Biomedical subjects

A E Siperstein

Publications and source records attributed to A E Siperstein.

At least 73 records · Page 4Linked 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

Prospective evaluation of the safety and efficacy of laparoscopic jejunostomy.

We prospectively assessed the safety and efficacy of laparoscopic jejunostomy done by 11 surgeons in 8 medical centers using the T-fastener technique. In all, 23 men and 13 women aged 19 to 84 (mean, 59) years required enteral feeding, but could not undergo gastrostomy and had no contraindication to laparoscopy. Of these patients, 12 had head and neck cancer and 11 had neurologic swallowing dysfunction. The procedure took 25 to 180 minutes (mean, 75). Three (8%) early cases were converted to open jejunostomy because of accidental enterotomies caused by inappropriate techniques that were avoided in later cases. Minor technical problems, such as passing a needle through the back wall of the jejunum, occurred in 7 patients, but they were easily corrected and produced no complications. Feedings were routinely begun within 24 hours of the surgical procedure. All jejunostomy catheters functioned well. This is a safe and effective technique when done by experienced laparoscopic surgeons, and serious complications are rare.

Adult↗

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

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↗

PubMed1993

Diagnosis, treatment, and outcome of follicular thyroid carcinoma.

BACKGROUND: There have been numerous studies concerning the diagnosis, treatment, and prognosis of patients with papillary thyroid carcinoma, but relatively few addressing patients with follicular carcinoma. METHODS: The authors analyzed their experience with 65 patients who underwent 96 thyroid operations for pure follicular thyroid carcinoma from 1956 to 1990. RESULTS: The patients were 43 women and 22 men with a mean age of 45 years who were followed postoperatively for a mean of 10.4 years. Fifty-two patients (80%) were seen initially with a solitary thyroid nodule, and 24 (37%) had symptoms at presentation. Median tumor size was 2.2 cm. Fine-needle aspiration biopsy was performed in 20 patients, revealing a follicular neoplasm in 18 patients (90%) and an inadequate specimen in 2 patients. Nineteen patients received thyroid-stimulating hormone (TSH)-suppressive thyroid hormone therapy for an average of 4.5 months before surgery; tumor size remained the same in 10 patients (53%), increased in 5 (26%), and decreased in 2 (11%). At presentation, six patients had lymph node involvement, three had locally invasive tumors, and two had distant metastases. Initial operative treatment was lobectomy in 32 patients (49%), total thyroidectomy in 15 patients (23%), lobectomy plus contralateral partial or subtotal lobectomy in 11 patients (17%), and lesser procedures in 7 patients (11%). Twenty-nine patients had a completion total thyroidectomy, so that final surgical treatment consisted of total thyroidectomy in 44 patients (68%). Among 39 patients having intraoperative frozen section, only 3 (8%) were correctly diagnosed as having cancer. Permanent complications occurred during 3 of the 96 operations. Three patients (5%) have died of thyroid cancer (one with anaplastic transformation) since thyroidectomy, and two are living with distant metastatic disease. CONCLUSIONS: Patients with follicular thyroid cancer, when first examined, usually have solitary thyroid nodules that are follicular neoplasms by aspiration cytology, and these nodules fail to regress in response to TSH-suppressive therapy. Frozen section rarely aids in management. The preferred treatment for follicular neoplasms is lobectomy followed by completion total thyroidectomy for histologically proven carcinomas larger than 1.0 cm. Total thyroidectomy allows use of thyroglobulin and radioiodine scanning to detect and treat metastatic disease. Complications of thyroidectomy were uncommon, and the mortality rate in treated patients was relatively low.

Adenocarcinoma, Follicular↗

PubMed1993

Thyrotropin stimulates invasion and growth of follicular thyroid cancer cells via PKC- rather than PKA-activation.

The signal transduction of TSH in invasion and growth of FTC 133, a human follicular thyroid cancer cell line, was investigated. TSH (0.01-1 mIU/ml) stimulated invasion of FTC 133 by 21% and growth by 20% of basal. Cyclic AMP-stimulators and inhibitors had no effect at any concentration. The PKC-agonist TPA enhanced invasion and growth by 15%, whereas staurosporine, a PKC-antagonist, inhibited them by 32% and 60%, respectively. The latter also reversed TSH stimulation. EGF enhanced invasion (42%) and growth of FTC 133 (25%). Staurosporine did not reverse EGF stimulation. The tyrosine kinase antagonist genistein reversed EGF, but not TSH stimulation. Pertussis toxin inhibited invasion (18%) and growth (22%). Cholera toxin was less inhibitive. We demonstrated for the first time, that TSH stimulates invasion and growth of human thyroid cancer cells in vitro by PKC- rather than PKA-stimulation.

