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Biomedical subjects

K W Schmid

Publications and source records attributed to K W Schmid.

At least 19 recordsLinked to original sources
PubMed2007

The C allele of the GNB3 C825T polymorphism of the G protein beta3-subunit is associated with an increased risk for the development of oncocytic thyroid tumours.

Carriers of the C allele of the common C825T polymorphism in the GNB3 gene of the G protein have been associated with the development of follicular thyroid adenomas. Since the C allele of this polymorphism is related to a lower signalling capacity, it was speculated whether the C825T polymorphism may play a particular role in oncocytic thyroid tumours, which are recognized for their reduced ability to synthesize thyroid-specific proteins and hormones, although they possess an intact thyroid-stimulating hormone receptor-adenylyl cyclase system. Using pyrosequencing, both the genotype distribution and the allele frequency of the C825T polymorphism were investigated in a series of 104 patients with oncocytic thyroid tumours of follicular cell origin [58 adenomas, 41 follicular thyroid carcinomas (FTCs), and five papillary thyroid carcinomas (PTCs)]; the results were compared with those obtained from 321 age and gender-matched healthy blood donors and a series of 327 non-oncocytic thyroid tumours of follicular cell origin (119 adenomas, 80 FTCs, and 186 PTCs). Analysis of the genotype distribution (comparing oncocytic with non-oncocytic tumours of the present series) revealed a significantly increased odds ratio (OR) for CC versus TT (OR = 4.22; p = 0.011) and CC versus CT (OR = 1.62; p = 0.049) carriers to develop an oncocytic thyroid tumour; ORs to develop an oncocytic thyroid tumour were also increased comparing the genotype distribution between the group of oncocytic tumours and healthy controls for CC versus TT (OR = 3.73; p = 0.017) and CC versus all T carriers (OR = 1.56; p = 0.034). Oncocytic thyroid tumours as a group showed a statistically significant increase of the C-allele frequency when compared with all non-oncocytic tumours (p = 0.0039) as well as healthy blood donors (p = 0.017). The results strongly suggest that the C allele of the GNB3 C825T polymorphism of the G protein beta3-subunit is associated with an increased risk for the development of oncocytic thyroid tumours. This polymorphism may thus be considered a (co)factor favouring the development of oncocytic thyroid tumours, although the biological mechanism(s) underlying this association remain obscure.

Adenoma↗
PubMed2007

Activation of extracellular regulated kinases (ERK1/2) but not AKT predicts poor prognosis in colorectal carcinoma and is associated with k-ras mutations.

Signal transduction and modulation represent central mechanisms in cellular processes such as cell-cycle regulation, oncogenesis, and apoptosis. The aim of this study was to determine the prognostic relevance of two kinases important in the regulation of cell proliferation and apoptosis in 135 colorectal cancer cases: AKT and extracellular regulated kinases (ERK1/2). We investigated the relationship of phospho-ERK1/2 (pERK1/2) and phospho-AKT (pAKT) with associated parameters (EGFR, COX-2, cyclin-D1), proliferative activity (Ki-67), and apoptosis (TUNEL) using immunohistochemistry. Additionally, the k-ras gene was screened for mutations to determine its putative association with ERK1/2 activation. Activation of ERK1/2 but not AKT correlated statistically with the presence of k-ras mutations (P = 0.015). Survival analysis of phospho-ERK1/2 immunoexpression showed a significant correlation with decreased overall survival (OS). The multivariate Cox regression analysis identified pERK1/2 as an independent prognostic parameter (P = 0.005). Activation of ERK1/2 in colorectal cancer may indicate aggressive tumor behavior and may constitute an independent prognostic factor. Furthermore, our data suggest that mutations of the k-ras oncogene may induce activation of ERK1/2. We propose immunohistochemical determination of pERK1/2 status as a promising candidate for the identification of high-risk patients who would benefit from new anticancer drugs targeting the ERK pathway.

Colorectal Neoplasms↗
PubMed2006

Overexpression of cyclo-oxygenase-2 is an independent predictor of unfavourable outcome in node-negative breast cancer, but is not associated with protein kinase B (Akt) and mitogen-activated protein kinase (ERK1/2, p38) activation or with Her-2/neu signalling pathways.

