liu.seSearch for publications in DiVA
Change search
Refine search result
12 1 - 50 of 70
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Rows per page
  • 5
  • 10
  • 20
  • 50
  • 100
  • 250
Sort
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
  • Standard (Relevance)
  • Author A-Ö
  • Author Ö-A
  • Title A-Ö
  • Title Ö-A
  • Publication type A-Ö
  • Publication type Ö-A
  • Issued (Oldest first)
  • Issued (Newest first)
  • Created (Oldest first)
  • Created (Newest first)
  • Last updated (Oldest first)
  • Last updated (Newest first)
Select
The maximal number of hits you can export is 250. When you want to export more records please use the 'Create feeds' function.
  • 1.
    Albert, Jörg G
    et al.
    First Department of Medicine, Martin-Luther-University Halle-Wittenberg, Germany.
    Gimm, Oliver
    General Surgery, Martin-Luther-University Halle-Wittenberg, Germany.
    Stock, Karsten
    Department of Radiology, Martin-Luther-University Halle-Wittenberg, Germany.
    Bilkenroth, Udo
    Department of Pathology, Martin-Luther-University Halle-Wittenberg, Germany.
    Marsch, Wolfgang C H
    Department of Dermatology, Martin-Luther-University Halle-Wittenberg, Germany.
    Helmbold, Peter
    Department of Dermatology, University of Heidelberg, Germany.
    Small-bowel endoscopy is crucial for diagnosis of melanoma metastases to the small bowel: a case of metachronous small-bowel metastases and review of the literature.2007In: Melanoma research, ISSN 0960-8931, E-ISSN 1473-5636, Vol. 17, no 5, 335-8 p.Article in journal (Refereed)
  • 2.
    Aljabery, Firas
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland.
    Shabo, Ivan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping. Endocrine and Sarcoma Surgery Unit, Department of Molecular Medicine and Surgery, Karolinska Institute, Stockholm, Sweden; Department of Breast and Endocrine Surgery, Karolinska University Hospital, Solna Stockholm, Sweden .
    Olsson, Hans
    Linköping University, Department of Clinical and Experimental Medicine, Division of Neuro and Inflammation Science. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Jahnson, Staffan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Urology in Östergötland. Linköping University, Faculty of Medicine and Health Sciences.
    Radio-guided sentinel lymph node detection and lymph node mapping in invasive urinary bladder cancer: a prospective clinical study.2017In: BJU International, ISSN 1464-4096, E-ISSN 1464-410X, Vol. 120, no 3, 329-336 p.Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES: To investigate the possibility of detecting sentinel lymph nodes (SNs) in patients with urinary bladder cancer (BCa) intra-operatively and whether the histopathological status of the identified SNs reflected that of the lymphatic field.

    PATIENTS AND METHODS: We studied 103 patients with BCa pathological stage T1-T4 who were treated with cystectomy and pelvic lymph node (LN) dissection during 2005-2011 at the Department of Urology, Linköping University Hospital. Radioactive tracer Nanocoll 70 MBq and blue dye were injected into the bladder wall around the primary tumour before surgery. SNs were detected ex vivo during the operation with a handheld Geiger probe (Gamma Detection System; Neoprobe Corp., Dublin, OH, USA). All LNs were formalin-fixed, sectioned three times, mounted on slides and stained with haematoxylin and eosin. An experienced uropathologist evaluated the slides.

    RESULTS: The mean age of the patients was 69 years, and 80 (77%) were male. Pathological staging was T1-12 (12%), T2-20 (19%), T3-48 (47%) and T4-23 (22%). A mean (range) number of 31 (7-68) nodes per patient were examined, totalling 3 253 nodes. LN metastases were found in 41 patients (40%). SNs were detected in 83 of the 103 patients (80%). Sensitivity and specificity for detecting metastatic disease by SN biopsy (SNB) varied between LN stations, with average values of 67% and 90%, respectively. LN metastatic density (LNMD) had a significant prognostic impact; a value of ≥8% was significantly related to shorter survival. Lymphovascular invasion (LVI) occurred in 65% of patients (n = 67) and was significantly associated with shorter cancer-specific survival (P < 0.001).

    CONCLUSION: We conclude that SNB is not a reliable technique for peri-operative localization of LN metastases during cystectomy for BCa; however, LNMD has a significant prognostic value in BCa and may be useful in the clinical context and in BCa oncological and surgical research. LVI was also found to be a prognostic factor.

  • 3.
    Anlauf, M
    et al.
    Department of Pathology, University of Kiel, Kiel, Germany.
    Perren, A
    Department of Pathology, University of Zürich, Zürich, Switzerland.
    Henopp, T
    Department of Pathology, University of Kiel, Kiel, Germany.
    Rudolf, T
    Department of Pathology, University of Zürich, Zürich, Switzerland.
    Garbrecht, N
    Department of Pathology, University of Kiel, Kiel, Germany.
    Schmitt, A
    Department of Pathology, University of Zürich, Zürich, Switzerland.
    Raffel, A
    Department of General, Visceral and Pediatric Surgery, University of Düsseldorf, North Rhine‐Westphalia, Germany.
    Gimm, O
    Department of General and Visceral Surgery, University of Halle, Halle, Germany.
    Weihe, E
    Department of Molecular Neuroscience, Department of Anatomy and Cell Biology, University of Marburg, Marburg, Germany.
    Knoefel, W T
    Department of General, Visceral and Pediatric Surgery, University of Düsseldorf, North Rhine‐Westphalia, Germany.
    Dralle, H
    Department of General and Visceral Surgery, University of Halle, Halle, Germany.
    Heitz, Ph U
    Department of Pathology, University of Zürich, Zürich, Switzerland.
    Komminoth, P
    Department of Pathology, Kantonsspital Baden, Baden, Switzerland.
    Klöppel, G
    Department of Pathology, University of Kiel, Kiel, Germany.
    Allelic deletion of the MEN1 gene in duodenal gastrin and somatostatin cell neoplasms and their precursor lesions.2007In: Gut, ISSN 0017-5749, E-ISSN 1468-3288, Vol. 56, no 5, 637-44 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Patients with a multiple endocrine neoplasia type 1 (MEN1)-associated Zollinger-Ellison syndrome (ZES) show multifocal duodenal gastrinomas and precursor lesions.

    AIMS: To test these lesions for loss of heterozygosity (LOH) of the MEN1 gene locus on chromosome 11q13, and to investigate whether the MEN1-related endocrine cell changes also involved somatostatin cells.

    MATERIAL AND METHODS: Tissue specimens from six patients with MEN1 and ZES were analysed by immunohistochemistry and immunofluorescence. LOH analysis was performed by fluorescence in situ hybridisation (FISH), using probes containing the MEN1 gene locus and the centromere 11 (C11) region. For simultaneous analysis of hormones and allelic deletions, a combined FISH/immunofluorescence protocol was established.

    RESULTS: 28 of a total of 33 duodenal neuroendocrine tumours (NETs) were gastrin-producing tumours; 13/28 (46.4%) revealed LOH on 11q13 and/or C11. Five of the NETs were somatostatin-expressing tumours, two revealing LOH. Allelic loss was detected in tumours as small as 300 microm (gastrin) and 400 microm (somatostatin) in diameter. The gastrin-producing tumours showed different deletion/retention patterns. Hyperplastic somatostatin cell lesions, similar to those of the gastrin cells, were present in all patients. The hyperplastic lesions of both cell lines consistently retained both 11q13 alleles.

    CONCLUSIONS: Allelic deletion of the MEN1 gene may reflect a pivotal event in the development of multifocal gastrin and somatostatin cell neoplasms in the duodenum of patients with MEN1. The observation of distinct deletion patterns in small synchronous tumours supports the concept that each gastrin-producing tumour in an individual MEN1 patient arises from an independent cell clone.

  • 4.
    Anlauf, Martin
    et al.
    Department of Pathology, University of Kiel, Kiel, Germany.
    Enosawa, Tetsuji
    Department of Pathology, University of Kiel, Germany / First Department of Pathology, Showa University, Japan.
    Henopp, Tobias
    Department of Pathology, University of Kiel, Germany.
    Schmitt, Anja
    Department of Pathology, University of Zurich, Switzerland.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Department of General, Visceral, and Vascular Surgery, Halle/Saale, Germany.
    Brauckhoff, Michael
    Department of General, Visceral, and Vascular Surgery, Halle/Saale, Germany.
    Dralle, Henning
    Department of General, Visceral, and Vascular Surgery, Halle/Saale, Germany.
    Musil, Anette
    Department of Pathology, University of Halle, Halle, Germany.
    Hauptmann, Steffen
    Department of Pathology, University of Halle, Halle, Germany.
    Perren, Aurel
    Department of Pathology, Technische Universitat Munchen, Klinikum Rechts der Isar, Germany.
    Klöppel, Günter
    Department of Pathology, University of Kiel, Kiel, Germany.
    Primary lymph node gastrinoma or occult duodenal microgastrinoma with lymph node metastases in a MEN1 patient: the need for a systematic search for the primary tumor.2008In: American Journal of Surgical Pathology, ISSN 0147-5185, E-ISSN 1532-0979, Vol. 32, no 7, 1101-5 p.Article in journal (Refereed)
    Abstract [en]

    Gastrinoma tissue has been found frequently in lymph nodes located near the duodenum without a known primary tumor. Therefore, it has been suggested that a primary lymph node gastrinoma exists. We report on a 38-year-old woman suffering from multiple endocrine neoplasia type 1 (MEN1) confirmed by menin gene mutation analysis. MEN1 disease started with primary hyperparathyroidism followed by Cushing disease, the detection of tumors of the pituitary, adrenal cortex, and the pancreas and also an elevated serum gastrin level. An octreotide scan revealed 4 tumors in the upper abdomen. A selective arterial calcium stimulation test located the source of the hypergastrinemia to the area of the gastroduodenal and the superior mesenteric arteries. Total pancreatoduodenectomy was performed and conventional histopathologic examination revealed a well-differentiated cystic neuroendocrine tumor of the pancreas expressing glucagon and accompanied by several microadenomas. In addition, 3 suprapancreatic lymph nodes with gastrin-positive endocrine tissue were found. None of the pancreatic microadenomas expressed gastrin and no duodenal endocrine tumor was found despite careful macroscopic examination. Only after complete embedding of the duodenal and pancreatic tissue in 65 paraffin blocks, 2 microgastrinomas (0.45 and 0.8 mm in diameter) were identified in the duodenum. It is concluded that duodenal gastrinomas that give rise to lymph node metastases may be so tiny that they are easily overlooked in a routine examination and that systematic tissue monitoring is required to identify them.

  • 5.
    Anlauf, Martin
    et al.
    Department of Pathology, University of Kiel, Germany.
    Garbrecht, Nele
    Department of Pathology, University of Kiel, Germany.
    Henopp, Tobias
    Department of Pathology, University of Kiel, Germany.
    Schmitt, Anja
    Department of Pathology, University of Zürich, Switzerland.
    Schlenger, Regina
    Department of Pathology and Department of Forensic Medicine, University of Kiel, Germany.
    Raffel, Andreas
    Department of General, Visceral and Pediatric Surgery, University of Düsseldorf, Germany.
    Krausch, Markus
    Department of General, Visceral and Pediatric Surgery, University of Düsseldorf, Germany.
    Gimm, Oliver
    Department of General and Visceral Surgery, University of Halle-Wittenberg, Germany.
    Eisenberger, Claus F
    Department of General, Visceral and Pediatric Surgery, University of Düsseldorf, Germany.
    Knoefel, Wolfram T
    Department of General, Visceral and Pediatric Surgery, University of Düsseldorf, Germany.
    Dralle, Henning
    Department of General and Visceral Surgery, University of Halle-Wittenberg, Germany.
    Komminoth, Paul
    Department of Pathology, University of Zürich, Switzerland / Department of Pathology, Kantonsspital Baden, Switzerland.
    Heitz, Philipp U
    Department of Pathology, University of Zürich, Switzerland.
    Perren, Aurel
    Department of Pathology, University of Zürich, Switzerland.
    Klöppel, Gunter
    Department of Pathology, University of Kiel, Germany.
    Sporadic versus hereditary gastrinomas of the duodenum and pancreas: distinct clinico-pathological and epidemiological features.2006In: World Journal of Gastroenterology, ISSN 1007-9327, E-ISSN 2219-2840, Vol. 12, no 34, 5440-6 p.Article in journal (Refereed)
    Abstract [en]

    Gastrinomas are defined as gastrin secreting tumors that are associated with Zollinger-Ellison syndrome (ZES). ZES is characterized by elevated fasting gastrin serum levels, positive secretin stimulation test and clinical symptoms such as recurrent peptic ulcer disease, gastroesophageal reflux disease and occasional diarrhea. Genetically, nonhereditary (sporadic) gastrinomas are distinguished from hereditary gastrinomas, which are associated with multiple endocrine neoplasia type 1 (MEN1) syndrome. In general, duodenal gastrinomas are small and solitary if they are sporadic and multiple as well as hereditary. The sporadic gastrinomas occur in the duodenum or in the pancreas while the hereditary gastrinomas almost all occur in the duodenum. Our series of 77 sporadic duodenal neuroendocrine tumors (NETs) includes 18 patients (23.4%) with gastrinomas and ZES. Of 535 sporadic NETs in the pancreas collected from the NET archives of the departments of pathology in Zurich, Switzerland, and Kiel, Germany, 24 patients (4.5%) suffered from sporadic pancreatic gastrinomas and ZES. These NETs have to be distinguished from tumors with immunohistochemical positivity for gastrin but without evidence of ZES. An additional 19 patients suffered from MEN1 and ZES. These patients showed exclusively duodenal gastrinomas, but not pancreatic gastrinomas. The prognosis of sporadic and MEN1-associated duodenal gastrinomas is better than that of pancreatic gastrinomas, since they progress slowly to liver metastasis. In summary, sporadic and MEN1-associated gastrinomas in the duodenum and pancreas show different clinico-pathological and genetic features. The incidence of sporadic duodenal gastrin-producing tumors is increasing, possibly due to optimized diagnostic procedures. In contrast, pancreatic MEN1-associated gastrinomas seem to be extremely rare. A considerable subset of tumors with immunohistochemical expression of gastrin but without evidence of ZES should be designated as functionally inactive NETs expressing gastrin, but not as gastrinomas.

  • 6.
    Arnesen, Thomas
    et al.
    Haukeland Hospital, Norway .
    Glomnes, Nina
    University of Bergen, Norway .
    Stromsoy, Siri
    University of Bergen, Norway .
    Knappskog, Stian
    University of Bergen, Norway .
    Heie, Anette
    Haukeland Hospital, Norway .
    Akslen, Lars A.
    University of Bergen, Norway .
    Grytaas, Marianne
    Haukeland Hospital, Norway .
    Varhaug, Jan Erik
    Haukeland Hospital, Norway .
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Brauckhoff, Michael
    Haukeland Hospital, Norway .
    Outcome after surgery for primary hyperaldosteronism may depend on KCNJ5 tumor mutation status: a population-based study from Western Norway2013In: Langenbeck's archives of surgery (Print), ISSN 1435-2443, E-ISSN 1435-2451, Vol. 398, no 6, 869-874 p.Article in journal (Refereed)
    Abstract [en]

    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. less thanbrgreater than less thanbrgreater thanTwenty-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. less thanbrgreater than less thanbrgreater thanTen 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. less thanbrgreater than less thanbrgreater thanKCNJ5 mutations are associated with a better surgical outcome. Preoperative identification of the mutation status might have impact on surgical strategy (total vs. subtotal adrenalectomy).