Alkaloids↗

PubMed1993

Tumoral calcinosis. Controversies in the etiology and alternatives in the treatment.

OBJECTIVE: To examine our experience and review the literature concerning the diagnosis, origin, and treatment of tumoral calcinosis (TC). DESIGN/SETTING: Case series based on patients with TC treated in University of California-San Francisco hospitals from 1981 to 1992 and the review of the patients described in the English-language literature. PATIENTS: The study included a total of 17 patients: 10 women and seven men. MAIN OUTCOME MEASURES: Sex, age, origin, symptoms, localization, treatment, and morbidity. RESULTS: Seven men and six women, from 32 to 62 years of age, had known disorders of calcium metabolism, and four women, from 37 to 84 years of age, did not. The main causes of the calcium metabolic disorder were secondary hyperparathyroidism in 11 patients (85%) and primary hyperparathyroidism in two patients. In three patients there was a history of trauma at the involved site and in one patient the origin was unknown. Swelling and pain are the most common presenting complaints. Generalized pruritus was observed in 54% of the patients with metabolic disorders (P < .001) but not in patients without metabolic disorders. Among our patients with metabolic disorders, TC occurred most frequently at the shoulder (46%) and elbow (31%). Eleven patients with secondary hyperparathyroidism had received calcium carbonate to bind phosphate, a high level of calcium in the dialysate, and calcitriol (1,25-vitamin D) either orally, intravenously, or both, and three received epoetin alfa (Epogen). Following parathyroidectomy, the patients with hyperparathyroidism improved symptomatically, although calcifications did not change in size. One patient had the calcifications resected and did well, whereas another was treated by subtotal resection and had a recurrence 3 years later. All four of our patients without a metabolic disorder had complete resection of TC with no recurrence. CONCLUSION: We believe TC is becoming more common in uremic patients with secondary hyperparathyroidism because of recent changes in the medical treatment of these patients. The increased use of calcium carbonate to bind phosphate as well as calcitriol and calcium to suppress parathyroid function and possibly epoetin alfa are causing more patients to develop TC.

Adult↗

PubMed1993

Increased phospholipase C activity in neoplastic thyroid membrane.

The phospholipase C (PLC)-protein kinase C (PKC) signal transduction pathway appears to be important for cellular growth of many normal and neoplastic tissues. Because alterations in the thyroid-stimulating hormone (TSH) receptor-adenylate cyclase-protein kinase A system in some thyroid tumors do not correlate with tumor size, invasiveness, or metastatic potential, we studied the PLC activity in both normal and neoplastic thyroid tissues from 11 patients. Five of these patients had follicular adenomas and 6 had papillary carcinomas. An 8,000 x g membrane fraction and a 105,000 x g cytosol fraction were prepared from the normal and neoplastic human thyroid tissues. PLC hydrolyzes phosphatidylinositol, 4,5-diphosphate (PIP2) to diacylglycerol (DAG) and inositol 1,4,5-triphosphate (IP3). Phospholipase C activity was determined measuring the hydrolysis of [3H]-PIP2. The activity of PLC in the neoplastic thyroid tissue membrane fraction (20.91 +/- 2.28 nmol PIP2 hydrolyzed/mg protein/120 min) was higher than that in normal thyroid membrane (14.27 +/- 0.82) (p < 0.05). In contrast, PLC activity was similar in the neoplastic (16.12 +/- 0.86 nmol PIP2 hydrolyzed/mg protein/120 min) and normal (16.66 +/- 0.60) cytosol. There was no difference between PLC activity in the membrane fraction from adenomas (21.21 +/- 3.71 nmol PIP2 hydrolyzed/mg protein/120 min) when compared with thyroid carcinomas (20.67 +/- 3.14). Neoplastic thyroid membranes have greater PLC activity than that found in normal thyroid membranes from the same patients. Although PLC activity in benign and malignant thyroid membranes was similar, the increased PLC activity in thyroid neoplasms may be responsible for or contribute to the enhanced growth of some thyroid tumors.

Adenoma↗

PubMed1993

Double parathyroid adenomas. Clinical and biochemical characteristics before and after parathyroidectomy.

