Management of primary and renal hyperparathyroidism: guidelines from the German Association of Endocrine Surgeons (CAEK).

BACKGROUND AND AIMS: The purpose of this review is to provide updated recommendations for the surgical management of primary (pHPT) and renal (rHPT) hyperparathyroidism, formulating a new guideline of the German Association of Endocrine Surgeons (CAEK). METHODS: Evidence-based recommendations for the diagnosis and therapy of pHPT and rHPT were assessed by a multidisciplinary panel using PubMed for a comprehensive literature search together with a structured consensus dialogue (S2k guideline of the Association of the German Scientific Medical Societies, AWMF). RESULTS: During the last 20 years, a variety of new preoperative localization procedures, such as sestamibi-SPECT, 4D-CT, and various PET/CT procedures, were established for pHPT. High-resolution imaging, together with intraoperative parathyroid hormone (IOPTH) measurement, enabled focused or minimally invasive surgery to become the most favored surgical technique. Patients with pHPT and nonlocalizing imaging have a higher risk of multiglandular disease. Surgical therapy provides very high cure rates, with a clear relation to the surgeon's experience in parathyroid procedures. Reoperative parathyroidectomy, children with pHPT or familial forms, and parathyroid carcinoma are addressed and require special surgical expertise. A multidisciplinary team of experienced nephrologists, transplant, and endocrine surgeons should assess the diagnosis and treatment of renal HPT. CONCLUSION: Surgery is the only curative treatment for pHPT and should be considered for all patients with pHPT. For rHPT, a more selective approach is required, and parathyroidectomy is indicated only when conservative treatment options fail. In parathyroid carcinoma, the adequacy of local resection influences local disease control.

Surgical therapy of adrenal tumors: guidelines from the German Association of Endocrine Surgeons (CAEK).

BACKGROUND AND AIMS: Previous guidelines addressing surgery of adrenal tumors required actualization in adaption of developments in the area. The present guideline aims to provide practical and qualified recommendations on an evidence-based level reviewing the prevalent literature for the surgical therapy of adrenal tumors referring to patients of all age groups in operative medicine who require adrenal surgery. It primarily addresses general and visceral surgeons but offers information for all medical doctors related to conservative, ambulatory or inpatient care, rehabilitation, and general practice as well as pediatrics. It extends to interested patients to improve the knowledge and participation in the decision-making process regarding indications and methods of management of adrenal tumors. Furthermore, it provides effective medical options for the surgical treatment of adrenal lesions and balances positive and negative effects. Specific clinical questions addressed refer to indication, diagnostic procedures, effective therapeutic alternatives to surgery, type and extent of surgery, and postoperative management and follow-up regime. METHODS: A PubMed research using specific key words identified literature to be considered and was evaluated for evidence previous to a formal Delphi decision process that finalized consented recommendations in a multidisciplinary setting. RESULTS: Overall, 12 general and 52 specific recommendations regarding surgery for adrenal tumors were generated and complementary comments provided. CONCLUSION: Effective and balanced medical options for the surgical treatment of adrenal tumors are provided on evidence-base. Specific clinical questions regarding indication, diagnostic procedures, alternatives to and type as well as extent of surgery for adrenal tumors including postoperative management are addressed.

Immune regulatory plasmacytoid dendritic cells selectively accumulate in perithyroidal lymph nodes of patients with Graves disease: implications for the understanding of autoimmunity.