  • 7.
    Bausch, Birke
    et al.
    Department of Nephrology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
    Borozdin, Wiktor
    Institute for Human Genetics and Anthropology, University of Freiburg, Freiburg, Germany / Center of Human Genetics, Freiburg, Germany.
    Mautner, Victor F
    Department of Maxillofacial Surgery, University Hospital Eppendorf, Hamburg, Germany.
    Hoffmann, Michael M
    Department of Laboratory Medicine, University Medical Center Freiburg, D-79106 Freiburg, Germany.
    Boehm, Detlef
    Department of Nephrology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
    Robledo, Mercedes
    Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain.
    Cascon, Alberto
    Hereditary Endocrine Cancer Group, Centro Nacional de Investigaciones Oncologicas, Madrid, Spain.
    Harenberg, Tomas
    Department of Nephrology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
    Schiavi, Francesca
    Istituto Oncologico Veneto Instituto di Ricovero e Cura a Carattere Scientifico, Padova, Italy.
    Pawlu, Christian
    Department of Nephrology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
    Peczkowska, Mariola
    Department of Hypertension, Institute of Cardiology, Warsaw, Poland.
    Letizia, Claudio
    Department of Clinical Sciences, University of Rome La Sapienza, Rome, Italy.
    Calvieri, Stefano
    Department of Dermatology, University of Rome La Sapienza, Rome, Italy.
    Arnaldi, Giorgio
    Department of Endocrinology, Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy.
    Klingenberg-Noftz, Rolf D
    Medical Clinic I, Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany.
    Reisch, Nicole
    Department of Endocrinology, Ludwig-Maximilians-University of Munich, Munich, Germany.
    Fassina, Ambrogio
    Department of Pathology, University of Padova, Padova, Italy.
    Brunaud, Laurent
    Department of Digestive and Endocrine Surgery, University Hospital Nancy, University of Nancy, Nancy, France.
    Walter, Martin A
    Institute of Nuclear Medicine, Division of Endocrinology, University of Basel, Basel, Switzerland.
    Mannelli, Massimo
    Department of Clinical Pathophysiology, Endocrine Unit, University of Florence, Florence, Italy.
    MacGregor, Graham
    Blood Pressure Unit, Department of Cardiovascular Sciences, St. George’s University, London, United Kingdom.
    Palazzo, F Fausto
    Endocrine Surgery Unit, Hammersmith Hospital, London, United Kingdom.
    Barontini, Marta
    Centro de Investigaciones Endocrinologicas-Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
    Walz, Martin K
    Department of Surgery, Kliniken Essen-Mitte, Essen, Germany.
    Kremens, Bernhard
    Department of Pediatrics, University of Essen, Essen, Germany.
    Brabant, Georg
    Department of Endocrinology, Medizinische Hochschule, Hannover, Germany.
    Pfäffle, Roland
    Department of Pediatrics, University of Leipzig, Leipzig, Germany.
    Koschker, Ann-Cathrin
    Department of Internal Medicine I-Endocrine and Diabetes, University of Wuerzburg, Wuerzburg, Germany.
    Lohoefner, Felix
    Department of Surgery, Hospital of the German Red Cross, Berlin, Germany.
    Mohaupt, Markus
    Department of Nephrology and Hypertension, University of Berne, Berne, Switzerland.
    Gimm, Oliver
    Department of Visceral Surgery, University of Halle, Halle, Germany.
    Jarzab, Barbara
    Department of Nuclear Medicine and Endocrine Oncology, M. Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Gliwice, Poland.
    McWhinney, Sarah R
    Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA / Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
    Opocher, Giuseppe
    Istituto Oncologico Veneto Instituto di Ricovero e Cura a Carattere Scientifico, Padova, Italy.
    Januszewicz, Andrzej
    Department of Hypertension, Institute of Cardiology, Warsaw, Poland.
    Kohlhase, Jürgen
    Institute for Human Genetics and Anthropology, University of Freiburg, Freiburg, Germany / Center of Human Genetics, Freiburg, Germany.
    Eng, Charis
    Genomic Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195, USA / Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
    Neumann, Hartmut P H
    Department of Nephrology, University Medical Center Freiburg, D-79106 Freiburg, Germany.
    Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1.2007In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 92, no 7, 2784-92 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Neurofibromatosis type 1 (NF1) is a pheochromocytoma-associated syndrome. Because of the low prevalence of pheochromocytoma in NF1, we ascertained subjects by pheochromocytoma that also had NF1 in the hope of describing the germline NF1 mutational spectra of NF1-related pheochromocytoma.

    MATERIALS AND METHODS: An international registry for NF1-pheochromocytomas was established. Mutation scanning was performed using denaturing HPLC for intragenic variation and quantitative PCR for large deletions. Loss-of-heterozygosity analysis using markers in and around NF1 was performed.

    RESULTS: There were 37 eligible subjects (ages 14-70 yr). Of 21 patients with corresponding tumor available, 67% showed somatic loss of the nonmutated allele at the NF1 locus vs. 0 of 12 sporadic tumors (P = 0.0002). Overall, 86% of the 37 patients had exonic or splice site mutations, 14% large deletions or duplications; 79% of the mutations are novel. The cysteine-serine rich domain (CSR) was affected in 35% but the RAS GTPase activating protein domain (RGD) in only 13%. There did not appear to be an association between any clinical features, particularly pheochromocytoma presentation and severity, and NF1 mutation genotype.

    CONCLUSIONS: The germline NF1 mutational spectra comprise intragenic mutations and deletions in individuals with pheochromocytoma and NF1. NF1 mutations tended to cluster in the CSR over the RAS-GAP domain, suggesting that CSR plays a more prominent role in individuals with NF1-pheochromocytoma than in NF1 individuals without this tumor. Loss-of-heterozygosity of NF1 markers in NF1-related pheochromocytoma was significantly more frequent than in sporadic pheochromocytoma, providing further molecular evidence that pheochromocytoma is a true component of NF1.

  • 8.
    Bausch, Birke
    et al.
    Albert Ludwigs University, Germany.
    Schiavi, Francesca
    Ist Ricovero and Cura Carattere Science, Italy.
    Ni, Ying
    Cleveland Clin, OH 44106 USA.
    Welander, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Microbiology and Molecular Medicine. Linköping University, Faculty of Medicine and Health Sciences.
    Patocs, Attila
    Semmelweis University, Hungary; Semmelweis University, Hungary.
    Ngeow, Joanne
    National Cancer Centre Singapore, Singapore; Nanyang Technology University, Singapore.
    Wellner, Ulrich
    University of Lubeck, Germany.
    Malinoc, Angelica
    Albert Ludwigs University, Germany.
    Taschin, Elisa
    Ist Ricovero and Cura Carattere Science, Italy.
    Barbon, Giovanni
    Ist Ricovero and Cura Carattere Science, Italy.
    Lanza, Virginia
    Ist Ricovero and Cura Carattere Science, Italy.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Stenman, Adam
    Karolinska Institute, Sweden.
    Larsson, Catharina
    Karolinska Institute, Sweden.
    Svahn, Fredrika
    Karolinska Institute, Sweden.
    Chen, Jin-Lian
    Cleveland Clin, OH 44106 USA.
    Marquard, Jessica
    Cleveland Clin, OH 44106 USA.
    Fraenkel, Merav
    Hadassah Hebrew University, Israel.
    Walter, Martin A.
    University Hospital, Switzerland.
    Peczkowska, Mariola
    Institute Cardiol, Poland.
    Prejbisz, Aleksander
    Institute Cardiol, Poland.
    Jarzab, Barbara
    Maria Sklodowska Curie Mem Cancer Centre and Institute Oncol, Poland.
    Hasse-Lazar, Kornelia
    Maria Sklodowska Curie Mem Cancer Centre and Institute Oncol, Poland.
    Petersenn, Stephan
    Centre Endocrine Tumors, Germany.
    Moeller, Lars C.
    University of Duisburg Essen, Germany.
    Meyer, Almuth
    HELIOS Klin, Germany.
    Reisch, Nicole
    Ludwigs Maximilians University of Munich, Germany.
    Trupka, Arnold
    City Hospital, Germany.
    Brase, Christoph
    University of Erlangen Nurnberg, Germany.
    Galiano, Matthias
    University Hospital Erlangen, Germany.
    Preuss, Simon F.
    University of Cologne, Germany.
    Kwok, Pingling
    University of Regensburg, Germany.
    Lendvai, Nikoletta
    Semmelweis University, Hungary.
    Berisha, Gani
    Albert Ludwigs University, Germany.
    Makay, Ozer
    Ege University, Turkey.
    Boedeker, Carsten C.
    HELIOS Hanseklinikum Stralsund, Germany.
    Weryha, Georges
    University of Nancy, France.
    Racz, Karoly
    Semmelweis University, Hungary.
    Januszewicz, Andrzej
    Institute Cardiol, Poland.
    Walz, Martin K.
    Kliniken Essen Mitte, Germany; Kliniken Essen Mitte, Germany.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Opocher, Giuseppe
    Ist Ricovero and Cura Carattere Science, Italy.
    Eng, Charis
    Cleveland Clin, OH 44106 USA; Cleveland Clin, OH 44106 USA.
    Neumann, Hartmut P. H.
    Albert Ludwigs University, Germany.
    Clinical Characterization of the Pheochromocytoma and Paraganglioma Susceptibility Genes SDHA, TMEM127, MAX, and SDHAF2 for Gene-Informed Prevention2017In: JAMA Oncology, ISSN 2374-2437, E-ISSN 2374-2445, Vol. 3, no 9, 1204-1212 p.Article in journal (Refereed)
    Abstract [en]

    IMPORTANCE Effective cancer prevention is based on accurate molecular diagnosis and results of genetic family screening, genotype-informed risk assessment, and tailored strategies for early diagnosis. The expanding etiology for hereditary pheochromocytomas and paragangliomas has recently included SDHA, TMEM127, MAX, and SDHAF2 as susceptibility genes. Clinical management guidelines for patients with germline mutations in these 4 newly included genes are lacking. OBJECTIVE To study the clinical spectra and age-related penetrance of individuals with mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes. DESIGN, SETTING, AND PATIENTS This study analyzed the prospective, longitudinally followed up European-American-Asian Pheochromocytoma-Paraganglioma Registry for prevalence of SDHA, TMEM127, MAX, and SDHAF2 germline mutation carriers from 1993 to 2016. Genetic predictive testing and clinical investigation by imaging from neck to pelvis was offered to mutation-positive registrants and their relatives to clinically characterize the pheochromocytoma/paraganglioma diseases associated with mutations of the 4 new genes. MAIN OUTCOMES AND MEASURES Prevalence and spectra of germline mutations in the SDHA, TMEM127, MAX, and SDHAF2 genes were assessed. The clinical features of SDHA, TMEM127, MAX, and SDHAF2 disease were characterized. RESULTS Of 972 unrelated registrants without mutations in the classic pheochromocytoma- and paraganglioma-associated genes (632 female [65.0%] and 340 male [35.0%]; age range, 8-80; mean [SD] age, 41.0 [13.3] years), 58 (6.0%) carried germline mutations of interest, including 29 SDHA, 20 TMEM127, 8 MAX, and 1 SDHAF2. Fifty-three of 58 patients (91%) had familial, multiple, extra-adrenal, and/or malignant tumors and/or were younger than 40 years. Newly uncovered are 7 of 63 (11%) malignant pheochromocytomas and paragangliomas in SDHA and TMEM127 disease. SDHA disease occurred as early as 8 years of age. Extra-adrenal tumors occurred in 28 mutation carriers (48%) and in 23 of 29 SDHA mutation carriers (79%), particularly with head and neck paraganglioma. MAX disease occurred almost exclusively in the adrenal glands with frequently bilateral tumors. Penetrance in the largest subset, SDHA carriers, was 39% at 40 years of age and is statistically different in index patients (45%) vs mutation-carrying relatives (13%; P amp;lt; .001). CONCLUSIONS AND RELEVANCE The SDHA, TMEM127, MAX, and SDHAF2 genes may contribute to hereditary pheochromocytoma and paraganglioma. Genetic testing is recommended in patients at clinically high risk if the classic genes are mutation negative. Gene-specific prevention and/or early detection requires regular, systematic whole-body investigation.

  • 9.
    Benn, Diana E
    et al.
    Department of Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney 2006, Australia.
    Gimenez-Roqueplo, Anne-Paule
    Department of Genetics, Hôpital Européen Georges Pompidou, Assistance Publique des Hôpitaux de Paris, L’Institut National de la Santé et de la Recherche Médicale (INSERM) U36, Collège de France, University Paris 5, Paris 75015, France.
    Reilly, Jennifer R
    Department of Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney 2006, Australia.
    Bertherat, Jérôme
    Department of Endocrinology, INSERM U567, Hôpital Cochin Assistance Publique des Hôpitaux de Paris, University Paris 5, Paris 75014, France.
    Burgess, John
    Department of Endocrinology, Royal Hobart Hospital, Tasmania 7001, Australia.
    Byth, Karen
    National Health and Medical Research Council Clinical Trials Centre, University of Sydney, Sydney 2006, Australia.
    Croxson, Michael
    Department of Endocrinology, Greenlane Clinical Centre, Auckland, New Zealand.
    Dahia, Patricia L M
    Departments of Medicine and Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78229-3900.
    Elston, Marianne
    Department of Endocrinology, Waikato Hospital, Hamilton, New Zealand.
    Gimm, Oliver
    Department of General, Visceral and Vascular Surgery, Martin Luther University Halle-Wittenberg, Halle 06097, Germany.
    Henley, David
    Department of Endocrinology and Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia 6009, Australia.
    Herman, Philippe
    Department of Otorhinolaryngology and Head and Neck Surgery, Hôpital Lariboisière, Assistance Publique des Hopitaux de Paris, Paris 75010, France.
    Murday, Victoria
    West of Scotland, Regional Genetics Services, Yorkhill G3 8SJ, Scotland.
    Niccoli-Sire, Patricia
    Department of Endocrinology, Hôpital de la Timone, Assistance Publique des Hôpitaux de Marseille, Marseille 13385, France.
    Pasieka, Janice L
    Department of Surgery, Faculty of Medicine, University of Calgary, Calgary, Canada T2N 1N4.
    Rohmer, Vincent
    Department of Endocrinology, Hôpital d’Angers, Angers 49033, France.
    Tucker, Kathy
    Hereditary Cancer Clinic, Prince of Wales Hospital and School of Medicine, University of New South Wales, Sydney, New South Wales 2052, Australia.
    Jeunemaitre, Xavier
    Department of Genetics, Hôpital Européen Georges Pompidou, Assistance Publique des Hôpitaux de Paris, L’Institut National de la Santé et de la Recherche Médicale (INSERM) U36, Collège de France, University Paris 5, Paris 75015, France.
    Marsh, Deborah J
    Department of Cancer Genetics, Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Sydney 2006, Australia.
    Plouin, Pierre-François
    Department Hypertension, Hôpital Européen Georges Pompidou, Assistance Publique des Hôpitaux de Paris, L’Institut National de la Santé et de la Recherche Médicale (INSERM) U36, Collège de France, University Paris 5, Paris 75015, France.
    Robinson, Bruce G
    Department of Endocrinology, Royal North Shore Hospital, Sydney 2065, Australia.
    Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes.2006In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 91, no 3, 827-36 p.Article in journal (Refereed)
    Abstract [en]

    CONTEXT: The identification of mutations in genes encoding peptides of succinate dehydrogenase (SDH) in pheochromocytoma/paraganglioma syndromes has necessitated clear elucidation of genotype-phenotype associations.

