Publications by authors named "Christian Fottner"

35 Publications

Multiple modes of cell death in neuroendocrine tumors induced by artesunate.

Phytomedicine 2020 Dec 3;79:153332. Epub 2020 Sep 3.

Department of Pharmaceutical Biology, Institute of Pharmaceutical and Biomedical Sciences, Johannes Gutenberg University, Mainz, Germany. Electronic address:

Background: The paucity of effective treatment in neuroendocrine tumors (NETs) encouraged us to investigate the therapeutic value of artesunate (ART) promised by its inhibitory effect against various tumors and broad safety profile.

Methods: We evaluated the impact of ART on three NET cell lines, BON-1, QGP-1 and NCI-H727 on cellular and molecular levels.

Results: Our results showed that ART induced endoplasmic reticulum (ER) stress through phosphorylation of eIF2α, which further gave rise to autophagy in all three NET cell lines. Specifically, apoptosis and ferroptosis were also observed in BON-1 cells, which made BON-1 cell line more vulnerable upon ART treatment. The different sensitivities presented on the three cell lines also associated with a differential regulation of p21 on the long run. Co-treatment with p21 inhibitor UC2288 showed an additive effect on QGP-1 and NCI-H727 cell lines indicating p21 upregulation in these two cell lines might confer resistance towards ART treatment.

Conclusions: It is possible to include ART in the treatment of NETs in the future.
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http://dx.doi.org/10.1016/j.phymed.2020.153332DOI Listing
December 2020

High-Grade Neuroendocrine Carcinoma of the Head and Neck: Human Papillomavirus Status and PD-L1 Expression.

ORL J Otorhinolaryngol Relat Spec 2019;81(5-6):309-316. Epub 2019 Sep 24.

Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center Mainz, Mainz, Germany,

Background: Human papillomavirus (HPV)-related head and neck squamous cell carcinoma represents an important subgroup of head and neck cancer, but HPV occurs also in the less common neuroendocrine carcinomas (NEC). The PD-1/PD-L1 pathway appears to be activated in pulmonary NEC and correlates with a higher mutation burden, but the potential of NEC to respond to checkpoint inhibitors is unknown to a large extent.

Objectives: To determine the HPV status of NEC of the head and neck region and to investigate the expression of PD-1 and its ligands PD-L1 and PD-L2.

Methods: Surgical tumor samples from 2006 to 2017 were analyzed. HPV status was determined by p16 immunohistochemistry (IHC) and multiplex PCR. IHC using the Cologne Score was performed for PD-1, PD-L1, and PD-L2.

Results: Seven NEC tumor samples were analyzed, three of them showed HPV type 18. Expression of PD-1 and PD-L1 differed widely and showed no correlation to HPV status. IHC showed an overexpression of PD-L2 in most of the patients.

Conclusions And Significance: A multicentric analysis of NEC is needed to further evaluate the role of HPV as well as immunocheckpoints with regard to inflammatory immune response in genesis and clinical course of this rare tumor entity. Biomarkers for selection of novel treatment regimens, including immunotherapeutic approaches, are warranted.
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http://dx.doi.org/10.1159/000502325DOI Listing
July 2020

PD-L1 Expression and Immune Cell Infiltration in Gastroenteropancreatic (GEP) and Non-GEP Neuroendocrine Neoplasms With High Proliferative Activity.

Front Oncol 2019 7;9:343. Epub 2019 May 7.

Department of Endocrinology and Metabolism, I Medical Clinic, University Hospital, Johannes Gutenberg University of Mainz, Mainz, Germany.

The potential of neuroendocrine neoplasms (NEN) to respond to checkpoint inhibitors is largely unknown and full of great expectations. Immunohistochemical (IHC) studies of programmed cell death ligand 1 (PD-L1) expression in the tumor microenvironment and its implications in predicting the response to checkpoint inhibition is a very active subject. Currently, the combined analysis of PD-L1 expression and tumor-associated immune cell (TAIC) infiltration is considered the best predictive marker of therapeutic response. Here we investigated the expression of PD-L1 on tumor cells (TC) and tumor-infiltrating immune cells (IC) by IHC in 68 NEN samples with a high proliferation rate (Ki-67 >20%) from 57 patients and in 22 samples we correlated it with TAIC density by assessing intratumoral infiltration of CD3+, CD8+, and CD68+ cells. Furthermore, the tumor microenvironment was evaluated according to the classification of Teng et al. We detected PD-L1 expression in 31.6% of NEN G3. Its expression usually was weak and more IC than TC expressed PD-L1. The proportion of tumors positive for PD-L1 was comparable in NEN from different sites of origin but varied depending on tumor differentiation and disease extension. No positive IHC staining was found in 3 well-differentiated neuroendocrine tumors (NETs) with a proliferation rate above 20% (NET G3). When analyzing TAIC, we rarely (18.2%) detected intratumoral CD8+ cells, whereas infiltration by CD3+ and CD68+ cells was more common (45.5 and 59.1%, respectively). By combining CD3+ cells and PD-L1 status, we identified the immune ignorant phenotype of tumor microenvironment as being the most common phenotype, supporting the concept of a preferably combined immunotherapeutic approach in neuroendocrine carcinoma (NEC).
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http://dx.doi.org/10.3389/fonc.2019.00343DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6514221PMC
May 2019

Peptide Receptor Radionuclide Therapy Combined With Chemotherapy in Patients With Neuroendocrine Tumors.

Clin Nucl Med 2019 May;44(5):e329-e335

From the Departments of Nuclear Medicine and.

Purpose: Combinations of therapies may enhance therapeutic effects without significantly increasing the incidence of adverse events. However, there are few data regarding survival after concomitant chemotherapy and peptide receptor radionuclide therapy (PRRT) with [Lu]Lu-octreotate in patients with neuroendocrine tumors (NETs). Thus, we explored the outcome of this combination of therapies.

Methods: Fifteen patients with somatostatin receptor-positive, rapidly progressive G2/G3 NETs during chemotherapy or PRRT alone from 2 German cancer centers were included in the retrospective analysis. The patients received a combination of PRRT and chemotherapy with temozolomide (n = 3) or temozolomide plus capecitabine (n = 12). To evaluate the effects of the combined treatment, we assessed the responses, survival, and adverse events.

Results: The cumulative administered activity of [Lu]Lu-octreotate had a median of 21.3 GBq after 3 cycles of combination therapy. The patients exhibited a median progression-free survival of 7.1 months and a median overall survival of 25.3 months. The clinical benefit (objective response and stable disease) rates were as follows: 55% of patients according to CT, 38% in [F]F-FDG PET/CT, and 44% in [Ga]Ga-DOTATOC PET/CT. One patient with rapidly progressing liver metastases experienced grade 4 liver failure according to the Common Terminology Criteria for Adverse Events (version 5.0). Four other patients (27%) experienced significantly elevated (grade 3) liver parameters.