UNLABELLED: Endocrine orbitopathy (EO) is the most common extrathyroidal manifestation of Graves disease (GD) but the involvement of the underlying immunological dysregulations remains largely unknown. The major source for IFNa-production, plasmacytoid dendritic cells (PDC) are fundamentally involved in the integration of TH1 and TH2 immune responses but also implicated in the pathogenesis of autoimmune diseases such as lupus. AIM: To establish whether PDC may play a role in GD autoimmune reaction and in the pathogenesis of EO. MATERIAL AND METHODS: In a series of six sequential patients with GD as well as six further patients with multinodular goiter, cervical lymph nodes (LN) were sampled and preserved in the setting of thyroid resection. In parallel, peripheral blood samples were collected. The frequency of PDC from the peripheral blood and lymph nodes were determined. Mononuclear cells (MC) were enriched from lymph nodes and peripheral blood using Fiquoll-hypaque density gradient centrifugation. Mononuclear cells were stained using BDCA-2-PE and CD123-FITC monoclonal antibodies and their frequency subsequently analyzed using fluorescence activated cell sorting (FACS). Dead cells were excluded from analysis by appropriate gating strategies and propidium iodide (PI) staining. RESULTS: In all patients with GD (with or without EO), PDC frequency was significantly increased in perithyroidal LN as compared to LN of patient not suffering form autoimmune diseases, e. g. patients with multinodular goiter (p < 0.01). The number of PDC infiltrating lymph nodes (LN-PDC) was also higher when compared to peripheral blood PDC (pB-PDC) of patients with multinodular goiter (p < 0.05). Finally, LN-PDC counts in perithyroidal lymph nodes of patients with GD were substantially increased when compared to pB-PDC of the same patients (p < 0.01) indicating a migration and accumulation of PDC in the draining LN. CONCLUSIONS: We found evidence that PDC selectively accumulate in perithyoidal LN of patients with GD, but not other thyroid diseases such as multinodular goiter. Based on their central importance in the pathogenesis of autoimmune processes such as in lupus erythematoides, we suggest that the migration and accumulation of PDC in an anatomical joining point between the thyroid gland and orbita may be of critical importance for the initiation and maintenance of a chronic autoimmune stimulation. This implies a so far unknown role for PDC in GD and as putative cellular targets for new therapeutic approaches.

Long-term results of surgical treatment in Graves' disease orbitopathy. Is there a correlation between the extent of thyroidectomy and the course of orbithopathy?

UNLABELLED: The place of thyroidectomy in the management of the Graves' disease patients with endocrine orbitopathy (EO) is still controversial. The aim of this study was to evaluate the course of EO according to the extent of thyroid resection. METHODS: A retrospective cross-sectional study was performed on a series of 171 cases of Graves'disease, operated in the period 1987-2002 in the Department of Surgery of the Philipps University, Marburg. The severity of EO at the time of operation was assessed according to NOSPECS classification and a structured telephone interview was conducted in order to appraise the long term results. RESULTS: Complete data acquisition was possible in 153 patients (89%). There were 123 women with a median age of 36 years (range 10-75) and 30 men with a median age of 33 years (range 22-65). Concerning the severity of EO, 70 patients (45.8%) had no ocular symptoms (group I). The 83 patients with clinical eye disease were divided in group II--63 patients (76%) with moderate syndrome and group III--20 patients (24%) with marked symptoms of EO. 12 patients received total thyroidectomy, 96 had Dunhill-resection and in 45 patients subtotal resection was performed. A median follow-up period of 96 months (range 12-216 months) was recorded. Post-operatively, of the 83 patients with EO, 53 patients (63.8%) declared an improvement of EO, in 29 patients (34.9%) the disease was stable and only one patient declared the worsening of EO. The extent of thyroid resection did not correlate with the postoperative course of orbitopathy. CONCLUSION: Thyroid surgery for GD improves the course of EO, independent of the extent of resection.

The impact of parathyroid gland autotransplantation during bilateral thyroid surgery for Graves' disease on postoperative hypocalcaemia.