BACKGROUND AND AIM: The production of prostaglandins is regulated by cyclo-oxygenases (COXs), which also have a role in tumour development and progression in various malignancies, including breast cancer. The mechanisms by which COX-2 contributes to unfavourable prognosis are still poorly understood. The association between expression of COX-2 and possible linked signalling pathways-namely, Akt, extracellular regulated kinases (ERK1/2), the stress-activated kinase p38 or Her-2/neu-is assessed in a series of 113 node-negative breast cancers. RESULTS: COX-2 was identified as an independent prognostic factor (p = 0.034) in node-negative breast cancer by survival analysis. The lack of a relationship between COX-2 expression and activated Akt, Erk1/2, p38 and Her-2/neu was indicated by statistical analysis. CONCLUSIONS: The prognostic effect of COX-2 expression on lymph node-negative breast cancer is confirmed-COX-2 is probably not regulated by HER-2, Akt, Erk1/2 or p38. Further studies are necessary for the elucidation of the signalling pathways responsible for the modification of COX-2 expression and the increased aggressiveness of breast cancers overexpressing COX-2.

Aged↗
PubMed2006

[Therapy related alterations to the thyroid gland].

Therapy related alterations to the thyroid gland are associated with more or less specific morphological changes. The therapy (thyrostatic drugs, radio-iodine) may be administered for the treatment of thyroid dysfunction (hyperthyroidism), or the thyroid gland is involved during or after the treatment (irradiation, various drugs) of primarily non-thyroid related diseases. The present review summarizes the most important morphological changes related to therapy.

Amiodarone↗
PubMed2006

[Salivary gland-like tumors of the breast].

A subset of rare benign and malignant breast tumors with and without myoepithelial differentiation are morphologically and histogenetically similar to salivary gland tumors, but may differ in incidence and clinical behavior. The clinicopathological, immunohistochemical, molecular and prognostic features of ten salivary gland-like tumor entities of the breast are discussed and compared with their respective counterparts in the salivary glands.

Adenoma↗
PubMed2005

Relationship and prognostic significance of phospho-(serine 166)-murine double minute 2 and Akt activation in node-negative breast cancer with regard to p53 expression.

The Akt signalling pathway plays a central role in tumourigenesis. Activation of Akt is related to a more aggressive phenotype in various human cancers, including breast cancer. Its activation contributes to cancer progression via pleiotropic effects, including suppression of apoptosis and modulation of cell cycle regulation. Murine double minute 2 (MDM2) is an oncoprotein that inhibits the function of p53 tumour suppressor protein. Cell culture studies show that Akt-related phosphorylation of MDM2 at serine 166 allows MDM2 to gain nuclear entry and fulfil its p53 regulating function. This study was designed to analyse the relationship of phospho-MDM2 (pMDM2) expression with Akt activation to determine a possible prognostic relevance of pMDM2 in node-negative breast cancer with respect to Akt activation and p53 status. pMDM2, phospho-Akt (pAkt) and p53 protein expression status were analysed immunohistochemically in 121 paraffin-embedded breast cancer cases. Expression of pMDM2 correlated with Akt activation (P<0.001). Univariate analysis identified pMDM2 as a prognostic factor (P=0.0458) in node-negative breast cancers. The unfavourable prognostic significance was even more pronounced in tumours with a pMDM2(+)/pAkt(+) immunophenotype (P=0.0205). Stratification into a p53-negative subgroup further strengthened the adverse prognostic influence. These data confirm that MDM2 phosphorylation at serine 166 is mediated by Akt kinase. Besides the prognostic impact of pMDM2, our findings suggest that Akt-mediated modulation of the MDM2/p53 complex contributes to increased tumour aggressiveness especially in p53-negative breast cancers. However, due to the relatively small number of patients in this cohort, the results obtained need to be confirmed by larger cohorts.

Biomarkers, Tumor↗
PubMed2005

Endoscopic treatment of large primary adrenal tumours.

BACKGROUND: Endoscopic adrenalectomy has become the treatment of choice for small benign adrenal tumours but should not be used for malignant lesions. It is debatable whether large and therefore potentially malignant primary adrenal tumours should be removed by minimally invasive techniques. METHODS: Three hundred and eighty primary adrenal tumours in 368 patients (142 male and 226 female; mean(s.d.) age 48.9(14.4) years) were excised by laparoscopic or retroperitoneoscopic adrenalectomy. Adrenal neoplasias exceeded 6 cm in diameter (range 6-13 cm) in 33 patients (18 male and 15 female; age 42.6(14.2) years). RESULTS: There were no deaths. Patients with large tumours had an increased conversion rate (P = 0.039), longer operating time (P < 0.001) and greater intraoperative blood loss (P = 0.007) than those with smaller lesions, but a similar overall morbidity rate (P = 0.207). Six malignant tumours were identified (diameter 4-10 cm; four phaeochromocytomas and two adrenocortical carcinomas). Local recurrence developed in two patients and distant metastasis occurred in all six patients with malignant lesions. CONCLUSION: Endocopic adrenalectomy perfomed by an experienced surgeon should be the treatment of choice for tumours exceeding 6 cm in diameter.

