Hartmut P H Neumann

University of Freiburg, Freiburg, Baden-Württemberg, Germany

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Publications (257)1551.03 Total impact

  • Hartmut P H Neumann · Wouter de Herder
    Endocrine Related Cancer 08/2015; 22(4):E5-7. DOI:10.1530/ERC-15-0340 · 4.81 Impact Factor
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    ABSTRACT: At least 12 genes (FH, HIF2A, MAX, NF1, RET, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, and VHL) have been implicated in inherited predisposition to phaeochromocytoma (PCC), paraganglioma (PGL), or head and neck paraganglioma (HNPGL) and a germline mutation may be detected in more than 30% of cases. Knowledge of somatic mutations contributing to PCC/PGL/HNPGL pathogenesis has received less attention though mutations in HRAS, HIF2A, NF1, RET, and VHL have been reported. To further elucidate the role of somatic mutation in PCC/PGL/HNPGL tumourigenesis, we employed a next generation sequencing strategy to analyse "mutation hotspots" in 50 human cancer genes. Mutations were identified for HRAS (c.37G>C; p.G13R and c.182A>G; p.Q61R) in 7.1% (6/85); for BRAF (c.1799T>A; p.V600E) in 1.2% (1/85) of tumours; and for TP53 (c.1010G>A; p.R337H) in 2.35% (2/85) of cases. Twenty-one tumours harboured mutations in inherited PCC/PGL/HNPGL genes and no HRAS, BRAF, or TP53 mutations occurred in this group. Combining our data with previous reports of HRAS mutations in PCC/PGL we find that the mean frequency of HRAS/BRAF mutations in sporadic PCC/PGL is 8.9% (24/269) and in PCC/PGL with an inherited gene mutation 0% (0/148) suggesting that HRAS/BRAF mutations and inherited PCC/PGL genes mutations might be mutually exclusive. We report the first evidence for BRAF mutations in the pathogenesis of PCC/PGL/HNPGL.
    International Journal of Endocrinology 04/2015; 2015:138573. DOI:10.1155/2015/138573 · 1.95 Impact Factor
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    ABSTRACT: Background: Endolymphatic sac tumors (ELSTs) are, with a prevalence of up to 16%, a component of von Hippel-Lindau (VHL) disease. Data from international registries regarding heritable fraction and characteristics, germline VHL mutation frequency, and prevalence are lacking. Methods: Systematic registration of ELSTs from international centers of otorhinolaryngology and from multidisciplinary VHL centers' registries was performed. Molecular genetic analyses of the VHL gene were offered to all patients. Results: Our population-based registry comprised 93 patients with ELST and 1789 patients with VHL. The prevalence of VHL germline mutations in apparently sporadic ELSTs was 39%. The prevalence of ELSTs in patients with VHL was 3.6%. ELST was the initial manifestation in 32% of patients with VHL-ELST. Conclusion: Prevalence of ELST in VHL disease is much lower compared to the literature. VHL-associated ELSTs can be the first presentation of the syndrome and mimic sporadic tumors, thus emphasizing the need of molecular testing in all presentations of ELST. © 2015 Wiley Periodicals, Inc. Head Neck, 2015.
    Head & Neck 04/2015; DOI:10.1002/hed.24067 · 2.64 Impact Factor
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    ABSTRACT: The aim of this study was to assess the usefulness of somatostatin receptor scintigraphy (SRS) using (99m)Tc-[HYNIC, Tyr3]-Octreotide (TOC) and (123)I-mIBG in patients with SDHx-related syndromes in which paragangliomas were detected by computed tomography (CT) and establish an optimal imaging diagnostic algorithm in SDHx-mutation carriers. All carriers with clinical and radiological findings suggesting paragangliomas were screened by SRS and (123)I-mIBG. Lesions were classified by body regions: head and neck (HN), chest, abdomen with pelvis, adrenal gland and metastasis. We evaluated 46 SDHx gene-mutation carriers (32 index cases, 14 relatives; 28 SDHD, 16 SDHB, 2 SDHC). In this group, 102 benign tumors were found in 39 studied patients and malignant disease was diagnosed in 7 patients. In benign tumors, sensitivity of SRS was estimated at 77% and (123)I-mIBG at 22.0%. The SRS and mIBG sensitivity was found to be clearly region-dependent (P<0.001). The highest SRS sensitivity was found in HNP (91.4%) and the lowest was found in abdominal paragangliomas and pheochromocytomas (40%, 42.9%). The highest (123)I-mIBG sensitivity was found in pheochromocytomas (sensitivity 100%) and the lowest in HNP (sensitivity 3.7%). In metastatic disease SRS was superior to mIBG (sensitivity 95.2 vs. 23.8%, respectively). SRS and (123)I-mIBG SPECT sensitivity in SDHx patients is highly body region-dependent. In malignant tumors SRS is superior to (123)I-mIBG SPECT. © 2015 S. Karger AG, Basel.