Conclusions: According to different imaging modalities, the combination of PRRT and temozolomide +/- capecitabine led to disease control in 38% to 55% of the progressive NETs after PRRT or chemotherapy alone failed. The overall survival in this extensively pretreated group of patients was nearly 25 months. The majority of patients did not experience any serious adverse events.
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http://dx.doi.org/10.1097/RLU.0000000000002532DOI Listing
May 2019

Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia.

Oncol Res Treat 2018 26;41(5):306-312. Epub 2018 Apr 26.

Background: Well-differentiated neuroendocrine neoplasms (NENs) are usually controlled by antiproliferative, local ablative and/or radionuclide therapies, whereas poorly differentiated NENs generally require cytotoxic chemotherapy. However, treatment options for patients with advanced/metastatic high-grade NENs remain limited.

Method: Review of the literature and international congress abstracts on the efficacy and safety of immunotherapy by checkpoint inhibition in advanced/metastatic NENs.

Results: Evidence points to an important role of immune phenomena in the pathogenesis and treatment of neuroendocrine tumors (NETs). Programmed cell death 1 (PD-1) protein and its ligand are mainly expressed in poorly differentiated NENs. Microsatellite instability and high mutational load are more pronounced in high-grade NENs and may predict response to immunotherapy. Clinical experience of immune checkpoint blockade mainly exists for Merkel cell carcinoma, a high-grade cutaneous neuroendocrine carcinoma (NEC), which has led to approval of the anti-PD-1 antibody avelumab. In addition, there is anecdotal evidence for the efficacy of checkpoint inhibitors in large-cell lung NECs, ovarian NECs and others, including gastroenteropancreatic NENs. Currently, phase II studies investigate PDR001, pembrolizumab, combined durvalumab and tremelimumab, and avelumab treatment in patients with advanced/metastatic NENs.

Conclusion: Immune checkpoint inhibitors are a promising therapeutic option, especially in progressive NECs or high-grade NETs with high tumor burden, microsatellite instability, and/or mutational load.
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http://dx.doi.org/10.1159/000488996DOI Listing
August 2019

The impact of the IGF-1 system of cancer cells on radiation response - An study.

Clin Transl Radiat Oncol 2017 Dec 5;7:1-8. Epub 2017 Oct 5.

Department of Endocrinology and Metabolic Diseases, University Medical Center, Mainz, Germany.

Background: Overexpression of the insulin-like growth factor-1 receptor (IGF-1R) is associated with increased cell proliferation, differentiation, transformation, and tumorigenicity. Additionally, signaling involved in the resistance of cancer cells to radiotherapy originates from IGF-1R. The purpose of this study was to investigate the role of the IGF-1 system in the radiation response and further evaluate its effect on the expression of DNA repair pathway genes.

Methods: To inhibit the IGF-1 system, we stably transfected the Caco-2 cell line to express a kinase-deficient IGF-1R mutant. We then studied the effects of this mutation on cell growth, the response to radiation, and clonogenic survival, as well as using a cell viability assay to examine DNA damage and repair. Finally, we performed immunofluorescence for γ-H2AX to examine double-strand DNA breaks and evaluated the expression of 84 key genes involved in DNA repair with a real-time PCR array.

Results: Mutant IGF-1R cells exhibited significantly blunted cell growth and viability, compared to wild-type cells, as well as reduced clonogenic survival after γ-irradiation. However, mutant IGF-1R cells did not show any significant delays in the repair of radiation-induced DNA double-strand breaks. Furthermore, expression of mutant IGF-1R significantly down-regulated the mRNA levels of BRCA2, a major protein involved in homologous recombination DNA repair.

Conclusion: These results indicate that blocking the IGF-1R-mediated signaling cascade, through the expression of a kinase-deficient IGF-1R mutant, reduces cell growth and sensitizes cancer cells to ionizing radiation. Therefore, the IGF-1R system could be a potential target to enhance radio-sensitivity and the efficacy of cancer treatments.
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http://dx.doi.org/10.1016/j.ctro.2017.09.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5862664PMC
December 2017

Hormone secreting gastro-entero-pancreatic neuroendocrine neoplasias (GEP-NEN): When to consider, how to diagnose?

Rev Endocr Metab Disord 2017 12;18(4):393-410

Schwerpunkt Endokrinologie und Stoffwechselerkrankungen, I. Medizinischen Klinik und Poliklinik; ENETS center of excellence, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Langenbeckstrasse 1, 55101, Mainz, Germany.

Neuroendocrine neoplasms of the digestive system (GEP-NEN) represent a heterogeneous group of malignancies with various clinical presentation and prognosis. GEP-NENs can potentially affect all organs of the gastrointestinal tract; characteristically they share the biological property to produce and secrete peptides and neuroamines. About 30% of GEP-NENs are hormonally active and can cause specific clinical syndromes. The clinical presentation mainly depends on the primary site of the tumor and its functionality. Because of the wide spectrum of clinical symptoms and their misperceived rarity, diagnosis of GEP-NENs is often delayed for years and tumors are detected first in an advanced stage. Early identification of a specific hormonal syndrome can significantly impact tumor diagnosis and treatment, moreover the preoperative management of NEN hormonal release avoids potential life threatening hormonal crisis. However, GEP-NEN diagnostic work-up is challenging, it requires a multidisciplinary team and needs particular experience; standardized protocols and clinical experience are essential for a proper endocrine diagnostic work-up. In addition to the biochemical diagnostic, further radiologic and endoscopic imaging modalities are required moreover, somatostatin-receptor based functional imaging, using either Octreotide-scintigraphy or novel PET-based techniques with specific isotopes like Ga-DOTA-octreotate, plays an important role for the detection of the primary tumor as well as for the evaluation of the tumor extent.
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http://dx.doi.org/10.1007/s11154-017-9438-8DOI Listing
December 2017

Interdisciplinary treatment of diabetic foot wounds in the elderly: Low risk of amputations and mortality and good chance of being mobile with good quality of life.

Diab Vasc Dis Res 2017 01 20;14(1):55-58. Epub 2016 Oct 20.

Department of Gastroenterology and Diabetology, Klinikum Worms, Worms, Germany.

Aims: A major proportion of patients with diabetic foot syndrome are older than 65 years. Little is known about outcomes of these elderly patients.

Methods: We analysed 245 treatment cases in an observational single-centre study for comorbidities and outcomes over a 6-month period.

