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P Goretzki

Publications and source records attributed to P Goretzki.

At least 19 recordsLinked to original sources
PubMed2002

Effects of the putatively oncogenic protein kinase Calpha D294G mutation on enzymatic activity and cell growth and its occurrence in human thyroid neoplasias.

A point mutation of protein kinase Calpha (PKCalpha) has been described in pituitary adenomas and in follicular adenomas and thyroid carcinomas. The mutation results in an exchange of aspartic acid into a glycine of the amino acid 294 of PKCalpha, which is located adjacent to the Ca (2+)-binding hinge region and has been proposed as an activation inhibitor. To investigate its biochemical sequelae, we constructed the mutated enzyme and expressed it in human embryonic kidney cells (HEK). The K M of the purified enzyme for Ca (2+) and its K M for the substrate MBP 4 - 14 was not altered by the mutation. Translocation of PKCalpha to HEK cell membranes upon activation was not changed and the mutant potently inhibited cell proliferation upon 5-fold stable overexpression in HEK cells. Thus, loss of function in mutated PKCalpha was excluded. A screen for the mutation using a restriction assay with a sensitivity of at least 8 % for the mutated DNA did not show any mutation in 11 carcinoma and 13 adenomatous thyroid samples. We conclude that the A294G mutation of PKCalpha does not detectably affect its biochemical properties in vitro or in vivo, and is at least rare in thyroid neoplasias, in Germany.

Biological Transport↗
PubMed2001

Soluble Fas is increased in hyperthyroidism independent of the underlying thyroid disease.

In Hashimoto's thyroiditis, Fas-induced apoptosis is one of the mechanisms leading to cell destruction, whereas thyroid tissue in Graves' disease is prevented from it. The soluble form of the Fas molecule produced by alternative splicing prevents from apoptosis. We measured soluble Fas in the sera of 112 patients with Graves' disease, 21 patients with toxic goiter, and 24 patients with subclinical hyperthyroidism due to suppressive therapy with levothyroxine after near-total resection of the thyroid gland for nodular goiter. Soluble Fas was increased in thyrotoxic patients, toxic goiter, and patients with subclinical hyperthyroidism. Decreased levels of soluble Fas were found in euthyroid patients with Graves' disease after surgery, whereas soluble Fas was normal in euthyroid patients with Graves' disease receiving antithyroid drug treatment and in patients in stable remission. There was a good correlation between soluble Fas with free T(3) (r = 0.6) and free T(4) (r = 0.5). Our results show that soluble Fas is increased in hyperthyroidism independent of the underlying thyroid disease.

Adult↗
PubMed2000

Therapeutic experience of 65 cases with organic hyperinsulinism.

INTRODUCTION: The treatment for insulinoma is enucleation or resection, which are associated with various degrees of morbidity, including fistulas, pseudocysts, and necessity for reoperations. PATIENTS: We evaluated the outcome of 65 patients operated on for organic hyperinsulinism at an experienced university hospital (Department of Surgery, Heinrich-Heine University, Düsseldorf, Germany) between 1990 and 1998. Procedures included enucleation (n=37), left-sided resection (n=19), combination of enucleation from the head and left-sided resection (n=4), subtotal left pancreatectomy (n=2), and pancreaticoduodenectomy (n=3). RESULTS: In 47 out of the 65 patients (72%), the expected benign solitary insulinoma was found. Seven patients had malignant tumors and another eight had multiple tumors (including two with multiple endocrine neoplasia type 1 (MEN-1)), and three had nesidioblastosis. In total, 20 patients (31%) developed postoperative drainage of high amylase containing fluid, which in all but three cases resolved with conservative therapy. The three patients who developed fistulas and the three patients who developed pseudocysts underwent reoperative surgery. Seventeen (41%) of the patients who underwent enucleation (10 from the pancreatic head; 50%) and six (25%) of the resected patients demonstrated these complications. Postoperative glucose metabolism was normalized in all patients. CONCLUSION: Resection, especially in the head of the pancreas, demonstrates lower complication rates than enucleation. We propose resection for tumors that are large, malignant, situated close to pancreatic duct, and are multiple, including in MEN-1. For tumors in the head, pancreaticoduodenectomy may be an occasional choice.