    Neuroendocrinology 03/2015; 101(4). DOI:10.1159/000381458 · 4.37 Impact Factor
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    ABSTRACT: The precise diagnosis of thyroid neoplasias will guide surgical management. Primary thyroid paraganglioma has been rarely reported. Data on prevalence, immunohistochemistry and molecular genetics in a systematic series of such patients are pending. We performed a multinational population-based study on thyroid paraganglioma and analyzed prevalence, immunohistochemistry and molecular genetics. Patients with thyroid paraganglioma were recruited from the European-American-Head-and-Neck-Paraganglioma-Registry. Demographic and clinical data were registered. Histopathology and immunohistochemistry were reinvestigated. All patients with thyroid paraganglioma underwent molecular genetic analyses of the genes SDHA, SDHB, SDHC, SDHD, VHL, RET, TMEM127, and MAX. Analyses included Sanger sequencing and MLPA for detection of large rearrangements. Of 947 registrants, 8 candidates were initially identified. After immunohistochemical analyses of these 8, 5 (0.5%) were confirmed with thyroid paraganglioma. Immunohistochemistry was positive for chromogranin, synaptophysin and S-100 and negative for calcitonin in all 5 thyroid paragangliomas whereas the 3 excluded candidate tumors stained for pan-cytokeratin. Germline variants, likely representing mutations, were found in 4 of the 5 confirmed-thyroid paraganglioma cases, 2 each in SDHA and SDHB, whereas the excluded cases had no mutation in the tested genes. Thyroid paraganglioma is a finite entity which must be differentiated from medullary thyroid carcinoma, because medical, surgical and genetic management for each is different. Notably, ~80% of thyroid paragangliomas are associated with germline mutations, with implications for additional tumors and a potential risk for the family. As opposed to sporadic tumors, surgical management and extent of resection are different for heritable tumors, each guided by the precise gene involved.
    Endocrine Related Cancer 01/2015; 22(2). DOI:10.1530/ERC-14-0558 · 4.81 Impact Factor
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    Dimitri Barski · Samer Ezziddin · Sebastian Heikaus · Hartmut P H Neumann
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    ABSTRACT: This case describes a 50-yr-old man who was admitted to the Urology Ward upon the suspicion of a left kidney tumor. As part of the pre-operative check-up, an ultrasound and computed tomography of the kidneys were conducted. The results confirmed the initial diagnosis. The postoperative diagnosis was extra-adrenal pararenal phaeochromocytoma (ePCC) with succinate dehydrogenase complex, subunit B (SDHB) gene mutation. During the follow-up, a second tumor was detected by 3,4-dihydroxy-6-F-18-fluoro-L-phenylalanine positron emission tomography/computed tomography F-DOPA-PET CT that resulted in another surgery with complete resection of the tumor. The patient and his family were counseled by a genetic laboratory and remain under surveillance.