Results: In all, 122 patients had peripheral arterial disease which was significantly increasing with age (n = 245, df = 1, χ = 23.06, p ⩽ 0.0001). Increasing age correlated positively with decreasing rate of revascularisations (n = 122, df = 1, χ = 4.23, p = 0.039). In total, 23 (9.3%) patients died in the observation period. In-hospital mortality was 2.8%, percentage of major amputations 2.8%. In the invasively treated subgroup, 13 out of 67 patients died within the observation period. Death after revascularisation was independent of age (n = 67, df = 1, χ = 2.05, p = 0.153). Mobility decreased in the whole study group with increasing age. The risk of decrease with age was not influenced by revascularisation status.

Conclusion: With careful interdisciplinary evaluation, elderly patients with diabetic foot syndrome can be treated with favourable outcome. Mobility before and after treatment deserves more attention as a predictor of treatment success and outcome parameter.
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http://dx.doi.org/10.1177/1479164116666477DOI Listing
January 2017

Impact of combined FDG-PET/CT and MRI on the detection of local recurrence and nodal metastases in thyroid cancer.

Cancer Imaging 2016 Nov 3;16(1):37. Epub 2016 Nov 3.

Department of Nuclear Medicine, Johannes Gutenberg-University Medical Center, Langenbeckstr. 1, D-55131, Mainz, Germany.

Background: Suspected recurrence of thyroid carcinoma is a diagnostic challenge when findings of both a radio iodine whole body scan and ultrasound are negative. PET/CT and MRI have shown to be feasible for detection of recurrent disease. However, the added value of a consensus reading by the radiologist and the nuclear medicine physician, which has been deemed to be helpful in clinical routines, has not been investigated. This study aimed to investigate the impact of combined FDG-PET/ldCT and MRI on detection of locally recurrent TC and nodal metastases in high-risk patients with special focus on the value of the multidisciplinary consensus reading.

Materials And Methods: Forty-six patients with suspected locally recurrent thyroid cancer or nodal metastases after thyroidectomy and radio-iodine therapy were retrospectively selected for analysis. Inclusion criteria comprised elevated thyroglobulin blood levels, a negative ultrasound, negative iodine whole body scan, as well as combined FDG-PET/ldCT and MRI examinations. Neck compartments in FDG-PET/ldCT and MRI examinations were independently analyzed by two blinded observers for local recurrence and nodal metastases of thyroid cancer. Consecutively, the scans were read in consensus. To explore a possible synergistic effect, FDG-PET/ldCT and MRI results were combined. Histopathology or long-term follow-up served as a gold standard. For method comparison, sensitivity, specificity, positive and negative predictive values, and diagnostic accuracy were calculated.

Results: FDG-PET/ldCT was substantially more sensitive and more specific than MRI in detection of both local recurrence and nodal metastases. Inter-observer agreement was substantial both for local recurrence (κ = 0.71) and nodal metastasis (κ = 0.63) detection in FDG-PET/ldCT. For MRI, inter-observer agreement was substantial for local recurrence (κ = 0.69) and moderate for nodal metastasis (κ = 0.55) detection. In contrast, FDG-PET/ldCT and MRI showed only slight agreement (κ = 0.21). However, both imaging modalities identified different true positive results. Thus, the combination created a synergistic effect. The multidisciplinary consensus reading further increased sensitivity, specificity, and diagnostic accuracy.

Conclusions: FDG-PET/ldCT and MRI are complementary imaging modalities and should be combined to improve detection of local recurrence and nodal metastases of thyroid cancer in high-risk patients. The multidisciplinary consensus reading is a key element in the diagnostic approach.
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http://dx.doi.org/10.1186/s40644-016-0096-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5093960PMC
November 2016

Associations between depression and diabetes in the community: do symptom dimensions matter? Results from the Gutenberg Health Study.

PLoS One 2014 15;9(8):e105499. Epub 2014 Aug 15.

Department of Psychosomatic Medicine and Psychotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

Objectives: While a bidirectional relationship between diabetes and depression has been established, there is little knowledge if the associations are due to somatic-affective or cognitive-affective dimensions of depression.

Research Design And Methods: In a population-based, representative survey of 15.010 participants we therefore studied the associations of the two dimensions of depression with diabetes and health care utilization among depressed and diabetic participants. Depression was assessed by the Patient Health Questionnaire PHQ-9.

Results: We found a linear and consistent association between the intensity of depression and the presence of diabetes increasing from 6.9% in no or minimal depression to 7.6% in mild, 9% in moderate and 10.5% in severe depression. There was a strong positive association between somatic-affective symptoms but not with cognitive-affective symptoms and diabetes. Depression and diabetes were both independently related to somatic health care utilisation.

Conclusions: Diabetes and depression are associated, and the association is primarily driven by the somatic-affective component of depression. The main limitation of our study pertains to the cross-sectional data acquisition. Further longitudinal work on the relationship of obesity and diabetes should differentiate the somatic and the cognitive symptoms of depression.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0105499PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4134314PMC
December 2015

DNA double strand breaks as predictor of efficacy of the alpha-particle emitter Ac-225 and the electron emitter Lu-177 for somatostatin receptor targeted radiotherapy.

PLoS One 2014 7;9(2):e88239. Epub 2014 Feb 7.

University Medical Centre, Department of Nuclear Medicine, Mainz, Germany.

Rationale: Key biologic effects of the alpha-particle emitter Actinium-225 in comparison to the beta-particle emitter Lutetium-177 labeled somatostatin-analogue DOTATOC in vitro and in vivo were studied to evaluate the significance of γH2AX-foci formation.

Methods: To determine the relative biological effectiveness (RBE) between the two isotopes (as - biological consequence of different ionisation-densities along a particle-track), somatostatin expressing AR42J cells were incubated with Ac-225-DOTATOC and Lu-177-DOTATOC up to 48 h and viability was analyzed using the MTT assay. DNA double strand breaks (DSB) were quantified by immunofluorescence staining of γH2AX-foci. Cell cycle was analyzed by flow cytometry. In vivo uptake of both radiolabeled somatostatin-analogues into subcutaneously growing AR42J tumors and the number of cells displaying γH2AX-foci were measured. Therapeutic efficacy was assayed by monitoring tumor growth after treatment with activities estimated from in vitro cytotoxicity.

Results: Ac-225-DOTATOC resulted in ED50 values of 14 kBq/ml after 48 h, whereas Lu-177-DOTATOC displayed ED50 values of 10 MBq/ml. The number of DSB grew with increasing concentration of Ac-225-DOTATOC and similarly with Lu-177-DOTATOC when applying a factor of 700-fold higher activity compared to Ac-225. Already 24 h after incubation with 2.5-10 kBq/ml, Ac-225-DOTATOC cell-cycle studies showed up to a 60% increase in the percentage of tumor cells in G2/M phase. After 72 h an apoptotic subG1 peak was also detectable. Tumor uptake for both radio peptides at 48 h was identical (7.5%ID/g), though the overall number of cells with γH2AX-foci was higher in tumors treated with 48 kBq Ac-225-DOTATOC compared to tumors treated with 30 MBq Lu-177-DOTATOC (35% vs. 21%). Tumors with a volume of 0.34 ml reached delayed exponential tumor growth after 25 days (44 kBq Ac-225-DOTATOC) and after 21 days (34 MBq Lu-177-DOTATOC).

