High rates of ras codon 61 mutation in thyroid tumors in an iodide-deficient area.

Using polymerase chain reaction and sequence-specific oligonucleotide hybridization, the frequency of three ras oncogene mutations (N-ras, Ha-ras, and K-ras) in thyroid tumors (25 adenomas, 16 follicular carcinomas, and 22 papillary carcinomas) was investigated in both iodide-deficient and iodide-sufficient areas. The ras oncogene mutation rate was significantly higher in the iodide-deficient area, being 85 versus 17% in the adenomas, and 50 versus 10% in the follicular carcinomas. No mutations were found in papillary carcinomas. The most common mutation site was Ha-ras codon 61 with Gln----Arg substitution. Two ras mutations at codon 61 (Gln----Lys in N-ras and Gln----Arg in Ha-ras) were found in a microfollicular adenoma specimen from Eastern Hungary. We conclude that dietary iodine may modulate ras oncogene mutations, and that in the iodide-deficient area, ras oncogene activation may play a more important role in the initiation and/or maintenance of follicular tumors. Additional factors are, however, necessary to initiate carcinogenesis.

Gene profiling identifies genes specific for well-differentiated epithelial thyroid tumors.

Thyroid nodules are common. It would very helpful if genetic markers that can diagnose malignancy from fine needle aspiration samples were available. Few such markers has been thus identified and none are specific. Large panels of potential markers can be screened by microarray technology. Studies done to date have concentrated on single tumor types and thus provide no help in identifying tumor subtype specific markers. To that end we have studied gene profiles of 5 types of benign and malignant thyroid nodular tissue (multinodular goiter, follicular adenoma, papillary and follicular carcinomas). We have identified 195 genes whose differential expression clustered into clinically relevant groups. Twenty-eight genes were selected for further confirmation using real time quantitative polymerase chain reaction. Despite the differences in the microarray panels used, we confirmed the differential regulation of 12 genes previously reported in thyroid cancer, although we found the expression of several genes to be regulated in other histological tumor subtypes than originally described. We found, PCSK2, TRIB1, RAP1 GA1 to be specifically overexpressed in follicular cancer and S100A4 and GK2 in papillary carcinoma. SERP1, RNASE 2 and STATA5 were suppressed in papillary thyroid cancer. We have thus identified new potential markers specific to malignant thyroid tumors. It is apparent that a range of nodular thyroid tissue using large tumor sample numbers is necessary to establish robust markers for malignancy and to categorize tumors on the basis of small tumor samples.

Methimazole blocks Graves' IgG but not interferon-gamma HLA-DR expression by thyroid cells.

We have expanded our early observation that a potent Graves' IgG preparation induces HLA-DR expression on thyroid cells, by showing that four randomly-selected Graves' IgG's were also capable of inducing DR antigens on thyroid cells. The effect of Graves' IgG was specific to thyroid cells, as it did not induce MHC Class II molecule expression on endothelial cells whereas interferon-gamma and immune complexes did so. The anti-thyroid drug methimazole was capable of rapidly reducing Graves' IgG-induced DR expression but to a much lesser extent than brought about by interferon-gamma. We conclude that Graves' IgG propagates thyroid-specific autoaggression by continued induction of DR antigens and than an important means whereby methimazole brings about remission is by reducing this induction.

Expression of HLA-DR antigens by thyroid cells: the effect of Graves' IgG.

We have investigated factors which influence HLA-DR expression on thyroid cells. While bTSH (100 mU/ml) did not enhance HLA-DR expression, it increased when brought about by IFN-gamma. Graves' IgG showed a dose-dependent (0.1-2 mg/ml) increase in DR expression and at a concentration of 2 mg/ml prolonged the time for which DR was expressed. The pathway of DR induction by Graves' IgG apparently differs from that by IFN-gamma. The humoral response in Graves' disease, by inducing DR expression, may be instrumental in propagating thyroid specific autoimmunity.

B lymphocyte subsets in Hashimoto's thyroiditis.