    06/2014; 67(2):162-6. DOI:10.5173/ceju.2014.02.art9
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    ABSTRACT: Background: The purpose of this study was to give an overview on hereditary syndromes associated with head and neck paragangliomas (HNPGs). Methods: Our methods were the review and discussion of the pertinent literature. Results: About one third of all patients with HNPGs are carriers of germline mutations. Hereditary HNPGs have been described in association with mutations of 10 different genes. Mutations of the genes succinate dehydrogenase subunit D (SDHD), succinate dehydrogenase complex assembly factor 2 gene (SDHAF2), succinate dehydrogenase subunit C (SDHC), and succinate dehydrogenase subunit B (SDHB) are the cause of paraganglioma syndromes (PGLs) 1, 2, 3, and 4. Succinate dehydrogenase subunit A (SDHA), von Hippel-Lindau (VHL), and transmembrane protein 127 (TMEM127) gene mutations also harbor the risk for HNPG development. HNPGs in patients with rearranged during transfection (RET), neurofibromatosis type 1 (NF1), and MYC-associated factor X (MAX) gene mutations have been described very infrequently. Conclusion: All patients with HNPGs should be offered a molecular genetic screening. This screening may usually be restricted to mutations of the genes SDHD, SDHB, and SDHC. Certain clinical parameters can help to set up the order in which those genes should be tested.
    Head & Neck 06/2014; 36(6). DOI:10.1002/hed.23436 · 2.64 Impact Factor
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    ABSTRACT: Background: The prevention of medullary thyroid cancer in patients with multiple endocrine neoplasia type 2 syndrome has demonstrated the ability of molecular diagnosis and prophylactic surgery to improve patient outcomes. However, the other major neoplasia associated with multiple endocrine neoplasia type 2, phaeochromocytoma, is not as well characterised in terms of occurrence and treatment outcomes. In this study, we aimed to systematically characterise the outcomes of management of phaeochromocytoma associated with multiple endocrine neoplasia type 2. Methods: This multinational observational retrospective population-based study compiled data on patients with multiple endocrine neoplasia type 2 from 30 academic medical centres across Europe, the Americas, and Asia. Patients were included if they were carriers of germline pathogenic mutations of the RET gene, or were first-degree relatives with histologically proven medullary thyroid cancer and phaeochromocytoma. We gathered clinical information about patients'RET genotype, type of treatment for phaeochromocytoma (ie, unilateral or bilateral operations as adrenalectomy or adrenal-sparing surgery, and as open or endoscopic operations), and postoperative outcomes (adrenal function, malignancy, and death). The type of surgery was decided by each investigator and the timing of surgery was patient driven. The primary aim of our analysis was to compare disease-free survival after either adrenal-sparing surgery or adrenalectomy. Findings: 1210 patients with multiple endocrine neoplasia type 2 were included in our database, 563 of whom had phaeochromocytoma. Treatment was adrenalectomy in 438 (79%) of 552 operated patients, and adrenal-sparing surgery in 114 (21%). Phaeochromocytoma recurrence occurred in four (3%) of 153 of the operated glands after adrenal-sparing surgery after 6-13 years, compared with 11 (2%) of 717 glands operated by adrenalectomy (p=0.57). Postoperative adrenal insufficiency or steroid dependency developed in 292 (86%) of 339 patients with bilateral phaeochromocytoma who underwent surgery. However, 47 (57%) of 82 patients with bilateral phaeochromocytoma who underwent adrenal-sparing surgery did not become steroid dependent. Interpretation: The treatment of multiple endocrine neoplasia type 2-related phaeochromocytoma continues to rely on adrenalectomies with their associated Addisonian-like complications and consequent lifelong dependency on steroids. Adrenal-sparing surgery, a highly successful treatment option in experienced centres, should be the surgical approach of choice to reduce these complications.
    The Lancet Oncology 04/2014; 15(6). DOI:10.1016/S1470-2045(14)70154-8 · 24.69 Impact Factor
  • Hartmut P H Neumann
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    ABSTRACT: Extract: The fascination of hereditary tumor diseases, especially von Hippel-Lindau disease (VHL) and pheochromocytoma, has dominated my academic life for three decades. My background was the warm and rich atmosphere which gave me my parents, Colonel Joachim Neumann and Mechtild Zuckschwerdt, PhD, MA, descendent of an industrial family from Magdeburg. Together with 3 sisters and a brother, I spent my youth in Brunswick, Hamburg and Bonn with a classical education including Latin and Greek. I served 2 years in the artillery of the German army. From 1969 until 1974, I studied medicine at the Universities of Bonn and Heidelberg ...