Conclusion: γH2AX-foci formation, triggered by beta- and alpha-irradiation, is an early key parameter in predicting response to internal radiotherapy.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0088239PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3917860PMC
May 2015

Phenotypic variability and risk of malignancy in SDHC-linked paragangliomas: lessons from three unrelated cases with an identical germline mutation (p.Arg133*).

J Clin Endocrinol Metab 2014 Mar 1;99(3):E489-96. Epub 2014 Jan 1.

Institute of Clinical Chemistry and Laboratory Medicine (J.K.B., S.S., K.J.L., H.R.), Institute of Pathology (A.S., E.S.), Department of Endocrinology and Metabolism, I Medical Department (M.M.W., C.F.), Department of Otorhinolaryngology (K.P., D.K., W.J.M.), Department of Endocrine Surgery (T.J.M.), Department of Nuclear Medicine (M.M.), and Institute of Human Genetics (O.B.), University Medical Center Mainz, 55131 Mainz, Germany.

Context: Mutations in the four subunits of succinate dehydrogenase (SDH) are the cause for the hereditary paraganglioma (PGL) syndrome types 1-4 and are associated with multiple and recurrent pheochromocytomas and PGLs. SDHC mutations most frequently result in benign, nonfunctional head-and neck PGLs (HNPGLs). The malignant potential of SDHC mutations remains unclear to date.

Objectives: We report a patient with malignant PGL carrying a SDHC mutation and compare her case with two others of the same genotype but presenting with classic benign HNPGLs. Loss of heterozygosity (LOH) was demonstrated in the malignant PGL tissue.

Design: In three unrelated patients referred for routine genetic testing, SDHB, SDHC, and SDHD genes were sequenced, and gross deletions were excluded by multiplex ligation-dependent probe amplification (MLPA). LOH was determined by pyrosequencing-based allele quantification and SDHB immunohistochemistry.

Results: In a patient with a nonfunctioning thoracic PGL metastatic to the bone, the lungs, and mediastinal lymph nodes, we detected the SDHC mutation c.397C>T predicting a truncated protein due to a premature stop codon (p.Arg133*). We demonstrated LOH and loss of SDHB protein expression in the malignant tumor tissue. The two other patients also carried c.397C>T, p.Arg133*; they differed from each other with respect to their tumor characteristics, but both showed benign HNPGLs.

Conclusions: We describe the first case of a malignant PGL with distant metastases caused by a SDHC germline mutation. The present case shows that SDHC germline mutations can have highly variable phenotypes and may cause malignant PGL, although malignancy is probably rare.
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http://dx.doi.org/10.1210/jc.2013-3486DOI Listing
March 2014

Critical limb ischaemia is characterised by an increased production of whole blood reactive oxygen species and expression of TREM-1 on neutrophils.

Atherosclerosis 2013 Aug 18;229(2):396-403. Epub 2013 Jun 18.

Department of Internal Medicine II, University Medical Center of The Johannes Gutenberg-University Mainz, Germany.

Background: Atherosclerosis is a chronic inflammatory process involving polymorphonuclear neutrophils (PMN) and formation of reactive oxygen species (ROS). The aim of the present study was to investigate the phenotype of inflammatory cells in regard to the expression of triggering receptor expressed on myeloid cells (TREM)-1 and its soluble form (sTREM-1) as well as its relationship with oxidative stress in peripheral artery disease (PAD) patients.

Methods: In total 90 patients with PAD (N = 30 intermittent claudication (IC) > 300 m absolute walking distance, N = 30 IC < 300 m absolute walking distance, N = 30 critical limb ischaemia (CLI)) and 30 control persons were included. ROS formation was measured at basal or stimulated conditions using the luminol analogue L-012 chemiluminescence. Peripheral blood leucocytes were analysed from whole blood by flow cytometry using different gating strategies to identify PMN and monocytes and analyse TREM-1 expression.

Results: CLI patients showed a significant higher ROS production at basal levels (p < 0.05) and upon stimulation with PDBu (p < 0.0001), LPS (p < 0.05) and zymosan A (p < 0.0001). TREM-1 was expressed significantly more on PMN of CLI patients (p < 0.01) in comparison to all other groups, whereas monocytic expression of TREM-1 was similar between all 4 groups. The serum concentration of its soluble form sTREM-1 however was increased in CLI and IC < 300 m patients (p < 0.0001). sTREM-1 concentrations correlated with basal ROS levels as wells with ROS production upon stimulation. Furthermore, we found the walking distance of IC patients to inversely correlate with sTREM-1 (rs = - 0.29; p = 0.03).

Conclusions: We found an increased oxidative stress as well as an increased expression of TREM-1 and serum levels of sTREM-1 in patients with CLI. IC < 300 m patients showed a similar patter in regard to oxidative stress, TREM-1 expression and sTREM-1 concentration. Thus, sTREM-1 might represent a potential inflammatory biomarker to evaluate the severity of PAD. Whether this implies the potential for therapeutic recommendations, i.e. conservative vs. interventional/operative treatment, or a possibility to monitor the efficacy of interventions, requires further studies.
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http://dx.doi.org/10.1016/j.atherosclerosis.2013.05.029DOI Listing
August 2013

Magnetic separation of encapsulated islet cells labeled with superparamagnetic iron oxide nano particles.

Xenotransplantation 2013 Jul-Aug;20(4):219-26. Epub 2013 Jun 23.

Endocrinology and Metabolic Diseases, University Medical Center, Johannes Gutenberg University Mainz, Germany.

Islet cell transplantation is a promising option for the restoration of normal glucose homeostasis in patients with type 1 diabetes. Because graft volume is a crucial issue in islet transplantations for patients with diabetes, we evaluated a new method for increasing functional tissue yield in xenogeneic grafts of encapsulated islets. Islets were labeled with three different superparamagnetic iron oxide nano particles (SPIONs; dextran-coated SPION, siloxane-coated SPION, and heparin-coated SPION). Magnetic separation was performed to separate encapsulated islets from the empty capsules, and cell viability and function were tested. Islets labeled with 1000 μg Fe/ml dextran-coated SPIONs experienced a 69.9% reduction in graft volume, with a 33.2% loss of islet-containing capsules. Islets labeled with 100 μg Fe/ml heparin-coated SPIONs showed a 46.4% reduction in graft volume, with a 4.5% loss of capsules containing islets. No purification could be achieved using siloxane-coated SPIONs due to its toxicity to the primary islets. SPION labeling of islets is useful for transplant purification during islet separation as well as in vivo imaging after transplantation. Furthermore, purification of encapsulated islets can also reduce the volume of the encapsulated islets without impairing their function by removing empty capsules.
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http://dx.doi.org/10.1111/xen.12042DOI Listing
March 2014

High incidence of extraadrenal paraganglioma in families with SDHx syndromes detected by functional imaging with [18F]fluorodihydroxyphenylalanine PET.

