No association of IL-1beta C + 3954 T polymorphism and thyroid disease.

Interleukin-1 is a potent pro inflammatory agent, has a direct influence on human thyroid cell function, and modulates cell growth in differentiated thyroid carcinoma cell lines. To evaluate whether a polymorphism on the IL-1beta gene has an influence on the incidence of thyroid disorders, we analyzed the C + 3954 T polymorphism in DNA samples of 673 individuals. 414 venous blood samples were collected from patients suffering from thyroid diseases (Graves' disease n = 53, euthyroid or hyperthyroid non-immunogenic benign thyroid disorders n = 240, thyroid carcinoma n = 121). 259 persons without thyroid disease served as a control. There was no statistically significant association between either of the thyroid alterations or functional conditions on the one hand and the examined genetic polymorphism on the other. Because of the large number of samples tested we can conclude with a high degree of confidence that there is no association between the genotype and the surveyed diseases.

Reoperative surgery for organic hyperinsulinism: indications and operative strategy.

Organic hyperinsulinism has a good chance of cure by operation, although patients with diffuse or multiple disease run a high risk of recurrence or persistence of disease. Surgical management and outcome in these patients are presented and discussed. Between 1986 and April 1997 a total of 62 patients were operated on for organic hyperinsulinism [solitary 48, multiple 3, multiple endocrine neoplasia type I (MEN-I) 2, diffuse 4, malignant 5]. Persistence or recurrence occurred in 10 patients (16%). Among the six that persisted, four were malignant and two benign. All four of those that recurred were benign. Patients with benign disease presented with multiple tumors (n = 3), MEN-I syndrome (n = 1), and diffuse/nodular hyperplasia (n = 2). The duration between diagnosis and reintervention ranged from 1 to 10 years. Preoperative diagnosis was able to localize tumors in three patients (computed tomography 1, angiography 2, calcium stimulation 1). Operative procedures were multiple enucleations in two patients with sporadic disease, subtotal resection plus enucleation in the case of MEN-I syndrome, subtotal resection for diffuse hyperplasia, left resection for adenomatosis, and tumor extirpation after multiple previous operations. Long-term clinical and biochemical cure was achieved in five of six patients (mean follow-up 5 years). Octreotide therapy shows good symptomatic control in the patient with operative failure. Reintervention for organic hyperinsulinism is successful (80% cure) and requires preoperative imaging and individual surgical management.

Redifferentiation therapy with retinoids: therapeutic option for advanced follicular and papillary thyroid carcinoma.

During the course of tumor progression the differentiated morphologic and functional characteristics of differentiated thyroid carcinomas (DTC) disappear. This corresponds to more aggressive growth, metastatic spread, and loss of iodine uptake. Experimental data give strong evidence that differentiated functions of iodine metabolism can be reinduced by retinoic acids. Results of a study performed in patients with advanced DTC are presented. Twenty patients with DTC (eight follicular, seven papillary, five oxyphilic) were selected for treatment with retinoic acid 1.5 mg/kg body weight/day over 5 weeks. All patients had advanced tumor stages with prior operative and radioiodine treatment. Extensive tumor invasion, distant metastatic spread, or insufficient or no radioiodine uptake precluded any conventional therapeutic option. The aim was to assess the changes under retinoid treatment. Iodine uptake increased in eight patients (three follicular, three papillary, two oxyphilic). Thyroglobulin (TG) as parameter for tumor mass and differentiation increased in 12 (63%) patients, decreased in 6 (32%), and did not change in 1 (5%). Retinoids do have an effect on differentiation status of DTC, reinducing iodine uptake in 50% of patients. TG levels do not always parallel a response in iodine uptake.

A frequent mutation/polymorphism in tumor suppressor gene INK4B (MTS-2) in papillary and medullary thyroid cancer.

BACKGROUND: Structural genetic changes of tumor suppressor genes MTS-1/INK4A and MTS-2/INK4B were demonstrated in a variety of human cancers but not in thyroid cancer until now. METHODS: Because MTS-2 encodes the tumor suppressor p15, a protein related to the transforming growth factor-beta inhibition of many epithelial cells such as thyrocytes, we investigated MTS-1 and MTS-2 genes in 87 thyroid cancers (29 papillary, 26 follicular, 31 medullary, and 1 anaplastic), 8 goiters, and 38 control DNAs by using a semiquantitative polymerase chain reaction technique. RESULTS: We failed to demonstrate homozygous deletions of MTS-1 and MTS-2 in thyroid tumors, but we demonstrated a highly frequent base pair exchange of the MTS-2 gene 27 codons upstream the 5' end of exon 2. This genetic change formerly described as polymorphism was found to a lesser degree (15%), in control DNA when compared with papillary thyroid cancer and medullary thyroid cancer (35% and 32%, respectively), and it paralleled a higher prevalence of extensive lymph node metastases in thyroid cancer (p < 0.01). In addition, we could demonstrate that genetic changes at site 27 upstream the 5' end of exon 2 were harbored as somatic mutations in 2 of 10 thyroid cancers with simultaneously investigated corresponding control tissue. CONCLUSIONS: We conclude that base pair exchange at this site most likely has biologic importance for the tumor suppressor p15 and may contribute to tumorigenesis and lymphatic spread of differentiated and medullary thyroid cancer.