OBJECTIVE: The aim of this study was to compare the rate of hypocalcaemia after bilateral thyroid resection for Graves' Disease in patients with and without parathyroid gland autotransplantation (PTAT). PATIENTS AND METHODS: A total of 153 patients following thyroid surgery for Graves' disease were studied. Patients were divided into three groups. Subgroup I comprised of 129 patients without PTAT, Subgroup II comprised of 19 patients with PTAT of one parathyroid gland and Subgroup III comprised of 6 patients with PTAT of two parathyroid glands. Association between PTAT and postoperative hypocalcaemia (PH) after thyroidectomy was investigated. RESULTS: There were 27/128 (21.1%) patients with transient and 10/128 (7.8%) patients with permanent hypocalcemia within Subgroup I. Among Subgroup II 4/19 (21.1%) patients developed transient and no patient developed permanent hypocalcaemia, while in Subgroup III 2/6 (33.3 %) patients developed transient hypocalcaemia which became persistent. Thus, the frequency of permanent postthyroidectomy hypocalcaemia (PH) was significantly higher in the Subgroup III with PTAT of two parathyroid glands when compared to the Subgroup I without PTAT (p=0.032) and Subgroup II with PTAT of only one parathyroid glands (p=0.012). CONCLUSION: PTAT of one parathyroid gland is an effective procedure to reduce the incidence of permanent hypoparathyroidism after bilateral surgery for Graves disease. Transient hypoparathyroidism was not influenced by PTAT.

Severe Graves' ophthalmopathy may be a risk factor for the development of postthyroidectomy hypocalcaemia.

PURPOSE: The aim of this study was to compare the rate of hypocalcaemia after thyroid resection in patients with versus patients without Graves' Ophthalmopathy (GO). PATIENTS AND METHODS: 153 patients following thyroid surgery for Grave's disease were studied. Patients were divided into three groups according to the severity of GO at the time of surgery using the NOSPECS classification. Subgroup I comprised of 70 patients without GO, subgroup II comprised of 63 patients with moderate GO and 20 patients with severe GO were assigned to Subgroup III. Association between severe ophthalmopathy and postoperative hypocalcaemia after thyroidectomy was investigated. RESULTS: 12/70 patients complained transient and 3/70 permanent hypocalcemia within subgroup I. 14/63 patients developed transient and 4/63 patients permanent hypocalcaemia within subgroup II. There were 7/20 patients with transient and 5/20 cases with permanent hypocalcaemia in the patient group with severe GO (subgroup III). The incidence of permanent postthyroidectomy hypocalcaemia was significantly higher in the subgroup III with severe GO when compared to the subgroup I without GO (p=0.004). CONCLUSION: Although postthyroidectomy hypocalcemia seems to be a multifactorial phenomenon, this study implicates unknown role of severe GO at time of surgery in the development of hypocalcaemia after thyroid surgery for Graves' disease. Therefore, patients with GO should be considered for surgery at high volume centres specialised in thyroid and parathyroid surgery.

Differential effects of cetuximab and AEE 788 on epidermal growth factor receptor (EGF-R) and vascular endothelial growth factor receptor (VEGF-R) in thyroid cancer cell lines.

This study evaluated the role of EGF and the effects of EGF-targeting drugs (Cetuximab, AEE 788) on growth, apoptosis, and autocrine VEGF-secretion of thyroid cancer (TC) cells. Autocrine activation of the epidermal growth factor receptor (EGF-R) is commonly regarded to contribute to the malignant phenotype of TC cells and may therefore represent a rational therapeutic target. Out of a number of TC cell lines two anaplastic (Hth74, C643), one follicular (FTC133), and one papillary thyroid cancer cell line (TPC1) were analyzed in depth for VEGF-R-and EGF-R-expression, basal and EGF-stimulated (1-100 ng/ml) VEGF protein secretion and proliferation. Subsequently the antiprolifereative and antiangiogenic effect of cetuximab (Erbitux), a monoclonal antibody that blocks the EGF-R and AEE 788, a novel dual-kinase inhibitor of EGF-R and VEGF-R were assessed, and the downstream EGF-R signal transduction was analyzed by means of detecting phosphorylated pEGF-R, pVEGF-R, pAkt, and p-MAPK. EGF stimulated VEGF-mRNA expression and protein secretion in all TC cell lines. The EGF-R antagonist Cetuximab consistently decreased VEGF secretion in all TC cell lines (min. 15%, n.s. in C643 cells and max. 90% in Hth74 cells, P < 0.05), but did not affect tumor cell proliferation in vitro. In contrast, the EGF-R- and VEGF-R-kinase inhibitor AEE 788 not only reduced VEGF secretion (min. 55%, P < 0.05 in C643 and max. 75%, P < 0.05, in FTC133), but also exhibited a dose-dependent inhibition of tumor cell proliferation (min. 75%, P < 0.05 in C643 and max. 95%, P < 0.05 in Hth74) and was a potent inductor of apoptosis in two of four TC cell lines. These effects were always accompanied by reduced levels of pEGF-R, pVEGF-R, pAkt, and pMAPK. Although inhibition of the EGF-receptor by Cetuximab potently disrupts autocrine secretion of VEGF, only the concurrent inhibition of the VEGF- and EGF receptor, e.g., by AEE 788 induces reduced proliferation and apoptosis in vitro. This suggests a particular rationale for the use of tyrosine kinase inhibitors with dual modes of action such as AEE 788 in thyroid cancer.