Eur J Nucl Med Mol Imaging 2013 Jun 2;40(6):889-96. Epub 2013 Feb 2.

Department of Nuclear Medicine, University Medical Centre of the Johannes Gutenberg University Mainz, Mainz, Germany.

Purpose: Knowledge of the genetic backgrounds of hereditary syndromes, which are increasingly being characterized, enables genetic screening of family members of affected patients. Upon detection of a mutation, genetic counselling and clinical screening including imaging modalities and biochemical analyses are commonly performed.

Methods: Unaffected, mutation-positive relatives of index patients with hereditary paraganglioma syndromes were offered PET imaging with [(18)F]fluorodihydroxyphenylalanine and the incidence of pathological findings was retrospectively analysed in relation to mutations of the succinate dehydrogenase enzyme complex. PET only or PET/CT was performed in 21 individuals from eight families with SDHD, one family with SDHC and two families with SDHB mutations. Screening was offered every 2 to 5 years.

Results: Of the 21 individuals, 14 showed paraganglioma during screening. In particular, in only 2 of 15 patients with a SDHD mutation were the findings completely unremarkable on PET screening. However, false-negative lesions for abdominal manifestations in two SDHD-positive patients were detected.

Conclusion: FDOPA PET is a sensitive imaging modality which should be offered to patients with a detected SDHx (SDHD) mutation, preferably using a hybrid technique.
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http://dx.doi.org/10.1007/s00259-013-2346-6DOI Listing
June 2013

The role of surgery in the management of recurrent adrenocortical carcinoma.

J Clin Endocrinol Metab 2013 Jan 12;98(1):181-91. Epub 2012 Nov 12.

Department of Internal Medicine I, Endocrine and Diabetes Unit, University Hospital Würzburg, University of Würzburg, Oberdürrbacher Strasse 6, D-97080 Würzburg, Germany.

Context: Surgery is the standard of care for localized adrenocortical carcinomas, but its role for recurrent disease is not well defined.

Objective: Our objective was to evaluate clinical outcome after surgery for recurrence.

Design: We conducted a retrospective analysis in 154 patients with first recurrence after initial radical resection from the German Adrenocortical Carcinoma Registry.

Main Outcome Measures: We evaluated progression-free survival (PFS) and overall survival (OS) by Kaplan-Meier method and identified prognostic factors by Cox regression analysis.

Result: A total of 101 patients underwent repeated surgery (radical resection, n = 78), and 99 received (additional) nonsurgical therapy. After a median of 6 (1-221) months, 144 patients (94%) experienced progression. Multivariate analysis adjusted for age, sex, tumor burden, time to first recurrence (TTFR), surgery for recurrence (including resection status), and additional therapy indicated that only two factors were significantly associated with shorter PFS [hazard ratio for progression: for TTFR ≤ 12 months, 1.8 (95% confidence interval = 1.3-2.6) vs. TTFR > 12 months; for macroscopically incomplete resection, 3.4 (1.5-7.9), and for no surgery, 3.4 (1.6-7.0) vs. microscopically complete (R0)-resection and OS [hazard ratio for death: for TTFR > 12 months, 3.1 (2.0-4.7) vs. TTFR ≤ 12 months; for macroscopically incomplete resection, 2.7 (1.1-6.9), and no surgery, 4.2 (1.8-9.6) vs. R0-resection]. Patients who had both TTFR over 12 months and R0-resection of recurrent tumors (n = 22) had the best prognosis (median PFS, 24 months; median OS, >60 months).

Conclusions: The best predictors of prolonged survival after first recurrence are TTFR over 12 months and R0-resection. Our data suggest that patients with longer TTFR and tumors amenable to radical resection should be operated, whereas individualized treatment decisions are needed for patients with short TTFR or with not completely resectable tumors.
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http://dx.doi.org/10.1210/jc.2012-2559DOI Listing
January 2013

Phenotypic characterisation of pro-inflammatory monocytes and dendritic cells in peripheral arterial disease.

Thromb Haemost 2012 Dec 23;108(6):1198-207. Epub 2012 Oct 23.

Department of Internal Medicine II, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

Atherosclerosis is a chronic inflammatory process involving antigen-presenting cells like monocytes and dendritic cells (DC). The aim of this study was to perform a phenotypic characterisation of these cell types in patients with different degrees of peripheral arterial disease (PAD). Sixty patients with PAD [N= 30 intermittent claudication (IC), N= 30 critical limb ischemia (CLI)] and 30 controls were included. Peripheral blood leucocytes were analysed from peripheral blood by flow cytometry using different gating strategies to directly identify and analyse monocytes, myeloid DC, (mDC) and plasmacytoid DC (pDC). PAD patients showed a significantly higher proportion of proinflammatory CD14++CD16+ monocytes (p<0.0001) compared with healthy individuals. We found an increased number of mDC/ml and a reduced number of pDC/ml (both p<0.01) in PAD patients, leading to a shift in the mDC/pDC ratio (p<0.01). As compared to patients with intermittent claudication, CLI patients presented a reduced expression of HLA-DR (p<0.01), CD86 and CD40 on both mDCs and pDCs (p<0.01). Peripheral blood monocytes show a proinflammatory phenotype in PAD patients compared to controls. In contrast, CLI patients show a reduced expression of proinflammatory markers. We hypothesise that severe ischaemia and/or prolonged inflammation in CLI might lead to a paradoxical attenuation in the proinflammatory membrane pattern of circulating mononuclear cells, possibly hindering an adequate regulatory function of mDCs and pDCs and favouring the progression of disease.
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http://dx.doi.org/10.1160/TH12-05-0327DOI Listing
December 2012

One single-time-point kidney uptake from OctreoScan correlates with number of desintegrations measured over 72 hours and calculated for the 6.7 hours half-life nuclide (177)Lu.

Clin Nucl Med 2012 Oct;37(10):e245-8

Klinik und Poliklinik für Nuklearmedizin, Universitätsmedizin Mainz, Mainz, Germany.

Aim: In somatostatin receptor-targeted therapy, renal toxicity is an expected side effect, and therefore pretherapeutic dosimetry based on a measured kinetics is preferable. In contrast, a convenient one single-time-point scan might also reveal relevant information on expected dose to organs. However, very early time points might not reflect the true retention by the renal cortex and therefore be of limited value to predict dose for the long-lived 177Lu.