Two B lymphocyte subsets are identified on the basis of possession or lack of a surface molecule, CD5. The CD5+ B lymphocytes synthesize autoantibodies and in the process rearrange proximal variables of immunoglobulin genes. We have here studied the proportion and absolute counts of CD5+ B lymphocytes in the peripheral blood of 31 patients with Hashimoto's thyroiditis and related the findings to their HLA phenotypes and clinical features. Although the percentage and absolute number of surface immunoglobulin-positive (B) lymphocytes was comparable in patients to those in twenty controls, % CD5+ was significantly higher in the patient group (38.1 +/- 11.6 [+/- S.D.] vs. 27.9 +/- 10.1, p = 0.009). The absolute CD5+ cells (microliters) were also higher in patients with Hashimoto's thyroiditis (77.90 +/- 37.50 vs. 55.1 +/- 29.8, p = 0.020). The proportion of CD5+ cells was even higher in HLA-DR3 positive patients (43.1% +/- 7.2, n = 13) compared to six DR3+ controls (26.17% +/- 9.7, p = 0.0005). The difference between DR3- patients and controls was not significant (28.6% +/- 10.5 vs. 34.4% +/- 13.0). As the CD5 molecule may be induced on activated B lymphocytes, this study suggests that Hashimoto's thyroiditis is associated with an increase of activated B lymphocytes engaged in autoantibody synthesis. This defect is particularly obvious in DR3+ patients.

Cytogenetic analyses of three papillary carcinomas and a follicular adenoma of the thyroid.

Cytogenetic data of three papillary carcinomas and a follicular adenoma using direct preparations or cell cultures or both after 7 to 60 days in vitro are presented. Although karyotype of the follicular adenoma proved completely normal, in each of the three papillary carcinomas a modal chromosome number in the diploid range and a deleted 11q were observed. In case 1 the del(11)(q23) was associated with rearrangement of chromosome 1 and other marker chromosomes. Our results suggest that 11q deletion may be specific for papillary carcinoma of the thyroid.

Effects of indomethacin and prostaglandins I2 and E2 on the tone of human isolated mesenteric arteries.

The actions of indomethacin (IND), PGE2 and PGI2 were studied on the tone of isolated mesenteric arteries obtained from operated patients. The cyclooxygenase inhibitors IND (3 mumol/l) and suprofen (0.58 mumol/l) increased the resting tone and potentiated the contractile responses to electrical stimulation and noradrenaline. Low concentrations of PGE2 (0.7-5.6 X 10(-9) mol/l) decreased the baseline tone and reduced the stimulation-evoked contractions whereas higher concentrations (from 5.7 X 10(-8) mol/l) increased the tone of vessels. PGI2 (0.7-10.8 X 10(-9) mol/l) also relaxed IND-treated arteries but, in contrast to PGE2, it did not produce contraction even at a concentration of 10(-6) mol/l. Prostacyclin reduced the tone evoked and sustained by a high concentration of PGE2 or PGF2 alpha, the IC50 values being 46.2 or 7.9 X 10(-9) mol/l, respectively. The contractile responses to electrical stimulation and to noradrenaline were also inhibited by PGI2 (IC50 5.6 and 6.8 X 10(-9) mol/l, respectively). These results suggest that the smooth muscle cells of human mesenteric arteries are just as sensitive to IND, PGE2 and PGI2 as are those from laboratory animals. Our observations may be of clinical importance.

Rapid cytological diagnosis during thyroid surgery.

The authors report the results of the use of intra-operative cytological examinations of the thyroid gland. In their hands, the method has a 96.3% accuracy in 757 patients with thyroid disorder. Benign conditions and malignant tumours can be correctly diagnosed. False negative diagnosis can arise with well-differentiated follicular carcinoma and the differentiation of follicular adenoma may be difficult. Atypical adenomas may give a false positive diagnosis. The incorrect diagnosis of chronic lymphocytic thyroiditis is unlikely when sufficient attention is given to the whole clinical picture.

Differentiated thyroid cancer and outcome in iodine deficiency.