Adolescent↗
PubMed1999

Expression of wild-type ret, ret/PTC and ret/PTC variants in papillary thyroid carcinoma in Germany.

INTRODUCTION: Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy. Although the clinical course is usually rather benign, a subset of tumors is more aggressive. The ret/PTC oncogene was found only in PTC, with varying frequencies of up to 30%. Recently, two new variants of ret/PTC could be identified in post-Chernobyl PTCs, which raised the possibility that the prevalence of ret/PTC in non-radiation-induced PTCs might be higher than previously described. Normal thyroid cells do not express wild-type ret, but there is evidence that ret activation from any cause, including wild-type ret, occurs in more than a half of papillary tumors. METHODS: We used reverse transcription polymerase chain reaction and sequencing to examine wild-type ret and all five forms of ret/PTC known today in 99 PTCs from Hannover, Dusseldorf, Halle and Regensburg. Our method could also detect other variants within the known breakpoint regions. The presence of the ret tyrosine-kinase domain was examined by immunohistochemistry. RESULTS: Seven PTC1-positive tumors and one PTC3-positive tumor (8%), but none with the new variants or other variants of PTC1, 2 or 3 could be detected. Of 43 tumors examined, 20 showed expression of wild-type ret mRNA and staining of ret protein located predominantly to the cell membrane. CONCLUSION: Variants of ret/PTC do not substantially contribute to non-radiation-related ret/PTC-positive tumors, and the prevalence of ret/PTC in Germany is low in contrast to the high rate of wild-type ret expression. Thus, expression of wild-type ret should be examined for pathogenic, prognostic and possible therapeutic implications.

Carcinoma, Papillary↗
PubMed1997

Differential loss of heterozygosity in familial, sporadic, and uremic hyperparathyroidism.

Various genetic loci harboring oncogenes, tumor suppressor genes, and genes for calcium receptors have been implicated in the development of parathyroid tumors. We have carried out loss of heterozygosity (LOH) studies in chromosomes 1p, 1q, 3q, 6q, 11q, 13q, 15q, and X in a total of 89 benign parathyroid tumors. Of these, 28 were sporadic parathyroid adenomas from patients with no family history of the disease, 41 were secondary parathyroid tumors, 5 were from patients with a history of previous irradiation to the neck, 12 were from patients with a family history of hyperparathyroidism, and 3 were parathyroid tumors related to multiple endocrine neoplasia type 1 (MEN1). In addition, we determined the chromosomal localization of a second putative calcium-sensing receptor, CaS, for inclusion in the LOH studies. Based on analysis of somatic cell hybrids and fluorescent in situ hybridization to metaphase chromsomes, the gene for CaS was mapped to chromosomal region 2q21-q22. The following results were obtained from the LOH studies: (1) out of the 24 tumors that showed LOH, only 4 had more than one chromosomal region involved, (2) in the tumors from uremic patients, LOH of chromosome 3q was detected in a subset of the tumors, (3) LOH of the MEN1 region at 11q13 was the most common abnormality found in both MEN1-related and sporadic parathyroid tumours but was not a feature of the other forms of parathyroid tumors, (4) LOH in 1p and 6q was not as frequent as previously reported, and (5) tumor suppressor genes in 1q and X might have played a role, particularly on the X chromosome, in the case of familial parathyroid adenomas. We therefore conclude that the tumorigenesis of familial, sporadic, and uremic hyperparathyroidism involves different genetic triggers in a non-progressive pattern.

Adenoma↗
PubMed1996

Microsatellite instability and mutation analysis of hMSH2 and hMLH1 in patients with sporadic, familial and hereditary colorectal cancer.