Adolescent↗
PubMed2005

Gene signatures of testicular seminoma with emphasis on expression of ets variant gene 4.

Gene expression patterns of testicular seminoma were analysed applying oligonucleotide microarrays in 40 specimens of different tumour stages (pT1, pT2, pT3) and in normal testes. Transcripts of maternally expressed 3 transcripts were expressed in seminoma without correlation with delta-like 1 homologue expression indicating an impaired imprinting status in seminoma. Interestingly, the transcripts of bromodomain-containing 2 and nuclear autoantigenic sperm protein associated with spermatogenesis were significantly upregulated in progressing tumour stages. Transcription factors TEA domain family member 4 and ETS variant gene 4 (ETV4), weakly expressed in normal testis, were strongly augmented during tumourigenesis. For ETV4 expression, a significant correlation with the increased expression of matrix metalloproteinase 2 and a disintegrin and metalloproteinase domain 15 was determined. The ETV4 protein was localised to nuclei of spermatogonia and revealed an intense staining in seminoma cells. Taken together, we characterised additional transcription factors and spermatogenesis-associated genes involved in the progression of seminoma.

Adenovirus E1A Proteins↗
PubMed2005

Differential expression of the human somatostatin receptor subtypes sst1 to sst5 in various adrenal tumors and normal adrenal gland.

Somatostatin (SRIF) is a widely distributed peptide with growth-inhibiting effects in various tumors. So far, five distinct human SRIF receptor subtypes (sst1-sst5) have been identified. We investigated expression of the five ssts in various adrenal tumors and in normal adrenal gland. Tissue was obtained from ten pheochromocytomas (PHEOs), nine cortisol-secreting adenomas (CPAs), eleven aldosterone secreting adenomas (APAs) and eight non-functional adenomas (NFAs) after retroperitoneoscopic surgery, and used for RNA extraction. Adrenal tissue surrounding the tumor was available for analysis in twenty-seven cases. Receptor expression was studied by RT-PCR using sst-specific primers and subsequently confirmed by Southern blotting. Expression of all five receptor subtypes was observed in RNA obtained from normal adrenal gland. Furthermore, each receptor subtype was expressed in more than 50 % of all tumors analyzed. No sst5 expression was found in PHEOs, while sst1 was present in nearly all of these tumors. Only a few of the CPAs expressed subtypes sst1 and sst4. Expression of all five subtypes was distributed equally in APAs. No sst4 was found in any of the NFAs. Differential expression of ssts in various adrenal tumors may point to new aspects in the pathogenesis of these adenomas. Furthermore, the presence of specific ssts could expand the diagnostic and therapeutic strategies during management. New subtype specific analogues of SRIF may be used in the future depending on the type of adrenal tumor and receptor subtype expressed.

Adenoma↗
PubMed2005

Prognostic value of c-erbB-2 expression in papillary thyroid carcinoma.

AIMS: c-erbB-2 overexpression has been shown to be a potential marker of aggressive biological behaviour in a varity of tumours, whereas its role played in thyroid papillary thyroid carcinoma (PTC) remains unclear. Objective of the study is to determine whether c-erbB-2 overexpression correlates with the clinical course. METHODS: We have studied 32 PTC by a two-step immunocytochemical staining procedure for paraffin-embedded specimens (DAKO Hercep-Test). Semiquantitative evaluations were performed, based on the intensity of immunostaining and the percentage of tumor cells. RESULTS: 34% (11/32) of the PTC showed a membranous overexpression of the HER2/neu oncoprotein. Correlating the pathological and clinical data revealed that 81% (9/11) c-erbB-2 positive patients and only 33% (7/21) c-erbB-2 negative patients developed a tumor recurrence or a progression (p = 0.02 in Fisher's exact test). 3/11 c-erbB-2 positive patients died from PTC whereas all (21/21) c-erbB-2 negative patients are still alive (p = 0.03). CONCLUSIONS: Our results strongly suggest that c-erbB-2 oncoprotein overexpression is related to the clinical course of PTC.