Evaluation of liver function tests to predict operative risk in liver surgery.

Despite numerous studies in the past it is not possible yet to predict postoperative liver failure and safe limits for hepatectomy. In this study the following liver function tests ICG-ER (indocyaninegreen elimination rate), GEC (galactose elimination capacity) and MEGX-F (monoethylglycinexylidid formation) are examined with regard to loss of liver tissue and prediction of operative risk. Liver function tests were assessed in 20 patients prior to liver resection and on the 10th. postoperative day. Liver and tumor volume were measured by ultrasound and pathologic specimen and the parenchymal resection rate was calculated. In patients without cirrhosis (n = 10) ICG-ER and MEGX-F remained unchanged after resection, GEC was reduced but did not correspond to the resection rate. Patients with cirrhosis (n = 10) had a significantly lower ICG-ER and GEC before resection than patients without cirrhosis. After resection these tests were unchanged. Patients with liver related complications and cirrhosis (n = 5) had lower ICG-ER and GEC than patients with cirrhosis and no complications. In the postoperative course all liver function tests in these patients were significantly lower compared to preoperative results. Comparing liver function tests ICG serves best to indicate postoperative liver failure. Liver function tests do not correspond with loss of liver tissue.

Principals of limited or radical surgery for differentiated thyroid cancer.

Since the late sixties standard total thyroidectomy with or without selective radical neck dissection depending on the extent of the disease has become the routine surgical procedure for differentiated thyroid carcinoma (DTC;-papillary, follicular). This strategy has contributed remarkably to the increase of cure rates for various reasons. Only recently, in the last decade, has limited radicality with only unilateral lobectomy (= hemithyroidectomy) with or without partial contralateral resection been advocated as being sufficient for selected early tumor stages. We have analyzed a series of 252 patients, 174 (69%) being papillary and 78 (31%) follicular. Primary operation was done in 117 patients (46%) while 135 patients (54%) underwent reoperative surgery at this institution for either completion of radicality or because of loco-regional recurrence. From our evaluation we draw the conclusion that limited radicality (unilateral operation or subtotal) is justified only in pT-1-tumors in younger age (< 45 yrs) in order to avoid recurrence and unnecessary reoperation. On the other hand generous indication for reoperation is justified with the overall chance of almost 60% cure rate. All adjuvant treatment, mainly radioiodine should be applied thereafter.

Unusual features of multiple endocrine neoplasia.

In addition to the common presentations of the multiple endocrine neoplasia (MEN) syndromes, unusual organ involvement as rare manifestations of a single disease may occur. Among our patients we have identified four cases in which unusual features of MEN were present. In the first patient, bilateral adrenal cortical adenoma, parathyroid adenoma, multiple pancreatic tumors, and follicular thyroid carcinoma were observed. The second patient suffered from thymic carcinoid, parathyroid hyperplasia, gastrinoma, and pituitary adenoma. Additionally, one family was discovered in which medullary thyroid carcinoma (MTC), Hirschsprung's disease, and pheochromocytoma occurred and another family had MTC and ovarian cancer. Based on these observations, we stress the importance of screening for MEN syndromes in all patients with pathologic findings in any endocrine organ.

Management of primary hyperparathyroidism caused by multiple gland disease.

Multiple gland parathyroid disease is the pathological finding in primary hyperparathyroidism (HPT) in about 10% to 20% of all patients and in approximately a third of all patients with persistent or recurrent disease. The variability of multiple gland disease spans from 2 adenomas to diffuse hyperplasia in patients with multiple endocrine neoplasia type 1. This variability calls into question the proposed common pathophysiologic background in all of these cases. As primary treatment of multiple gland primary HPT, subtotal parathyroidectomy and thymectomy or total parathyroidectomy and heterotopic autotransplantation including thymectomy can be equally advocated. Recurrent hyperparathyroidism frequently occurs in cases of diffuse parathyroid hyperplasia. This must be considered especially in patient follow up and before each surgical procedure. Thus, a defined but adaptable therapeutic regimen might prevent permanent hypoparathyroidism and persistent hyperparathyroidism.

Growth regulation of normal thyroids and thyroid tumors in man.