    OBJECTIVE: Our objective was to determine genotype-phenotype associations in a cohort of patients with pheochromocytoma/paraganglioma syndromes and succinate dehydrogenase subunit B (SDHB) or subunit D (SDHD) mutations.

    DESIGN, SETTING, AND PARTICIPANTS: The International SDH Consortium studied 116 individuals (83 affected and 33 clinically unaffected) from 62 families with pheochromocytoma/paraganglioma syndromes and SDHB or SDHD mutations. Clinical data were collected between August 2003 and September 2004 from tertiary referral centers in Australia, France, New Zealand, Germany, United States, Canada, and Scotland.

    MAIN OUTCOME MEASURES: Data were collected on patients with pheochromocytomas and/or paragangliomas with respect to onset of disease, diagnosis, genetic testing, surgery, pathology, and disease progression. Clinical features were evaluated for evidence of genotype-phenotype associations, and penetrance was determined.

    RESULTS: SDHB mutation carriers were more likely than SDHD mutation carriers to develop extraadrenal pheochromocytomas and malignant disease, whereas SDHD mutation carriers had a greater propensity to develop head and neck paragangliomas and multiple tumors. For the index cases, there was no difference between 43 SDHB and 19 SDHD mutation carriers in the time to first diagnosis (34 vs. 28 yr, respectively; P = 0.3). However, when all mutation carriers were included (n = 112), the estimated age-related penetrance was different for SDHB vs. SDHD mutation carriers (P = 0.008).

    CONCLUSIONS: For clinical follow-up, features of SDHB mutation-associated disease include a later age of onset, extraadrenal (abdominal or thoracic) tumors, and a higher rate of malignancy. In contrast, SDHD mutation carriers, in addition to head and neck paragangliomas, should be observed for multifocal tumors, infrequent malignancy, and the possibility of extraadrenal pheochromocytoma.

  • 10.
    Brauckhoff, Michael
    et al.
    University Halle Wittenberg.
    Machens, Andreas
    University Halle Wittenberg.
    Hess, Soeren
    University Halle Wittenberg.
    Lorenz, Kerstin
    University Halle Wittenberg.
    Gimm, Oliver
    Östergötlands Läns Landsting, Anaesthesiology and Surgical Centre, Department of Surgery UHL. Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Brauckhoff, Katrin
    University Halle Wittenberg.
    Sekulla, Carsten
    University Halle Wittenberg.
    Dralle, Henning
    University Halle Wittenberg.
    Premonitory symptoms preceding metastatic medullary thyroid cancer in MEN 2B: An exploratory analysis2008In: SURGERY, ISSN 0039-6060, Vol. 144, no 6, 1044-1050 p.Article in journal (Refereed)
    Abstract [en]

    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-specifitc 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 MEW 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 MEAT 2B.

  • 11.
    Brauckhoff, Michael
    et al.
    Department of General, Visceral, and Vascular Surgery, Halle/Saale, Germany.
    Meinicke, Anja
    Department of General, Visceral, and Vascular Surgery, Halle/Saale, Germany.
    Bilkenroth, Udo
    Institute for Pathology, Martin-Luther-University of Halle-Wittenberg, Halle/Saale, Germany.
    Lorenz, Kerstin
    Department of General, Visceral, and Vascular Surgery, Halle/Saale, Germany.
    Brauckhoff, Katrin
    Department of General, Visceral, and Vascular Surgery, Halle/Saale, Germany.
    Gimm, Oliver
    Department of General, Visceral, and Vascular Surgery, Halle/Saale, Germany.
    Thanh, Phuong Nguyen
    Department of General, Visceral, and Vascular Surgery, Halle/Saale, Germany.
    Dralle, Henning
    Department of General, Visceral, and Vascular Surgery, Halle/Saale, Germany.
    Long-term results and functional outcome after cervical evisceration in patients with thyroid cancer.2006In: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Vol. 140, no 6, 953-9 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Surgical strategy in patients with thyroid cancer (TC) infiltrating the aerodigestive system is controversial. This study was undertaken to examine the long-term results of cervical evisceration (CE).

    PATIENTS AND METHODS: Since 1995, 14 consecutive patients with advanced TC underwent total laryngectomy (LE, n = 6) or esophagolaryngectomy (ELR, n = 8). Patients with unusual thyroid neoplasms or metastases to the thyroid (n = 3) were excluded. For esophageal reconstruction, free jejunal grafts (n = 6) and gastric tubes (n = 2) were used.

    RESULTS: Procedure-related morbidity and mortality were 42% and 14%, respectively. ELR was associated with a significant higher frequency of complications and reoperations compared with LE. Twelve-month and 30-month survival rates were 73% and 55%, respectively; 85% of the patients were satisfied with the surgical results. There were no long-term problems concerning food intake in the ELR patients. Two ELR patients were able to learn a substitutive voice.

    CONCLUSIONS: Cervical evisceration in patients with TC is associated with significant perioperative morbidity and mortality requiring careful patient selection. Regarding long-term survival, local tumor control, and patient's satisfaction, however, CE should be taken into account in suitable patients with advanced TC.

  • 12.
    Carlander, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Koch, C
    Phys Technical Bundesanstalt.
    Brudin, L
    Kalmar Hospital.
    Nordborg, C
    Sahlgrens University Hospital.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Johansson, K
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Heat Production, Nerve Function, and Morphology following Nerve Close Dissection with Surgical Instruments2012In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 36, no 6, 1361-1367 p.Article in journal (Refereed)
    Abstract [en]

    The aim of the present study was to compare an ultrasonically activated instrument (US), monopolar electrosurgery, and bipolar electrosurgery (ES) with respect to heat production, nerve function, and nerve morphology following in vivo application. less thanbrgreater than less thanbrgreater thanThe biceps femoris muscle of anesthetized rats was cut in a standardized manner longitudinally 1 mm adjacent to the sciatic nerve using US shears, a monopolar ES knife, or a bipolar ES scissors. Activation time and temperature were recorded continuously within 1-4 mm of the activation site ipsilateral and contralateral to the nerve with two thermoelectric microsensors. Temperature rise and time delay of reaching the temperature maximum, as an expression of heat spread within tissue, maximum temperature, and thermal dose (equivalent time of exposure at 43A degrees C) were measured and calculated. A total of 49 functional experiments were conducted. The electromyographic (EMG) potential was recorded distally. Nerve dysfunction was defined as more than 10% loss of the evoked EMG amplitude. Forty-eight nerves were coded and submitted to blind histopathological examination, and morphological damage was graded on a 4-grade scale. less thanbrgreater than less thanbrgreater thanThe maximum temperature elevation and the thermal dose were significantly higher for the bipolar ES compared with the US instrument ( = 0.024, = 0.049), and with much less variation of results for the US instrument. The monopolar ES maximum temperature and thermal dose were lower, but a very large variation occurred, probably as a result of more random electrical spread to the ground electrode and muscle motion artifacts. Functional loss was least common in the US group-without being significant-compared to bipolar and monopolar ES. Moderate and severe morphological damage was significantly less common in the US group than in the monopolar ES group ( = 0.041). We found no statistically significant correlation between the highest temperatures and the degree of morphological damage or functional loss less thanbrgreater than less thanbrgreater thanThe temperature elevation depends strongly on the distance to the activated instrument. The bipolar ES scissors generates a higher maximum temperature and thermal dose with a greater variation in than the US. Functional loss and severe morphological damage were uncommon in all groups.

  • 13.
    Carlander, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Department of Surgery and Center for Clinical Research Uppsala University.
    Wagner, Philippe
    Department of Surgery and Center for Clinical Research Uppsala University, Västmanland County Hospital, Västerås, Sweden.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Nordenström, Erik
    Department of Surgery, Lund University Hospital, Malmö, Sweden.
    Jansson, Svante
    Department of Surgery, Sahlgrenska University Hospital Gothenburg, Göteborg, Sweden.
    Bergkvist, Leif
    Department of Surgery and Center for Clinical Research Uppsala University, Västmanland County Hospital, Västerås, Sweden.
    Johansson, Kenth
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Medicine and Health Sciences. Department Surgery, Västervik Hospital, Västervik,Gothenburg, Göteborg, Sweden .
    Risk of Complications with Energy-Based Surgical Devices in Thyroid Surgery: A National Multicenter Register Study2016In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 40, no 1, 117-123 p.Article in journal (Refereed)
    Abstract [en]

    Background

    Energy-based surgical devices (EBD) combining cutting and coagulation are increasingly used in thyroid surgery. However, there is a lack of information about potential benefits and risk of complications outside controlled trials. The aims of this national multicenter register study were to describe the use of EDB, their potential effect on complication rates, and on operation time.

    Materials and methods

    The Scandinavian Quality Register for Thyroid and Parathyroid surgery includes 35 surgical units in Sweden and covered 88 % of the thyroid procedures performed during 2008–2009. The use of the EBD was specifically registered for 12 months, and 1297 patients were included. Surgically related complications and operation time were evaluated. The clamp-and-tie group (C-A-T) constituted the control group for comparison with procedures where EBD was used.

    Results

    The thyroid procedures performed included C-A-T (16.6 %), bipolar electrosurgery (ES: 56.5 %), electronic vessel sealing (EVS: 12.2 %), and ultrasonic dissection (UD: 14.5 %). Mean operative time was longer with EVS (p < 0.001) and shorter with UD (p < 0.05) than in the other groups. The bipolar ES group and the EVS group had higher incidence of calcium treatment at discharge and after 6 weeks than the UD group. No significant difference in nerve injury was found between the groups. There was a significant more frequent use of topical hemostatic agents in the EBD group compared to C-A-T.

    Conclusion

    In this national multicenter study, the use of UD shortened and EVS increased operating time. There was a higher risk of calcium treatment at discharge and after 6 weeks after use of EVS and bipolar ES than after UD use. There was a significant more frequent use of topical hemostatic agents in the EBD groups compared to C-A-T.

  • 14.
    Christofer Juhlin, C.
    et al.
    Yale University, CT 06520 USA; Yale University, CT 06520 USA; Karolinska Institute, Sweden.
    Stenman, Adam
    Karolinska Institute, Sweden.
    Haglund, Felix
    Karolinska Institute, Sweden.
    Clark, Victoria E.
    Yale University, CT 06520 USA.
    Brown, Taylor C.
    Yale University, CT 06520 USA; Yale University, CT 06520 USA.
    Baranoski, Jacob
    Yale University, CT 06520 USA.
    Bilguvar, Kaya
    Yale University, CT 06520 USA; Yale University, CT 06520 USA.
    Goh, Gerald
    Yale University, CT 06520 USA; Yale University, CT 06520 USA.
    Welander, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Svahn, Fredrika
    Karolinska Institute, Sweden.
    Rubinstein, Jill C.
    Yale University, CT 06520 USA; Yale University, CT 06520 USA.
    Caramuta, Stefano
    Karolinska Institute, Sweden.
    Yasuno, Katsuhito
    Yale University, CT 06520 USA.
    Guenel, Murat
    Yale University, CT 06520 USA.
    Backdahl, Martin
    Karolinska Institute, Sweden.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Prasad, Manju L.
    Yale University, CT 06520 USA.
    Korah, Reju
    Yale University, CT 06520 USA; Yale University, CT 06520 USA.
    Lifton, Richard P.
    Yale University, CT 06520 USA; Yale University, CT 06520 USA; Yale Centre Mendelian Genom, CT USA.
    Carling, Tobias
    Yale University, CT 06520 USA; Yale University, CT 06520 USA.
    Whole-exome sequencing defines the mutational landscape of pheochromocytoma and identifies KMT2D as a recurrently mutated gene2015In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 54, no 9, 542-554 p.Article in journal (Refereed)
    Abstract [en]

    As subsets of pheochromocytomas (PCCs) lack a defined molecular etiology, we sought to characterize the mutational landscape of PCCs to identify novel gene candidates involved in disease development. A discovery cohort of 15 PCCs wild type for mutations in PCC susceptibility genes underwent whole-exome sequencing, and an additional 83 PCCs served as a verification cohort for targeted sequencing of candidate mutations. A low rate of nonsilent single nucleotide variants (SNVs) was detected (6.1/sample). Somatic HRAS and EPAS1 mutations were observed in one case each, whereas the remaining 13 cases did not exhibit variants in established PCC genes. SNVs aggregated in apoptosis-related pathways, and mutations in COSMIC genes not previously reported in PCCs included ZAN, MITF, WDTC1, and CAMTA1. Two somatic mutations and one constitutional variant in the well-established cancer gene lysine (K)-specific methyltransferase 2D (KMT2D, MLL2) were discovered in one sample each, prompting KMT2D screening using focused exome-sequencing in the verification cohort. An additional 11 PCCs displayed KMT2D variants, of which two were recurrent. In total, missense KMT2D variants were found in 14 (11 somatic, two constitutional, one undetermined) of 99 PCCs (14%). Five cases displayed somatic mutations in the functional FYR/SET domains of KMT2D, constituting 36% of all KMT2D-mutated PCCs. KMT2D expression was upregulated in PCCs compared to normal adrenals, and KMT2D overexpression positively affected cell migration in a PCC cell line. We conclude that KMT2D represents a recurrently mutated gene with potential implication for PCC development. (c) 2015 The Authors. Genes, Chromosomes and Cancer Published by Wiley Periodicals, Inc.

  • 15.
    Dammann, R.
    et al.
    Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
    Schagdarsurengin, U.
    Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
    Seidel, C.
    Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
    Trümpler, C.
    Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
    Hoang-Vu, C.
    Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
    Gimm, Oliver
    Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
    Dralle, H.
    Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
    Pfeifer, G. P.
    Beckman Research Institute, City of Hope, Cancer Center, Duarte, California, USA.
    Brauckhoff, M.
    Martin-Luther-University Halle-Wittenberg, Halle/Saale, Germany.
    Frequent promoter methylation of tumor-related genes in sporadic and men2-associated pheochromocytomas2005In: Experimental and clinical endocrinology & diabetes, ISSN 0947-7349, Vol. 113, no 1, 1-7 p.Article in journal (Refereed)
    Abstract [en]

    Hypermethylation of CpG island promoters is associated with transcriptional inactivation of tumor suppressor genes in neoplasia. Inactivation of p16 and Pten was related to the development of pheochromocytomas. In this report, we investigated the methylation status of the p16INK4a cell cycle inhibitor gene and other prominent tumor-related genes ( PTEN, RASSF1 A, CDH1, MSH2, MLH1, VHL, and TIMP3) in sporadic and multiple endocrine neoplasia type 2 (MEN2) pheochromocytomas by methylation-specific PCR. Hypermethylation was detected in 48 % of pheochromocytomas for RASSF1 A, 24 % for p16, 36 % for MSH2, 16 % for CDH1, and 8 % for PTEN. No VHL, MLH1, and TIMP3 methylation was observed. Interestingly, the frequency of p16 inactivation in familial tumors was higher (5 out of 12, 42 %) than in sporadic tumors (1 out of 13, 8 %; p = 0.047) and RASSF1 A inactivation was more common in the hereditary tumors (58 %) compared to the sporadic tumors (38 %). Combined methylation of RASSF1 A and p16 was found only in MEN2-related pheochromocytomas. Thus, a subset of hereditary pheochromocytomas displays preferential methylation of p16 and RASSF1 A.