Adolescent↗
PubMed2005

Guidelines on radioiodine therapy for differentiated thyroid carcinoma: impact on clinical practice.

AIM: For the examination of the impact on clinical practice of the guidelines for differentiated thyroid carcinoma (DTC), treatment data from the ongoing Multicenter Study Differentiated Thyroid Carcinoma (MSDS) were analyzed. PATIENTS, METHODS: Patients were randomized to adjuvant external beam radiotherapy (RTx) or no RTx in addition to standard therapy in TNM stages pT4 pN0/1/x M0/x (UICC, 5th ed. 1997). All patients were to receive the same treatment regimen consisting of thyroidectomy, ablative radioiodine therapy (RIT), and a diagnostic 131I whole-body scintigraphy (WBS) 3-4 months after RIT. RESULTS: Of 339 eligible patients enrolled between January 2000 and March 2004, 273 could be analyzed. Guideline recommendations by the German Society for Nuclear Medicine from 1999 and 1992 were complied with within 28% and 82% with regard to the interval between surgery and RIT (4 vs. 4-6 weeks), in 33% and 84% with regard to 131I activity for RIT (1-3 vs. 1-4 GBq; +/- 10%), and in 16% and 60% with regard to 131I activity for WBS (100-300 vs. 100-400 MBq; +/- 10%). CONCLUSIONS: The 1999 guideline revision appears to have had little impact on clinical practice. Further follow-up will reveal if guideline compliance had an effect on outcomes.

Combined Modality Therapy↗
PubMed2004

Impact of disease activity on thyroid diseases in patients with acromegaly: basal evaluation and follow-up.

In patients with acromegaly, the exact incidence of thyroid disorders is still controversial and less is known about the impact of disease activity and successful treatment. To address this issue, we investigated 73 acromegalic patients (age 55 +/- 13 yr; mean +/- SD) by ultrasonography in comparison to an age-matched control group (54 +/- 1 yr) in the same moderate iodine deficient area (retrospective study). These non-acromegalic volunteers (n = 199) were examined in the same clinic during a thyroid screening test. At the time of examination, 52 (71.2 %) of the acromegalic patients were active, 17 (23.3 %) were cured, and 4 (5.5 %) were controlled with somatostatin analogues. The prevalence of goiter (normal range < 18 ml female, < 25 ml male) was significantly higher (82.2 %) in the mixed group of acromegalics (active, well controlled, cured; n = 73) and in the active group (90.4 %) than in the control group (n = 199, 18.1 %, p < 0.001). Thyroid nodules were found in 63.0 % of the mixed group of acromegalics and in 71.2 % of patients with active disease (33.1 % in controls, p < 0.001). (99 m)Tc scintigraphy revealed thyroid autonomy in 9/73 (12.3 %) and cold nodules in 19/73 (26.0 %) patients. Thyroid cancer was diagnosed in 4 (5.5 %) of acromegalic patients (3 papillary and 1 follicular carcinoma). We found a weak correlation between the disease duration and the initial thyroid volume (r = 0.54, p < 0.0056). Thirty-seven newly diagnosed acromegalics were followed over a period of 7.3 +/- 4.1 years. 5 (13.5 %) of these patients remained active, 8 (21.6 %) were controlled with somatostatin analogues, and 24 (64.9 %) were cured. The mean age, sex distribution, disease duration, prevalence of TSH-deficiency, and initial thyroid volume (46 +/- 11 ml in active, 42 +/- 7 ml in controlled, and 45 +/- 5 ml in cured patients) did not differ statistically between the three groups. In patients with active acromegaly, thyroid volume increased by 19.5 +/- 8.1 %. In contrast, thyroid volume decreased in the group of medically controlled and cured acromegalics (- 21.5 +/- 7.1 %; p < 0.005 and - 24.2 +/- 5.7 %; p < 0.002, respectively). No correlation was found between thyroid volume and TSH levels, levothyroxine and/or iodide administration neither in TSH sufficient nor in TSH insufficient patients. In conclusion, successful treatment of patients with active acromegaly decreases thyroid volume. Cold nodules and thyroid cancer frequently occur in acromegalic patients.

Acromegaly↗
PubMed2004

Immunohistochemical determination of somatostatin receptor subtypes 1, 2A, 3, 4, and 5 in various adrenal tumors.