Spatial perception predicts laparoscopic skills on virtual reality laparoscopy simulator.

OBJECTS: This study evaluates the influence of visual-spatial perception on laparoscopic performance of novices with a virtual reality simulator (LapSim(R)). MATERIALS AND METHODS: Twenty-four novices completed standardized tests of visual-spatial perception (Lameris Toegepaste Natuurwetenschappelijk Onderzoek [TNO] Test(R) and Stumpf-Fay Cube Perspectives Test(R)) and laparoscopic skills were assessed objectively, while performing 1-h practice sessions on the LapSim(R), comprising of coordination, cutting, and clip application tasks. Outcome variables included time to complete the tasks, economy of motion as well as total error scores, respectively. RESULTS: The degree of visual-spatial perception correlated significantly with laparoscopic performance on the LapSim(R) scores. Participants with a high degree of spatial perception (Group A) performed the tasks faster than those (Group B) who had a low degree of spatial perception (p = 0.001). Individuals with a high degree of spatial perception also scored better for economy of motion (p = 0.021), tissue damage (p = 0.009), and total error (p = 0.007). CONCLUSION: Among novices, visual-spatial perception is associated with manual skills performed on a virtual reality simulator. This result may be important for educators to develop adequate training programs that can be individually adapted.

[Operative management and long-term survival in patients with neuroendocrine tumors of the pancreas--experience with 144 patients]. / Operative Therapie und Langzeitüberleben bei neuroendokrinen Pankreastumoren--Erfahrungen bei 144 Patienten.

BACKGROUND AND OBJECTIVE: To evaluate the outcome of patients with pancreatic endocrine tumors (PETs) in a tertiary referral centre. METHODS: 144 patients with PETs that underwent surgery between 1987 and 2005 at our institution were retrospectively evaluated. The diagnosis of gastrinoma, insulinoma, vipoma and non-functioning PETs was based on clinical symptoms, biochemical tests and histopathology. RESULTS: 144 patients were identified for this study, 20% with a MEN1-syndrome. 172 operations were performed, 122 initial operations and 50 reoperations. Enucleation of the tumor and distal pancreatic resections were the main type of operations. In 23 patients liver metastases were resected. After a median follow up of 67 months (range 1-339), 74 of 144 (51%) patients are still alive without evidence of disease. No patient with a benign tumor and no MEN1-patients died because of PETs. The 5, 10, and actuarial 20-year survival rate for patients with malignant tumors were 75%, 70% and 65%, respectively. The survival rate was significantly related to the type of tumor (benign vs. malignant: p = 0.0002), the patients age at time of initial operation (<50 years vs. >50 years: p = 0.0007), the genetic background of the tumor (sporadic vs. MEN1: p = 0.0312) and the development of metastases after the initial operation (none or lymph node metastases vs. distant metastases: p = 0.01). CONCLUSION: We show that an aggressive surgical approach leads to cure in patients with benign PETs. Although long-term cure can only be achieved in a proportion of patients with malignant PETs, significant long-term palliation can be achieved.