Patients And Methods: Dosimetry with 111In-octreotide was performed in 24 patients, and the number of disintegrations (ND) were calculated for 177Lu. Uptake values for each time point were correlated with ND.

Results: The fitting algorithm was best with biexponential equations in 18 patients. Mean biologic half-life of the alpha component was 6 hours (+/-12 hours) and for the beta component 82 hours (+/-38 hours). For the early time points, correlation with ND was generally poor. For later time points, correlation increased markedly after 4 hours (4 hours: r = 0.83, 72 hours: r = 0.93) and were also capable of predicting dosimetry to some extent.

Conclusion: In conclusion, thorough quantification of the 4 hours single-time-point scans seems to be enough to predict the expected renal dose for radionuclide therapies to some degree.
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http://dx.doi.org/10.1097/RLU.0b013e318248550cDOI Listing
October 2012

Head and neck paragangliomas: Report of 175 patients (1989-2010).

Head Neck 2012 May 20;34(5):632-7. Epub 2011 Jun 20.

Department of Otorhinolaryngology-Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.

Background: Attention of the otorhinolaryngologist needs to be drawn to the versatile aspects of head and neck paragangliomas (PGLs).

Methods: This study is a retrospective, nonrandomized clinical study of all 175 individuals with PGLs treated in our department between 1989 and 2010. A genetic analysis was performed on 86 patients.

Results: The 175 patients presented 224 head and neck PGLs as well as 2 thyroid papillary carcinomas. Genetic analysis resulted in 1 patient positive for a von Hippel-Lindau (VHL) gene mutation and 34 for succinate dehydrogenase (SDH) gene mutations (22 SDHD, 7 SDHC, and 5 SDHB), 12 of the latter carrying a novel mutation. Thirty-three patients (18.9%) had multiple PGLs and 11 patients (6.3%) had a malignant paraganglioma. SDH-mutation carriers had multiple tumors in 64.7% and malignant paragangliomas in 20.6%.

Conclusions: Multifocal occurrence, potential malignancy, genetic aspects, possible coincidence of thyroid carcinoma, and hormone production have to be considered in patients with head and neck PGLs.
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http://dx.doi.org/10.1002/hed.21790DOI Listing
May 2012

Molecular imaging of gastroenteropancreatic neuroendocrine tumors.

Gastroenterol Clin North Am 2010 Dec 8;39(4):923-35. Epub 2010 Oct 8.

Department of Nuclear Medicine, University of Mainz, Langenbeckstr 1, Mainz 55131, Germany.

Somatostatin-receptor scintigraphy has become an obligatory molecular imaging method in the management of patients with neuroendocrine tumors when metastatic disease is suspected. Using positron emission tomography and new somatostatin analogues, sensitivity of somatostatin receptor imaging has further increased. With a combination of morphologic imaging methods, such as hybrid imaging by PET/CT, this method represents the method of choice in many centers and efforts are under way to translate somatostatin receptor imaging onto a cellular level by endoscopic confocal microscopy. Other clinically relevant functional pathways in neuroendocrine tumors that are accessible by PET imaging are glucose metabolism and amine precursor uptake and decarboxylation.
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http://dx.doi.org/10.1016/j.gtc.2010.08.031DOI Listing
December 2010

One-step ¹⁸F-labeling of carbohydrate-conjugated octreotate-derivatives containing a silicon-fluoride-acceptor (SiFA): in vitro and in vivo evaluation as tumor imaging agents for positron emission tomography (PET).

Bioconjug Chem 2010 Dec 17;21(12):2289-96. Epub 2010 Nov 17.

Department of Nuclear Medicine, Hospital of the Ludwig-Maximilians-University, Munich, Germany.

The synthesis, radiolabeling, and initial evaluation of new silicon-fluoride acceptor (SiFA) derivatized octreotate derivatives is reported. So far, the main drawback of the SiFA technology for the synthesis of PET-radiotracers is the high lipophilicity of the resulting radiopharmaceutical. Consequently, we synthesized new SiFA-octreotate analogues derivatized with Fmoc-NH-PEG-COOH, Fmoc-Asn(Ac₃AcNH-β-Glc)-OH, and SiFA-aldehyde (SIFA-A). The substances could be labeled in high yields (38 ± 4%) and specific activities between 29 and 56 GBq/μmol in short synthesis times of less than 30 min (e.o.b.). The in vitro evaluation of the synthesized conjugates displayed a sst2 receptor affinity (IC₅₀ = 3.3 ± 0.3 nM) comparable to that of somatostatin-28. As a measure of lipophilicity of the conjugates, the log P(ow) was determined and found to be 0.96 for SiFA-Asn(AcNH-β-Glc)-PEG-Tyr³-octreotate and 1.23 for SiFA-Asn(AcNH-β-Glc)-Tyr³-octreotate, which is considerably lower than for SiFA-Tyr³-octreotate (log P(ow) = 1.59). The initial in vivo evaluation of [¹⁸F]SiFA-Asn(AcNH-β-Glc)-PEG-Tyr³-octreotate revealed a significant uptake of radiotracer in the tumor tissue of AR42J tumor-bearing nude mice of 7.7% ID/g tissue weight. These results show that the high lipophilicity of the SiFA moiety can be compensated by applying hydrophilic moieties. Using this approach, a tumor-affine SiFA-containing peptide could successfully be used for receptor imaging for the first time in this proof of concept study.
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http://dx.doi.org/10.1021/bc100316cDOI Listing
December 2010

Detection of papillary thyroid carcinoma by analysis of BRAF and RET/PTC1 mutations in fine-needle aspiration biopsies of thyroid nodules.

World J Surg 2010 Nov;34(11):2595-603

Endocrine Surgery, University Medical Center, Gutenberg University Mainz, Langenbeckstr. 1, 55101, Mainz, Germany.

Background: Activating mutations of the oncogene BRAF or rearrangements of the tyrosine kinase receptor RET are observed in up to 80% of papillary thyroid carcinomas (PTCs). The predominant BRAF V600E mutation has not been detected in benign thyroid tissue so far, so consequently, this assumedly pathognomonic alteration is qualified to improve the preoperative diagnosis of PTC.

Methods: Two hundred ninety preoperatively harvested fine-needle aspiration biopsies (FNABs) underwent routine cytologic assessment. BRAF V600E mutation analysis was performed by mutation-specific PCR using the same cell material; a hybrid-specific RT-PCR assay was used for detection of RET/PTC1 rearrangements. Detected genetic alterations were verified by direct sequencing. Definitive histopathology was obtained in 93/290 lesions following surgery of the respective thyroid nodule.