  • 16.
    Dutta, Ravi Kumar
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Genetics of primary hyperaldosteronism2016In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 23, no 10, R437-R454 p.Article, review/survey (Refereed)
    Abstract [en]

    Hypertension is a common medical condition and affects approximately 20% of the population in developed countries. Primary aldosteronism is the most common form of secondary hypertension and affects 8-13% of patients with hypertension. The two most common causes of primary aldosteronism are aldosterone-producing adenoma and bilateral adrenal hyperplasia. Familial hyperaldosteronism types I, II and III are the known genetic syndromes, in which both adrenal glands produce excessive amounts of aldosterone. However, only a minority of patients with primary aldosteronism have one of these syndromes. Several novel susceptibility genes have been found to be mutated in aldosterone-producing adenomas: KCNJ5, ATP1A1, ATP2B3, CTNNB1, CACNA1D, CACNA1H and ARMC5. This review describes the genes currently known to be responsible for primary aldosteronism, discusses the origin of aldosterone-producing adenomas and considers the future clinical implications based on these novel insights.

  • 17.
    Dutta, Ravi Kumar
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Welander, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Brauckhoff, Michael
    Haukeland University Hospital, Bergen; University of Bergen, Norway .
    Walz, Martin
    Klinikum Essen Mitte, Essen, Germany .
    Alesina, Piero
    Klinikum Essen Mitte, Essen, Germany .
    Arnesen, Thomas
    Haukeland University Hospital, Bergen; University of Bergen, Norway.
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Complementary somatic mutations of KCNJ5, ATP1A1, and ATP2B3 in sporadic aldosterone producing adrenal adenomas2014In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 21, no 1, L1-L4 p.Article in journal (Other academic)
    Abstract [en]

    n/a

  • 18.
    Franz, F
    et al.
    Clinic of Endocrinology and Nephrology, Department of Internal Medicine, Neurology and Dermatology, University of Leipzig, Leipzig, Germany.
    Weidinger, C
    Clinic of Endocrinology and Nephrology, Department of Internal Medicine, Neurology and Dermatology, University of Leipzig, Leipzig, Germany.
    Krause, K
    Clinic of Endocrinology and Nephrology, Department of Internal Medicine, Neurology and Dermatology, University of Leipzig, Leipzig, Germany.
    Gimm, Oliver
    Department of General, Visceral, and Vascular Surgery, Martin-Luther-University of Halle-Wittenberg, Halle/Saale, Germany.
    Dralle, H
    Department of General, Visceral, and Vascular Surgery, Martin-Luther-University of Halle-Wittenberg, Halle/Saale, Germany.
    Führer, D
    Department of Endocrinology & Metabolism and Division of Laboratory Research, University Hospital Essen, Essen, Germany.
    The Transcriptional Regulation of FOXO Genes in Thyrocytes.2016In: Hormone and Metabolic Research, ISSN 0018-5043, E-ISSN 1439-4286, Vol. 48, no 9, 601-6 p.Article in journal (Refereed)
    Abstract [en]

    FOXO transcription factors are key regulators of DNA damage repair, proliferation and apoptosis in thyrocytes. Thyroid malignancies show impaired FOXO function. In this study, we investigated the transcriptional regulation of FOXO isoforms in thyroid epithelial cells. mRNA expression of FOXO isoforms (FOXO1, 3 and 4) was determined in FRTL-5 cells stimulated with different growth factors and H2O2. Furthermore, the impact of PI3K/AKT signalling on FOXO transcription was investigated in PI3K p110α mutant FRTL-5 cells and regulatory dependence of FOXO transcription on FOXO was studied in FRTL-5 cells with hFOXO3 overexpression. Finally, mRNA expression levels of FOXO isoforms were determined in human epithelial thyroid tumours. Growth factor deprivation induced transcription of FOXO1, 3 and 4, whereas insulin stimulation decreased FOXO1 and FOXO4 transcription in FRTL-5 cells. Inhibition of the PI3K/AKT cascade amplified FOXO1 and FOXO4 expression. In contrast, H2O2 and TSH did not influence FOXO transcription in thyrocytes. Overexpression of PI3K p110α inhibited FOXO3 and induced FOXO4 transcription. In human thyroid tumours, FOXO1 and FOXO3 mRNA levels were significantly downregulated in papillary thyroid carcinoma when compared to normal tissues. In contrast, follicular thyroid carcinomas showed significant upregulation of FOXO4 mRNA.In this paper, we demonstrate an influence of PI3K signalling on FOXO transcription in thyrocytes. Moreover, we show that thyroid cancers exhibit alterations in FOXO transcription besides the previously reported alterations in posttranslational FOXO3 regulation. These findings may add to the concept of targeting the PI3K pathway in advanced thyroid cancers.

  • 19.
    Georgitsi, Marianthi
    et al.
    Department of Medical Genetics, 00014 University of Helsinki, Finland.
    Raitila, Anniina
    Department of Medical Genetics, 00014 University of Helsinki, Finland.
    Karhu, Auli
    Department of Medical Genetics, 00014 University of Helsinki, Finland.
    van der Luijt, Rob B
    Department of Medical Genetics, University Medical Centre Utrecht, 3508 GA Utrecht, The Netherlands.
    Aalfs, Cora M
    Department of Clinical Genetics, Academic Medical Centre, 1105 AZ Amsterdam, The Netherlands.
    Sane, Timo
    Department of Endocrinology, Helsinki University Central Hospital, 00029 Helsinki, Finland.
    Vierimaa, Outi
    Department of Clinical Genetics, Oulu University Hospital, 90029 Oulu, Finland.
    Mäkinen, Markus J
    Department of Pathology, University of Oulu, 90014 Oulu, Finland.
    Tuppurainen, Karoliina
    Department of Pathology, University of Oulu, 90014 Oulu, Finland.
    Paschke, Ralph
    Medical Department III, Leipzig University, 04103 Leipzig, Germany.
    Gimm, Oliver
    Department of Surgery, Martin Luther University Halle-Wittenberg, 06120 Halle, Germany.
    Koch, Christian A
    Division of Endocrinology, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.
    Gündogdu, Sadi
    Division of Endocrinology-Metabolism and Diabetes, Cerrahpaşa Medical Faculty, University of Istanbul, 34303 Istanbul, Turkey.
    Lucassen, Anneke
    Wessex Clinical Genetics Service, Princess Anne Hospital, SO16 5YA Southampton, United Kingdom.
    Tischkowitz, Marc
    Departments of Human Genetics, Oncology, and Medicine, McGill University, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Quebec, Canada H3T 1E2.
    Izatt, Louise
    Department of Clinical Genetics, New Guy’s House, Guy’s Hospital, London SE1 9RT, United Kingdom.
    Aylwin, Simon
    Department of Medicine, King’s College Hospital, Denmark Hill, London SE5 9RS, United Kingdom.
    Bano, Gul
    Department of Endocrinology and Diabetes, Thomas Addison Unit, London SW17 0QT, United Kingdom.
    Hodgson, Shirley
    Department of Clinical Genetics, St. Georges, University of London, London SW17 ORE, United Kingdom.
    De Menis, Ernesto
    Department of Internal Medicine, General Hospital, 31100 Treviso, Italy.
    Launonen, Virpi
    Department of Medical Genetics, 00014 University of Helsinki, Finland.
    Vahteristo, Pia
    Department of Medical Genetics, 00014 University of Helsinki, Finland.
    Aaltonen, Lauri A
    Department of Medical Genetics, 00014 University of Helsinki, Finland.
    Germline CDKN1B/p27Kip1 mutation in multiple endocrine neoplasia.2007In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 92, no 8, 3321-5 p.Article in journal (Refereed)
    Abstract [en]

    CONTEXT: Germline mutations in the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome, but in up to 20-25% of clinical MEN1 cases, no MEN1 mutations can be found. Recently, a germline mutation in the CDKN1B gene, encoding p27(Kip1), was reported in one suspected MEN1 family with two acromegalic patients.

    OBJECTIVE: Our objective was to evaluate the role of CDKN1B/p27(Kip1) in human tumor predisposition in patients clinically suspected of MEN1 but testing negative for MEN1 germline mutation as well as in familial and sporadic acromegaly/pituitary adenoma patients.

    DESIGN: Genomic DNA was analyzed for germline mutations in the CDKN1B/p27(Kip1) gene by PCR amplification and direct sequencing.

    SETTING: The study was conducted at nonprofit academic research and medical centers.

    PATIENTS: Thirty-six Dutch and one German suspected MEN1 patient, who previously tested negative for germline MEN1 gene mutations, were analyzed. In addition, 19 familial and 50 sporadic acromegaly/pituitary adenoma patients from Europe and the United States were included in the study.

    MAIN OUTCOME MEASURES: We analyzed germline CDKN1B/p27(Kip1) mutations in individuals with pituitary adenoma and MEN1-like features.

    RESULTS: A heterozygous 19-bp duplication (c.59_77dup19) leading to a truncated protein product was identified in one Dutch patient with suspected MEN1 phenotype, pituitary adenoma, carcinoid tumor, and hyperparathyroidism (one of 36, 2.8%). No mutations were detected in either familial or sporadic acromegaly/pituitary adenoma patients.

    CONCLUSIONS: Our results support the previous finding that germline CDKN1B/p27(Kip1) mutations predispose to a human MEN1-like condition. However, such mutations appear uncommon in suspected MEN1 cases and rare or nonexistent in familial or sporadic acromegaly/pituitary adenoma patients.

  • 20.
    Gill, Anthony J
    et al.
    Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia.
    Clarkson, Adele
    Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, Australia.
    Gimm, Oliver
    Department of General, Visceral and Vascular Surgery, Martin Luther University, Halle-Wittenberg, Germany.
    Keil, Juliane
    Institute of Pathology, Martin Luther University, Halle-Wittenberg, Germany.
    Dralle, Henning
    Department of General, Visceral and Vascular Surgery, Martin Luther University, Halle-Wittenberg, Germany.
    Howell, Viive M
    Department of Human Genetics, University of Michigan, Ann Arbor, MI, USA.
    Marsh, Deborah J
    Kolling Institute of Medical Research, Royal North Shore Hospital, University of Sydney, Sydney, Australia.
    Loss of nuclear expression of parafibromin distinguishes parathyroid carcinomas and hyperparathyroidism-jaw tumor (HPT-JT) syndrome-related adenomas from sporadic parathyroid adenomas and hyperplasias.2006In: American Journal of Surgical Pathology, ISSN 0147-5185, E-ISSN 1532-0979, Vol. 30, no 9, 1140-9 p.Article in journal (Refereed)
    Abstract [en]

    Parathyroid carcinoma is notoriously difficult to diagnose with confidence in borderline cases. Commonly there is a long lag time between diagnosis and clinical evidence of malignant behavior even in histopathologically straightforward lesions. There is therefore a need for a novel adjunctive marker to assist in the diagnosis of carcinoma. Parafibromin is the protein encoded by the putative tumor suppressor gene HRPT2. Mutations predicted to inactivate parafibromin were first detected in the germline of patients with hyperparathyroidism-jaw tumor (HPT-JT) syndrome. Subsequently, somatic mutations have been identified in the majority of sporadic carcinomas. We performed immunohistochemistry for parafibromin on 115 parathyroid tissues comprising 4 HPT-JT-related tumors (3 adenomas and 1 carcinoma), 11 sporadic parathyroid carcinomas, 79 sporadic adenomas, 3 multiple endocrine neoplasia 2A-related adenomas, 2 sporadic primary hyperplasias, 2 multiple endocrine neoplasia (MEN)-1-related hyperplasias, 6 secondary hyperplasias, 4 tertiary hyperplasias, and 4 normal parathyroid glands. There was complete absence of nuclear staining in 3 of 4 (75%) HPT-JT-related tumors and 8 of 11 (73%) sporadic parathyroid carcinomas and focal weak staining in 1 of 4 HPT-JT tumors and 2 of 11 sporadic parathyroid carcinomas. Only 1 parathyroid carcinoma exhibited diffuse strong nuclear expression of parafibromin. In contrast, 98 of 100 non-HPT-JT-related benign parathyroids showed diffuse strong nuclear positivity and 2 of 100 showed weak positive staining. We conclude that, in the correct clinical and pathologic context, complete absence of nuclear staining for parafibromin is diagnostic of parathyroid carcinoma or an HPT-JT-related tumor.

  • 21.
    Gimm, O
    et al.
    Universitäts- und Poliklinik für Allgemein-, Viszeral- und Gefäßchirurgie, Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Straße 40, 06097, Halle/Saale, Deutschland.
    Dralle, H
    Universitäts- und Poliklinik für Allgemein-, Viszeral- und Gefäßchirurgie, Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Straße 40, 06097, Halle/Saale, Deutschland.
    [Lymphadenectomy for thyroid and lymph node carcinomas].2007In: Der Chirurg, ISSN 0009-4722, E-ISSN 1433-0385, Vol. 78, no 3, 182, 184-8, 190 p.Article in journal (Refereed)
    Abstract [de]

    In general, primary surgery of thyroid carcinoma should consist of total thyroidectomy and lymph node dissection of the cervicocentral compartment. Exceptions are cases of papillary microcarcinoma and prophylactic surgery due to multiple type 2A endocrine neoplasia. Lymph node dissection beyond the cervicocentral compartment also should be compartment-oriented. It is generally indicated if lymph node metastases have been proven. Concerning clinically proven medullary thyroid carcinoma, bilateral cervicolateral lymph node dissection is generally indicated, since lymph node metastases may be missed preoperatively but are often found histologically. In patients with parathyroid carcinoma, en bloc ipsilateral cervicocentral lymph node dissection should be performed in addition to parathyroidectomy and hemithyroidectomy. Lymph node dissection should always be performed systematically, since lymph node metastases may be missed both clinically and by imaging techniques.

  • 22.
    Gimm, O
    et al.
    Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Martin-Luther-Universität Halle-Wittenberg, Germany.
    Lorenz, K
    Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Martin-Luther-Universität Halle-Wittenberg, Germany.
    Nguyen Thanh, P
    Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Martin-Luther-Universität Halle-Wittenberg, Germany.
    Schneyer, U
    Endokrinologie Klinik für Innere Medizin II, Martin-Luther-Universität Halle-Wittenberg, Germany.
    Bloching, M
    Klinik für Hals- Nasen- Ohrenheilkunde, Gesichts- und Halschirurgie, Martin-Luther-Universität Halle-Wittenberg, Germany.
    Howell, V M
    Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Australia.
    Marsh, D J
    Kolling Institute of Medical Research, Royal North Shore Hospital and University of Sydney, Australia.
    Teh, B T
    Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan, USA.
    Krause, U
    Institut für Pathologie, Martin-Luther-Universität Halle-Wittenberg, Germany.
    Dralle, H
    Klinik für Allgemein-, Viszeral- und Gefäßchirurgie, Martin-Luther-Universität Halle-Wittenberg, Germany.
    [Prophylactic parathyroidectomy for familial parathyroid carcinoma].2006In: Der Chirurg, ISSN 0009-4722, E-ISSN 1433-0385, Vol. 77, no 1, 15-24 p.Article in journal (Refereed)
    Abstract [de]

    In contrast to primary hyperparathyroidism, parathyroid carcinoma is a rare disease. In patients with hyperparathyroidism jaw tumor (HPT-JT) syndrome, caused by germline mutations in HRPT2, the development of parathyroid carcinoma is estimated to be 10-15%. This review summarizes the clinical and molecular genetic data of about 100 patients in the literature and three of our own cases. Unfortunately, osteofibromas, which might enable timely diagnosis of HPT-JT syndrome, occur in only about 30% of patients; about 80% have uniglandular disease. Based on the current data, a general recommendation to perform prophylactic parathyroidectomy cannot be given. However, thorough screening of patients at risk is mandatory. Of note in patients thought to have sporadic parathyroid carcinoma, germline HRPT2 mutations are found in up to 20%. Hence, any patient with parathyroid carcinoma should undergo HRPT2 mutation analysis.