Functional thyrotropin receptor attenuates malignant phenotype of follicular thyroid cancer cells.

Thyrotropin (TSH) is a thyroid-specific growth factor inducing differentiated function and growth of thyrocytes in vitro. In thyroid cancer, loss of TSH-receptor (TSHR) expression is a sign of de-differentiation and is believed to contribute to the malignant phenotype. The present studies aimed to determine the in vitro and in vivo effects of functioning TSHR in the follicular thyroid cancer cell line HTC, a subclone of FTC133 cells, lacking endogenous expression of TSHR, and HTCtshr+ cells transfected with human TSHR-cDNA. HTCtshr+ cells grew faster in vitro (doubling time 1.15 vs 1.56 d, p < 0.05) and TSH caused a dose-dependent growth response. Adhesion to and invasion through reconstituted basement membrane were reduced in HTCtshr+ cells, but when stimulated with TSH increased to levels comparable to naïve HTC cells. In vivo, tumor latency was 11 d for naïve HTC as compared to 21 d for HTCtshr+ xenografts. Smaller tumor volumes were registered for HTCtshr+ cells (250 +/- 217 vs 869 +/- 427 mm3, p < 0.05). Angiogenesis, as determined by vascular surface density (VSD) of experimental tumors, was enhanced in naïve HTC tumors (VSD 0.87 +/- 0.1 microm-1 vs 0.55 +/- 0.2 microm-1 in HTCtshr+, p < 0.05). VEGF secretion was more pronounced in naïve HTC cells stimulated with EGF, than in HTCtshr+ cells stimulated with either TSH or EGF. In conclusion, regained expression of functional TSHR in the follicular thyroid cancer cell line HTC alters in vitro features commonly associated with the malignant phenotype. Smaller tumors and reduced angiogenesis of xenotransplanted HTC cells with functioning TSHR suggest a less aggressive in vivo phenotype. The present data highlight the pivotal role of TSHR to affect transformed thyrocytes in vitro and in vivo. They also suggest a role for EGF as a modulator of angiogenesis in thyrocytes devoid of TSHR.

Negative stress-coping strategies among novices in surgery correlate with poor virtual laparoscopic performance.

BACKGROUND: This study explored the impact of habitual stress-coping strategies on the laparoscopic performance of novices in surgery using a virtual reality simulator. METHODS: The SVF78 stress-coping questionnaire was administered to 12 medical students in their final year of medical school (camera holders) and to 12 inexperienced surgical residents (postgraduate years 1-3). The questionnaire included devaluation during stressful situations, distractions from stressful situations, control over stressful reactions and negative coping strategies such as stress avoidance and need for social support. Assessment of laparoscopic dexterity was based on the results of performance on a virtual reality simulator. The variables of time taken to complete the task, errors and economy of motion were analysed, with a higher score indicating poor performance. Pearson and non-parametric Spearman correlations were used to compare the subjects' results on the SVF78 with those on the LapSim. RESULTS: Time taken to complete the task correlated with high values in distractive stress-coping strategies (P = 0.002) and high values in negative stress-coping strategies (P = 0.042). CONCLUSION: Ineffective stress-coping strategies correlate with poor virtual laparoscopic performance. The need for effective intraoperative stress-coping strategies is evident.

Targeting the EGF/VEGF-R system by tyrosine-kinase inhibitors--a novel antiproliferative/antiangiogenic strategy in thyroid cancer.