Results: While cytology alone diagnosed 13/30 malignancies (22 PTCs, 4 FTCs, 1 MTC, 1 UTC, 2 metastases), five additional malignancies were identified by supplementary mutation analysis. Cytology classified eight FNABs as benign, while postoperative histology demonstrated a thyroid malignancy (6 PTCs, 1 FTC, 1 metastasis). In four of these eight cases, the genetic analysis detected a BRAF V600E mutation or a RET/PTC1 rearrangement. Classifying both suspicious and malignant FNAB results as positive cytology results, supplementary genetic testing increased the overall sensitivity of FNAB from 70.4 to 85.7%, the positive predictive value (PPV) from 59.4 to 64.9%, and the negative predictive value (NPV) from 84.0 to 91.3%.

Conclusions: Supplementary mutation analysis of RET and especially of the BRAF V600E mutation in FNABs is a fast and probably cost-effective assay in routine diagnostic setting. Mutation analyses of PTC-specific genetic alterations improve the preoperative identification and prognostic assessment of thyroid malignancies and therefore enable an optimized surgical strategy.
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http://dx.doi.org/10.1007/s00268-010-0729-4DOI Listing
November 2010

Impact of pathognomonic genetic alterations on the prognosis of papillary thyroid carcinoma. ESES vienna presentation.

Langenbecks Arch Surg 2010 Sep 18;395(7):877-83. Epub 2010 Jul 18.

Endocrine Surgery, University Medical Center, Johannes Gutenberg University Mainz, Langenbeckstrasse 1, 55101 Mainz, Germany.

Introduction: BRAF mutations and RET or NTRK1 rearrangements were identified as causing events that drive the malignant transformation of the thyroid follicular cell. The impact of these alterations on the course of papillary thyroid carcinoma (PTC) is still unsettled.

Patients And Methods: Tumor tissues of 290 (98 male, 192 female) patients were intra-operatively snap frozen or harvested from archival paraffin-embedded blocks and used for extraction of DNA and RNA. Comprehensive analysis of RET/PTC and NTRK1 rearrangements was carried out by multiplex screening RT-PCR, hybrid-specific RT-PCR and sequencing of detected hybrids. A mutation-specific PCR was used for BRAF analysis.

Results: The BRAF V600E mutation was detected in 122/290 (42%), RET rearrangements in 20/137 (14.6%), and NTRK1 rearrangements in 15/93 (16.1%) PTCs. One hundred forty one out of 290 (48.6%) PTCs demonstrated none of the genetic alterations studied. Eight PTCs expressed two different mutations (1 RET/PTC + BRAF, 6 NTRK1 + BRAF, 1 RET/PTC + NTRK1). Tumor-specific survival analysis (mean follow-up, 5.5 years) demonstrated no significant difference, but a tendency toward worse prognosis of BRAF-positive patients compared to BRAF-negative patients or rearrangement-positive patients, respectively.

Conclusion: Long-term follow-up data on large tumor panels are needed to disclose significant survival differences of prognostic predictors on PTC. This study provides further evidence that patients harboring BRAF-V600E-positive PTCs may experience an unfavorable course of the disease compared to patients with tumors carrying other genetic alterations.
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http://dx.doi.org/10.1007/s00423-010-0682-6DOI Listing
September 2010

Diagnosis and treatment of pancreatic metastases of a papillary thyroid carcinoma.

Thyroid 2010 Jan;20(1):93-8

Endocrine Surgery, Clinic of General and Abdominal Surgery, University Medical Center, Gutenberg University Mainz, Mainz, Germany.

Background: Apart from regional lymph node metastases, systemic metastases occur sporadically in papillary thyroid carcinomas (PTC). The lung and bones are the most frequent localizations. Additionally known but extremely rare locations are metastases of the skeletal muscles, ovaries, submandibular gland, sphenoidal sinus, brain, adrenals, and, as shown in only two previously published cases to date, the pancreas.

Summary: In this article we report about two additional patients with pancreatic metastases from PTC. There is almost no prior experience about therapeutic approaches to this type of metastases. In both patients distant metastases within the pancreas were successfully removed. Postoperative histology confirmed the diagnoses. Supplemental genetic analysis did not demonstrate a BRAF V600E mutation or expression of a RET/PTC1 rearrangement in one case, but revealed a BRAF V600E mutation in the second case. Surgery avoided impending complications maintaining quality of life. One patient had a tumor-specific survival of 42 months. The other patient has occult disease.

Conclusions: Our two patients benefited of a calculated aggressive surgical action. Thus, if low perioperative mortality and morbidity can be warranted, surgical measures are justifiable in selected cases.
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http://dx.doi.org/10.1089/thy.2009.0026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2833176PMC
January 2010

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

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

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

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

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

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

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

Identification and prevention of genotyping errors caused by G-quadruplex- and i-motif-like sequences.

Clin Chem 2009 Jul 30;55(7):1361-71. Epub 2009 Apr 30.

Department of Clinical Chemistry and Laboratory Medicine, Johannes Gutenberg University Mainz, Mainz, Germany.

Background: Reliable PCR amplification of DNA fragments is the prerequisite for most genetic assays. We investigated the impact of G-quadruplex- or i-motif-like sequences on the reliability of PCR-based genetic analyses.

Methods: We found the sequence context of a common intronic polymorphism in the MEN1 gene (multiple endocrine neoplasia I) to be the cause of systematic genotyping errors by inducing preferential amplification of one allelic variant [allele dropout (ADO)]. Bioinformatic analyses and pyrosequencing-based allele quantification enabled the identification of the underlying DNA structures.

Results: We showed that G-quadruplex- or i-motif-like sequences can reproducibly cause ADO. In these cases, amplification efficiency strongly depends on the PCR enzyme and buffer conditions, the magnesium concentration in particular. In a randomly chosen subset of candidate single-nucleotide polymorphisms (SNPs) defined by properties deduced from 2 originally identified ADO cases, we confirmed preferential PCR amplification in up to 50% of the SNPs. We subsequently identified G-quadruplex and i-motifs harboring a SNP that alters the typical motif as the cause of this phenomenon, and a genomewide search based on the respective motifs predicted 0.5% of all SNPs listed by dbSNP and Online Mendelian Inheritance in Man to be potentially affected.

Conclusions: Undetected, the described phenomenon produces systematic errors in genetic analyses that may lead to misdiagnoses in clinical settings. PCR products should be checked for G-quadruplex and i-motifs to avoid the formation of ADO-causing secondary structures. Truly affected assays can then be identified by a simple experimental procedure, which simultaneously provides the solution to the problem.
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http://dx.doi.org/10.1373/clinchem.2008.118661DOI Listing
July 2009

Clinical predictors for germline mutations in head and neck paraganglioma patients: cost reduction strategy in genetic diagnostic process as fall-out.

Cancer Res 2009 Apr 7;69(8):3650-6. Epub 2009 Apr 7.