    Endocrine Related Cancer 01/2014; 21(3). DOI:10.1530/ERC-13-0528 · 4.81 Impact Factor
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    ABSTRACT: 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. 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. LOH was found in more than 50 % of the VHL-associated PCCs, and was correlated with a significant decrease (p < 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.
    World Journal of Surgery 12/2013; 38(3). DOI:10.1007/s00268-013-2373-2 · 2.64 Impact Factor
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    ABSTRACT: A third of patients with paraganglial tumors, pheochromocytoma and paraganglioma, carry germline mutations in one of the susceptibility genes, RET, VHL, NF1, SDHAF2, SDHA, SDHB, SDHC, SDHD, TMEM127 and MAX. Despite increasing importance, data for long-term prognosis are scarce in pediatric presentations. The European-American-Pheochromocytoma-Paraganglioma-Registry, with a total of 2001 patients with confirmed paraganglial tumors, was the platform for this study. Molecular genetic and phenotypic classification and assessment of gene-specific long-term outcome with second and/or malignant paraganglial tumors and life expectancy was performed in patients diagnosed <18 years. Of 177 eligible registrants, 80% had mutations, 49% VHL, 15% SDHB, 10% SDHD, 4% NF1 and one patient each in RET, SDHA and SDHC. A second primary paraganglial tumor developed in 38% with increasing frequency over time, reaching 50% at 30 years after initial diagnosis. Their prevalence was associated with hereditary disease (p=0.001), particularly in VHL and SDHD mutation carriers (VHL vs others, p=0.001, SDHD vs others, p=0.042). A total of 16 (9%) patients with hereditary disease had malignant tumors, 10 at initial diagnosis and another 6 during follow-up. The highest prevalence was associated with SDHB (SDHB vs others, p<0.001). Eight patients died (5%), all of whom had germline mutations. Mean life expectancy was 62 years with hereditary disease. Hereditary disease and the underlying germline mutation define the long-term prognosis of pediatric patients in terms of prevalence and time of second primaries, malignant transformation and survival. Based on these data, gene-adjusted, specific surveillance guidelines can help effective preventive medicine.
    Endocrine Related Cancer 10/2013; 21(1). DOI:10.1530/ERC-13-0415 · 4.81 Impact Factor
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    ABSTRACT: Head and neck paragangliomas, rare neoplasms of the paraganglia composed of nests of neurosecretory and glial cells embedded in vascular stroma, provide a remarkable example of organoid tumor architecture. To identify genes and pathways commonly deregulated in head and neck paraganglioma, we integrated high-density genome-wide copy number variation (CNV) analysis with microRNA and immunomorphological studies. Gene-centric CNV analysis of 24 cases identified a list of 104 genes most significantly targeted by tumor-associated alterations. The “NOTCH signaling pathway” was the most significantly enriched term in the list (P = 0.002 after Bonferroni or Benjamini correction). Expression of the relevant NOTCH pathway proteins in sustentacular (glial), chief (neuroendocrine) and endothelial cells was confirmed by immunohistochemistry in 47 head and neck paraganglioma cases. There were no relationships between level and pattern of NOTCH1/JAG2 protein expression and germline mutation status in the SDH genes, implicated in paraganglioma predisposition, or the presence/absence of immunostaining for SDHB, a surrogate marker of SDH mutations. Interestingly, NOTCH upregulation was observed also in cases with no evidence of CNVs at NOTCH signaling genes, suggesting altered epigenetic modulation of this pathway. To address this issue we performed microarray-based microRNA expression analyses. Notably 5 microRNAs (miR-200a,b,c and miR-34b,c), including those most downregulated in the tumors, correlated to NOTCH signaling and directly targeted NOTCH1 in in vitro experiments using SH-SY5Y neuroblastoma cells. Furthermore, lentiviral transduction of miR-200s and miR-34s in patient-derived primary tympano-jugular paraganglioma cell cultures was associated with NOTCH1 downregulation and increased levels of markers of cell toxicity and cell death. Taken together, our results provide an integrated view of common molecular alterations associated with head and neck paraganglioma and reveal an essential role of NOTCH pathway deregulation in this tumor type. Electronic supplementary material The online version of this article (doi:10.1007/s00401-013-1165-y) contains supplementary material, which is available to authorized users.