AIM: In thyroid cancer (TC), endothelial growth factor (EGF) has been associated with dedifferentiation, tumor cell proliferation, and angiogenesis. Vascular endothelial growth factor (VEGF) has been documented to be the main stimulator of angiogenesis in the thyroid gland. Patients with undifferentiated thyroid cancer are in desperate need of new therapeutic strategies because common protocols of therapy usually fail. The aim of this study, therefore, was to evaluate two tyrosine-kinase inhibitors (TKI, ZD 1839 gefitinib and ZD 6474 vandetanib), directed against the EGF/VEGF receptor for possible antitumor therapy in thyroid cancer. METHODS: EGF/VEGF-R was documented in anaplastic (Hth74, C643), follicular (FTC133), and papillary (TPC1) thyroid cancer cell lines by Western blot analysis. The antiproliferative effect of two TKI (0.1-10 microM) on thyroid cancer cell lines in vitro was quantified by MTT assay, the antiangiogenic effect by assessing secretion of VEGF by enzyme-linked immunosorbent assay (R&D Systems). ZD 1839 is mainly directed against EGF-R and ZD 6474 against VEGF-R (AstraZeneca, UK), single applications and combinations of compounds were evaluated. RESULTS: EGF-R and VEGF-R as well as the phosphorylated receptor were documented in all of the cell lines. Administration of ZD1839 led to an up to 90% reduction of cell number in Hth74, 80% in C643, 50% in FTC133, and 90% in TPC1 (p < 0.05). ZD1839 induced a decrease of VEGF secretion between 30% in C643 and 90% in Hth74. Administration of ZD6474 led to an up to 95% reduction of cell number in Hth74, 85% in C643, 90% in FTC133, and 90% in TPC1 (p < 0.05). The ZD6474 induced decrease of VEGF secretion ranged between 20% (FTC133) and 60% (TPC1). Combinations of IC50 concentrations of TKI showed synergistic effects, resulting in additional inhibition of proliferation between 50 and 90% compared to single drug administration. CONCLUSION: The EGF/EGF-R system resembles a powerful VEGF-stimulating pathway in all histiotypes of TC and can be inhibited by TKI. TKI directed against EGF-R as well as VEGF-R inhibit tumor cell proliferation and VEGF secretion in vitro. Combinations of TKI are more effective than strategies using single agents. It is suggested that targeting EGF-R/VEGF-R-mediated pathways may have therapeutic potential in some undifferentiated thyroid cancers.

Antisense p53 decreases production of VEGF in follicular thyroid cancer cells.

Inactivating mutations of wild-type p53 (WTp53) tumor suppressor gene are common in anaplastic thyroid cancer (ATC) and are associated with poor prognosis. Mutated p53 (MTp53) has been implicated with angiogenesis. Therefore, the potential of MTp53 knockout by oligodeoxyribonucleotide phosphorothioates (ODNs) to affect VEGF production of undifferentiated thyroid cancer cells with a recessive MTp53 mutation was evaluated. Transient transfection with 20 bp ODNs complementary to portions of exon 10 of p53 and a negative control ODN (HIV-RT) were carried out in FTC-133 cells. In vitro secretion of VEGF protein was quantified by EIA and correlated to cell numbers, which was evaluated by in vitro MTT assay. Transfection of undifferentiated thyroid cancer cells with ODN reduced VEGF secretion of FTC-133 cells following transfection by 34% as compared to the negative control (cells transfected with ODN-HIV; p = 0.03). These results suggest that transient MTp53 knockout with ODNs complementary to p53 nucleotide sequences impair secretion of VEGF in the undifferentiated thyroid cancer cell line FTC-133.

Clinical background is required for optimum performance with a VR laparoscopy simulator.

OBJECTIVE: To determine the role of clinical background when assessing the learning effect using a virtual-reality (VR) laparoscopy simulator (LapSim). MATERIALS AND METHODS: Test subjects were 12 final-year medical students (Group A) and 12 inexperienced residents (Group B) with no previous experience of VR simulators. First, to establish a baseline, both groups performed the "clip application" task twice. They then completed a training program of increasing difficulty (coordination, cutting and clip application), after which both groups were re-tested using a difficult level of the "cutting" task as an endpoint measurement. Time to complete the tasks, as well as trauma and precision parameters, were scored. RESULTS: Before training, times to complete the baseline task, as well as parameters of trauma and precision, were similar for both groups. After training, Group B (residents) completed the cutting task significantly faster than Group A (students). However, the former group also showed significant improvement in trauma and precision parameter scores in the endpoint measurement. CONCLUSION: These results suggest that clinical background and understanding of the clinical value of a training program lead to faster acquisition and improvement of laparoscopic skills as performed on the laparoscopy simulator. Thus, medical students or other personnel not involved in practical surgery may be unsuitable as candidates for assessing the value of a VR training program.