AIMS: Factors influencing prognosis and long-term outcome of thyroid cancer have been described by several groups. We wished to asses the previously described prognostic factors in a moderately iodine deficient region in Hungary. METHODS: Four hundred and fifty-four out of 492 patients who had surgery for papillary thyroid cancer (PTC, 386 cases) and follicular thyroid cancer (FTC, 106 cases) between 1971 and 1998 were analyzed. Survival curves were compared using the Kaplan-Meier method and Cox regression analysis. RESULTS: The 10 and 20-year survival rates were 87.9 and 84% for PTC, and 78.2 and 78.2% for FTC. In PTC, extrathyroidal invasion (p<0.0001), lymph node metastasis (p<0.0001), distant metastasis (p<0.0001), and age over 40 years (p=0.002) were significant adverse predictors. In FTC, extrathyroidal invasion (p=0.003) distant metastases (p<0.0001), and age over 40 years (p=0.011) were significant adverse predictors. CONCLUSION: Iodine intake did not appear to influence survival. The incidence of follicular cancer, which has less favourable prognosis, was higher in iodine deficient regions. This supports the importance of iodine supplementation in these areas.

[Prognostic significance of nuclear DNA content in highly malignant thyroid tumors]. / Die prognostische Bedeutung des nukleären DNS-Gehalts bei hochmalignen Schilddrüsentumoren.

The nuclear DNA content of tumour cells is correlated with the clinical outcome of a wide range of malignant disorders, among them thyroid neoplasia. The authors performed DNA determinations by means of the Feulgen cytofluorimetric method and demonstrate the connection between ploidy and biological aggressivity in cases of highly malignant thyroid tumours. The nuclear DNA content was measured in fresh surgical specimens from 53 patients suffering from malignancy, 13 of which proved pathohistologically to be highly malignant: 8 were anaplastic giant cell carcinomas, 3 squamous cell carcinomas and 2 were malignant lymphomas. 4 of the 8 giant cell carcinomas contained co-existent well-differentiated areas, namely follicular carcinomas in 3 patients and a papillary carcinoma in the 4th patient. 11 of the patients died of cancer, 9 within the 1st year. A different DNA distribution was found in the two survivors over a 10-year follow-up period. One of them showed a diploid cell population and the other facultative polyploidy, as opposed to the aneuploid pattern found in the 11 deceased patients. Both patterns confirm the correlation with a favourable outcome.

[Management of lung and bone metastases from thyroid cancers of differentiated structures]. / Differenciált szerkezetü pajzsmirigyrákok tüdö- és csontáttéteinek kezelése.

During a period of thirty years (1959-1989) 374 patients underwent surgery for differentiated thyroid carcinoma at the 1st Department of Surgery of the University Medical School in Debrecen. Distant metastases were found in the lungs or bones in 36 patients (9.6%). In 20 patients the first clinical sign of the primary disease was the distant metastasis. The aspects of surgical treatment depended on whether the metastases were solitary or multiple, capable or uncapable of radioiodine uptake. Whereas the majority of pulmonary metastases respond well to 131I-treatment the therapy of bone metastases is multidisciplinary. The 5-year survival rate was 47%, the 10-year one 19%.

[Value of thyroglobulin determination in the follow up treatment of patients with thyroid cancer]. / Thyreoglobulin meghatározások értéke differenciált pajzsmirigycarcinomában szenvedö betegek utókezelésében.

Tg measurements were performed regularly in 96 thyroid carcinomas in order to evaluate metastases and local recurrencies. Elevated Tg level was detected in 11 patient. 7 of them were operated on because of local recurrencies and lymph node metastases. All patients that needed reoperation had elevated Tg level. During the follow up period no patient needed reoperation who had elevated Tg level or metastases detected by other diagnostic procedures. Summarising the results they found the Tg level measurements valuable in the follow up of patients with differentiated thyroid cancer. The Tg level measurements can supplement or sometimes replace 131J thyroid scanning.

[The role of bile in the development of colon cancer induced by 1,2-dimethyl hydrazine in rats]. / Az epe szerepe az 1,2-dimetilhidrazin-indukálta vastagbéldaganatok kialakulásában, patkányban.

Experimental operative models were created in order to investigate the role of the bile acids in the development of colon cancer in rats. These techniques changed the concentration of bile acids in different parts of the colon, and the daily fecal total bile acid levels. The relationship between these changes and the development of 1,2-dimethylhydrazin-induced colon cancer was studied. Significantly more tumors than in the control group were found if the daily total bile acid level and the concentration of bile acids in the left subsite of the large bowel was increased. Our results suggest that bile acids, as promoting factors, may play a role in the development of colon cancer in rats.