    Acta Neuropathologica 08/2013; 126(4). DOI:10.1007/s00401-013-1165-y · 10.76 Impact Factor
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    ABSTRACT: Sporadic and hereditary forms of renal cell carcinoma (RCC), von Hippel-Lindau (VHL) disease and the familial paraganglioma syndromes are closely related in terms of their clinical, molecular, and genetic aspects. Most RCCs occur sporadically and the heritable fraction of RCC is estimated to be just 2-4%. An understanding of the molecular genetic basis, the disease-specific and gene-specific biology and the clinical characteristics of these cancer syndromes is of utmost importance for effective genetic diagnosis and appropriate treatment. In addition, such insight will improve our understanding of sporadic RCCs. To date, 10 different heritable RCC syndromes have been described. VHL syndrome is the oldest known hereditary RCC syndrome. Similar to VHL disease, phaeochromocytoma is a major manifestation of the paraganglioma syndromes types 1, 3 and 4 in which RCCs have been reported. These syndromes are therefore regarded as VHL-related disorders and are included in this Review. Multifocal tumours, bilateral occurrence, a young age at diagnosis and/or family history are clinical red flags suggestive of hereditary disease and should trigger referral for genetic and molecular analysis. The identification of an underlying genetic alteration enables gene-specific risk assessment and opens up the possibility of a tailored follow-up strategy and specific surveillance protocols as the basis of effective preventive medicine. The important goals of preventive medicine are to increase the life expectancy of affected patients and to improve their quality of life. The study of seemingly rare hereditary syndromes and their susceptibility genes has consistently revealed clues regarding the aetiology and pathogenesis of these diseases, and can aid diagnosis and the development of therapeutics for patients affected by much more common sporadic counterparts.
    Nature Reviews Nephrology 07/2013; 9(9). DOI:10.1038/nrneph.2013.144 · 8.54 Impact Factor
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    ABSTRACT: Subarachnoid hemorrhage from ruptured intracranial aneurysms is associated with a severe prognosis. Preventive treatment of unruptured intracranial aneurysms is possible and recommended. However, the identification of risk patients by genetic analyses is not possible because of lack of candidate genes. Collagen type I α2 (COL1A2) has been associated with the presence of aneurysms in patients from Japan, China, and Korea. In this study, we investigate whether COL1A2 is a possible aneurysm candidate gene in the German population. Patients admitted with intracranial aneurysms to our department and collaborating departments were enrolled. Three single-nucleotide polymorphisms (SNPs) of the COL1A2 gene, namely rs42524 in exon 28, rs1800238 in exon 32, and rs2621215 in intron 46 were investigated using restriction enzymes and sequencing. HapMap data were used for comparison of allelic frequencies with the normal population by χ(2) test to identify significant associations between genotypes and the presence of aneurysms. Two hundred sixty-nine patients were enrolled into the study. There was a significant correlation with the presence of aneurysms for the GC allele of the SNP rs42524 in exon 28 (P = .02). The other polymorphisms did not show significant correlations. The COL1A2 gene is associated with intracranial aneurysms in a subset of the German population. However, it is not responsible for the majority of aneurysms, and further candidate genes need to be identified to develop sensitive genetic screening for patients at risk.
    Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 06/2013; 23(2). DOI:10.1016/j.jstrokecerebrovasdis.2013.04.038 · 1.67 Impact Factor
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    ABSTRACT: Background: The role of autosomal dominant polycystic kidney disease (ADPKD) as a risk factor for renal cell carcinoma (RCC) is still under discussion. Data on prevalence of RCC in ADPKD are limited, especially on a large population scale. The aim of this study was to analyze the prevalence of RCC in ADPKD kidneys and characterize the clinical features of this coincidence. Methods: Based on our histopathological registry for ADPKD and the Else Kröner-Fresenius Registry, we retrospectively reviewed malignant and benign renal lesions in patients with ADPKD who had undergone renal surgery from 1988 to 2011. Results: 240 ADPKD patients underwent 301 renal surgeries. Mean age at surgery was 54 years. Overall, 16 malignant and 11 benign lesions were analyzed in 301 kidneys (5.3%; 3.7%), meaning that 12/240 (5%; 1:20) patients presented with malignant renal lesions. 66.7% (8/12) of these patients had undergone dialysis prior to surgery. We found 10/16 (63%) papillary RCC, 5/16 (31%) clear cell RCC, and 1/16 (6%) papillary noninvasive urothelial cancer. Regarding all renal lesions, 6/17 (35.3%) patients had more than one histological finding in their kidneys. In 2 cases, metachronous metastases were removed. Mean follow-up was 66.7 months. Conclusion: Kidney-related prevalence of RCC in ADPKD kidneys was surprisingly high. Whether or not this is due to chronic dialysis or due to the underlying disease is still speculative. Like other cystic renal diseases with an increased risk for RCC, the attending physician should be aware of the malignant potential of ADPKD, especially with concomitant dialysis.