OBJECTIVE: There is considerable debate about whether double parathyroid adenomas are a discrete entity or represent hyperplasia with parathyroid glands of varying sizes. This distinction is important because it impacts on the extent of parathyroid resection and the success of the parathyroid operation. SUMMARY BACKGROUND DATA: Double parathyroid adenomas have been reported to occur in 1.7% to 9% of patients with primary hyperparathyroidism (HPT). It is important for surgeons to differentiate between double adenoma and hyperplasia with glands of varying sizes using gross examination during the initial procedure because microscopic findings of a small biopsy specimen at frozen-section examination may not be diagnostic. METHODS: From 1982 to 1992, 416 unselected patients (309 women and 107 men) with primary HPT without familial HPT or multiple endocrine neoplasia (MEN) were treated by one surgeon at the University of California at San Francisco. Double adenoma occurred in 49 patients, solitary adenoma in 309 patients, and hyperplasia in 58 patients. The authors analyzed the clinical manifestations, the preoperative and postoperative serum levels of calcium, phosphate, and parathyroid hormone (PTH), and the success rate and outcome after parathyroidectomy and compared their results in 49 patients with double adenomas to the results for patients with solitary adenomas or hyperplasia. RESULTS: Ten of the patients with double adenomas (20.4%) were referred for persistent HPT after removal of one abnormal parathyroid gland. The ages of the patients with double adenoma, single adenoma, and hyperplasia were 61 +/- 14, 56 +/- 15, and 58 +/- 7 years, respectively. Fatigue, muscle weakness, and bone pain were common in patients with double adenomas, whereas nephrolithiasis occurred more frequently in patients with solitary adenoma (p = 0.0001). Serum calcium and PTH levels (per cent of upper limit of normal) fell from 11.5 +/- 1.2 mg/dL and 487% to 9.5 +/- 0.8 mg/dL and 61% for patients with double adenomas; from 11.9 +/- 0.9 mg/dL and 378% to 9.3 +/- 1.4 mg/dL and 101% for patients with single adenoma; and from 10.9 +/- 0.5 mg/dL and 418% to 9.1 +/- 0.7 mg/dL and 94% for patients with hyperplasia, respectively. There was no recurrence in the patients with double adenomas with a mean follow-up time of 5.8 years. CONCLUSIONS: Double adenomas are a discrete entity and occur more often in older patients. Patients with double adenomas can be successfully treated by removal of the two abnormal glands.

Adenoma↗

PubMed1993

Thyroid-stimulating hormone activates phospholipase C in normal and neoplastic thyroid tissue.

BACKGROUND: Thyroid-stimulating hormone (TSH) stimulates thyroid growth through two signal transduction pathways: the G protein-adenylate cyclase system and the G protein-phospholipase C (PLC) system. The adenylate cyclase system has been studied extensively, but there is little information available concerning PLC activity in thyroid neoplasms. METHODS: Human thyroid membranes were incubated for 30 minutes at 37 degrees C in the presence or absence of bovine TSH (300 mU/ml). PLC activity was assayed by liberation of inositol phosphates from the enzymatic hydrolysis of tritiated phosphatidylinositol bisphosphate. Fifty-six tissues were assayed (normal, 23; multinodular goiter, 5; follicular adenoma, 9; and differentiated thyroid cancer, 19 [9 low risk and 10 high risk]). RESULTS: TSH significantly increased PLC activity in normal, benign, and most malignant thyroid neoplasms. Although there were no differences in basal or TSH-stimulated PLC activity between the groups of normal thyroid, multinodular goiter, follicular adenoma, or the cancers, one half of the high-risk cancers had an aberrant PLC response. CONCLUSIONS: This is the first demonstration that TSH stimulates PLC activity in normal and neoplastic human thyroid tissue. Aberrant TSH-stimulated PLC activity was present in half of the aggressive thyroid neoplasms.

Enzyme Activation↗

PubMed1992

Normocalcemic hyperparathyroidism. Biochemical and symptom profiles before and after surgery.

Patients with normocalcemic hyperparathyroidism represent a diagnostic and therapeutic challenge. It is unclear to what extent these patients benefit from surgery in terms of correction of their serum chemistry abnormalities and their symptoms. We studied 142 patients: 23 with normocalcemic hyperparathyroidism (serum calcium levels below 2.62 mmol/L), 35 with intermittent hypercalcemia, and 84 with hypercalcemic hyperparathyroidism. Serum chemistry analyses and a standardized questionnaire of symptoms were completed before and after surgery. Overall, patients in the normocalcemic group reported a similar frequency of preoperative symptoms; had a similar reduction in postoperative symptoms; and had a similar normalization of serum calcium, parathormone, and phosphate levels as those in the two control groups. This study indicates that factors other than elevated serum calcium levels are in large part responsible for the symptoms of hyperparathyroidism and that these patients benefit from operation.

Adenoma↗

PubMed1992

Reoperative thyroid surgery.