  • 23.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Medullary thyroid carcinoma - Characteristics, diagnostics, therapy and follow-up [Medulläres Schilddrüsenkarzinom - Besonderheiten, Diagnostik, Therapie und Nachsorge]2012In: Klinikarzt, ISSN 0341-2350, Vol. 41, no 10, 476-480 p.Article in journal (Refereed)
    Abstract [en]

    Medullary thyroid carcinoma (MTC) is a rare malignant tumor of the thyroid gland, it probably accounts for about 3 - 8% of all thyroids cancers. In contrast to the majority of thyroid cancers that develop from thyreocytes, MTC has its origins in parafollicular C cells. Among others, these cells synthesize calcitonin which thus represents a very sensitive tumor marker. MTC is not responsive to the usually employed conventional radio-iodine therapy because C cells, in contrast to threocytes, do not take up iodine. This fact places additional demands on surgical treatment. The management of MTCs that are not suitable for operative treatment because of their inoperable nature or, respectively, due to the presence of distant disseminated metastases is a hot topic of current intensive research. © Georg Thieme Verlag KG · Stuttgart · New York.

  • 24.
    Gimm, Oliver
    University of Halle, Germany.
    Pheochromocytoma-associated syndromes: genes, proteins and functions of RET, VHL and SDHx2005In: Familial Cancer, ISSN 1389-9600, E-ISSN 1573-7292, Vol. 4, no 1, 17-23 p.Article in journal (Refereed)
    Abstract [en]

    Pheochromocytoma are tumors derived from chromaffin cells that secrete catecholamines. These catecholamines may lead to increased blood pressure and even death. Historically, pheochromocytoma have been described as 10 tumor, i.e. about 10 were believed to be malignant, 10 were found to be extra-adrenal, and 10 were meant to be bilateral. Also, about 10 were considered to be hereditary. In these instances, they were most often part of either the multiple endocrine neoplasia type 2 (MEN 2) syndrome or the von Hippel-Lindau (VHL) disease. The genes (RET and VHL) involved have been known for several years and their function is the subject of ongoing investigation. Very recently, several genes (SDHD, SDHB, and SDHC) that belong to the mitochondrial complex II have been identified to be involved in the so-called pheochromocytoma-paraganglioma syndrome. Only SDHD and SDHB have so far been implicated in the pathogenesis of pheochromocytoma.

  • 25.
    Gimm, Oliver
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    Arnesson, Lars-Gunnar
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery UHL.
    Olofsson, Pia
    Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery UHL. Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Morales, Olallo
    Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery UHL.
    Juhlin, Claes
    Östergötlands Läns Landsting, Centre for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery UHL. Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences.
    Super-selective venous sampling in conjunction with quickPTH for patients with persistent primary hyperparathyroidism: report of five cases2012In: Surgery today (Print), ISSN 0941-1291, E-ISSN 1436-2813, Vol. 42, no 6, 570-576 p.Article in journal (Refereed)
    Abstract [en]

    Selective venous sampling (SVS) helps to interpret imaging results in patients with persistent primary hyperparathyroidism (pHPT). However, one of the drawbacks of conventional SVS may be low "spatial resolution", depending on the sample size. We modified SVS in the following way: first, patients underwent conventional SVS with up to 11 parathyroid hormone (PTH) samples taken. The quickPTH assay was used to measure PTH levels. The patients subsequently underwent super-selective venous sampling (super-SVS) in the region with the highest quickPTH level in the same session. The subjects were five consecutive patients with persistent pHPT investigated by various imaging techniques, none of which was considered conclusive. Therefore, all five patients underwent super-SVS, which was done successfully in four. Re-evaluation of the imaging results of these four patients resulted in localization of the parathyroid adenoma. Curative surgery was performed successfully in all four patients during the study period. Super-SVS increases the "spatial resolution" of conventional SVS and may have advantages when imaging results of patients with persistent pHPT are interpreted. Its true value must be analyzed in larger studies.

  • 26.
    Gimm, Oliver
    et al.
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting.
    Castellone, Maria Domenica
    CNR c/o Dipartimento di Biologia e Patologia Cellulare e Molecolare, Istituto di Oncologia Sperimentale “G. Salvatore”, Università Federico II, Napoli, Italy.
    Hoang-Vu, Cuong
    Universitätsklinik und Poliklinik für Allgemein-, Viszeral- und Gefäßchirurgie, Martin-Luther Universität, Halle, Germany.
    Kebebew, Electron
    Endocrine Oncology Section, Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
    Biomarkers in thyroid tumor research: new diagnostic tools and potential targets of molecular-based therapy2011In: Journal of Thyroid Research, ISSN 2090-8067, E-ISSN 2042-0072, Vol. 2011, 631593Article in journal (Refereed)
    Abstract [en]

    n/a

  • 27.
    Gimm, Oliver
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Östergötland.
    DeMicco, Catherine
    Fac Med, Lab Anat and Cytologie Pathol, Marseille.
    Perren, Aurel
    University of Bern.
    Giammarile, Francesco
    University of Lyon 1.
    Walz, Martin K
    Kliniken Essen Mitte.
    Brunaud, Laurent
    University of Nancy.
    Malignant pheochromocytomas and paragangliomas: a diagnostic challenge2012In: Langenbeck's archives of surgery (Print), ISSN 1435-2443, E-ISSN 1435-2451, Vol. 397, no 2, 155-177 p.Article, review/survey (Refereed)
    Abstract [en]

    Introduction Malignant pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare disorders arising from the adrenal gland, from the glomera along parasympathetic nerves or from paraganglia along the sympathetic trunk. According to the WHO classification, malignancy of PCCs and PGLs is defined by the presence of metastases at non-chromaffin sites distant from that of the primary tumor and not by local invasion. The overall prognosis of metastasized PCCs/PGLs is poor. Surgery offers currently the only change of cure. Preferably, the discrimination between malignant and benign PCCs/PGLs should be made preoperatively. less thanbrgreater than less thanbrgreater thanMethods This review summarizes our current knowledge on how benign and malignant tumors can be distinguished. less thanbrgreater than less thanbrgreater thanConclusion Due to the rarity of malignant PCCs/PGLs and the obvious difficulties in distinguishing benign and malignant PCCs/PGLs, any patient with a PCC/PGL should be treated in a specialized center where a multidisciplinary setting with specialized teams consisting of radiologists, endocrinologist, oncologists, pathologists and surgeons is available. This would also facilitate future studies to address the existing diagnostic and/or therapeutic obstacles.

  • 28.
    Gimm, Oliver
    et al.
    Department of General, Visceral, and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06097, Halle/Saale, Germany.
    Heyn, Viola
    Department of General, Visceral, and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06097, Halle/Saale, Germany.
    Krause, Ulf
    Institute of Pathology, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06097, Halle/Saale, Germany .
    Sekulla, Carsten
    Department of General, Visceral, and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06097, Halle/Saale, Germany.
    Ukkat, Jörg
    Department of General, Visceral, and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06097, Halle/Saale, Germany.
    Dralle, Henning
    Department of General, Visceral, and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Strasse 40, 06097, Halle/Saale, Germany.
    Prognostic significance of disseminated tumor cells in the connective tissue of patients with medullary thyroid carcinoma.2006In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 30, no 5, 847-52 p.Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Disseminated tumor cells in the connective tissue (CT-DTCs) do not have any connection to a primary tumor or the lymph nodes. They are identified quite often in patients with medullary thyroid carcinoma (MTC), but nothing is known regarding their prognostic significance.

    METHODS: Among 450 patients with MTC, 69 (15%) were identified as having CT-DTCs. A case-control group of patients without CT-DTCs was selected. The two groups were matched concerning TNM classification, age, heredity, and sex. Because many patients with CT-DTCs had extrathyroidal tumor extension (pT4 category), distant metastases (M1 category), or both, only 35 matched pairs could be identified. The TNM classification in both groups was as follows: pT1, n = 8; pT2, n = 15; pT3, n = 4; pT4, n = 8; pN0, n = 4; pN1, n = 31; M0, n = 30; M1, n = 5. The mean age was 46.8 +/- 17.0 years in the CT-DTC group and 44.4 +/- 15.0 years in the case-control group (NS).

    RESULTS: In both groups, 23 patients had sporadic MTC, and 12 patients had hereditary MTC. Neither mean basal preoperative nor postoperative calcitonin levels differed significantly between the two groups. In contrast, none of the patients with CT-DTCs was biochemically cured (normal calcitonin level after pentagastrin stimulation) compared to eight patients without CT-DTCs (P < 0.005). The two groups did not differ concerning other parameters (basal calcitonin level > 3000 pg/ml, more than 10 lymph node metastases, more than two involved locoregional lymph node compartments, mediastinal lymph node metastases) that have been reported to correlate with the lack of or almost (< 10%) lack of biochemical cure.

    CONCLUSIONS: In patients with MTC, disseminated tumor cells in the connective tissue correlate with advanced tumor stages and appear to be of prognostic significance.

  • 29.
    Gimm, Oliver
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Juhlin, Claes
    Linköping University, Department of Clinical and Experimental Medicine, Surgery. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Morales, Olallo
    Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology in Linköping.
    Persson, Anders
    Linköping University, Center for Medical Image Science and Visualization (CMIV). Linköping University, Department of Medical and Health Sciences, Radiology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre for Medical Imaging, Department of Radiology in Linköping.
    Dual-Energy Computed Tomography Localizes Ectopic Parathyroid Adenoma2010In: The Journal of Clinical Endocrinology & Metabolism, ISSN 0021-972X, Vol. 95, no 7, 3092-3093 p.Article in journal (Refereed)
    Abstract [en]

    Dual-energy computed tomography (DECT) can acquire two datasets showing different attenuation levels allowing collectionof additional information about the elementary chemical compositionof the scanned material. Color can then be assigned accordingto the 80- and 140-kV computed tomography (CT) values to obtaina color-mapped, dual-energy image. DECT has been used extensivelyin our department in postmortem CT with excellent results (1).One of the advantages of DECT is that iodine contrast uptakein soft tissue can be quantified. We were wondering about itsability to localize parathyroid adenomas (PAs).

  • 30.
    Gimm, Oliver
    et al.
    Department of General, Visceral and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, 06097 Halle/Saale, Germany.
    Krause, Ulf
    Institute of Pathology, Martin-Luther-University Halle-Wittenberg, 06097 Halle/Saale, Germany.
    Brauckhoff, Michael
    Department of General, Visceral and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, 06097 Halle/Saale, Germany.
    Hoang-Vu, Cuong
    Department of General, Visceral and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, 06097 Halle/Saale, Germany.
    Dralle, Henning
    Department of General, Visceral and Vascular Surgery, Martin-Luther-University Halle-Wittenberg, 06097 Halle/Saale, Germany.
    Distinct expression of galectin-3 in pheochromocytomas.2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1073, 571-7 p.Article in journal (Refereed)
    Abstract [en]

    Unless distant metastases or local invasion are present, the diagnosis of malignant pheochromocytoma is challenging. Hence, biological markers are sought after and we thought to examine galectin-3 in such a role. Four malignant and 24 benign (10 sporadic, 14 hereditary) pheochromocytomas were analyzed for the expression of galectin-3. One malignant pheochromocytoma with distant metastases showed strong and one malignant undifferentiated pheochromocytoma with local invasion showed partly strong cytoplasmic staining. Nine of 10 sporadic and all hereditary benign pheochromocytomas had absent/weak staining. One benign sporadic pheochromocytoma had moderate cytoplasmic staining. The distinct expression in various types of pheochromocytomas is intriguing and requires further investigation.

  • 31.
    Gimm, Oliver
    et al.
    Department of General, Visceral and Vascular Surgery, University of Halle, Ernst-Grube-Str. 40, 06097, Halle, Germany .
    König, Evelyn
    Department of General, Visceral and Vascular Surgery, University of Halle, Ernst-Grube-Str. 40, 06097, Halle, Germany .
    Thanh, Phuong Nguyen
    Department of General, Visceral and Vascular Surgery, University of Halle, Ernst-Grube-Str. 40, 06097, Halle, Germany .
    Brauckhoff, Michael
    Department of General, Visceral and Vascular Surgery, University of Halle, Ernst-Grube-Str. 40, 06097, Halle, Germany .
    Karges, Wolfram
    Division of Endocrinology, University of Ulm, Ulm, Germany.
    Dralle, Henning
    Department of General, Visceral and Vascular Surgery, University of Halle, Ernst-Grube-Str. 40, 06097, Halle, Germany .
    Intra-operative quick insulin assay to confirm complete resection of insulinomas guided by selective arterial calcium injection (SACI).2007In: Langenbeck's archives of surgery (Print), ISSN 1435-2443, E-ISSN 1435-2451, Vol. 392, no 6, 679-84 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND AND AIMS: Insulinomas are rare endocrine disorders. Pre-operatively, conventional imaging techniques often fail to localise the tumor. In addition, due to the lack of quick insulin assays, intra-operative confirmation of complete resection was impossible until recently.

    MATERIALS AND METHODS: Six patients with biochemical evidence of an insulinoma underwent pre-operative localisation studies and selective arterial calcium injection (SACI). In addition, insulin was measured before surgery and every 10-15 min after resection of the tumor using a quick insulin assay.

    RESULTS: Pre-operative localisation studies identified the tumor correctly as follows: endosonography: three of four, magnetic resonance imaging: two of four and SACI: six of six. Tumors in the head and body were enucleated while those in the tail were resected (n = 2, each). Those three patients, in whom magnetic resonance imaging and/or endosonography could localise the tumors pre-operatively, underwent laparoscopic surgery while the remaining three patients underwent open surgery. Intra-operatively, insulin dropped to normal levels within 20 min in all cases. After a follow-up of 0.8-3 years, all patients remained biochemically cured.

    CONCLUSIONS: Pre-operatively, SACI appears to be a very sensitive localisation technique and may be most helpful in guiding the surgeon if conventional imaging techniques fail to localise the tumor. Complete removal of an insulinoma can be reliably predicted using a quick insulin assay.