[Change in the surgical treatment of benign adrenal gland tumors. Laparoscopic adrenalectomy]. / Szemlélet- és stratégiaváltás a jóindulatú mellékvesedaganatok sebészi kezelésében. Laparoszkópos adrenalectomia.

UNLABELLED: Since 1995 fifty-two patient was operated on the Ist Department of the Surgery (DEOEC) due to uni- and bilateral tumor of the adrenal gland. Between May 1999, and December 2000 the authors performed 11 transperitoneal laparoscopic adrenalectomies (LA). Conversion due to bleeding in 3 cases and due to suspected malignancy in 1 case was necessary. This malignant lesion could have been resected during the open surgery after only the temporary dissection of the right renal vein. Complete resection was carried out in 9 cases. In 2 cases where a well circumscribed adenoma or teratoma was visualized, only enucleation was performed. The complication rate was low (1 ptx). Blood replacement was not necessary. The operation mean time was not any longer in LA compared to the open surgical approach. Preoperatively adrenaline (A), noradrenaline (NA), metadrenaline (metA), normetadrenaline (normetA) and vanillylmandelic acid (VMA) were measured in 24-h urine samples. Adrenal imagery consisted in all patients of abdominal computed tomography and in 4 patients adrenal magnetic resonance imaging but [131I] metaiodobenzylguanidine (MIBG) and octreotide scintigraphy were not performed. CONCLUSION: In the authors experience laparoscopic adrenalectomy is absolutely superior to the open surgery for the benign diseases of the adrenal gland not bigger than 6 cm. A short, uncomplicated and painless postoperative period can be achieved for the patients, with the same efficacy and safety compared to the conventional surgery. Enucleation without the whole adrenal gland excision is also possible.

[Complications of laparoscopic cholecystectomy]. / Laparoszkópos cholecystectomiák szövódményei.

Number of bile duct injuries is rising with the spreading of laparoscopic cholecystectomy. Authors analyse the complications in the last 8 years, especially the bile duct injuries. During this period 1657 laparoscopic cholecystectomies were performed. Complication occurred in 28 cases during the intra- and postoperative period (1.68%). Main bile duct injury was detected in 7 cases (0.42%), while leakage from a Luschka's duct appeared in 10 patients. Three bleeding complications, 2 injuries of the duodenum and in 3 cases severe intraabdominal infection was observed. Four patients died (0.24%).

[Differentiated thyroid carcinoma: prognostic factors]. / Differenciált pajzsmirigy carcinoma: prognosztikai faktorok vizsgálata.

Factors influencing prognosis and long term outcome of thyroid cancer have been described by several groups. It is, however, not clear how the moderate iodine deficiency in Hungary can influence the previously described prognostic factors by other means than shifting differentiated cancer incidence toward the follicular type. Data of 423 out of 472 patients who had been operated on for papillary (372) and follicular (100) thyroid cancer between 1971 and 1997 at our institution have been analyzed retrospectively. Histological specimens were re-evaluated and, if needed, revised. Survival curves were compared using the Kaplan-Meier method. The overall 5 and 10 year survival rates were 93% and 89% for papillary, and 92% and 80% for follicular carcinoma. As an independent factor extrathyroidal invasion (papillary p = 0.000, follicular p = 0.000), lymph node involvement (papillary p = 0.000, follicular 0.011), distant metastases (papillary p = 0.000, follicular p = 0.000), and age over 40 years (papillary p = 0.000, follicular p = 0.000) had negative influence on survival. Multifocality, gender, type of surgery (total or near-total thyroidectomy vs. less than near-total thyroidectomy), and lymphocytic infiltration did not influence survival. Iodine intake did not influence survival, however, the incidence of follicular cancer was higher in iodine deficient regions. When analyzing the papillary and follicular groups separately by Cox regression, extrathyroidal invasion (p = 0.008), lymph node metastasis (p = 0.004), distant metastasis (p = 0.000), and age over 40 years (p = 0.000) were significant predictors in the papillary group, while only tumor extrathyroidal invasion (p = 0.019), and distant metastases (p = 0.000) were significant negative factors in the follicular group.