Our studies using thyrocyte membranes from different human thyroid tissues, monolayer cultures of human thyrocytes, and the permanant cell line FTC-133 demonstrate the stimulatory effect of TSH on metabolism, DNA synthesis, and cell growth in human thyrocytes. Up- and down-regulation of cAMP cell content fails to show direct effects on DNA synthesis and cell growth in primary thyrocyte cultures in man. Increased AC responsiveness to TSH in adenomatous human thyroid tissues, when compared to normal thyroids of the same patient (p less than 0.005), is thus of only questionable importance for thyroid tumor growth. The permanant cell line FTC-133 was established from differentiated follicular human thyroid cancer cells. FTC-133 cells proved to be of particular usefulness in assessing growth regulation of human thyroid tissue. These cells could be propagated in serum free medium, showed thyroglobulin immunoreactivity and EGF receptors, lacked any fibroblast contamination, and responded to TSH and local active growth factors such as EGF and IGF with a stimulated [3H]thymidine incorporation. The latter could be shown in primary cell cultures of normal and pathological human thyrocytes as well. Additional to the stimulatory effect of TSH and IGF on [3H]thymidine incorporation, these substances show an additive effect when incubated simultaneously. Locally active growth factors and endocrine growth stimulation by TSH therefore act synergistically on thyrocyte growth in human thyrocyte cultures. Whether the TSH effect on cell growth is related to its stimulation of AC remains as yet questionable.

The importance of screening for medullary thyroid carcinoma in families of patients with MEN 2.

Family screening for medullary thyroid cancer (MTC) is important for detecting members of multiple endocrine neoplasia type 2 (MEN 2) families who may be gene carriers but show no clinical evidence of the disease. Most members of our MEN 2 families are screened yearly by measuring basal and pentagastrin-stimulated calcitonin (CT) levels. A 15-year-old first-degree relative of an affected member of the D-kindred showed a normal basal and an elevated stimulated CT level. Clinical examination, ultrasonography, and scintigraphy were normal. Thyroidectomy and bilateral neck dissection revealed a multicentric MTC with no lymph node involvement. In the O-kindred we detected elevated basal and/or stimulated CT levels in three asymptomatic first-degree relatives. At surgery we found a small multicentric MTC in one family member, C-cell hyperplasia in another member, and bilateral lymph node metastases in one member who had been previously thyroidectomized. Basal and stimulated CT estimations in MEN 2 family members provide an effective method for detecting MTC in early, treatable stages.

Nerve growth factor (NGF) sensitizes human medullary thyroid carcinoma (hMTC) cells for cytostatic therapy in vitro.

Medullary thyroid carcinoma (hMTC) cells were established from nine patients with MTC disease to initiate a new approach of adjuvant medical therapy in these patients. We measured calcitonin (CT) secretion, DNA synthesis, and cell proliferation in vitro and their response to various substances. Nerve growth factor (NGF) (0.01 to 10 micrograms/ml), glucagon (0.01 to 100 micrograms/ml), and isoproterenol (4 to 500 micrograms/ml) stimulated CT secretion and DNA synthesis in hMTC cells. Other substances, calcium (1.0 to 15 mmol), pentagastrin (1.0 to 50 mumol), dibutyryl-cyclic-adenosine-monophosphate (1.0 to 100 mumol), and phorbol ester TPA (1.0 to 100 nmol), stimulated CT secretion but not DNA synthesis. In addition, NGF enhanced cell proliferation of hMTC cells 2- to 3- fold and caused an increased sensitivity of these cells for chemotherapy in vitro. Thus 0.5 microgram/ml doxorubicin (half-maximal effective dose) induced a cell death rate of up to 32.8%, which was enhanced by preincubation with NGF to 68.1% (1.0 microgram/ml, NGF) and to 100% (10.0 micrograms/ml, NGF), respectively. Pulsative stimulation of APUD cell carcinomas with NGF may therefore improve the response rate of these tumors to chemotherapy, which would be of significant clinical importance for patients with residual postoperative MTC tissue.

Can the use of an endoscopic Congo red test decrease the incidence of incomplete proximal gastric vagotomy?

The endoscopic Congo red test allows accurate and rapid evaluation of the completeness of vagotomy and may result in a lower incidence of postoperative incomplete vagotomy. This report describes 44 patients tested during proximal gastric vagotomy. Evidence of incomplete vagotomy was found in over 95% at the conclusion of the conventional operation. Importantly, the test was a guide to further operative maneuvers which abolished the evidence of incomplete vagotomy upon subsequent testing. The endoscopic Congo red test satisfies the requirements for an ideal test for complete vagotomy: it is easily performed, does not require special equipment, and can be repeated several times if necessary to verify that desired effects have been achieved. The wider use of this test, therefore, appears justified.