While octreotide binds with high affinity to sst2a only, the new analogue SOM230 demonstrates high affinity for sstl, 3, and 5, in addition. We examined the immunohistochemical expression of somatostatin receptor subtypes (sst) in 7 pheochromocytomas (PHEO), 5 Conn adenomas (CONN), 9 Cushing adenomas (CUSH), 7 nonfunctioning tumors (NFA), and 4 adrenal carcinomas (CA). About one third of the PHEO were positive for sst1, 2a, and 5. Less than 30% of cells were stained in the majority of these tumors. Each of the PHEO expressed sst3 with more than 60% of cells stained. Two thirds of the NFA revealed positive staining for sst1, 2a, and 3 with less than 30% of cells affected. Sst5 was expressed in nearly all of the NFA with positive staining in 30-60% of tumor cells. Nearly all CUSH and CONN were positive for the subtypes evaluated. In the majority of these tumors, less than 30% of cells were positively stained. Fifty percent of CA expressed sst2a and 3 with positive staining in 30-100% of cells. None of them expressed sst1. Somatostatin receptors are expressed in adrenal tumors with a tumor-specific distribution pattern. This may offer new diagnostic and therapeutic possibilities.

Adenoma↗
PubMed2004

Erdheim-Chester disease: case report with multisystemic manifestations including testes, thyroid, and lymph nodes, and a review of literature.

Erdheim-Chester disease is a rare non-Langerhans' cell histiocytosis with characteristic radiological and histological features. This entity is defined by a mononuclear infiltrate consisting of lipid laden, foamy histiocytes that stain positively for CD68. About half of those affected have extraskeletal manifestations, including involvement of the hypothalamus-pituitary axis, lung, heart, retroperitoneum, skin, liver, kidneys, spleen, and orbit. This report describes the case of a 50 year old white man who presented with hypogonadism and diabetes insipidus. At necropsy, extensive organ involvement was found, including the testes, thyroid, and lymph nodes. This is the first report of thyroid and lymph node infiltration in this disease. Because of the endocrinological symptoms, neurosarcoidosis and hypophysitis are important diseases in the differential diagnosis. This report also includes a review of the literature concerning rare organ manifestations and patients presenting primarily with similar symptoms.

Erdheim-Chester Disease↗
PubMed2004

Epidermal growth factor receptor as a novel therapeutic target in anaplastic thyroid carcinomas.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive human malignancies, with a median survival of up to 6 months. Such a bad prognosis under the present treatment procedures suggests the need for novel approaches in the management of this disease. Since some epidermal growth factor receptor (EGFR) inhibitors are now in clinical trials and few data are available concerning EGFR expression in anaplastic thyroid carcinomas, we tried to estimate a possible overexpression of this receptor in a larger tumor series. Twenty-five ATCs, including 3 ATCs with poorly differentiated thyroid carcinoma (PDTC) parts, were immunohistochemically investigated with a mouse monoclonal antibody directed against EGFR (EGFR pharmDX kit). The tumors revealed primarily a distinct membranous staining pattern, and in several tumor cells an additional cytoplasmic reactivity could be observed. The anaplastic carcinomas presented with 5 of 25 (20%) without EGFR reaction, 10 of 25 (40%) with reactivity, and 10 of 25 (40%) with overexpression of the receptor. All ATCs with PDTC parts (100%) showed EGFR overexpression. Cytoplasmic reactivity was observed in 56% of all ATCs. A significant correlation was calculated for EGFR overexpression and cytoplasmic staining (P = 0.036). Concerning receptor overexpression, ATCs were significantly different from ATCs with PDTC parts (P = 0.023). For the first time, we present EGFR overexpression in ATC in a larger tumor series, demonstrating that EGFR overexpression is a common finding in ATC. For at least one-third of all anaplastic thyroid carcinomas, EGFR seems to be a promising agent for the targeted molecular therapy of these extraordinarily aggressive tumors.

Aged↗
PubMed2003

[Hyperplasia of the thyroid gland].

Hyperplasia of the follicular epithelium (goitre) is the most common morphological change in the thyroid seen by the pathologist. The present paper deals with the aetiology, epidemiology and clinical features of thyroid hyperplasia and its differential diagnosis from thyroid adenoma. Neoplastic hyperplasia of the calcitonin-producing thyroid C cells gives rise to familial medullary carcinoma. The second part of the paper deals with the definition of neoplastic C cell hyperplasia and its discrimination from physiological C cell hyperplasia.

Humans↗