  • 32.
    Hahn, Michael A
    et al.
    University of Sydney.
    Howell, Viive M
    University of Sydney.
    Gill, Anthony J
    University of Sydney.
    Clarkson, Adele
    University of Sydney.
    Weaire-Buchanan, Graham
    University of Sydney.
    Robinson, Bruce G
    University of Sydney.
    Delbridge, Leigh
    University of Sydney.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Surgery in Östergötland.
    Schmitt, Wolfgang D
    University of Halle.
    Teh, Bin T
    Van Andel Research Institute.
    Marsh, Deborah J
    University of Sydney.
    CDC73/HRPT2 CpG island hypermethylation and mutation of 5 -untranslated sequence are uncommon mechanisms of silencing parafibromin in parathyroid tumors2010In: ENDOCRINE-RELATED CANCER, ISSN 1351-0088, Vol. 17, no 1, 273-282 p.Article in journal (Refereed)
    Abstract [en]

    The tumor suppressor HRPT2/CDC73 is mutated in constitutive DNA from patients with the familial disorder hyperparathyroidism-jaw tumor syndrome and in similar to 70% of all parathyroid carcinomas. In a number of HRPT2 mutant tumors however, expression of the encoded protein parafibromin is lost in the absence of a clear second event such as HRPT2 allelic loss or the presence of a second mutation in this tumor suppressor gene. We sought to determine whether hypermethylation of a 713 bp CpG island extending 648 nucleotides upstream of the HRPT2 translational start site and 65 nucleotides into exon 1 might be a mechanism contributing to the loss of expression of parafibromin in parathyroid tumors. Furthermore, we asked whether mutations might be present in the 5-untranslated region (5-UTR) of HRPT2. We investigated a pool of tissue from 3 normal parathyroid glands, as well as 15 individual parathyroid tumor samples including 6 tumors with known HRPT2 mutations, for hypermethylation of the HRPT2 CpG island. Methylation was not identified in any specimens despite complete loss of parafibromin expression in two parathyroid carcinomas with a single detectable HRPT2 mutation and retention of the wild-type HRPT2 allele. Furthermore, no mutations of a likely pathogenic nature were identified in the 5-UTR of HRPT2. These data strongly suggest that alternative mechanisms such as mutation in HRPT2 intronic regions, additional epigenetic regulation such as histone modifications, or other regulatory inactivation mechanisms such as targeting by microRNAs may play a role in the loss of parafibromin expression.

  • 33.
    Haj-Hosseini, Neda
    et al.
    Linköping University, Department of Biomedical Engineering, Division of Biomedical Engineering. Linköping University, Faculty of Science & Engineering.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Höög, Anders
    Linköping University, Department of Clinical and Experimental Medicine, Divison of Neurobiology. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Johansson, Kenth
    Landstinget i Kalmar län och Sahlgrenska universitetssjukhus, Västra Götalandsregion.
    Optiska metoder för identifiering av bisköldkörtel och sköldkörtel2017Conference paper (Refereed)
    Abstract [sv]

    Identifiering av bisköldkörtlar är viktigt vid sköldkörtel- och bisköldkörtelkirurgi och kan vara svårt då de liknar omgivande vävnad såsom fett och lymfkörtlar. Peroperativ detektering av dessa vävnader kan förbättra möjligheten att bota patienter med hyperparathyroidism och minska risken för bisköldkörtelskador vid thyroideakirurgi. Optiska metoder är potentiella tekniker för att möjliggöra detta. Optiska tekniker utvärderades på vävnadsprover från patienter vid bisköldkörtel- och sköldkörteloperation. Teknikerna bestod av nära infraröd fluorescens (NIR) spektroskopi och optisk koherenstomografi (OCT) som ger en bild av vävnadens mikrostruktur liknande till ultraljud med högre upplösning (10 μm).

  • 34.
    Haj-Hosseini, Neda
    et al.
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, Faculty of Medicine and Health Sciences.
    Petersson, Pernilla
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Medicine and Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Shabo, Ivan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Optical Coherence Tomography for Pathological Analysis of Thyroid2016Conference paper (Refereed)
  • 35.
    Haj-Hosseini, Neda
    et al.
    Linköping University, Department of Biomedical Engineering, Biomedical Instrumentation. Linköping University, The Institute of Technology.
    Stepp, Herbert
    Ludwig Maximilians Universitet, München.
    Markwardt, Niklas
    Ludwig Maximilians Universitet, München.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Shabo, Ivan
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Region Östergötland, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Optical biopsy during thyroid and parathyroid surgery2015Conference paper (Refereed)
  • 36.
    Howell, Viive M
    et al.
    Kolling Institute of Medical Research, Royal North Shore Hospital and the Department of Molecular Medicine, University of Sydney, Sydney, Australia.
    Cardinal, John W
    Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Queensland, Australia.
    Richardson, Anne-Louise
    Kolling Institute of Medical Research, Royal North Shore Hospital and the Department of Molecular Medicine, University of Sydney, Sydney, Australia.
    Gimm, Oliver
    Department of General, Visceral, and Vascular Surgery, Martin Luther University, Halle-Wittenberg, Germany.
    Robinson, Bruce G
    Kolling Institute of Medical Research, Royal North Shore Hospital and the Department of Molecular Medicine, University of Sydney, Sydney, Australia.
    Marsh, Deborah J
    Kolling Institute of Medical Research, Royal North Shore Hospital and the Department of Molecular Medicine, University of Sydney, Sydney, Australia.
    Rapid mutation screening for HRPT2 and MEN1 mutations associated with familial and sporadic primary hyperparathyroidism.2006In: Journal of Molecular Diagnostics, ISSN 1525-1578, E-ISSN 1943-7811, Vol. 8, no 5, 559-66 p.Article in journal (Refereed)
    Abstract [en]

    Familial hyperparathyroidism, a disease of the parathyroid glands, may occur in conjunction with pituitary and pancreatic tumors (multiple endocrine neoplasia type I), kidney and bone tumors (hyperparathyroidism jaw tumor syndrome), or alone (familial isolated hyperparathyroidism). This study describes the development and validation of rapid scanning for mutations in two tumor suppressor genes linked to familial hyperparathyroidism-MEN1 and HRPT2. Denaturing high-performance liquid chromatography mutation scanning for MEN1 was performed using a set of 10 amplicons covering the nine coding exons and flanking intronic regions and for HRPT2 using a set of three amplicons for exons 1, 2, and 7 and flanking intronic regions, in which 80% of the mutations identified to date are located. All 52 MEN1 mutations or polymorphisms, 46 known and six unknown, were successfully detected. Mutation detection in exon 9 was not confounded by the presence of the common polymorphism D418D. In addition, all 10 HRPT2 mutations were successfully detected, and a two-step approach was able to distinguish IVS2 common polymorphisms from exon 2 mutations. The development of rapid denaturing high performance liquid chromatography mutation scanning of MEN1 and HRPT2 facilitates a molecular diagnosis of the associated familial syndromes for both clinically affected and at-risk family members.

  • 37.
    Jangland, Eva
    et al.
    Institutionen för kirurgiska vetenskaper, Uppsala Universitet.
    Becker, Deborah
    School of Nursing, University of Pennsylvania, USA.
    Börjeson, Sussanne
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Oncology.
    Doherty, Caroline
    Adult Gerontology Acute Care Nurse Practitioner Program, Phildelphia, Pennsylvania, USA.
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
    Griffith, Patricia
    School of Nursing, University of Pennsylvania, USA.
    Johansson, AnnaKarin
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Health Sciences.
    Juhlin, Claes
    Avdelningen för kirurgi, Uppsala Universitetssjukhus.
    Pawlow, Patricia
    School of Nursing, University of Pennsylvania, USA.
    Sicoutris, Corinna
    School of Nursing, University of Pennsylvania, USA.
    Yngman-Uhlin, Pia
    Linköping University, Department of Medical and Health Sciences, Division of Nursing Science. Linköping University, Faculty of Health Sciences.
    The development of a Swedish Nurse Practitioner Program - a request from clinicians and a process supported by US experience2013In: Journal of Nursing Education and Practice, ISSN 1925-4040, E-ISSN 1925-4059, Vol. 4, no 2, 38-48 p.Article in journal (Refereed)
    Abstract [en]

    High nursing turnover and a shortage of nurses in acute hospital settings in Sweden challenge health care systems to deliver and ensure safe care. Advanced nursing roles implemented in other countries have offered nurses new career opportunities and had positive effects on patient safety, effectiveness of care, and patient satisfaction. The advanced nursing position of Nurse Practitioner has existed for many years in the United States, while similar extended nursing roles and changes in the scope of nursing practice are being developed in many other countries. In line with this international trend, the role of Nurse Practitioner in surgical care has been proposed for Sweden, and a master’s programme for Acute Nurse Practitioners has been in development for many years. To optimize and facilitate the introduction of this new nursing role and its supporting programme, we elicited the experiences and support of the group who developed a Nurse Practitioner programme for a university in the US. This paper describes this collaboration and sharing of experiences during the process of developing a Swedish Nurse Practitioner programme. We also discuss the challenges of implement- ting any new nursing role in any national health care system. We would like to share our collaborative experiences and thoughts for the future and to open further national and international dialogue about how best to expand the scope of practice for nurses in acute hospital care, and thereby to improve patient care in Sweden and elsewhere.

  • 38.
    Jarbo, Caroline
    et al.
    Rudbeck Laboratory, Uppsala University, Sweden.
    Buckley, Patrick
    Rudbeck Laboratory, Uppsala University, Sweden.
    Piotrowski, Arkadiusz
    Rudbeck Laboratory, Uppsala University, Sweden.
    Mantripragada, Kiran
    Rudbeck Laboratory, Uppsala University, Sweden.
    Benetkiewicz, Magdalena
    Rudbeck Laboratory, Uppsala University, Sweden.
    Diaz de Ståhl, Teresita
    Rudbeck Laboratory, Uppsala University, Sweden.
    Langford, Cordelia
    The Wellcome Trust Sanger Institute, Cambridge, UK.
    Gregory, Simon
    The Wellcome Trust Sanger Institute, Cambridge, UK.
    Dralle, Henning
    Martin Luther University of Halle, Germany.
    Gimm, Oliver
    Martin Luther University of Halle, Germany.
    Bäckdahl, Martin
    Karolinska University Hospital, Stockholm, Sweden.
    Geli, Janos
    Karolinska University Hospital, Stockholm, Sweden.
    Larsson, Catharina
    Karolinska University Hospital, Stockholm, Sweden.
    Westin, Gunnar
    Uppsala University Hospital, Sweden.
    Åkerström, Göran
    Uppsala University Hospital, Sweden.
    Dumanski, Jan
    Rudbeck Laboratory, Uppsala University, Sweden.
    Detailed assessment of chromosome 22 aberrations in sporadic pheochromocytoma using array-CGH2006In: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 118, no 5, 1159-1164 p.Article in journal (Refereed)
    Abstract [en]

    Pheochromocytoma is a predominantly sporadic neuroendocrine tumor derived from the adrenal medulla. Previous low resolution LOH and metaphase-CGH studies reported the loss of chromosomes 1p, 3q, 17p and 22q at various frequencies. However, the molecular mechanism(s) behind development of sporadic pheochromocytoma remains largely unknown. We have applied high-resolution tiling-path microarray-CGH with the primary aim to characterize copy number imbalances affecting chromosome 22 in 66 sporadic pheochromocytomas. We detected copy number alterations on 22q at a frequency of 44%. The predominant finding was monosomy 22 (30%), followed by terminal deletions in 8 samples (12%) and a single interstitial deletion. We further applied a chromosome 1 tiling-path array in 7 tumors with terminal deletions of 22q and found deletions of 1p in all cases. Our overall results suggest that at least 2 distinct regions on both 22q and 1p are important in the tumorigenesis of sporadic pheochromocytoma. A large proportion of pheochromocytomas also displayed indications of cellular heterogeneity. Our study is to our knowledge the first array-CGH study of sporadic pheochromocytoma. Future analysis of this tumor type should preferably be performed in the context of the entire human genome using genome-wide array-CGH, which is a superior methodological approach. Supplemental material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.

  • 39.
    Karger, Stefan
    et al.
    Clinic of Endocrinology and Nephrology, Department of Internal Medicine, Neurology and Dermatology, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
    Krause, Kerstin
    Clinic of Endocrinology and Nephrology, Department of Internal Medicine, Neurology and Dermatology, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
    Engelhardt, Cornelia
    Clinic of Endocrinology and Nephrology, Department of Internal Medicine, Neurology and Dermatology, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
    Weidinger, Carl
    Clinic of Endocrinology and Nephrology, Department of Internal Medicine, Neurology and Dermatology, University of Leipzig, Liebigstraße 18, 04103 Leipzig, Germany.
    Gimm, Oliver
    Department of General, Visceral, and Vascular Surgery, Martin Luther University of Halle‐Wittenberg, Ernst‐Grube‐Straße 40, 06120 Halle, Saale, Germany.
    Dralle, Henning
    Department of General, Visceral, and Vascular Surgery, Martin Luther University of Halle‐Wittenberg, Ernst‐Grube‐Straße 40, 06120 Halle, Saale, Germany.
    Sheu-Grabellus, Sien-Yi
    Institute of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany.
    Kurt Werner, Schmid
    Institute of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany.
    Fuhrer, Dagmar
    Clinic of Endocrinology and Metabolic Disorders, University of Duisburg‐Essen, Hufelandstraße 55, D-45147 Essen, Germany.
    Distinct pattern of oxidative DNA damage and DNA repair in follicular thyroid tumours.2012In: Journal of molecular endocrinology, ISSN 1479-6813, Vol. 48, no 3, 193-202 p.Article in journal (Refereed)
    Abstract [en]

    Increased oxidative stress has been linked to thyroid carcinogenesis. In this paper, we investigate whether oxidative DNA damage and DNA repair differ in follicular adenoma (FA) and follicular thyroid carcinoma (FTC). 7,8-Dihydro-8-oxoguanine (8-OxoG) formation was analysed by immunohistochemistry in 46 FAs, 52 FTCs and 18 normal thyroid tissues (NTs). mRNA expression of DNA repair genes OGG1, Mut Y homologue (MUTYH) and endonuclease III (NTHL1) was analysed by real-time PCR in 19 FAs, 25 FTCs and 19 NTs. Induction and repair of oxidative DNA damage were studied in rat FRTL-5 cells after u.v. irradiation. Moreover, activation of DNA damage checkpoints (ataxia telangiectasia mutated (ATM) and H2A histone family, member X (H2AFX (H2AFX))) and proliferation index (MIB-1) were quantified in 28 non-oxyphilic and 24 oxyphilic FTCs. Increased nuclear and cytosolic 8-OxoG formation was detected in FTC compared with follicular adenoma, whereby cytosolic 8-OxoG formation was found to reflect RNA oxidation. Significant downregulation of DNA repair enzymes was detected in FTC compared with FA. In vitro experiments mirrored the findings in FTC with oxidative stress-induced DNA checkpoint activation and downregulation of OGG1, MUTYH and NTHL1 in FRTL-5 cells, an effect that, however, was reversible after 24  h. Further analysis of FTC variants showed decreased oxidative DNA damage, sustained checkpoint activation and decreased proliferation in oxyphilic vs non-oxyphilic FTC. Our data suggest a pathophysiological scenario of accumulating unrepaired DNA/RNA damage in FTC vs counterbalanced DNA/RNA damage and repair in FA. Furthermore, this study provides the first evidence for differences in oxidative stress defence in FTC variants with possible implications for therapeutic response and prognostic outcome.

