patients had benign follicular adenomas and six patients had differentiated thyroid carcinomas. An 8000 X g particulate fraction that is rich in thyroid plasma membranes was prepared, and the activity of AC was determined by the conversion of alpha-32P-ATP to P32-cAMP. Thyroid neoplasms had a greater AC response to TSH than did normal thyroid tissue removed from the same patients (p less than 0.001). The AC response to NaF and Gpp(NH)p was greater in the neoplastic thyroid tissue, although in these experiments the increase was not significant. In contrast, the AC response to forskolin was comparable in normal (573 +/- 129) and neoplastic (526 +/- 132) thyroid tissue (mean +/- SEM). The effects of NaF, Gpp(NH)p, and forskolin on AC activity were additive with TSH when used at concentrations for optimal AC activity. Low concentrations of NaF and Gpp(NH)p stimulated AC activity whereas high concentrations of NaF and Gpp(NH)p assayed either together or separately inhibited AC activity. When forskolin and NaF were assayed together there was a greater than additive effect or potentiated effect on activity. Basal AC activity was increased in the presence of manganese (Mn+2) (2 mM) over magnesium (Mg+2) (2 mM) (p less than 0.001), whereas TSH-stimulated (p less than 0.01) and Gpp(NH)p-stimulated AC activity (p less than 0.05) were lower in the presence of Mn+2 than Mg+2. There was an excellent correlation between basal AC activity and AC activity in response to forskolin in both normal and neoplastic thyroid tissue, whereas there was no correlation between basal AC activity and TSH-stimulated AC activity in the thyroid neoplasms. These data suggest that the abnormality responsible for the greater AC response to TSH in neoplastic thyroid tissue is proximal to the catalytic unit of AC and most probably is due to an alteration in the guanyl nucleotide regulatory protein or in the coupling of the guanyl nucleotide regulatory protein to either the receptor or the catalytic unit of AC.(ABSTRACT TRUNCATED AT 400 WORDS)

Estrogen and thyroid-stimulating hormone (TSH) receptors in neoplastic and nonneoplastic human thyroid tissue.

Estrogen-binding receptors (ER) and thyroid-stimulating hormone (TSH) receptors were observed in the cytosol and in a membrane particulate fraction, respectively, in most neoplastic and nonneoplastic human thyroid tissues. Fourteen of 15 thyroid neoplasms and 6 of 15 nonneoplastic thyroid specimens had estrogen receptors (assuming the sensitivity of our estrogen receptor assay is 0.2 fmole/mg protein), and 14 of 15 thyroid neoplasms and 11 of 15 nonneoplastic thyroid specimens had a high affinity, low capacity TSH receptor. Neoplastic thyroid tissue had more ER (2.35 +/- 0.70/fmole/mg protein) than nonneoplastic thyroid tissue (0.57 +/- 0.181/fmole/mg protein) removed from the same patients (P less than 0.05). The Kd for ER did not differ in nonneoplastic (0.41 +/- 0.090 nM) and neoplastic (0.311 +/- 0.048 nM) thyroid tissue. The number of TSH receptors was comparable in neoplastic (0.609 +/- 0.191 pmole/mg protein) and in nonneoplastic (0.765 +/- 0.181 pmole/mg protein) thyroid tissue removed from the same patients who had the ER studies. The maximal adenylate cyclase response to TSH was greater in the neoplastic (147 +/- 26.9 pmole/mg protein/30 min) than in nonneoplastic thyroid tissue (32.8 +/- 6.69 pmole/mg protein/30 min) (P less than 0.001) suggesting a greater metabolic responsiveness of the neoplastic thyroid tissue to TSH. No correlation was evident, however, between the number of estrogen and TSH receptors in nonneoplastic and neoplastic thyroid tissue (r = 0.226). This study demonstrates that neoplastic human thyroid tissues have both estrogen receptors and TSH receptors. The neoplastic tissue also has a greater AC response to TSH than nonneoplastic thyroid tissue.

Characterization of the thyrotropin receptor-adenylate cyclase system in neoplastic human thyroid tissue.