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

Multiple genes and their variants that lend susceptibility to many diseases will play a major role in clinical routine. Genetics-based cost reduction strategies in diagnostic processes are important in the setting of multiple susceptibility genes for a single disease. Head and neck paraganglioma (HNP) is caused by germline mutations of at least three succinate dehydrogenase subunit genes (SDHx). Mutation analysis for all 3 costs approximately US$2,700 per patient. Genetic classification is essential for downstream management of the patient and preemptive management of family members. Utilizing HNP as a model, we wanted to determine predictors to prioritize the most heritable clinical presentations and which gene to begin testing in HNP presentations, to reduce costs of genetic screening. Patients were tested for SDHB, SDHC, and SDHD intragenic mutations and large deletions. Clinical parameters were analyzed as potential predictors for finding germline mutations. Cost reduction was calculated between prioritized gene testing compared with that for all genes. Of 598 patients, 30.6% had SDHx germline mutations: 34.4% in SDHB, 14.2% SDHC, and 51.4% SDHD. Predictors for an SDHx mutation are family history [odds ratio (OR), 37.9], previous pheochromocytoma (OR, 10.9), multiple HNP (OR, 10.6), age
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http://dx.doi.org/10.1158/0008-5472.CAN-08-4057DOI Listing
April 2009

Elevated serum levels of IGF-binding protein 2 in patients with non-seminomatous germ cell cancer: correlation with tumor markers alpha-fetoprotein and human chorionic gonadotropin.

Eur J Endocrinol 2008 Sep 4;159(3):317-27. Epub 2008 Jun 4.

Schwerpunkt Endokrinologie und Stoffwechselerkrankungen, I. Medizinische Klinik und Poliklinik der Johannes Gutenberg Universität Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany.

Background/aims: Alterations of the IGF system have been described in several different types of cancer. However, no information is available about the role of the IGF system in patients with non-seminomatous germ cell cancer.

Methods: Free IGF-I, IGF-II, acid-labile subunit, and IGF-binding proteins (IGFBPs) 1-4 were analyzed by specific RIAs in 32 patients with untreated non-seminomas and compared with IGFBP levels of 38 healthy controls. Serum IGFBPs were analyzed by western ligand blotting (WLB) and immunoblotting. In 16 patients, IGFBP profiles were measured before, during, and after treatment.

Results: In patients with testicular cancer, IGF-II levels were on average 1.44-fold higher than in the healthy control group (1027+/-48 ng/ml versus 711+/-30 ng/ml, P<0.0001). IGFBP-2 levels were on average 2.6-fold higher (586+/-58 ng/ml versus 226+/-17 ng/ml, P<0.001). During follow-up, a decrease in IGFBP-2 levels was observed in all successfully treated patients, which correlated closely with a decrease in the tumor markers alpha-fetoprotein and human chorionic gonadotropin. Additionally, in all patients with recurrent disease, a significant further increase in IGFBP-2 levels (from 358+/-97 to 976+/-260 ng/ml) was detected. IGFBP-3 levels, as measured by RIA, were not different in patients with testicular cancer compared with controls. However, WLB analysis demonstrated markedly decreased intact IGFBP-3 bands in untreated patients and a significant increase after successful therapy.

Conclusion: Our results demonstrate that markedly elevated IGF-II and IGFBP-2 serum levels in patients with non-seminomatous germ cell cancer, showing a significant decrease after successful therapy and an increase in recurrent disease. Additionally, indirect evidence points to an increased proteolytic activity for IGFBP-3 in untreated testicular cancer patients.
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http://dx.doi.org/10.1530/EJE-08-0033DOI Listing
September 2008

Somatostatin-producing neuroendocrine tumors of the duodenum and pancreas: incidence, types, biological behavior, association with inherited syndromes, and functional activity.

Endocr Relat Cancer 2008 Mar;15(1):229-41

Department of Pathology, University of Kiel, Michaelisstr 11, Kiel, Germany.

Somatostatin-producing neuroendocrine tumors (SOM-NETs) of the duodenum and pancreas appear to be heterogeneous. To determine their clinicopathological profiles, respective data were analyzed on a series of 82 duodenal and 541 pancreatic NETs. In addition, the clinical records of 821 patients with duodenal or pancreatic NETs were reviewed for evidence of a somatostatinoma syndrome. Predominant or exclusive expression of somatostatin was found in 21 (26%) duodenal and 21 (4%) pancreatic NETs. They were classified as sporadic (n=31) or neurofibromatosis type 1 (NF1)-associated duodenal NETs (n=3), gangliocytic paragangliomas (GCPGs; n=6), or poorly differentiated neuroendocrine carcinomas (pdNECs; n=2). In addition, five duodenal and four pancreatic SOM-NETs were found in five patients with multiple endocrine neoplasia type 1 (MEN1). Metastases occurred in 13 (43%) patients with sporadic or NF1-associated SOM-NETs, but in none of the duodenal or pancreatic MEN1-associated SOM-NETs or GCPGs. Sporadic advanced (stage IV) SOM-NETs were more commonly detected in the pancreas than in the duodenum. None of the patients (including the 821 patients for whom only the clinical records were reviewed) fulfilled the criteria of a somatostatinoma syndrome. Our data show that somatostatin expression is not only seen in sporadic NETs but may also occur in GCPGs, pdNECs, and hereditary NETs. Surgical treatment is effective in most duodenal and many pancreatic SOM-NETs. MEN1-associated SOM-NETs and GCPGs follow a benign course, while somatostatin-producing pdNECs are aggressive neoplasms. The occurrence of the so-called somatostatinoma syndrome appears to be extremely uncommon.
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http://dx.doi.org/10.1677/ERC-07-0157DOI Listing
March 2008

Malignant paraganglioma caused by a novel germline mutation of the succinate dehydrogenase D-gene--a case report.

Head Neck 2008 Jul;30(7):964-9

Department of Otorhinolaryngology, Johannes Gutenberg-University Medical School, Mainz, Germany.

Background: Paragangliomas of the head and neck are rare, mostly benign tumors. Approximately 10% to 15% of paragangliomas are caused by mutations in the succinate dehydrogenase (SDH) genes B, C, or D. These are often multifocal as part of paraganglioma syndromes and hormone secreting, and malignant particularly associated with mutations in SDHB.

Methods And Results: A 29-year-old man was seen with recurrent paraganglioma. The patient's father reportedly suffered from bilateral carotid body tumors. Imaging studies showed metastases in both lungs and the liver. There was no increased hormone production by the tumor. Sequence analysis of the SDH genes revealed a novel C to T nonsense mutation in the first exon of the SDHD gene (R17X).

Conclusions: A novel mutation in the SDHD gene associated with malignant paraganglioma is reported. This case underscores the relevance of family history and genetic analysis, thus permitting early detection of unaffected carriers. These have to be monitored clinically, biochemically and by imaging techniques.
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http://dx.doi.org/10.1002/hed.20746DOI Listing
July 2008