  • 40.
    Karger, Stefan
    et al.
    Division of Endocrinology and Diabetes, Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Street 27, 04103 Leipzig, Germany.
    Weidinger, Carl
    Division of Endocrinology and Diabetes, Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Street 27, 04103 Leipzig, Germany.
    Krause, Kerstin
    Division of Endocrinology and Diabetes, Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Street 27, 04103 Leipzig, Germany.
    Sheu, Sien-Yi
    Institute of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany.
    Aigner, Thomas
    Institute of Pathology, University of Leipzig, Leipzig, Germany.
    Gimm, Oliver
    Department of Surgery, University of Halle-Wittenberg, Halle, Germany.
    Schmid, Kurt-Werner
    Institute of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany.
    Dralle, Henning
    Department of Surgery, University of Halle-Wittenberg, Halle, Germany.
    Fuhrer, Dagmar
    Division of Endocrinology and Diabetes, Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Street 27, 04103 Leipzig, Germany.
    FOXO3a: a novel player in thyroid carcinogenesis?2009In: Endocrine-Related Cancer, ISSN 1351-0088, Vol. 16, no 1, 189-99 p.Article in journal (Refereed)
    Abstract [en]

    The forkhead box transcription factor FOXO3a has recently been identified as central mediator of the cellular response to oxidative stress inducing cell cycle arrest or apoptosis. The aim of our study was to investigate the regulation of FOXO3a in the thyroid and to determine whether alterations in FOXO3a activity occur in thyroid carcinogenesis. In vitro, we demonstrate that FOXO3a activity is negatively regulated by the PI3K/Akt cascade promoting increased phosphorylation and cytoplasmatic accumulation of FOXO3a with decreased transcription of the target genes p27kip (CDKN1B) and Bim (BCL2L11), but increased expression of GADD45A. By contrast, we show that H(2)O(2) exposure activates FOXO3a in thyrocytes with JNK (MAPK8)-mediated nuclear accumulation of FOXO3a and increased expression of the cell cycle arrest genes p27kip and GADD45A. In vivo, we observed a marked cytoplasmatic accumulation of FOXO3a in differentiated thyroid cancers versus an exclusive nuclear accumulation in follicular adenoma and normal thyroid tissue. Moreover, this cytosolic accumulation of FOXO3a correlated with an increased phospho-Akt expression in thyroid malignancies and was accompanied by decreased expression of the FOXO targets p27kip and Bim and an increase in GADD45A mRNA expression in the thyroid cancers. Our data suggest FOXO3a as a novel player of cellular stress response in the thyroid, mediating the thyrocyte's fate either to survive or to undergo apoptosis. Furthermore, PI3K-dependent FOXO3a inactivation may be a novel pathomechanism for the escape from apoptosis in thyroid cancer cells, in particular in follicular thyroid carcinoma.

  • 41.
    Koch, Christian A
    et al.
    Division of Endocrinology and Nephrology, University of Leipzig, Germany.
    Gimm, Oliver
    Department of Surgery, University of Halle, Germany.
    Vortmeyer, Alexander O
    National Institutes of Health, NINDS, Bethesda, Maryland, USA.
    Al-Ali, Haifa K
    Division of Hematology and Oncology, University of Leipzig, Germany.
    Lamesch, Peter
    Department of Surgery, Sankt Georg Hospital, Leipzig, Germany.
    Ott, Rudolf
    Department of Surgery II, University of Leipzig, Germany.
    Kluge, Regine
    Department of Nuclear Medicine, University of Leipzig, Germany.
    Bierbach, Uta
    Division of Pediatric Hematology and Oncology, University of Leipzig, Germany.
    Tannapfel, Andrea
    Ruhr University of Bochum, Bochum, Germany.
    Does the expression of c-kit (CD117) in neuroendocrine tumors represent a target for therapy?2006In: Annals of the New York Academy of Sciences, ISSN 0077-8923, E-ISSN 1749-6632, Vol. 1073, 517-26 p.Article in journal (Refereed)
    Abstract [en]

    Neuroendocrine tumors are very heterogeneous, develop from a variety of tissues, and can be difficult to diagnose. Without the clinical manifestation of metastases, it is often difficult to characterize them as malignant. Even so-called completely (R0) resected tumors can spread clinically visible metastases within a few months after initial surgery. Treatment options for neuroendocrine tumors including pheochromocytoma are limited. Molecular targeted therapies using tyrosine kinase inhibitors might prove to be helpful in patients with these tumors. In an immunohistochemical study, we examined KIT in 26 pheochromocytomas, 8 of which were malignant (3 adrenal pheochromocytomas, 5 paragangliomas). KIT expression was found in one of these 8 malignant tumors. This 2.5-cm-large adrenal pheochromocytoma originated from a woman with neurofibromatosis type 1 and spread into spine, skull, and lung. KIT expression could be demonstrated in 5% of tumor cells. On the basis of KIT expression immunohistochemically, we treated patients with neuroendocrine (i.e., medullary thyroid cancer) and other tumors with imatinib 400 mg per day, but without efficacy after 2 months of therapy. Similar results were shown by other investigators. Therefore, monotherapy with imatinib may not be efficacious in patients with neuroendocrine tumors that express KIT. Tyrosine kinase inhibitors such as sorafenib that targets several receptors in addition to KIT may be more efficacious in treating patients with neuroendocrine tumors.

  • 42.
    Krause, Kerstin
    et al.
    Department of Internal Medicine, University of Leipzig, 04103 Leipzig, Germany.
    Eszlinger, Markus
    Department of Internal Medicine, University of Leipzig, 04103 Leipzig, Germany.
    Gimm, Oliver
    Department of Surgery, University of Halle, 06120 Halle, Germany .
    Karger, Stefan
    Department of Internal Medicine, University of Leipzig, 04103 Leipzig, Germany.
    Engelhardt, Cornelia
    Department of Internal Medicine, University of Leipzig, 04103 Leipzig, Germany.
    Dralle, Henning
    Department of Surgery, University of Halle, 06120 Halle, Germany .
    Fuhrer, Dagmar
    Department of Internal Medicine, University of Leipzig, 04103 Leipzig, Germany.
    TFF3-based candidate gene discrimination of benign and malignant thyroid tumors in a region with borderline iodine deficiency.2008In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 93, no 4, 1390-3 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: With the advent of microarray technology, increasing numbers of marker genes are proposed to distinguish benign and malignant thyroid lesions. However, most markers await confirmation through independent studies. In this paper, we re-evaluate the diagnostic potential of 10 proposed candidate genes in benign and malignant thyroid pathologies in a region with borderline iodine deficiency.

    METHODS: Quantitative real-time PCR was performed for CCND2, PLAB, PCSK2, HGD1, TFF3, B4GALT, LGALS3, ETS1, ADM3, and TG in 150 thyroid specimens, including 52 benign thyroid nodules (28 follicular adenoma and 24 adenomatous nodules), 52 corresponding normal thyroid tissues, 20 follicular carcinomas, 20 papillary carcinomas, and six undifferentiated carcinomas.

    RESULTS: On a single-gene basis, significant differences in mRNA expression were found for TFF3, PLAB, and ADM3 in benign thyroid nodules and thyroid malignancy. Using two-marker gene sets, we identified 11 combinations, which allowed both a distinction of benign and malignant thyroid nodules and a discrimination of follicular adenoma and carcinoma. However, for cancer prediction, analysis of a minimum of six genes per sample was necessary and allowed correct prediction of a benign thyroid lesion and thyroid cancer with 94% accuracy in the most discriminative set (TFF3/PLAB/TG/ADM3/HGD1/LGALS3).

    CONCLUSION: We confirm the applicability of a number of recently proposed marker genes for the distinction of benign and malignant thyroid tumor and suggest that their diagnostic usefulness is independent of the iodide supply. We propose that the most discriminative marker set identified in our validation study together with marker combinations proposed by other investigators should now be evaluated in multicenter trials.

  • 43.
    Krause, Kerstin
    et al.
    Medical Department, University of Leipzig, Ph.-Rosenthal-Str. 27, 04103 Leipzig, Germany.
    Karger, Stefan
    Medical Department, University of Leipzig, Ph.-Rosenthal-Str. 27, 04103 Leipzig, Germany.
    Gimm, Oliver
    Department of Surgery, University of Halle, Halle, Germany.
    Sheu, Sien-Yi
    Institute of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany.
    Dralle, Henning
    Department of Surgery, University of Halle, Halle, Germany.
    Tannapfel, Andrea
    Institute of Pathology, University of Bochum, Bochum, Germany.
    Schmid, Kurt Werner
    Institute of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany.
    Dupuy, Corinne
    Unité 486 Inserm, Université Paris 11, 92296 Châtenay-Malabry, Cedex, France.
    Fuhrer, Dagmar
    Medical Department, University of Leipzig, Ph.-Rosenthal-Str. 27, 04103 Leipzig, Germany.
    Characterisation of DEHAL1 expression in thyroid pathologies.2007In: European Journal of Endocrinology, ISSN 0804-4643, E-ISSN 1479-683X, Vol. 156, no 3, 295-301 p.Article in journal (Refereed)
    Abstract [en]

    UNLABELLED: Iodotyrosine dehalogenase 1 (DEHAL1) is a transmembrane protein involved in the recycling of iodide in the human thyroid. The aim of the present study was (I) to investigate whether DEHAL1 expression is different in differentially functioning thyroid pathologies and (II) to evaluate DEHAL1 as a possible marker of thyroid cell differentiation.

    DESIGN AND METHODS: Real-time PCR for DEHAL1 and its isoform DEHAL1B was performed in a series of 105 thyroid specimens, including toxic thyroid nodules (TTN), Graves' disease (GD) thyroids, benign cold thyroid nodules (CTN), normal thyroid tissues and thyroid cancers (follicular thyroid carcinomas (FTC), papillary thyroid carcinomas (PTC), partially differentiated thyroid cancers (PDTC) and anaplastic thyroid carcinomas (ATC)). In addition, DEHAL1 protein expression was studied by immunohistochemistry in 163 benign and malignant thyroid pathologies and normal thyroids.

    RESULTS: (I) The highest DEHAL1 mRNA levels were found in GD thyroids, while downregulation of DEHAL1 and DEHAL1B mRNA occurred in PTC and ATC (P<0.001 and <0.05 respectively); (II) DEHAL1 protein was overexpressed in TTNs and GD thyroids with predominant apical staining in all samples; (III) a weaker and patchy staining pattern was found in CTNs and normal thyroids; (IV) in differentiated thyroid cancers (FTC and PTC), a diffuse cytoplasmic DEHAL1 expression was found; and (V) in PDTC and ATC, DEHAL1 expression was faint or absent.

    CONCLUSION: Upregulation of DEHAL1 protein expression and sublocalisation of DEHAL1 at the apical cell pole in TTNs and GD thyroids is consistent with increased thyroid hormone turnover during thyrotoxicosis. Diffuse cytoplasmatic localisation or downregulation of DEHAL1 expression in thyroid cancers suggests alteration or loss of DEHAL1 function during thyroid cell dedifferentiation.

  • 44.
    Krause, Kerstin
    et al.
    Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Str. 27, D-04103 Leipzig, Germany.
    Karger, Stefan
    Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Str. 27, D-04103 Leipzig, Germany.
    Sheu, Sien-Yi
    Institute of Pathology and Neuropathology, University of Duisburg-Essen, Hufelandstraße 55, D-45122 Essen, Germany.
    Aigner, Thomas
    Institute of Pathology, University of Leipzig, Liebigstraße 26, D-04103 Leipzig, Germany.
    Kursawe, Romy
    Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Str. 27, D-04103 Leipzig, Germany.
    Gimm, Oliver
    Department of Surgery, University of Halle, Ernst-Grube-Straße 40, D-06120 Halle, Germany.
    Schmid, Kurt-Werner
    Institute of Pathology and Neuropathology, University of Duisburg-Essen, Hufelandstraße 55, D-45122 Essen, Germany.
    Dralle, Henning
    Department of Surgery, University of Halle, Ernst-Grube-Straße 40, D-06120 Halle, Germany.
    Fuhrer, Dagmar
    Division of Endocrinology, Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Str. 27, D-04103 Leipzig, Germany.
    Evidence for a role of the amyloid precursor protein in thyroid carcinogenesis.2008In: The Journal of endocrinology, ISSN 1479-6805, Vol. 198, no 2, 291-9 p.Article in journal (Refereed)
    Abstract [en]

    We have recently found an increased expression of amyloid precursor protein (APP) in cold thyroid nodules that are difficult to classify as a truly benign thyroid neoplasm or a lesion with the potential for further dedifferentiation. Since differences in APP activity have been found in other human cancers, we asked whether thyroid carcinogenesis might be associated with an altered APP expression and function. APP regulation was studied in vitro in differentiated (FRTL-5) and dedifferentiated follicular thyroid carcinomas (FTC-133) thyroid cells after specific inhibition or activation of the cAMP-PKA, the PI3K/AKT or the protein kinase c (PKC) cascades. In vivo analysis of APP expression and downstream signalling was performed in benign and malignant thyroid tissues. We found that upregulation of APP expression and sAPP secretion is induced by TSH in differentiated thyroid cells and by insulin in thyroid cancer cells. PKC is a strong activator of APP cleavage and in FTC-133 confers prolonged release of the APP ectodomain. FTC-133 but not FRTL-5 cells show a prominent cell surface expression of the APP ectodomain, which has been suggested to function as an autocrine growth factor. Thyroid cancers are characterized by APP upregulation, increased membrane targeting of the APP ectodomain and significantly increased mRNA levels of the APP scaffold proteins JIP1, ShcA and Fe65.

  • 45.
    Krause, Kerstin
    et al.
    Clinic for Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.
    Prawitt, Susanne
    Clinic for Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.
    Eszlinger, Markus
    Clinic for Endocrinology and Nephrology, University of Leipzig, Leipzig, Germany.
    Ihling, Christian
    Department of Pharmaceutical Chemistry and Bioanalytics, Martin Luther University of Halle- Wittenberg, Halle-Wittenberg, Germany.
    Sinz, Andrea
    Department of Pharmaceutical Chemistry and Bioanalytics, Martin Luther University of Halle- Wittenberg, Halle-Wittenberg, Germany.
    Schierle, Katrin
    Institute of Pathology, University of Leipzig, Leipzig.
    Gimm, Oliver
    Department of General, Visceral, and Vascular Surgery, Martin Luther University of Halle- Wittenberg, Halle-Wittenberg, Germany.
    Dralle, Henning
    Department of General, Visceral, and Vascular Surgery, Martin Luther University of Halle- Wittenberg, Halle-Wittenberg, Germany.
    Steinert, Frank
    Centre for Minimally Invasive and Laparoscopic Surgery, Helios Clinic Schkeuditz, Schkeuditz, University of Duisburg-Essen, Essen, Germany.
    Sheu, Sien-Yi
    nstitute of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany.
    Schmid, Kurt W
    nstitute of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany.
    Fuhrer, Dagmar
    Clinic for Endocrinology, University of Duisburg-Essen, Essen, Germany.
    Dissecting molecular events in thyroid neoplasia provides evidence for distinct evolution of follicular thyroid adenoma and carcinoma.2011In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 179, no 6, 3066-74 p.Article in journal (Refereed)
    Abstract [en]

    Benign hypofunctional cold thyroid nodules (CTNs) are a frequent scintiscan finding and need to be distinguished from thyroid carcinomas. The origin of CTNs with follicular morphologic features is unresolved. The DNA damage response might act as a physiologic barrier, inhibiting the progression of preneoplastic lesions to neoplasia. We investigated the following in hypofunctional follicular adenoma (FA) and follicular thyroid cancer (FTC): i) the mutation rate of frequently activated oncogenes, ii) the activation of DNA damage response checkpoints, and iii) the differential proteomic pattern between FA and FTC. Both FTC and FA, which did not harbor RAS, phosphoinositide-3-kinase, or PAX/peroxisome proliferator activated receptor-γ mutations, express various proteins in common and others that are more distinctly expressed in FTC rather than in FA or normal thyroid tissue. This finding is in line with the finding of constitutive DNA damage checkpoint activation (p-Chk2, γ-H2AX) and evidence for replicative stress causing genomic instability (increased cyclin E, retinoblastoma, or E2F1 mRNA expression) in FTC but not FA. We discuss the findings of the increased expression of translationally controlled tumor protein, phosphatase 2A inhibitor, and DJ-1 in FTC compared with FA identified by proteomics and their potential implication in follicular thyroid carcinogenesis. Our present findings argue for the definition of FA as a truly benign entity and against progressive development of FA to FTC.