Antisense p53 oligonucleotides inhibit proliferation and induce chemosensitivity in follicular thyroid cancer cells.

BACKGROUND: The potential of MTp53 knockout by oligodesoxyribonucleotide phosphothioates (ODNs) to affect proliferation, apoptosis and chemosensitivity in undifferentiated thyroid cancer (UTC) cells with a recessive MTp53 mutation was evaluated. MATERIALS AND METHODS: Transient transfections with ODNs complementary to p53 and control ODN (HIV-RT) were carried out in FTC 133 cells. In vitro proliferation was evaluated by cell counting of 10 random fields and by the MTT assay. A single pulse of 100 microg/ml Cytarabine was added to each well and the cells were incubated for an additional day. Chemosensitivity was calculated as the ratio of apoptotic and necrotic cells versus viable cells by flow cytometry (FACS). RESULTS: Transfection of UTC cells with ODN decreased the cell number by up to 70% (p < 0.002). The proliferation rate also decreased up to 35% (p < 0.03), without inducing apoptosis. ODNs rendered FTC cells sensitive to treatment with Cytarabine, inducing apoptosis in 35% of cells, as compared to 17% of cells transfected with the reverse transcriptase gene of HIV (ODN-HIV) and less than 10% of non-transfected cells (p < 0.05). CONCLUSION: Transient MTp53 knockout with ODNs complementary to p53 nucleotide sequences inhibited proliferation and increased chemosensitivity in the UTC cell line FTC133.

[The new role for endoscopic ultrasound in endocrinology: imaging of the adrenals and the endocrine pancreas]. / Die neue Rolle der Endosonographie in der Endokrinologie: Bildgebung der Nebennieren und des endokrinen Pankreas.

Endoscopic ultrasound imaging of the adrenals and the endocrine pancreas enriches the diagnostic repertoire and improves the clinical opportunities of endocrinology. Its resolution enables detection of tumors as small as 2-3 mm. Endoscopic ultrasound imaging is especially relevant in the diagnosis of insulinomas and primary hyperaldosteronism, because it has direct consequences in planning a diagnostic and therapeutic strategy.

Analysis by cDNA microarrays of gene expression patterns of human adrenocortical tumors.

OBJECTIVES: Adrenocortical carcinoma (ACC) is a rare malignant neoplasm with extremely poor prognosis. The molecular mechanisms of adrenocortical tumorigenesis are still not well understood. The comparative analysis by cDNA microarrays of gene-expression patterns of benign and malignant adrenocortical tumors allows us to identify new tumor-suppressor genes and proto-oncogenes underlying adrenocortical tumorigenesis. DESIGN AND METHODS: Total RNA from fresh-frozen tissue of 10 ACC and 10 benign adrenocortical adenomas was isolated after histologic confirmation of neoplastic cellularity of at least 85%. The reference consisted of pooled RNA of 10 normal adrenal cortex samples. Amplified RNA of tumor and reference was used to synthesize Cy3- and Cy5-fluorescently labeled cDNA in a flip-color technique. D-chips containing 11 540 DNA spots were hybridized and scanned and the images were analyzed by ImaGene 3.0 software. RESULTS: The comparative analysis of gene expression revealed many genes with more than fourfold expression difference between ACC and normal tissue (42 genes), cortical adenoma and normal tissue (11 genes), and ACC and cortical adenoma (21 genes) respectively. As confirmed by real-time PCR, the IGF2 gene was significantly upregulated in ACCs versus cortical adenomas and normal cortical tissue. Genes that were downregulated in adrenocortical tumors included chromogranin B and early growth response factor 1. CONCLUSIONS: Comprehensive expression profiling of adrenocortical tumors by the cDNA microarray technique is a very powerful tool to elucidate the molecular steps associated with the tumorigenesis of these ill-defined neoplasms. To evaluate the role of identified genes, further detailed analyses, including correlation with clinical data, are required.