To date, at least four genes involved in DNA mismatch repair, hMSH2, hMLH1, hPMS1 and hPMS2, have been demonstrated to be altered in the germline of patients with hereditary nonpolyposis colorectal cancer (HNPCC). Additionally, defective mismatch repair is thought to account for the observation of microsatellite instability (MIN) in tumors from these patients. The genetic defect responsible for the MIN+ phenotype in sporadic colorectal cancer, however, has yet to be clearly delineated. In order to better understand the role of somatic and germline alterations within hMSH2 and hMLH1 in the process of colorectal tumorigenesis, we examined the entire coding regions of both of these genes in seven patients with MIN+ sporadic colorectal cancer, 19 patients with familial colorectal cancer, and 20 patients meeting the strict Amsterdam criteria for HNPCC. Thirteen germline, two somatic, and four neutral alterations were identified. The two somatic mutations occurred in patients having familial cancer, while the germline mutations were distributed among one sporadic (14%), three familial (16%), and nine HNPCC (45%) cases. All patients with identified mutations in the mismatch repair genes, whose tumors were available for analysis, demonstrated MIN. On the other hand, we could not identify mutations in the subset of clinically defined HNPCC patients with MIN negative tumors nor in the majority (6/7) of MIN+ sporadic tumors.

Adaptor Proteins, Signal Transducing↗
PubMed1996

Allelic loss of the retinoblastoma tumor suppressor gene: a marker for aggressive parathyroid tumors?

Allelic loss of the retinoblastoma tumor suppressor gene has recently been shown to be highly specific for parathyroid carcinoma. It has been proposed that this genetic abnormality may have diagnostic and prognostic implications for parathyroid carcinoma, but to date no further studies are available to substantiate these findings. In the present study, three cases of atypical recurrent hyperparathyroidism were examined: a patient with parathyroid carcinoma and an autotransplanted adenoma that progressed into carcinoma, a patient with recurrent juvenile hyperparathyroidism, and a patient with severe recurrent secondary hyperparathyroid disease due to rapidly growing autotransplant. Six pairs each of sporadic parathyroid adenoma and secondary parathyroid disease were also studied for comparison. Allelic losses of RB and D13S71 at 13q14 was found in the parathyroid carcinoma and the corresponding autotransplant that had previously been considered benign tissue and in the case of recurrent juvenile hyperparathyroidism, but not in any of the other tumors. Our findings support the findings of the previous study that RB or 13q loss is specific for parathyroid tumors with increased aggressiveness and might be of clinical significance.

Adenoma↗
PubMed1995

[Differentiated thyroid gland carcinomas in "autonomous adenomas" in childhood].

Thyroid surgery is seldomly indicated in childhood and adolescence mainly because of suspicious nodules or proven carcinoma. Indications for operation in Graves disease and focal autonomy are discussed controversially, however. In a retrospective case control study two of our 6 patients up to 18 years demonstrated differentiated thyroid cancer with focal autonomy in the autonomous nodule. Other studies show similar results. Thyroid surgery is therefore warranted in all children and adolescents with focal thyroid autonomy.

Adenocarcinoma, Follicular↗
PubMed1993

Expression of the human TSH receptor in a human thyroid carcinoma cell line that lacks an endogenous TSH receptor: growth inhibition by cAMP.

The role of TSH and its receptor in controlling growth of thyroid carcinomas is far from well understood. In order to study this subject further we established a new human thyroid carcinoma cell line. We transfected human thyroid carcinoma cells lacking an endogenous TSH receptor with the human TSH receptor cDNA. Transfected cells, designated HTC-TSHr, expressed the TSH receptor mRNA and synthesized a functional TSH receptor with a TSH binding affinity in the order of magnitude of normal thyroid cells. In response to TSH stimulation HTC-TSHr cells accumulated cAMP, indicating a functional TSH receptor-adenylate cyclase system. However, HTC-TSHr cells did not concentrate iodide and lacked thyroglobulin immunoreactivity, although they did express low amounts of thyroglobulin mRNA. Proliferation of HTC-TSHr cells was inhibited by dibutyryl-cAMP and forskolin and also by TSH via the re-expressed TSH receptor.