BACKGROUND: Patients with thyroid cancer are sometimes denied repeat thyroid operations for fear of an increased risk of complications. METHODS: We therefore reviewed our experience in 114 patients with benign or malignant thyroid tumors who underwent 116 thyroid reoperations with or without other procedures. All patients had undergone at least one prior thyroid operation and 16 patients had undergone from two to four thyroid operations before referral. The initial histologic diagnosis before reoperation was thyroid carcinoma in 79 patients, papillary carcinoma in 47 patients, follicular carcinoma in 17 patients, medullary carcinoma in 9 patients, and Hürthle cell carcinoma in 6 patients. Benign disease was present in 35 patients. In 62 patients with cancer, reoperations were performed because of suspected persistent or recurrent disease; one of these patients underwent two reoperations by us. In 17 patients reoperation was to complete total thyroidectomy, primarily so that radioactive iodine could be used to scan for and treat metastatic disease. RESULTS: Among the 116 reoperations, 102 were completion total thyroidectomy, 8 were near-total or subtotal thyroidectomy, and 6 were completion lobectomy. Histologic examination at reoperation revealed thyroid carcinoma in 51 cases (64%) among the 79 patients who had undergone 80 operations for previous thyroid cancer. Recurrent or persistent cancer was present in 49 of 63 (78%) reoperations for patients with papillary, medullary, and Hürthle cell cancer but in only 2 of 17 (12%) patients with follicular cancer. Cancer also occurred in 8 cases (22%) of the 36 reoperations in 35 patients who initially had benign lesions. Complications included one permanent and one transient palsy of the recurrent laryngeal nerve; both occurred on the side of a previous partial or subtotal lobectomy. Other complications included temporary hypoparathyroidism in four patients, seromas in two patients, and a keloid in one patient. CONCLUSIONS: This study documents that reoperations can be performed with minimal morbidity. Thus patients should not be denied the chance to undergo removal of a persistent tumor or the remnant normal thyroid tissue because of the fear of complications.

Adolescent↗

PubMed1991

Diagnosis and management of asymptomatic hyperparathyroidism: safety, efficacy, and deficiencies in our knowledge.

Several recent articles question whether patients with asymptomatic hyperparathyroidism and minimal hypercalcemia should be treated by parathyroidectomy. We therefore reviewed our experience in 103 consecutive patients with primary hyperparathyroidism who were treated by parathyroidectomy to determine, first, how many of these patients had asymptomatic or symptomatic hyperparathyroidism, and second, did these patients benefit from parathyroidectomy? We also analyzed the safety of parathyroidectomy in 426 consecutive patients, including 79 who required reoperation for hyperparathyroidism, specifically looking for complications and the outcome of these procedures. Our study documents the following: (1) only 2 of 103 (2%) patients referred for parathyroidectomy had "true" asymptomatic hyperparathyroidism; (2) only symptoms of fatigue, bone pain, and weight loss correlated with the degree of hypercalcemia, whereas muscular weakness, psychiatric symptoms, nocturia, polyuria, recent memory loss, constipation, and nephrolithiasis did not; (3) only 1 of 15 patients who were referred as asymptomatic were truly asymptomatic after more thorough questioning, and all 14 improved following parathyroidectomy; (4) 81% of the patients who were referred with symptoms improved following parathyroidectomy; and (5) permanent complications occurred in only 4 patients. All but 1 had reoperations for persistent or recurrent hyperparathyroidism (3 vocal cord paralyses and 1 hypoparathyroidism requiring autotransplantation of cryopreserved parathyroid tissue). There was 1 death of an 84-year-old woman with hypercalcemic crisis. Thus, most patients with hyperparathyroidism are symptomatic and benefit symptomatically and metabolically from parathyroidectomy, which is a safe operation.

Female↗

PubMed1991

Increased stimulatory G protein in neoplastic human thyroid tissues.

Prior studies in our laboratory have shown that thyroid neoplasms produce increased amounts of cyclic adenosine monophosphate (cAMP). Thyroid-stimulating hormone receptors act through the stimulatory G protein (Gs) to activate adenylate cyclase, the enzyme responsible for cAMP production. The purpose of this study is to measure the activity and amount of Gs in human normal and neoplastic thyroid tissue to see whether alterations in Gs are responsible for the increased cAMP production seen in thyroid neoplasms. Four tumors with a high TSH-stimulated cyclase activity of 497.6 +/- 71.9 pmol/mg/30 min versus 35.9 +/- 13.5 pmol/mg/30 min for normal tissue from the same patients were studied. In reconstitution studies measuring Gs activity, neoplastic thyroid tissue produced 637 +/- 106 pmol cAMP/mg S49/mg thyroid membrane min versus 363 +/- 133 pmol cAMP/mg 549/mg thyroid membrane/min produced by normal thyroid tissue. Qualitative assessments of the amount of Gs present with cholera toxin-mediated adenosine diphosphate ribosylation showed increased Gs in thyroid tumors. Western blotting with antibodies directed against Gs showed a 3.3 +/- 0.6-fold increase in the amount of Gs in these thyroid tumors. These experiments identify an increase in the amount of an otherwise normal Gs as the biochemical defect responsible for the increased cAMP production in this group of tumors.

Adenocarcinoma↗