Differential pattern of integrin receptor expression in differentiated and anaplastic thyroid cancer cell lines.

Adhesion of tumor cells to the extracellular matrix (ECM) is a crucial step for the development of metastatic disease and is mediated by specific integrin receptor molecules (IRM). The pattern of metastatic spread differs substantially among the various histotypes of thyroid cancer (TC). However, IRM have only occasionally been characterized in TC until now. IRM expression was investigated in 10 differentiated (FTC133, 236, 238, HTC, HTC TSHr, XTC, PTC4.0/4.2, TPC1, Kat5) and two anaplastic TC cell lines (ATC, C643, Hth74), primary cultures of normal thyroid tissue (Thy1,3), and thyroid cancer specimens (TCS). Expression of 16 IRM (beta1-4, beta7, alpha1-6, alphaV, alphaIIb, alphaL, alphaM, alphaX) and of four IRM heterodimers (alpha2beta1, alpha5beta1, alphaVbeta3, alphaVbeta5), was analyzed by fluorescent-activated cell sorter (FACS) and immunohistochemical staining. Thyroid tumor cell adhesion to ECM proteins and their IRM expression in response to thyrotropin (TSH) was assessed. Follicular TC cell lines presented high levels of integrins alpha2, alpha3, alpha5, beta1, beta3 and low levels of alpha1, whereas papillary lines expressed a heterogenous pattern of IRM, dominated by alpha5 and beta1. ATC mainly displayed integrins alpha2, alpha3, alpha5, alpha6, beta1 and low levels of alpha1, alpha4 and alphaV. Integrin heterodimers correlated with monomer expression. Evaluation of TCS largely confirmed these results with few exceptions, namely alpha4, alpha6, and beta3. The ability of TC cell lines to adhere to purified ECM proteins correlated with IRM expression. TSH induced TC cell adhesion in a dose-dependent fashion, despite an unchanged array of IRM expression or level of a particular IRM. Thyroid carcinoma cell lines of different histogenetic background display profoundly different patterns of IRM expression that appear to correlate with tumor aggressiveness. In vitro adhesion to ECM proteins and IRM expression concur. Finally, TSH-stimulated adhesion of thyroid tumor cell lines to ECM may not be associated with altered IRM expression.

Endoscopic ultrasound imaging of insulinomas: limitations and clinical relevance.

Compared to other imaging methods, endoscopic ultrasound is the best procedure to localize insulinomas preoperatively. Positive finding furthermore confirms endocrinological diagnosis, especially considering the differential diagnosis of hypoglycaemia factitia by oral antidiabetics. However, it always has to be considered that endoscopic ultrasound imaging may reveal false positive and false negative results, and quality of the findings obtained by endoscopic ultrasound imaging depends to a large extent on the examiner's experience. An important issue of endoscopic ultrasound imaging in insulinomas nowadays is planning surgical strategy. As illustrated by three cases, endoscopic ultrasound imaging enables to identify patients that qualify for laparoscopic, minimal invasive surgery.

Successful treatment of solid-pseudopapillary tumor of the pancreas with multiple liver metastases.

The solid-pseudopapillary tumor (SPT) is a very rare pancreatic neoplasm that predominantly affects young females. About 450 cases have been described in the world literature and approximately 20% of the reported patients were children. The occurrence of SPT with distant metastases in children is extremely rare with only two previously reported cases. We now report a 16-year-old Asian girl with a large SPT and synchronous multiple liver metastases who was successfully treated in a 2-step strategy, including initial pylorus-preserving partial duodenopancreatectomy, right hemicolectomy, resection and allografting of the portal vein and secondary resection of 12 liver metastases. The patient is disease free after a follow-up of 18 months after resection of the primary tumor, suggesting that an aggressive surgical treatment might also be justified for metastasized SPT.