Base Sequence↗
PubMed1991

Correlated abnormalities of transforming growth factor-beta 1 response and p53 expression in thyroid epithelial cell transformation.

Using the thyroid follicular cell as a model for multi-stage carcinogenesis, we have investigated the role of two potential negative growth regulators ('anti-oncogenes') in epithelial tumour progression--transforming growth factor-beta 1 (TGF beta 1) and p53. Normal follicular cells, as expected, showed marked growth inhibition in response to TGF beta 1. Adenoma cells were equally inhibited. In contrast, spontaneously and SV40-immortalised follicular cell lines showing features of malignant transformation (notably loss of growth factor dependence) had lost all responsiveness to TGF beta 1, accompanied by a partial loss of its receptors. p53 protein was below detectable limits in normal and in adenoma cells but in contrast very high levels were observed in all three transformed lines. In the SV40-immortalised cells, this was expected in view of the known stabilising effect of the viral large T protein. In the spontaneous line we found strong evidence for point mutation of p53, which is known to have the same effect. Both mechanisms result in loss of p53 tumour suppressor function despite increased protein content. We conclude that loss of inhibition by TGF beta and inactivation of p53 are important steps in in vitro immortalisation and/or in vivo tumour progression in human thyroid follicular cells, and speculate that p53 may mediate or be required for the inhibitory signal normally induced by TGF beta 1.

Adenoma↗
PubMed1986

[The cold thyroid nodule].

A "cold" thyroid nodule basically always carries the risk of being "malignant". Scintigraphy and sonography can not differentiate between benign and malignant. The best means to discriminate the risk of "cold nodules" is by way of fine needle aspiration biopsy. In general the operative indication for "cold" nodules can be generous. In high suspicion the best surgical strategy is "hemithyroidectomy" as primary operation.

Biopsy, Needle↗
PubMed1985

Thyroid function after surgery for autonomous and non-autonomous nodular endemic goitre--effect of iodide-substitution.

The aim of this study was to evaluate the influence of postoperative iodide-substitution on the function of thyroid remnants of different quality and quantity in order to define the appropriate prophylaxis (iodide or thyroid hormone) to prevent recurrent goitre. In a prospective, randomized clinical trial, the following patients were examined: group I: simple, non-autonomous nodular goitre, bilateral thyroidectomy (n = 40); group II: simple, non-autonomous nodular goitre, "selective" (unilateral) thyroidectomy (n = 40); group III: autonomous nodular goitre, bilateral thyroidectomy (n = 40); group IV: autonomous nodular goitre, "selective" (unilateral) thyroidectomy (n = 35). The following parameters were measured 6 and 12 weeks postoperatively. Serum-total-T4, -T3, -TSH, TRH-test, 99mTc-Thyroid-Uptake (TcTU). Six weeks postoperatively the 4 groups were separately randomized into controls and treatment groups, who received 200 micrograms iodide/day orally. Six weeks postoperatively, patients in group I had lower T4 levels and both basal and stimulated TSH were higher than in the other groups, however no significant differences were observed in T3, T4/T3 ratio and TcTU. Twelve weeks postoperatively patients from groups I, II and III, who had been treated with iodide, had lower T3 and TcTU values but higher T4 and T4/T3 than the appropriate controls. Basal and stimulated TSH showed no differences between controls and iodide-treated patients in these groups. In group IV, T4 and T3 showed a tendency to elevation (n.s.), and basal and stimulated TSH as well as TcTU were lower in patients with iodide.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical Trials as Topic↗
PubMed1983

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.

Adenylyl Cyclases↗
PubMed1983

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.

Adolescent↗