Experiments were performed to determine whether the TSH receptor-adenylate cyclase (AC) system in benign and malignant thyroid neoplasms differs from the TSH receptor-AC system in normal thyroid tissue removed from the same patients. TSH binding and AC assays were performed using the same in vitro conditions. TSH binding was rapid, reversible, saturable, and hormone specific in particulate fractions from both normal and neoplastic thyroid tissue. A positive correlation existed between the equilibrium constants for [125I]bovine ([125I]bTSH) TSH binding and the concentration of TSH required to activate AC, suggesting that binding sites were coupled to AC in neoplastic thyroid tissue. Mean values for dissociation constants (Kd1 and Kd2), capacity (site 2), as determined by Scatchard analysis, and nonspecific binding (NSB) for the TSH receptors were lower in neoplastic thyroid. Some normal thyroid tissue appeared to lack a high affinity site, and some tumors lacked a low affinity binding site. Hormone specificities (bTSH, human (h) TSH, hLH, hFSH, hGH, hACTH, and glucagon) in normal thyroid and neoplastic tissue were virtually identical. hFSH, hACTH, hGH, and glucagon failed to inhibit [125I]bTSH binding or stimulate AC in either normal or neoplastic thyroid tissue, whereas hLH inhibited [125I]bTSH binding and stimulated AC, but required 10- to 100-fold higher concentrations than hTSH or bTSH. The specific binding and NSB of [125I]bTSH in both normal and neoplastic thyroid tissue was highest at pH 7.0 and lowest at pH 8.3. In contrast to bTSH binding, TSH stimulation of AC was lowest at pH 7.0 in both normal and neoplastic tissues and highest at pH levels of 7.5-8.0. TSH binding and TSH stimulation of AC activity were highest in the absence of NaCl and decreased progressively as the salt concentration was increased in both normal and neoplastic thyroid tissues. Increasing the sucrose concentration and, thus, the osmolarity of the system had a minimal effect on the binding of [125I]bTSH. Preincubation with ammonium sulfate did not significantly influence binding. Basal AC activity and the AC response to TSH were greater in neoplastic thyroid than in normal tissues. These studies demonstrate that changes in salt concentration and pH affect the TSH receptor-cyclase system in a comparable fashion in normal and neoplastic thyroid tissues. The discriminatory properties of the TSH receptor are also maintained in thyroid neoplasms. Thyroid tumors, however, have a higher affinity for TSH and display a greater AC response to TSH than normal thyroid tissue.

Thyrotropin binding and adenylate cyclase activation in normal and neoplastic human thyroid tissue: lack of effect of thyroglobulin.

The effects of bovine TSH (bTSH) and bovine (bTg) and human thyroglobulin (hTg) on the binding of [125I] bTSH and the activation of adenylate cyclase (AC) were studied in both normal and neoplastic human thyroid homogenates in vitro using adenylate cyclase conditions. [125I]bTSH bound specifically and with high affinity to a particulate fraction from normal thyroid and from benign and malignant thyroid neoplasms; this binding was inhibited by unlabeled bTSH (approximate Kd = 10.0 mU/ml for normal tissue; Kd = 2.5 mU/ml for thyroid neoplasms). Half-maximal activation of AC was obtained at a TSH concentration of approximately 2.5 mU/ml for both normal and neoplastic thyroid tissue, indicating that the high affinity TSH receptors are coupled to AC, at least in the neoplastic thyroid tissue. bTg and hTg did not inhibit [125I]bTSH binding to high affinity TSH receptors in either normal or neoplastic thyroid tissue. bTSH increased AC activity up to 25-fold in neoplastic thyroid tissue and up to 4-fold in normal thyroid tissue, whereas at concentrations up to 1 mg/ml, bTg had no effect. The current study demonstrates that bTSH binds to specific, high affinity receptors and stimulates AC activity in both normal and neoplastic thyroid tissue. bTg and hTg, under the conditions used in this experiment, do not influence TSH binding to its high affinity receptor in these tissues. Since Tg does not influence high affinity TSH binding or AC activity in a particulate fraction rich in plasma membranes from normal or neoplastic thyroid tissue, it is unlikely to have a modulating role on TSH action at the thyroid plasma membrane.

Thyrotropin binding and adenylate cyclase stimulation in thyroid neoplasms.

Experiments were performed to determine whether thyroid-stimulating hormone (TSH) receptors coupled to adenylate cyclase are present in both benign and differentiated malignant thyroid tumors, and to identify abnormalities in the TSH receptor-adenylate cyclase system in neoplastic thyroid tissue. TSH binding and adenylate cyclase assays were performed under the same in vitro cyclase conditions. 125I-bovine TSH was incubated with an 8,000 X g thyroid or thyroid tumor particulate fraction from both normal and most neoplastic tissue two receptor sites were identified. The association constant for the high-affinity receptor from normal thyroid was 10.5 +/- 3.2 nM (mean +/- standard error) with a capacity of 0.8 +/- 0.3 pM/mg particulate protein. The association constant of the high-affinity receptor found in the particulate fraction from the thyroid adenomas was 3.5 +/- 0.5 nM with a capacity of 0.4 +/- 0.1 pM/mg particulate protein; for the thyroid carcinomas the association constant was 1.4 +/- 0.3 nM and the capacity 0.2 +/- 0.1 pM/mg particulate protein. The maximum adenylate cyclase response to TSH for particulate fractions from both benign and malignant tumors was greater (P less than 0.05) than in the particulate fraction from normal adjacent thyroid tissue. There was also a positive correlation between the equilibrium constants for 125I-bTSH binding and adenylate cyclase activation suggesting that binding sites are coupled to cyclase in the neoplastic tissue and that the binding observed in these experiments is of biologic consequence.