  • 46.
    Kugelberg, Johan
    et al.
    Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
    Welander, Jenny
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences.
    Schiavi, Francesca
    Veneto Institute Oncology IRCCS, Italy .
    Fassina, Ambrogio
    University of Padua, Italy .
    Backdahl, Martin
    Karolinska Institute, Sweden .
    Larsson, Catharina
    Karolinska Institute, Sweden .
    Opocher, Giuseppe
    Veneto Institute Oncology IRCCS, Italy University of Padua, Italy .
    Söderkvist, Peter
    Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Diagnostics, Department of Clinical Pathology and Clinical Genetics.
    Dahia, Patricia L.
    University of Texas Health Science Centre San Antonio, TX 78229 USA .
    Neumann, Hartmut P. H.
    University of Freiburg, Germany .
    Gimm, Oliver
    Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Center for Surgery, Orthopaedics and Cancer Treatment, Department of Surgery in Linköping.
    Role of SDHAF2 and SDHD in von Hippel-Lindau Associated Pheochromocytomas2014In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 38, no 3, 724-732 p.Article in journal (Refereed)
    Abstract [en]

    Background Pheochromocytomas (PCCs) develop from the adrenal medulla and are often part of a hereditary syndrome such as von Hippel-Lindau (VHL) syndrome. In VHL, only about 30 % of patients with a VHL missense mutation develop PCCs. Thus, additional genetic events leading to formation of such tumors in patients with VHL syndrome are sought. SDHAF2 (previously termed SDH5) and SDHD are both located on chromosome 11q and are required for the function of mitochondrial complex II. While SDHAF2 has been shown to be mutated in patients with paragangliomas (PGLs), SDHD mutations have been found both in patients with PCCs and in patients with PGLs. Materials and methods Because loss of 11q is a common event in VHL-associated PCCs, we aimed to investigate whether SDHAF2 and SDHD are targets. In the present study, 41 VHL-associated PCCs were screened for mutations and loss of heterozygosity (LOH) in SDHAF2 or SDHD. Promoter methylation, as well as mRNA expression of SDHAF2 and SDHD, was studied. In addition, immunohistochemistry (IHC) of SDHB, known to be a universal marker for loss of any part the SDH complex, was conducted. Results and conclusions LOH was found in more than 50 % of the VHL-associated PCCs, and was correlated with a significant decrease (p less than 0.05) in both SDHAF2 and SDHD mRNA expression, which may be suggestive of a pathogenic role. However, while SDHB protein expression as determined by IHC in a small cohort of tumors was lower in PCCs than in the surrounding adrenal cortex, there was no obvious correlation with LOH or the level of SDHAF2/SDHD mRNA expression. In addition, the lack of mutations and promoter methylation in the investigated samples indicates that other events on chromosome 11 might be involved in the development of PCCs in association with VHL syndrome.

  • 47.
    Liu, Yong
    et al.
    The Second Affiliated Hospital of Zhejiang University, Hangzhou, China.
    Chen, Li
    DThe Second Affiliated Hospital of Zhejiang University, Hangzhou, China.
    Peng, Shuyou
    The Second Affiliated Hospital of Zhejiang University, Hangzhou, China.
    Chen, Zhouxun
    The Second Affiliated Hospital of Zhejiang University, Hangzhou, China.
    Gimm, Oliver
    University of Halle, Germany.
    Finke, Rainer
    University of Halle, Germany.
    Hoang-Vu, Cuong
    The Second Affiliated Hospital of Zhejiang University, Hangzhou, China.
    The expression of CD97EGF and its ligand CD55 on marginal epithelium is related to higher stage and depth of tumor invasion of gastric carcinomas2005In: Oncology Reports, ISSN 1021-335X, Vol. 14, no 6, 1413-1420 p.Article in journal (Refereed)
    Abstract [en]

    CD97EGF is a member of the EGF-TM7 family of class II seven-transmembrane (7TM), and its cellular ligand CD55 (also known as decay accelerating factor; DAF) protects host cells from complement attack. To determine whether the expression levels of these two molecules are correlated with the clinicopathological features of gastric carcinomas, a total of 35 gastric carcinomas and their corresponding margins and normal specimens were investigated by RT-PCR, Western blot analysis and immunohistochemistry. Transcript levels of CD97EGFand CD55 were higher in tumors than those in the margin and normal epithelial mucous tissues (P<0.05). However, the expression levels of CD97EGF and CD55 mRNA had no correlation with the clinicopathological features of gastric carcinoma patients. All three groups of specimens were immunoreactive for CD97EGF and the CD55 protein. Strong and specific immunoreactivities of CD97EGF were located in the mucosal epithelia of the marginal basal membrane. Expression of CD97(EGF) in the margins showed a marked difference between the depth of tumor invasion T1 and T2, 3 and 4, and stages I and II/III/IV of gastric carcinomas (P<0.05). The expression of CD55 protein was highly correlated with CD97EGF (R=0.6483, P<0.001). Western blot analysis confirmed the expression and distribution patterns of CD97EGF and CD55. Our findings suggest that CD97EGF may play a role in the development and invasion of gastric carcinomas by binding its cellular ligand CD55. Detection of the CD97EGF expression in the tumor margin could be referred to as the molecular edge of gastric carcinomas.

  • 48.
    Lorenz, Kerstin
    et al.
    Martin-Luther University of Halle-Wittenberg, Germany.
    Brauckhoff, Michael
    Martin-Luther University of Halle-Wittenberg, Germany.
    Behrmann, Curd
    Martin-Luther University of Halle-Wittenberg, Germany.
    Sekulla, Carsten
    Martin-Luther University of Halle-Wittenberg, Germany.
    Ukkat, Jörg
    Martin-Luther University of Halle-Wittenberg, Germany.
    Brauckhoff, Katrin
    Martin-Luther University of Halle-Wittenberg, Germany.
    Gimm, Oliver
    Martin-Luther University of Halle-Wittenberg, Germany.
    Dralle, Henning
    Martin-Luther University of Halle-Wittenberg, Germany.
    Selective arterial chemoembolization for hepatic metastases from medullary thyroid carcinoma2005In: Surgery, ISSN 0039-6060, E-ISSN 1532-7361, Vol. 138, no 6, 986-993 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Hepatic metastases from medullary thyroid carcinoma (MTC) may impair quality of life by hypercalcitonemia-associated diarrhea and pain. In this prospective study, the effect of selective arterial chemoembolization (SACE) was evaluated.

    METHODS: Eleven patients with hepatic metastases from MTC received 1 to 9 courses of SACE using epirubicine. Symptomatic, biochemical, and morphologic responses on SACE were recorded.

    RESULTS: Symptomatic response was observed in all symptomatic patients. However, biochemical and radiologic response occurred only in 6 patients. Liver function was not affected by SACE. One patient with unexpected concurrent pheochromocytoma metastases died after the first course. Development of side effects in the course was observed in 8 patients but were only World Health Organization grade 1. Patients' satisfaction with SACE was excellent. Long-term follow-up found 7 patients alive (1-72 months). Three patients died with tumor 6, 12, and 24 months after SACE, respectively.

    CONCLUSION: SACE provided good symptom palliation for the majority of patients with hepatic metastases from MTC. However, transient remission or stabilization of hepatic metastases resulted in only 60%. Further studies using a randomized protocol are required.

  • 49.
    Lorenz, Kerstin
    et al.
    Department of General, Visceral and Vascular Surgery, Martin-Luther University of Halle-Wittenberg, Ernst-Grube-Straße 40, 06120, Halle/Saale, Germany.
    Gimm, Oliver
    Department of General, Visceral and Vascular Surgery, Martin-Luther University of Halle-Wittenberg, Ernst-Grube-Straße 40, 06120, Halle/Saale, Germany.
    Holzhausen, Hans Jürgen
    Department of Pathology, Martin-Luther University of Halle-Wittenberg, Ernst-Grube-Straße 40, 06120, Halle/Saale, Germany.
    Kittel, Stephan
    Department of General, Visceral and Vascular Surgery, Martin-Luther University of Halle-Wittenberg, Ernst-Grube-Straße 40, 06120, Halle/Saale, Germany.
    Ukkat, Jörg
    Department of General, Visceral and Vascular Surgery, Martin-Luther University of Halle-Wittenberg, Ernst-Grube-Straße 40, 06120, Halle/Saale, Germany.
    Thanh, Phuong Nguyen
    Department of General, Visceral and Vascular Surgery, Martin-Luther University of Halle-Wittenberg, Ernst-Grube-Straße 40, 06120, Halle/Saale, Germany.
    Brauckhoff, Michael
    Department of General, Visceral and Vascular Surgery, Martin-Luther University of Halle-Wittenberg, Ernst-Grube-Straße 40, 06120, Halle/Saale, Germany.
    Dralle, Henning
    Department of General, Visceral and Vascular Surgery, Martin-Luther University of Halle-Wittenberg, Ernst-Grube-Straße 40, 06120, Halle/Saale, Germany.
    Riedel's thyroiditis: impact and strategy of a challenging surgery.2007In: Langenbeck's archives of surgery (Print), ISSN 1435-2443, E-ISSN 1435-2451, Vol. 392, no 4, 405-12 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: No surgical standard for Riedel's thyroiditis (RT) is established. Salvage surgery follows severe cervical and compressive airway symptoms or strong suspicion of malignancy. Obscured planes and multi-infiltrative extension prevent sufficient surgery with considerate complications. No alternative definitive treatment is available. In failing conservative treatment, the role of surgery in RT remains unclear.

    MATERIALS AND METHODS: Clinical manifestation, treatment, outcome and follow-up in a unique series of eight consecutive patients with RT are presented.

    RESULTS: Seven female patients and one male patient with cervical tumor growth or thyroiditis underwent four total and three sub-total thyroidectomies, respectively, one patient declined remedial surgery. Complications were one bilateral laryngeal nerve palsy and one transient hypoparathyroidism. Histology confirmed RT with perithyroidal extension and excluded malignancy in all. Symptomatic relief of cervical and airway obstruction was achieved in all. Follow-up revealed two extensive mediastinal RT recurrences 1 and 6 years after surgery.

    CONCLUSION: Favourable symptomatic outcome and alleviation of steroids in the majority render surgery for RT valuable when conservative treatment fails. However, more radical procedures show no advantages and recurrences are not prevented. The demanding technique in RT requires special surgical expertise and highly recommends intra-operative neuromonitoring.

  • 50.
    Lorenz, Kerstin
    et al.
    Department of General, Visceral and Vascular Surgery, Martin-Luther University of Halle-Wittenberg, Klinikum Kröllwitz, Ernst-Grube-Strasse 40, 06097, Halle, Germany .
    Ukkat, Jörg
    Department of General, Visceral and Vascular Surgery, Martin-Luther University of Halle-Wittenberg, Klinikum Kröllwitz, Ernst-Grube-Strasse 40, 06097, Halle, Germany .
    Sekulla, Carsten
    Department of General, Visceral and Vascular Surgery, Martin-Luther University of Halle-Wittenberg, Klinikum Kröllwitz, Ernst-Grube-Strasse 40, 06097, Halle, Germany .
    Gimm, Oliver
    Department of General, Visceral and Vascular Surgery, Martin-Luther University of Halle-Wittenberg, Klinikum Kröllwitz, Ernst-Grube-Strasse 40, 06097, Halle, Germany .
    Brauckhoff, Michael
    Department of General, Visceral and Vascular Surgery, Martin-Luther University of Halle-Wittenberg, Klinikum Kröllwitz, Ernst-Grube-Strasse 40, 06097, Halle, Germany .
    Dralle, Henning
    Department of General, Visceral and Vascular Surgery, Martin-Luther University of Halle-Wittenberg, Klinikum Kröllwitz, Ernst-Grube-Strasse 40, 06097, Halle, Germany .
    Total parathyroidectomy without autotransplantation for renal hyperparathyroidism: experience with a qPTH-controlled protocol.2006In: World Journal of Surgery, ISSN 0364-2313, E-ISSN 1432-2323, Vol. 30, no 5, 743-51 p.Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Controversy regarding the optimal surgical treatment for secondary hyperparathyroidism (sHPT) continues. Subtotal parathyroidectomy (PTX) with a small remnant and total parathyroidectomy with autotransplantation prevail, although impaired by considerable recurrence rates. Concerns about postoperative management and long-term supplementation prevent broader acceptance of total parathyroidectomy without autotransplantation.

    MATERIALS AND METHODS: The standardized surgical procedure with intraoperative PTH assessment (qPTH) included cervical thymectomy, histological proof of four parathyroid specimens and obligatory cryopreservation of parathyroid tissue in all 23 patients undergoing total PTX without autotransplantation. Whenever qPTH did not normalize, complete cervical exploration of ectopic sites was performed. Another 64 patients with subtotal PTX for sHPT served as comparison for the postoperative course.

    RESULTS: There were 13 primary and 10 completion (5 persistent, 5 recurrent sHPT) total PTX with 14 concurrent thyroid resections performed. Mean preoperative PTH was 1.351 pg/ml (12-72 pg/ml) and serum calcium was 2.5 mmol/l (2.25-2.5 mmol/l). PTH showed intraoperative normalization in 15 patients and a 50% PTH reduction from preoperative values in all. Postoperative course was not significantly different from the subtotal PTX group and showed PTH within the normal range for 5 patients (4 < 35 pg/ml), 7 with PTH < 12 pg/ml, and 4 without measurable PTH. In 4 patients PTH did not normalize postoperatively. Serum calcium levels were below normal in all patients: < 2.25 mmol/l in 9, < 2.00 mmol/l in 7, and <1.8 mmol/l in 6 patients. Only 1 patient required intermittent early postoperative i.v. calcium supplementation, 6 patients received oral calcium and vitamin D supplement for low calcium levels, but no severe hypocalcemic symptoms were encountered. Mean postoperative hospital stay was 5 days. No recurrent laryngeal nerve palsies were encountered. Complications were two cervical bleedings following postoperative hemodialysis requiring evacuation.

    CONCLUSIONS: Total PTX without autotransplantation proves to be an equally safe and successful procedure for sHPT as subtotal PTX or total PTX with autotransplantation. Measurable PTH after total PTX as demonstrated in this study, supports the idea of uncontrollable isolated cell nests that are inevitably prone to stimulated growth with time. Therefore, total PTX is superior with regard to prevention of recurrence. Adequate supplementation with calcium and vitamin D, often necessary after subtotal PTX to suppress inadequate PTH and protect from recurrence, will prevent severe hypocalcemia and with the modern aluminium-diminishing dialysis regimen, development of adynamic bone disease appears less likely than feared. If necessary, cryopreserved parathyroid tissue can be autotransplanted on demand.

12 1 - 50 of 70
CiteExportLink to result list
Permanent link
Cite
Citation style
  • apa
  • harvard1
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • oxford
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf