Publications by authors named "Michael Brauckhoff"

63 Publications

Activating FGFR1 Mutations in Sporadic Pheochromocytomas.

World J Surg 2018 02;42(2):482-489

Department of Clinical and Experimental Medicine, Faculty of Medicine and Health Sciences, Linköping University, 58185, Linköping, Sweden.

Introduction: Pheochromocytomas are neuroendocrine tumors of the adrenal glands. Up to 40% of the cases are caused by germline mutations in one of at least 15 susceptibility genes, making them the human neoplasms with the highest degree of heritability. Recurrent somatic alterations are found in about 50% of the more common sporadic tumors with NF1 being the most common mutated gene (20-25%). In many sporadic tumors, however, a genetic explanation is still lacking.

Materials And Methods: We investigated the genomic landscape of sporadic pheochromocytomas with whole-exome sequencing of 16 paired tumor and normal DNA samples and extended confirmation analysis in 2 additional cohorts comprising a total of 80 sporadic pheochromocytomas.

Results: We discovered on average 33 non-silent somatic variants per tumor. One of the recurrently mutated genes was FGFR1, encoding the fibroblast growth factor receptor 1, which was recently revealed as an oncogene in pediatric brain tumors. Including a subsequent analysis of a larger cohort, activating FGFR1 mutations were detected in three of 80 sporadic pheochromocytomas (3.8%). Gene expression microarray profiling showed that these tumors clustered with NF1-, RET,- and HRAS-mutated pheochromocytomas, indicating activation of the MAPK and PI3K-AKT signal transduction pathways.

Conclusion: Besides RET and HRAS, FGFR1 is only the third protooncogene found to be recurrently mutated in pheochromocytomas. The results advance our biological understanding of pheochromocytoma and suggest that somatic FGFR1 activation is an important event in a subset of sporadic pheochromocytomas.
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http://dx.doi.org/10.1007/s00268-017-4320-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5762800PMC
February 2018

A Nationwide Study of Multiple Endocrine Neoplasia Type 2A in Norway: Predictive and Prognostic Factors for the Clinical Course of Medullary Thyroid Carcinoma.

Thyroid 2016 09 11;26(9):1225-38. Epub 2016 Aug 11.

2 Institute of Clinical Medicine, University of Oslo , Oslo, Norway .

Background: Multiple endocrine neoplasia type 2A (MEN 2A) is an autosomal dominant syndrome caused by activating germline mutations in the RET (REarranged during Transfection) proto-oncogene. MEN 2A has a strong (>95%) and age-dependent (5-25 years) clinical penetrance of medullary thyroid carcinoma (MTC). Several major studies have analyzed the predictive and prognostic factors for MEN 2A to find indicators that predict the optimal timing of prophylactic thyroidectomy. The aims of this study were to describe all known RET positive MEN 2A patients diagnosed in Norway and to evaluate the clinical course of MTC, as well as its predictive and prognostic factors.

Methods: This nationwide retrospective cohort study included data for 65 (14 index and 51 screening patients) out of a total of 67 MEN 2A patients with the RET gene mutation who were diagnosed in Norway since 1974. Data were collected by reviewing patient files. The variables analyzed were genotype, phenotype, preoperative basal calcitonin, age at thyroid surgery, central lymph node dissection and nodal status at primary surgery, number of surgical procedures, and biochemical cure. Of the 65 patients, 60 had undergone thyroid surgery. The median follow-up period was 9.9 years. The patients were divided into pre-RET-and RET-era, which included patients who had thyroid surgery before January 1, 1994, and after, respectively.

Results: In index and screening patients, MTC was found, respectively, in 100% and 45% of cases, central lymph node dissection at primary surgery was done for 64% and 52% of patients, and the median total number of surgical procedures was two (range 1-6) and one (range 1-4). At primary surgery, all patients (n = 13) with lymph node metastases had preoperative basal calcitonin levels ≥68 pg/mL, and all patients (n = 17) without central lymph node dissection and preoperative basal calcitonin <40 pg/mL were biochemically cured. Multivariate analysis showed that preoperative basal calcitonin was a significant predictive factor for MTC superior to age at thyroid surgery when analyzing the entire period (p = 0.009) and the RET-era separately (p = 0.021). Prognostic factors for biochemical cure were preoperative basal calcitonin, central lymph node dissection, and nodal status at primary surgery (p = 0.037, p = 0.002, and p = 0.005) when analyzing the entire period, but only nodal status at primary surgery when the RET-era was considered separately (p = 0.006).

Conclusions: Preoperative basal calcitonin alone can serve as an indicator for optimal timing and the extent of thyroid surgery for MEN 2A patients that could be considered safe. The results are consistent with previously reported data.
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http://dx.doi.org/10.1089/thy.2015.0673DOI Listing
September 2016

Impact of EMG Changes in Continuous Vagal Nerve Monitoring in High-Risk Endocrine Neck Surgery.

World J Surg 2016 Mar;40(3):672-80

Department of Surgery, Haukeland University Hospital, Jonas Lies vei 65, 5021, Bergen, Norway.

Background: Continuous vagal intraoperative neuromonitoring (CIONM) of the recurrent laryngeal nerve (RLN) may reduce the risk of RLN lesions during high-risk endocrine neck surgery such as operation for large goiter potentially requiring transsternal surgery, advanced thyroid cancer, and recurrence.

Methods: Fifty-five consecutive patients (41 female, median age 61 years, 87 nerves at risk) underwent high-risk endocrine neck surgery. CIONM was performed using the commercially available NIM-Response 3.0 nerve monitoring system with automatic periodic stimulation (APS) and matching endotracheal tube electrodes (Medtronic Inc.). All CIONM events (decreased amplitude/increased latency) were recorded.

Results: APS malfunction occurred on three sides (3%). A total of 138 CIONM events were registered on 61 sides. Of 138, 47 (34%) events were assessed as imminent (13 events) or potentially imminent (34 events) lesions, whereas 91 (66%) were classified as artifacts. Loss of signal was observed in seven patients. Actions to restore the CIONM baseline were undertaken in 58/138 (42%) events with a median 60 s required per action. Four RLN palsies (3 transient, 1 permanent) occurred: one in case of CIONM malfunction, two sudden without any significant previous CIONM event, and one without any CIONM event. The APS vagus electrode led to temporary damage to the vagus nerve in two patients.

Conclusions: CIONM may prevent RLN palsies by timely recognition of imminent nerve lesions. In high-risk endocrine neck surgery, CIONM may, however, be limited in its utility by system malfunction, direct harm to the vagus nerve, and particularly, inability to indicate RLN lesions ahead in time.
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http://dx.doi.org/10.1007/s00268-015-3368-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4746223PMC
March 2016

Post-PET ultrasound improves specificity of 18F-FDG-PET for recurrent differentiated thyroid cancer while maintaining sensitivity.

Acta Radiol 2015 Nov 13;56(11):1350-60. Epub 2015 Mar 13.

Section for Endocrine Surgery, Haukeland University Hospital, Bergen/Norway Department of Clinical Science, University of Bergen, Bergen/Norway.

Background: Positron emission tomography (PET) using fluor-18-deoxyglucose (18F-FDG) with or without computed tomography (CT) is generally accepted as the most sensitive imaging modality for diagnosing recurrent differentiated thyroid cancer (DTC) in patients with negative whole body scintigraphy with iodine-131 (I-131).

Purpose: To assess the potential incremental value of ultrasound (US) over 18F-FDG-PET-CT.

Material And Methods: Fifty-one consecutive patients with suspected recurrent DTC were prospectively evaluated using the following multimodal imaging protocol: (i) US before PET (pre-US) with or without fine needle biopsy (FNB) of suspicious lesions; (ii) single photon emission computed tomography (≥3 GBq I-131) with co-registered CT (SPECT-CT); (iii) 18F-FDG-PET with co-registered contrast-enhanced CT of the neck; (iv) US in correlation with the other imaging modalities (post-US). Postoperative histology, FNB, and long-term follow-up (median, 2.8 years) were taken as composite gold standard.

Results: Fifty-eight malignant lesions were identified in 34 patients. Forty lesions were located in the neck or upper mediastinum. On receiver operating characteristics (ROC) analysis, 18F-FDG-PET had a limited lesion-based specificity of 59% at a set sensitivity of 90%. Pre-US had poor sensitivity and specificity of 52% and 53%, respectively, increasing to 85% and 94% on post-US, with knowledge of the PET/CT findings (P < 0.05 vs. PET and pre-US). Multimodal imaging changed therapy in 15 out of 51 patients (30%).

Conclusion: In patients with suspected recurrent DTC, supplemental targeted US in addition to 18F-FDG-PET-CT increases specificity while maintainin sensitivity, as non-malignant FDG uptake in cervical lesions can be confirmed.
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http://dx.doi.org/10.1177/0284185115574298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4768638PMC
November 2015

A registry-based study of thyroid paraganglioma: histological and genetic characteristics.

Endocr Relat Cancer 2015 Apr 16;22(2):191-204. Epub 2015 Jan 16.

Section of Endocrine SurgeryDepartment of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, St. Adolf Stift, Academic Teaching Hospital University of Hamburg, Reinbek, GermanyDepartment of PathologyHelsinki University Central Hospital and University of Helsinki, Helsinki, FinlandDivision of EndocrinologyDepartment of Medicine, Helsinki University Central Hospital and University of Helsinki, Helsinki, FinlandFamilial Cancer Clinic and Onco-EndocrinologyVeneto Institute of Oncology, IRCCS, Padova, ItalyDepartment of Endocrine SurgeryUniversity of Bergen, Bergen, NorwayDepartment of HypertensionInstitute of Cardiology, Warsaw, PolandEndocrinologyDiabetes and Metabolism, University of Verona and Azienda Ospedaliera Universitaria Integrata Verona, Verona, ItalyUnits of Internal MedicineSanta Chiara General Hospital, Trento, ItalyDepartment of Internal MedicineGeneral Hospital, Montebelluna, Treviso, ItalyDepartment of Nuclear Medicine and Endocrine OncologyMaria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, PolandDepartment of Pathology and Laboratory DiagnosticsSkłodowska-Curie Memorial Institute of Oncology, Warsaw, PolandSection for Preventive MedicineDepartment of Nephrology and General Medicine, Albert-Ludwigs-University of Freiburg, Hugstetter Straße 55, 79106 Freiburg, GermanySection for PathologyDepartment of Clinical Medicine, Centre for Cancer Biomarkers CCBIO, University of Bergen, Bergen, NorwayDepartment of Tumor PathologyM.Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, PolandSurgical Pathology and Cytopathology UnitDepartment of Medicine, DIMED, University of Padova, Padova, ItalyDepartment of PathologySanta Chiara Regional Hospital, Trento, ItalyDepartment of PathologyMarienkrankenhaus, Hamburg, GermanyDepartment of GastroenterologyAlbert-Ludwigs-University of Freiburg, Freiburg, GermanyDepartment of EndocrinologyLa Timone Hospital, Hopitaux de Marseille

The precise diagnosis of thyroid neoplasias will guide surgical management. Primary thyroid paraganglioma has been rarely reported. Data on prevalence, immunohistochemistry (IHC), and molecular genetics in a systematic series of such patients are pending. We performed a multinational population-based study on thyroid paraganglioma and analyzed prevalence, IHC, and molecular genetics. Patients with thyroid paraganglioma were recruited from the European-American-Head-and-Neck-Paraganglioma-Registry. Demographic and clinical data were registered. Histopathology and IHC were re-investigated. All patients with thyroid paraganglioma underwent molecular genetic analyses of the SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, RET, TMEM127, and MAX genes. Analyses included Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA) for detection of large rearrangements. Of 947 registrants, eight candidates were initially identified. After immunohistochemical analyses of these eight subjects, 5 (0.5%) were confirmed to have thyroid paraganglioma. IHC was positive for chromogranin, synaptophysin, and S-100 and negative for calcitonin in all five thyroid paragangliomas, whereas the three excluded candidate tumors stained positive for pan-cytokeratin, a marker excluding endocrine tumors. Germline variants, probably representing mutations, were found in four of the five confirmed thyroid paraganglioma cases, two each in SDHA and SDHB, whereas the excluded cases had no mutations in the tested genes. Thyroid paraganglioma is a finite entity, which must be differentiated from medullary thyroid carcinoma, because medical, surgical, and genetic management for each is different. Notably, approximately 80% of thyroid paragangliomas are associated with germline variants, with implications for additional tumors and a potential risk for the family. As opposed to sporadic tumors, surgical management and extent of resection are different for heritable tumors, each guided by the precise gene involved.
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http://dx.doi.org/10.1530/ERC-14-0558DOI Listing
April 2015

Latencies longer than 3.5 ms after vagus nerve stimulation does not exclude a nonrecurrent inferior laryngeal nerve.

BMC Surg 2014 Aug 28;14:61. Epub 2014 Aug 28.

Department of Surgery, Haukeland University Hospital, Bergen, Norway.

Background: It has recently been reported that a signal latency shorter than 3.5 ms after electrical stimulation of the vagus nerve signify a nonrecurrent course of the inferior laryngeal nerve. We present a patient with an ascending nonrecurrent inferior laryngeal nerve. In this patient, the stimulation latency was longer than 3.5 ms.

Case Presentation: A 74-years old female underwent redo surgery due to a right-sided recurrent nodular goitre. The signal latency on electrical stimulation of the vagus nerve at the level of the carotid artery bifurcation was 3.75 ms. Further dissection revealed a nonrecurrent but ascending course of the inferior laryngeal nerve. Caused by the recurrent goitre, the nerve was elongated to about 10 cm resulting in this long latency.

Conclusion: This case demonstrates that the formerly proposed "3.5 ms rule" for identifying a nonrecurrent course of the inferior laryngeal nerve has exceptions. A longer latency does not necessarily exclude a nonrecurrent laryngeal nerve.
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http://dx.doi.org/10.1186/1471-2482-14-61DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4149872PMC
August 2014

High cardiac background activity limits 99mTc-MIBI radioguided surgery in aortopulmonary window parathyroid adenomas.

BMC Surg 2014 Apr 23;14:22. Epub 2014 Apr 23.

Department of Radiology, Centre for Nuclear Medicine/PET, Haukeland University Hospital, Jonas Liesvei 65, Bergen 5021, Norway.

Background: Radioguided surgery using 99m-Technetium-methoxyisobutylisonitrile (99mTc-MIBI) has been recommended for the surgical treatment of mediastinal parathyroid adenomas. However, high myocardial 99mTc-MIBI uptake may limit the feasibility of radioguided surgery in aortopulmonary window parathyroid adenoma.

Case Presentation: Two female patients aged 72 (#1) and 79 years (#2) with primary hyperparathyroidism caused by parathyroid adenomas in the aortopulmonary window were operated by transsternal radioguided surgery. After intravenous injection of 370 MBq 99mTc-MIBI at start of surgery, the maximum radioactive intensity (as counts per second) was measured over several body regions using a gamma probe before and after removal of the parathyroid adenoma. Relative radioactivity was calculated in relation to the measured ex vivo radioactivity of the adenoma, which was set to 1.0. Both patients were cured by uneventful removal of aortopulmonary window parathyroid adenomas of 4400 (#1) and 985 mg (#2). Biochemical cure was documented by intraoperative measurement of parathyroid hormone as well as follow-up examination. Ex vivo radioactivity over the parathyroid adenomas was 196 (#1) and 855 counts per second (#2). Before parathyroidectomy, relative radioactivity over the aortopulmonary window versus the heart was found at 1.3 versus 2.6 (#1) and 1.8 versus 4.8 (#2). After removal of the adenomas, radioactivity within the aortopulmonary window was only slightly reduced.

Conclusion: High myocardial uptake of 99mTc-MIBI limits the feasibility of radioguided surgery in aortopulmonary parathyroid adenoma.
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http://dx.doi.org/10.1186/1471-2482-14-22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4003509PMC
April 2014

Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study.

Lancet Oncol 2014 May 15;15(6):648-55. Epub 2014 Apr 15.

Department of Endocrinology, Maria Sklodowska Curie Memorial Center and Institute of Oncology, Warsaw, Poland.

Background: The prevention of medullary thyroid cancer in patients with multiple endocrine neoplasia type 2 syndrome has demonstrated the ability of molecular diagnosis and prophylactic surgery to improve patient outcomes. However, the other major neoplasia associated with multiple endocrine neoplasia type 2, phaeochromocytoma, is not as well characterised in terms of occurrence and treatment outcomes. In this study, we aimed to systematically characterise the outcomes of management of phaeochromocytoma associated with multiple endocrine neoplasia type 2.

Methods: This multinational observational retrospective population-based study compiled data on patients with multiple endocrine neoplasia type 2 from 30 academic medical centres across Europe, the Americas, and Asia. Patients were included if they were carriers of germline pathogenic mutations of the RET gene, or were first-degree relatives with histologically proven medullary thyroid cancer and phaeochromocytoma. We gathered clinical information about patients'RET genotype, type of treatment for phaeochromocytoma (ie, unilateral or bilateral operations as adrenalectomy or adrenal-sparing surgery, and as open or endoscopic operations), and postoperative outcomes (adrenal function, malignancy, and death). The type of surgery was decided by each investigator and the timing of surgery was patient driven. The primary aim of our analysis was to compare disease-free survival after either adrenal-sparing surgery or adrenalectomy.

Findings: 1210 patients with multiple endocrine neoplasia type 2 were included in our database, 563 of whom had phaeochromocytoma. Treatment was adrenalectomy in 438 (79%) of 552 operated patients, and adrenal-sparing surgery in 114 (21%). Phaeochromocytoma recurrence occurred in four (3%) of 153 of the operated glands after adrenal-sparing surgery after 6-13 years, compared with 11 (2%) of 717 glands operated by adrenalectomy (p=0.57). Postoperative adrenal insufficiency or steroid dependency developed in 292 (86%) of 339 patients with bilateral phaeochromocytoma who underwent surgery. However, 47 (57%) of 82 patients with bilateral phaeochromocytoma who underwent adrenal-sparing surgery did not become steroid dependent.

Interpretation: The treatment of multiple endocrine neoplasia type 2-related phaeochromocytoma continues to rely on adrenalectomies with their associated Addisonian-like complications and consequent lifelong dependency on steroids. Adrenal-sparing surgery, a highly successful treatment option in experienced centres, should be the surgical approach of choice to reduce these complications.
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http://dx.doi.org/10.1016/S1470-2045(14)70154-8DOI Listing
May 2014

Frequent EPAS1/HIF2α exons 9 and 12 mutations in non-familial pheochromocytoma.

Endocr Relat Cancer 2014 Jun 16;21(3):495-504. Epub 2014 Apr 16.

Department of Clinical and Experimental MedicineFaculty of Health Sciences, Linköping University, Linköping SE-58185, SwedenDepartment of Oncology-PathologyKarolinska Institutet, CCK, Karolinska University Hospital, Stockholm SE-17176, SwedenDepartment of SurgeryHaukeland University Hospital, Bergen, NorwayDepartment of Clinical ScienceUniversity of Bergen, Bergen NO-5021, NorwayDepartment of Molecular Medicine and SurgeryKarolinska Institutet, Karolinska University Hospital, Stockholm SE-17176, SwedenDepartment of SurgeryCounty Council of Östergötland, Linköping SE-58185, Sweden.

Pheochromocytomas are neuroendocrine tumors arising from the adrenal medulla. While heritable mutations are frequently described, less is known about the genetics of sporadic pheochromocytoma. Mutations in genes involved in the cellular hypoxia response have been identified in tumors, and recently EPAS1, encoding HIF2α, has been revealed to be a new gene involved in the pathogenesis of pheochromocytoma and abdominal paraganglioma. The aim of this study was to further characterize EPAS1 alterations in non-familial pheochromocytomas. Tumor DNA from 42 adrenal pheochromocytoma cases with apparently sporadic presentation, without known hereditary mutations in predisposing genes, were analyzed for mutations in EPAS1 by sequencing of exons 9 and 12, which contain the two hydroxylation sites involved in HIF2α degradation, and also exon 2. In addition, the copy number at the EPAS1 locus as well as transcriptome-wide gene expression were studied by DNA and RNA microarray analyses, respectively. We identified six missense EPAS1 mutations, three in exon 9 and three in exon 12, in five of 42 pheochromocytomas (12%). The mutations were both somatic and constitutional, and had no overlap in 11 cases (26%) with somatic mutations in NF1 or RET. One sample had two different EPAS1 mutations, shown by cloning to occur in cis, possibly indicating a novel mechanism of HIF2α stabilization through inactivation of both hydroxylation sites. One of the tumors with an EPAS1 mutation also had a gain in DNA copy number at the EPAS1 locus. All EPAS1-mutated tumors displayed a pseudo-hypoxic gene expression pattern, indicating an oncogenic role of the identified mutations.
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http://dx.doi.org/10.1530/ERC-13-0384DOI Listing
June 2014

Timing and extent of thyroid surgery for gene carriers of hereditary C cell disease--a consensus statement of the European Society of Endocrine Surgeons (ESES).

Langenbecks Arch Surg 2014 Feb 3;399(2):185-97. Epub 2013 Dec 3.

Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, Medical University, Währinger Gürtel 18-20, Vienna, 1090, Austria,

Purpose: This "consensus statement" aims to summarise the current evidence-based knowledge as to "timing" and planning the "extent" of thyroid surgery in terms of an optimal balance between the prevention of thyroid malignancy (involving metastasis) and the risks associated with more extended surgery (permanent hypoparathyroidism, permanent paralysis of the recurrent laryngeal nerve). Surgery "in time" is influenced by genetic findings and age. Basal (and stimulated) calcitonin levels may individualise the timing and extent of surgery.

Materials And Methods: The review of English-language studies addressing the management of REarranged during Transfection proto-oncogene mutation carriers including the time, extent of thyroid surgery and results. Evidence is mostly obtained from well-designed, non-experimental descriptive investigations, such as comparative, correlation and case-control studies (level III) with a grading of recommendation B, or from expert committee reports or opinions and/or the clinical experience of respected authorities (level IV) with a grading of recommendation C, respectively.

Results: "Risk level D" includes multiple endocrine neoplasia 2B cases. Thyroidectomy is recommended within the first year of life, preferably as soon as possible, due to the very early transformation of C cell hyperplasia to more aggressive tumours. Calcitonin levels may be less helpful. In patients with codon 634 mutations (risk level C), thyroidectomy between ages 2 and 4 years has been proposed based upon evidence of age-dependent and codon-specific progression of early medullary thyroid cancer. In "risk level B" (codons 609, 611, 618, 620, 630 and 804), tandem mutation (804-778) patients should undergo thyroidectomy before the age of 6 years. "Risk level A" includes patients with mutations in codons 321, 515, 533, 600, 603, 606, 635, 649, 666, 768, 776, 790, 791, 804 (single mutation), 833, 844, 861, 891 or 912. Surgery may be postponed until the age of 10 years. However, postponing surgery and avoiding central (level VI) neck dissection in patients with risk levels A to C are only justified in families with a less aggressive MTC history and in combination with the results of basal (and calcium- or pentagastrin-stimulated) serum calcitonin levels. The moment of transition from C cell hyperplasia to MTC seems to occur when calcitonin levels rise. In patients with normal basal and stimulated calcitonin levels, the chance of micro-MTC increases significantly.

Conclusions: Hereditary C cell disease acts as a model to apply the results of bedside genetic testing, age and calcitonin levels (genotype-age-calcitonin-concept) for the individual timing of thyroid surgery and its extent.
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http://dx.doi.org/10.1007/s00423-013-1139-5DOI Listing
February 2014

Classification of aerodigestive tract invasion from thyroid cancer.

Langenbecks Arch Surg 2014 Feb 24;399(2):209-16. Epub 2013 Nov 24.

Department of Surgery, Haukeland University Hospital, Jonas Lies vei 65, 5021, Bergen, Norway,

Background: Widely invasive extrathyroidal thyroid cancer invading the aerodigestive tract (ADT) including larynx, trachea, hypopharynx, and/or esophagus occurs in 1-8 % of patients with thyroid cancer and is classified as T4a (current UICC/AJCC system). The T4a stage is associated with impaired tumor-free survival and increased disease-specific mortality. Concerning prognosis and outcome, further subdivisions of the T4a stage, however, have not been made so far.

Methods: This study is based on a systematic review of the relevant literature in the PubMed database.

Results: Retrospective studies suggest a better outcome in patients with invasion of the trachea or the esophagus when compared to laryngeal invasion. Regarding surgical strategies, ADT invasion can be classified based on a three-dimensional assessment determining surgical resection options. Regardless of the invaded structure, tumor infiltration of the ADT can be subdivided into superficial, deep extraluminal, and intraluminal invasion. In contrast to superficial ADT invasion, allowing tangential incomplete wall resection (shaving/extramucosal esophagus resection), deeper wall and intraluminal invasions require complete wall resection (either window or sleeve). Based on the Dralle classification (types 1-6), particularly airway invasion, can be further classified according to the vertical and horizontal extents of tumor invasion.

Conclusions: The Dralle classification can be considered as a reliable subdivision system evaluated regarding surgical options as well as oncological outcome. However, further studies determining the prognostic impact of this technically oriented classification system are required.
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http://dx.doi.org/10.1007/s00423-013-1142-xDOI Listing
February 2014

Complementary somatic mutations of KCNJ5, ATP1A1, and ATP2B3 in sporadic aldosterone producing adrenal adenomas.

Endocr Relat Cancer 2014 Feb 8;21(1):L1-4. Epub 2014 Jan 8.

Department of Clinical and Experimental Medicine, Faculty of Health Sciences Linköping University, SE-58183, Linköping Sweden Department of Surgery Haukeland University Hospital, Bergen Norway Department of Surgical Sciences Institute of Medicine, University of Bergen, Bergen Norway Klinik für Chirurgie and Zentrum für Minimal Invasive Chirurgie, Klinikum Essen-Mitte, Essen Germany Department of Molecular Biology Institute of Medicine, University of Bergen, Bergen Norway Department of Clinical Genetics County Council of Östergötland, Linköping Sweden Department of Surgery County Council of Östergötland, Linköping Sweden.

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http://dx.doi.org/10.1530/ERC-13-0466DOI Listing
February 2014

Surgical curability of medullary thyroid cancer in multiple endocrine neoplasia 2B: a changing perspective.

Ann Surg 2014 Apr;259(4):800-6

*Department of General, Visceral and Vascular Surgery, University of Halle, Halle, Germany †Department of Surgery, Haukeland University Hospital, University of Bergen, Bergen, Norway ‡Department of Surgical Sciences, University of Bergen, Bergen, Norway §Medical Faculty, University of Oslo, Oslo, Norway ¶Central Laboratory, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.

Objective: This investigation aimed at exploring the suitability of nonendocrine manifestations preceding medullary thyroid cancer (MTC) for early diagnosis of multiple endocrine neoplasia type 2B (MEN 2B).

Background: MEN 2B patients, running a high risk of metastatic MTC, must be diagnosed early for biochemical cure.

Methods: Forty-four MEN 2B patients carrying inherited (3 patients) and de novo (41 patients) M918T RET mutations were examined for signs and symptoms prompting MEN 2B.

Results: All 3 patients with inherited mutations were diagnosed before the age of 1 year and cured of their C-cell disease. Among 41 patients with de novo mutations, MEN 2B was diagnosed in 12 patients after recognition of nonendocrine manifestations [intestinal ganglioneuromatosis (6 patients), oral symptoms (5 patients), ocular ("tearless crying") (4 patients), and skeletal stigmata (1 patient) alone or concomitantly]. In the remaining 29 patients with de novo mutations, the diagnosis of MEN 2B was triggered by symptomatic MTC (28 patients) or pheochromocytoma (1 patient). The former patients, being significantly (P < 0.001) younger (means of 5.3 vs 17.6 years) and having lower calcitonin levels (means of 115 vs 25,519 pg/mL), smaller tumors (67% vs 0% were ≤10 mm) and less often extrathyroidal extension (0% vs 81%), lymph node (42% vs 100%), and distant metastases (8% vs 79%), were biochemically cured more often (58% vs 0%).

Conclusions: MTC is curable in patients with de novo mutations when nonendocrine MEN 2B components are quickly appreciated and surgical intervention is performed before patients turn 4 years old.
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http://dx.doi.org/10.1097/SLA.0b013e3182a6f43aDOI Listing
April 2014

Outcome after surgery for primary hyperaldosteronism may depend on KCNJ5 tumor mutation status: a population-based study from Western Norway.

Langenbecks Arch Surg 2013 Aug 19;398(6):869-74. Epub 2013 Jun 19.

Department of Surgery, Haukeland University Hospital, 5021 Bergen, Norway.

Background: Primary aldosteronism (PA) is a frequent cause (about 10 %) of hypertension. Some cases of PA were recently found to be caused by mutations in the potassium channel KCNJ5. Our objective was to determine the mutation status of KCNJ5 and seven additional candidate genes for tumorigenesis: YY1, FZD4, ARHGAP9, ZFP37, KDM5C, LRP1B, and PDE9A and, furthermore, the surgical outcome of PA patients who underwent surgery in Western Norway.

Methods: Twenty-eight consecutive patients with aldosterone-producing adrenal tumors (20 patients with single adenoma, 8 patients with unilateral multiple adenomas or hyperplasia) who underwent surgery were included in this study. All patients were operated on by uncomplicated laparoscopic total adrenalectomy. Genomic DNA was isolated from tumor and non-tumor adrenocortical tissue, and DNA sequencing revealed the mutation status.

Results: Ten out of 28 (36 %) patients with PA displayed tumor mutations in KCNJ5 (p. G151R and L168R) while none were found in the corresponding non-tumor samples. No mutations were found in the other seven candidate genes screened. The presence of KCNJ5 mutations was associated with lower blood pressure and a higher chance for cure by surgery when compared to patients harboring the KCNJ5 wild type.

Conclusions: KCNJ5 mutations are associated with a better surgical outcome. Preoperative identification of the mutation status might have impact on surgical strategy (total vs. subtotal adrenalectomy).
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http://dx.doi.org/10.1007/s00423-013-1093-2DOI Listing
August 2013

Integrative genomics reveals frequent somatic NF1 mutations in sporadic pheochromocytomas.

Hum Mol Genet 2012 Dec 24;21(26):5406-16. Epub 2012 Sep 24.

Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.

Pheochromocytomas are neuroendocrine tumors of the adrenal medulla which can occur either sporadically or in the context of hereditary tumor syndromes. Whereas the genetic background of hereditary pheochromocytomas is becoming rather well-defined, very little is known about the more common sporadic form of the disease which constitutes ∼70% of all cases. In this study, we elucidate some of the molecular mechanisms behind sporadic pheochromocytoma by performing a comprehensive analysis of copy number alterations, gene expression, promoter methylation and somatic mutations in the genes RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, KIF1Bβ, TMEM127 and MAX, which have been associated with hereditary pheochromocytoma or paraganglioma. Our genomic and genetic analyses of 42 sporadic pheochromocytomas reveal that a large proportion (83%) has an altered copy number in at least one of the known susceptibility genes, often in association with an altered messenger RNA (mRNA) expression. Specifically, 11 sporadic tumors (26%) displayed a loss of one allele of the NF1 gene, which significantly correlated with a reduced NF1 mRNA expression. Subsequent sequencing of NF1 mRNA, followed by confirmation in the corresponding genomic DNA (gDNA), revealed somatic truncating mutations in 10 of the 11 tumors with NF1 loss. Our results thus suggest that the NF1 gene constitutes the most frequent (24%) target of somatic mutations so far known in sporadic pheochromocytomas.
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http://dx.doi.org/10.1093/hmg/dds402DOI Listing
December 2012

No outcome differences between a laparoscopic and retroperitoneoscopic approach in synchronous bilateral adrenal surgery.

World J Surg 2011 Dec;35(12):2698-702

Department of Surgery, University of Pisa, Pisa, Italy.

Background: Two main approaches have been described for endoscopic adrenalectomy: the transperitoneal approach with the patient in the lateral decubitus position (LA) and the retroperitoneal approach with the patient in the prone position (ERA). The goal of the present study was to compare the results of LA and ERA for endoscopic bilateral synchronous adrenalectomy.

Patients And Methods: Between 1994 and 2008, 34 patients underwent bilateral synchronous adrenalectomy in two referral centers: 20 patients underwent LA in Pisa (group A), and 14 patients underwent ERA in Halle (group B). Sex, age, preoperative diagnosis, body mass index, preoperative medical treatments, diameter of glands, blood loss, operative time, complications, conversion, intensive care unit stay, day of first oral intake, length of postoperative recovery, histology report, and outcome were analyzed.

Results: There were 7 men and 13 women in group A and 6 men and 8 women in group B. Mean age was 48.1 years in group A and 38.9 years in group B. Body mass index was similar in the two groups. Diameters of the glands were larger in group A than in group B, at 61.1 versus 42.8 mm for the right side and 64.1 versus 37.4 mm for the left side. Mean hospital stay was longer in group B (8.2 versus 5.25 days; P = 0.002), whereas the intensive care unit stay was longer in group A (1.44 versus 1 day).

Conclusions: It is not possible to determine which of the two approaches is better; both are feasible, safe, and effective and patient outcomes are almost the same.
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http://dx.doi.org/10.1007/s00268-011-1294-1DOI Listing
December 2011

Latencies shorter than 3.5 ms after vagus nerve stimulation signify a nonrecurrent inferior laryngeal nerve before dissection.

Ann Surg 2011 Jun;253(6):1172-7

Department of General, Visceral and Vascular Surgery, University Hospital Halle, Halle (Saale), Germany.

Objective: Quantitative electromyographic signals recorded after vagus nerve stimulation during intraoperative neuromonitoring (IONM) were analyzed for their clinical usefulness to identify and track a nonrecurrent inferior laryngeal nerve (NRLN) before dissection.

Background: A NRLN is anatomically shorter than a recurrent inferior laryngeal nerve (RLN). This disparity should cause differential latencies after vagus nerve stimulation during IONM, which may aid in distinguishing a NRLN from a RLN. Failure to identify a NRLN early on entails a great risk of nerve injury.

Methods: Included in this IONM case-control study were 18 cases with a NRLN and 36 controls with RLN anatomy matched for gender, age, body size, and underlying thyroid and parathyroid disease.

Results: All 18 NRLN were found in the right neck only. Cases with a NRLN had significantly shorter latencies than controls (medians of 2.7 vs. 4.6 ms; P < 0.001) but comparable amplitude and duration after stimulation of the right vagus nerve. With a latency threshold of <3.5 ms, sensitivity, specificity, positive and negative predictive value, and accuracy, respectively, were 100%, 94%, 100%, 97%, and 98% for diagnosis of a NRLN.

Conclusions: A latency threshold of 3.5 ms after ipsilateral vagus nerve stimulation during IONM was able to discriminate well between a NRLN and a RLN in adults, helping avoid injury to the aberrant nerve. Additional studies should explore latency thresholds in children and adolescents who have shorter inferior laryngeal nerves and conceivably shorter latencies than adults.
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http://dx.doi.org/10.1097/SLA.0b013e3182128b9eDOI Listing
June 2011

Electrophysiologic recurrent laryngeal nerve monitoring during thyroid and parathyroid surgery: international standards guideline statement.

Laryngoscope 2011 Jan;121 Suppl 1:S1-16

Department of Otology and Laryngology, Division of Thyroid and Parathyroid Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts 02114, USA.

Intraoperative neural monitoring (IONM) during thyroid and parathyroid surgery has gained widespread acceptance as an adjunct to the gold standard of visual nerve identification. Despite the increasing use of IONM, review of the literature and clinical experience confirms there is little uniformity in application of and results from nerve monitoring across different centers. We provide a review of the literature and cumulative experience of the multidisciplinary International Neural Monitoring Study Group with IONM spanning nearly 15 years. The study group focused its initial work on formulation of standards in IONM as it relates to important areas: 1) standards of equipment setup/endotracheal tube placement and 2) standards of loss of signal evaluation/intraoperative problem-solving algorithm. The use of standardized methods and reporting will provide greater uniformity in application of IONM. In addition, this report clarifies the limitations of IONM and helps identify areas where additional research is necessary. This guideline is, at its forefront, quality driven; it is intended to improve the quality of neural monitoring, to translate the best available evidence into clinical practice to promote best practices. We hope this work will minimize inappropriate variations in monitoring rather than to dictate practice options.
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http://dx.doi.org/10.1002/lary.21119DOI Listing
January 2011

Impact of extent of resection for thyroid cancer invading the aerodigestive tract on surgical morbidity, local recurrence, and cancer-specific survival.

Surgery 2010 Dec;148(6):1257-66

Department of General, Visceral and Vascular Surgery, University Hospital Halle, Germany.

Background: The appropriate resection for thyroid cancer invading the aerodigestive tract remains controversial.

Methods: A total of 174 patients underwent resections for aerodigestive tract invasion from differentiated thyroid cancer (103 patients), medullary thyroid cancer (40 patients), and undifferentiated thyroid cancers/unusual thyroid neoplasms (31 patients). In all, 82 patients submitted to transmural resections (window resection, sleeve resection, or cervical evisceration), 65 patients underwent nontransmural resections (shaving or extramucosal esophageal resections), and 27 patients had grossly incomplete resections. The measures of outcome included surgical morbidity, locoregional recurrence, and disease-specific survival.

Results: Surgical morbidity was 38% after transmural and 25% after nontransmural resection (P = .02). On histopathologic examination, surgical margins were microscopically involved in 9% of patients after transmural and 23% of patients after nontransmural resection (P = .014). At a mean follow-up of 35.3 months, locoregional recurrence developed in 10 (46%) of 22 patients with microscopically incomplete and 18 (15%) of 121 patients with microscopically complete resection (P = .001). After grossly complete resection, the mean disease-specific survival was 101.2, 69.8, and 25.5 months for differentiated thyroid cancer, medullary thyroid cancer, and undifferentiated thyroid cancer/unusual neoplasms, respectively (P < .001). This outcome was independent of the type of resection.

Conclusion: The type of cancer and resection are key determinants of outcome among thyroid cancer patients with aerodigestive tract invasion.
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http://dx.doi.org/10.1016/j.surg.2010.09.011DOI Listing
December 2010

Familial nonmedullary thyroid carcinoma-clinical relevance and prognosis. A European multicenter study. ESES Vienna presentation.

Langenbecks Arch Surg 2010 Sep 5;395(7):851-8. Epub 2010 Aug 5.

Department of General, Visceral, and Transplantation Surgery, University Hospital Ulm, Ulm, Germany.

Purpose: Approximately 5% of differentiated thyroid carcinomas are of familial origin. These familial nonmedullary thyroid carcinomas (FNMTC) have an increased risk of multifocal disease and lymph node involvement. Consequently, higher recurrence rates and decreased disease-specific survival rates are described. The best surgical approach is discussed controversially.

Patients And Methods: A survey among the international members of the German Society of Endocrine Surgeons revealed 20 families with two or more first-degree relatives with FNMTC. The mean age of the 41 patients (30 female, 11 male) with FNMTC was 40.6 years (18-73 years).

Results: Total thyroidectomy was performed in 31 of 41 patients (76%). Ninety-five percent of the tumors were papillary carcinomas. Two of 41 patients had follicular carcinomas. Ten patients (24%) with papillary carcinomas were diagnosed with Hashimoto's thyroiditis. The mean tumor size was 1.45 cm. FNMTC was multifocal in 12 patients (29%). A systematic lymph node dissection was performed in 21 of 41 patients (51%). Lymph nodes metastases were found in seven of these 21 patients. Twenty-eight of the patients (68%) underwent postoperative radioiodine ablation. After a mean follow-up of 7.2 years, 39 patients (95%) were disease free. One patient developed local recurrence and lung metastases, 10 and 25 years, respectively, after initial diagnosis. Another patient died 2 years postoperatively from advanced metastatic disease.

Conclusions: FNMTC is associated with an early onset of small, mostly papillary thyroid carcinomas and an increased risk of multifocality and lymph node involvement. Total thyroidectomy and systematic neck dissection are recommended together with radioiodine ablation. Screening for first-degree relatives should start at age 18 years.
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http://dx.doi.org/10.1007/s00423-010-0696-0DOI Listing
September 2010

Management of lymph fistulas in thyroid surgery.

Langenbecks Arch Surg 2010 Sep 21;395(7):911-7. Epub 2010 Jul 21.

Department of General, Visceral, and Vascular Surgery, University of Halle-Wittenberg, Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany.

Purpose: Postoperative lymphatic leakage following thyroid surgery represents a management problem with considerate potential morbidity, psychological, and economical impact. Conservative and surgical management strategies for high- and low-output lymph fistulas are inconsistent. Reliable criteria to predict outcome of conservative versus surgical treatment in clinically evident lymph fistula are lacking.

Material And Methods: A retrospective single-center chart review of consecutively quality-control-documented thyroid surgeries from January 1998 to December 2009 was performed to identify reported postoperative lymph fistulas. Documentation of surgical procedures, drainage, medical, and nutritional management was analyzed to identify risk factors for occurrence and criteria for management of evident lymph fistulas.

Results: There were 29 patients identified with postoperative clinical evidence of lymph fistulas following thyroid surgery; incidence was 0.5%. Indication to surgery comprised benign nodular goiter, recurrent nodular goiter, and thyroid carcinoma or local and lymphonodal carcinoma recurrences. There were 12 (41%) primary and 17 (59%) redo surgeries performed. Surgical procedures performed included thyroidectomy, completion thyroidectomy, and primary and redo central and lateral systematic microdissection of lymphatic compartments. All patients were initially submitted to fasting diet and medical treatment, successfully in 19 (66%), whereas ten (34%) patients underwent surgical intervention for fistula closure after failure of conservative treatment. Complications were one wound infection and fistula recurrence in five (26%) patients in the conservative group and two (20%) in the surgical group. Hospital stay was exceedingly prolonged in both groups with a median of 21 and 11 versus 6 days in patients with regular postoperative course following thyroid surgery.

Conclusions: Data of this series support definition of the two categories of high- and low-output fistulas according to drainage collection with >300 versus <200 ml/day. Fasting in low-output fistula facilitates conservative treatment with closed drainage, whereas in high-output fistulas surgical intervention should be sought. Attendant criteria for treatment stratification are equally important, like patient's compliance, nutritional, and general health status as well as evidence for wound infection. Surgical closure of lymph fistula may be demanding when identification of the secreting fistula is limited and even muscle flap fortification may fail. Ultimately, in unsuccessfully reoperated fistula recurrences, open drainage may become necessary. Lymph fistulas cause significantly prolonged hospital stay, possible critical clinical decay, and unfavorable cosmetic and oncologic outcome while the superior management remains to be defined.
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http://dx.doi.org/10.1007/s00423-010-0686-2DOI Listing
September 2010

What are normal quantitative parameters of intraoperative neuromonitoring (IONM) in thyroid surgery?

Langenbecks Arch Surg 2010 Sep 22;395(7):901-9. Epub 2010 Jul 22.

Department of General-, Visceral- and Vascular Surgery, University of Halle-Wittenberg, Ernst-Grube-Straße 40, 06120 Halle (Saale), Germany.

Purpose: This study aimed at definition of normal quantitative parameters in intraoperative neuromonitoring during thyroid surgery. Only few and single center studies described quantitative data of intraoperative neuromonitoring. Definition of normal parameters in intraoperative neuromonitoring is believed to be a prerequisite for interpretation of results and intraoperative findings when using this method. Moreover, these parameters seem important in regard to the prognostic impact of the method on postoperative vocal cord function.

Material And Methods: In a prospective multicenter study, quantitative analysis of vagal nerve stimulation pre- and postresection was performed in thyroid lobectomies. A standardized protocol determined set up and installation of neuromonitoring and defined assessment of quantitative parameters. Data of intraoperative neuromonitoring were respectively print-documented and centrally analyzed.

Results: In six participating centers a total of 1,289 patients with 1,996 nerves at risk underwent surgery for benign and malignant thyroid disease. Median amplitude was significantly larger for the right vs. left vagal nerve, latency was significantly longer for left vs. right vagal nerve and duration of the left vs. right vagal nerve significantly longer. Age disparities were only present in form of significantly higher amplitude in patients below 40 years; however, there is no continuous increase with age. Regarding gender, there was significantly higher amplitude and smaller latency in women compared to men. Duration of surgery revealed a reduction of amplitude with operative time; contrarily, latency and signal duration remained stable. The type of underlying thyroid disease showed no influence on quantitative parameters of intraoperative neuromonitoring.

Conclusions: Systematic data of multicenter evaluation on quantitative intraoperative neuromonitoring parameters revealed differences between left and right vagal nerves in regard to amplitude, latency and duration of signal, gender, and age. The nature of thyroid disease showed no significant influence on quantitative parameters of intraoperative neuromonitoring. This study presents for the first time collective data of a large series of nerves at risk in a multicenter setting. It seems that definitions of "normal" parameters are prerequisite for the interpretation of quantitative changes of intraoperative neuromonitoring during thyroid surgery to enable interpretation of influence on surgical strategy and prediction of postoperative vocal cord function.
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http://dx.doi.org/10.1007/s00423-010-0691-5DOI Listing
September 2010

Papillary thyroid cancer in children and adolescents does not differ in growth pattern and metastatic behavior.

J Pediatr 2010 Oct 2;157(4):648-52. Epub 2010 Jun 2.

Department of General Surgery, Martin Luther University, Halle (Saale), Germany.

Objective: To provide comprehensive clinicopathologic data, comparing the growth pattern and metastatic behavior of papillary thyroid cancer between children and adolescents.

Study Design: This clinicopathologic investigation included 83 consecutive patients ages 6 to 18 years operated on for papillary thyroid cancer at a tertiary referral center in Germany (1994 to 2009).

Results: There was no difference in sex distribution, re-operation rate, medical history of external radiation, multifocal tumor growth, number of thyroid cancers, extrathyroidal tumor growth, lymph node metastasis, numbers of involved and removed nodes or distant metastasis among patients ages 6 to 11, 12 to 15, and 16 to 18 years. Patients with extrathyroidal growth, unlike those with intrathyroidal growth, had larger tumors, especially in the oldest age group (means of 20, 26, and 44 mm for patients ages 6 to 11, 12 to 15, and 16 to 18 years; P=.015); the statistical significance was lost after correction for multiple testing.

Conclusion: Having comparable extent of disease, children should not undergo less extensive neck operations than adolescents for papillary thyroid cancer.
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http://dx.doi.org/10.1016/j.jpeds.2010.04.026DOI Listing
October 2010

Recurrent genomic alterations in benign and malignant pheochromocytomas and paragangliomas revealed by whole-genome array comparative genomic hybridization analysis.

Endocr Relat Cancer 2010 Sep 3;17(3):561-79. Epub 2010 Jun 3.

Department of Surgical Sciences, Uppsala University Hospital Rudbeck Laboratory, Uppsala University, SE-751 85 Uppsala, Sweden.

Pheochromocytomas and abdominal paragangliomas are adrenal and extra-adrenal catecholamine-producing tumours. They arise due to heritable cancer syndromes, or more frequently occur sporadically due to an unknown genetic cause. The majority of cases are benign, but malignant tumours are observed. Previous comparative genomic hybridization (CGH) and loss of heterozygosity studies have shown frequent deletions of chromosome arms 1p, 3q and 22q in pheochromocytomas. We applied high-resolution whole-genome array CGH on 53 benign and malignant pheochromocytomas and paragangliomas to narrow down candidate regions as well as to identify chromosomal alterations more specific to malignant tumours. Minimal overlapping regions (MORs) were identified on 16 chromosomes, with the most frequent MORs of deletion (> or = 32%) occurring on chromosome arms 1p, 3q, 11p/q, 17p and 22q, while the chromosome arms 1q, 7p, 12q and 19p harboured the most common MORs of gain (> or = 14%). The most frequent MORs (61-75%) in the pheochromocytomas were identified at 1p, and the four regions of common losses encompassed 1p36, 1p32-31, 1p22-21 and 1p13. Tumours that did not show 1p loss generally demonstrated aberrations on chromosome 11. Gain of chromosomal material was significantly more frequent among the malignant cases. Moreover, gain at 19q, trisomy 12 and loss at 11q were positively associated with malignant pheochromocytomas, while 1q gain was commonly observed in the malignant paragangliomas. Our study revealed novel and narrow recurrent chromosomal regions of loss and gain at several autosomes, a prerequisite for identifying candidate tumour suppressor genes and oncogenes involved in the development of adrenal and extra-adrenal catecholamine-producing tumours.
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http://dx.doi.org/10.1677/ERC-09-0310DOI Listing
September 2010

Clinical predictors and algorithm for the genetic diagnosis of pheochromocytoma patients.

Clin Cancer Res 2009 Oct 13;15(20):6378-85. Epub 2009 Oct 13.

Department of Nephrology, Section of Preventive Medicine, Albert-Ludwigs-University, Hugstetter Strasse 55, Freiburg, Germany.

Purpose: Six pheochromocytoma susceptibility genes causing distinct syndromes have been identified; approximately one of three of all pheochromocytoma patients carry a predisposing germline mutation. When four major genes (VHL, RET, SDHB, SDHD) are analyzed in a clinical laboratory, costs are approximately $3,400 per patient. The aim of the study is to systematically obtain a robust algorithm to identify who should be genetically tested, and to determine the order in which genes should be tested.

Experimental Design: DNA from 989 apparently nonsyndromic patients were scanned for germline mutations in the genes VHL, RET, SDHB, SDHC, and SDHD. Clinical parameters were analyzed as potential predictors for finding mutations by multiple logistic regression, validated by bootstrapping. Cost reduction was calculated between prioritized gene testing compared with that for all genes.

Results: Of 989 apparently nonsyndromic pheochromocytoma cases, 187 (19%) harbored germline mutations. Predictors for presence of mutation are age <45 years, multiple pheochromocytoma, extra-adrenal location, and previous head and neck paraganglioma. If we used the presence of any one predictor as indicative of proceeding with gene testing, then 342 (34.6%) patients would be excluded, and only 8 carriers (4.3%) would be missed. We were also able to statistically model the priority of genes to be tested given certain clinical features. E.g., for patients with prior head and neck paraganglioma, the priority would be SDHD>SDHB>RET>VHL. Using the clinical predictor algorithm to prioritize gene testing and order, a 44.7% cost reduction in diagnostic process can be achieved.

Conclusions: Clinical parameters can predict for mutation carriers and help prioritize gene testing to reduce costs in nonsyndromic pheochromocytoma presentations.
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http://dx.doi.org/10.1158/1078-0432.CCR-09-1237DOI Listing
October 2009

Urokinase receptor, MMP-1 and MMP-9 are markers to differentiate prognosis, adenoma and carcinoma in thyroid malignancies.

Int J Cancer 2009 Aug;125(4):894-901

Department of Experimental Surgery and Molecular Oncology of Solid Tumors, Mannheim Faculty, University of Heidelberg, and DKFZ Heidelberg, Mannheim, Germany.

The identification of high-risk patients with thyroid cancer and the preoperative differentiation between follicular adenoma and carcinoma remain clinically challenging. Our study was conducted to analyze whether the quantification of matrix metalloproteinases (MMPs) and urokinase-type plasminogen activator receptor (u-PAR) and transcription factor binding to the u-PAR promoter improve prognostic predictability and differential diagnosis of thyroid tumors. Tumor/normal tissue was collected from 69 prospectively followed patients with thyroid carcinomas (papillary, medullary, follicular and anaplastic, PTC, MTC, FTC and ATC) or follicular adenomas. U-PAR, MMP-1, MMP-7 and MMP-9 amounts were determined by ELISA, and transcription factor binding was determined by electrophoretic mobility shift assay. Binding of transcription factors to the u-PAR promoter was observed, but not associated with u-PAR expression. Carcinomas except MTC expressed significantly more u-PAR/MMPs than adenomas/normal tissues, this being associated with advanced pT- or M-stages. MMP-1 and MMP-9 were significantly higher in follicular carcinomas than in adenomas. In carcinomas, high u-PAR-gene expression correlated significantly with high MMP-9, the latter being associated with MMP-7 in normal tissues. Poor survival in differentiated tumors was associated in trend (p = 0.07); poor survival of all patients (p = 0.043) and especially of patients with carcinomas of follicular origin (including ATC), but not medullary carcinomas, were significantly associated with high u-PAR-protein (p = 0.015). Quantification of u-PAR is of prognostic relevance in thyroid carcinomas of non-c-cell origin, and u-PAR in part may be regulated nontranscriptionally in thyroid cancers. This is the first study to suggest MMP-1/-9 as significant differentiation markers between follicular adenoma and follicular carcinoma.
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http://dx.doi.org/10.1002/ijc.24462DOI Listing
August 2009

Premonitory symptoms preceding metastatic medullary thyroid cancer in MEN 2B: An exploratory analysis.

Surgery 2008 Dec;144(6):1044-50; discussion 1050-3

Department of General, Visceral and Vascular Surgery, Martin-Luther-University, Halle-Wittenberg, Germany.

Background: More than 90% of M918T carriers with multiple endocrine neoplasia type 2B (MEN 2B) harbor de novo mutations in the REarranged during Transfection (RET) protooncogene. DNA-based screening for RET germline mutations is rarely useful for early diagnosis, which thus is contingent on the clinical ascertainment of MEN 2B-specific symptoms as soon as they emerge. Little information exists about the presence of these symptoms in infancy.

Methods: Detailed information was gathered regarding the development of MEN 2B-associated symptoms from the parents of 25 M918T RET carriers and 50 age- and sex-matched controls with the use of a disease-specific questionnaire.

Results: Until the end of the study, at a median age of 16.2 (range, 0.5-34.9 years), all 25 M918T RET carriers had developed medullary thyroid cancer. By that time, 96%, 91%, 71%, 75%, and 28% of carriers displayed oral manifestations, ocular abnormalities, intestinal symptoms, musculoskeletal malformations, and pheochromocytoma, respectively. During the first year of life, fewer than 20% of carriers were found to express the typical MEN 2B phenotype, whereas 86% and 61% of these children, but none of the controls, were noted for their inability to cry tears and for constipation.

Conclusion: Because the classic MEN 2B phenotype is rare during the first year of life, more emphasis should be placed on the more subtle features of the syndrome. Additional studies are needed to validate the usefulness of the symptoms "inability to cry" and "constipation" for earlier diagnosis of MEN 2B.
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http://dx.doi.org/10.1016/j.surg.2008.08.028DOI Listing
December 2008

Insulinomatosis: a multicentric insulinoma disease that frequently causes early recurrent hyperinsulinemic hypoglycemia.

Am J Surg Pathol 2009 Mar;33(3):339-46

Department of Pathology, University of Kiel, Kiel, Germany.

Background: Multicentric insulinoma disease was characterized with regard to its histopathology, multiple endocrine neoplasia type 1 (MEN1) status, precursor lesions, and the risk of hyperinsulinemic hypoglycemia recurrence.

Methods: Fourteen patients with multicentric insulinoma disease were compared with 267 patients with sporadic and familial insulinomas. The tumors were classified according to the World Health Organization (WHO) criteria. The MEN1 status was defined clinically and by germline mutation analysis. Detection of the MEN1 gene locus was performed using fluorescence in situ hybridization. The surgical interventions and the duration of disease-free survival were recorded.

Results: Fourteen patients (5%) without evidence of MEN1 showed 53 macrotumors and 285 microtumors expressing exclusively insulin. In addition, they had small proliferative insulin-expressing monohormonal endocrine cell clusters (IMECCs). No allelic loss of the MEN1 locus was detected in 64 tumors. All but one patient had benign disease. Recurrent hypoglycemia occurred in 6/14 patients (11 recurrences; mean time to relapse 8.4 y). Thirteen patients with MEN1 (4.6%) showed 41 insulinomas and 133 tumors expressing islet hormones other than insulin. IMECCs were not detected. Allelic loss of the MEN1 locus was found in 17/19 insulinomas. Recurrent hypoglycemia occurred in 4/13 patients (4 recurrences; mean time to relapse 14.5 y). Solitary insulinomas were found in 254/281 patients (90.4%). IMECCs were absent. There was no recurrent hypoglycemia in 84 patients with benign insulinomas.

Conclusions: Insulinomatosis is characterized by the synchronous and metachronous occurrence of insulinomas, multiple insulinoma precursor lesions, and rare development of metastases, but common recurrent hypoglycemia. This disease differs from solitary sporadic and MEN1-associated insulinomas.
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http://dx.doi.org/10.1097/PAS.0b013e3181874ecaDOI Listing
March 2009
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