Experience with the endoscopic test for completeness of vagotomy. Results of application in two medical centers.

The need for a practicable and reliable test for completeness of vagotomy has been previously recognized. Until recently, all of the tests for completeness of vagotomy required cumbersome or delicate equipment or had deficiencies which prevented routine use. Recently we have modified the endoscopic Congo red test (ECRT) to allow more rapid and accurate performance; furthermore, we have found that the routine use of this test has affected the performance of proximal gastric vagotomy in our medical centers. At this time, we report the application of the ECRT in 41 patients at two medical centers, including patients from the University of Illinois at Chicago and the University of Marburg. The SIMPLIFIED ECRT, which is completed in less than five minutes, avoids the 15-20 minute delay required with other tests for complete vagotomy; it is the only test for complete vagotomy which can be performed intra- and postoperatively. To our knowledge, the test has not been performed previously in Europe. The similarity of results following ECRT in both settings reinforces our view that intraoperative testing affects the performance of vagotomy, and is useful in teaching aspects of operative vagotomy. The endoscopic test appears to be the test of choice for determining completeness of vagotomy.

Absence of high-affinity binding sites for beta-adrenergic blockers and lack of adenyl cyclase stimulation to beta-adrenergic stimulators in most normal and adenomatous human thyroid tissues.

To determine whether the beta-blocking drug propranolol had any physiologic effect on normal (n = 14) and adenomatous (n = 15) human thyroid tissues, experiments were performed to study the binding of the beta-blockers 125I-iodocyanopindolol (125I-ICYP) and 125I-iodohydroxybenzylpindolol (125I-IHYP) and the stimulation of adenyl cyclase (AC) by isoproterenol. 125I-ICYP and 125I-IHYP failed to show high-affinity binding in 27 of 29 specimens, whereas two (one normal and one adenomatous) thyroid tissues demonstrated high-affinity binding (Kd 5.5 +/- 1 X 10(-9) M) for 125I-ICYP. Thyroid-stimulating hormone (0.3 IU/ml), guanosine triphosphate (10(-4) M), and Gpp (NH)p(10(-4) M) stimulated AC in all thyroid tissues, although in two tissues (normal) Gpp (NH)p failed to cause a significant increase. Isoproterenol (10(-4) M), in contrast, had no effect on basal AC activity or on guanosine triphosphate, and Gpp (NH) p stimulated AC activity in 26 of the 29 thyroid tissues. In one of the two tissues that increased AC in response to isoproterenol, the beta-blocking drugs propranolol hydrochloride, bunitrolol hydrochloride, and tolilprolol hydrochloride decreased AC stimulation to isoproterenol at concentrations of 10(-6) M (p less than 0.05). Higher concentrations of propranolol (10(-4) - 10(-2) M) decreased AC stimulation to thyroid-stimulating hormone (p less than 0.01), not only in this responsive tissue but also in tissues that failed to demonstrate high-affinity binding for 125I-ICYP and AC stimulation to isoproterenol (p less than 0.01). Thus most normal and adenomatous human thyroid tissues lack beta-receptors and a functioning beta-receptor AC system. High concentrations of propranolol in vitro decreased AC response by thyroid-stimulating hormone, but this is probably a nonreceptor-mediated effect.

Surgery for hyperthyroidism: indications, pretreatment, operative strategy and results.

In an endemic area nodular toxic goitre is the dominating type of hyperthyroidism, while Graves' or Basedow's disease with diffuse toxic goitre accounts for only 25 to 30% of the patients. Since antithyroid drug therapy has poor permanent effect and recurrence rates of about 50 to 60% and radioiodine in turn requires higher doses and often repeated application, surgery is to be recommended as the primary treatment of choice for the nodular hyperthyroid goitre. -For Graves' disease the method of therapy is not as clear cut. Operation is indicated mainly when the disease is severe with a larger goitre or in younger age groups (below 40 years) where radioiodine may not be advisable. For preoperative treatment the use of antithyroid drugs in preferred, although iodine perhaps in combination with beta blockers may be used safely as well at least for moderate cases. In the presence of alternative means of treatment surgery should not exceed an operative risk of 0.5-1.5% with virtually no mortality. Our own experiences are based on a retrospective analysis of 702 patients from three hospitals.

Acute response to acid-base stress.

A method previously established in the experimental animal for predicting the acute response to either metabolic stress (bicarbonate administration) or respiratory stress(manipulation of oxygenator gas during cardiopulmonary bypass) has been extended to man. The method is based on a single nomogram. The accuracy of the nomogram is demonstrated using data from 13 patients on cardiopulmonary bypass. Similar agreement obtains between the nomogram and data reported by others. The nomogram can be used to estimate the therapeutically required dose of bicarbonate.