    Nephron Clinical Practice 06/2013; 123(1-2):13-21. DOI:10.1159/000351049 · 1.40 Impact Factor
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    ABSTRACT: Background: The rupture of intracranial aneurysms leads to subarachnoid hemorrhage, which is often associated with poor outcome. Preventive treatment of unruptured intracranial aneurysms is possible and recommended. However, the lack of candidate genes precludes identifying patients at risk by genetic analyses. We observed intracranial aneurysms in 2 patients with von Hippel-Lindau (VHL) disease and the known disease-causing mutation c.292T > C (p.Tyr98His) in the VHL tumor suppressor gene. This study investigates whether the VHL gene is a possible candidate gene for aneurysm formation. Methods: Patients with intracranial aneurysms admitted to our department between 2006 and 2009 were enrolled. The peripheral leukocyte DNA of 200 patients was investigated for sequence variations in the VHL gene using denaturing high performance liquid chromatography. Peripheral leukocyte DNA of 100 randomly sampled probands was investigated as a control group. The allelic frequencies of sequence variations between both groups were compared using the Fisher exact test. Results: Fourteen of 200 patients with intracranial aneurysms had sequence variations at 6 different loci in the VHL gene. In contrast, no sequence variations were identified in 100 probands in the control group (P = 0.0062). However, none of the single-sequence variations had a statistically significant difference in the allelic frequencies compared to the control group. Conclusions: There is accumulating evidence for a genetic basis of aneurysm development. Our investigations lead to the conclusion that the VHL gene is potentially involved in the formation of intracranial aneurysms in a subset of patients. Additional candidate genes need to be identified in order to develop sensitive genetic screening for at-risk patients.
    Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 02/2013; 22(4). DOI:10.1016/j.jstrokecerebrovasdis.2013.01.016 · 1.67 Impact Factor
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    ABSTRACT: The definitive universally accepted treatment for carotid body tumors (CBT) is surgery. The impact of surgery on cranial nerves and the carotid artery has often been underestimated. Alternatively, a few CBTs have been followed without treatment or irradiation. The goal of this study is to summarize the existing evidence concerning the efficacy and safety of surgery and external beam radiotherapy (EBRT) for CBT. Relevant articles were identified using strict criteria for systematic searches. Sixty-seven articles met the criteria which included 2,175 surgically treated patients. On the other hand, 17 articles including 127 patients treated with EBRT were found. Long-term control of the disease was obtained in 93.8 % of patients who received surgical treatment and in 94.5 % of the radiotherapy group. Surgery resulted in 483 (483/2,175 = 22.2 %) new cranial nerve permanent deficits, whereas in the EBRT group, no new deficits were recorded (p = 0.004). The common/internal carotid artery was resected in 271 (12.5 %) patients because of injury or tumor encasement, with immediate reconstruction in 212 (9.7 %) patients. Three percent (60) of patients developed a permanent stroke and 1.3 % (26) died due to postoperative complications. The major complications rates and the mortality after completion of the treatment also were significantly higher in surgical series compared to EBRT series. This systematic analysis highlights evidence that EBRT offers a similar chance of tumor control with lower risk of morbidity as compared to surgery in patients with CBT. This questions the traditional notion that surgery should be the mainstay of treatment.
    Archives of Oto-Rhino-Laryngology 02/2013; 271(1). DOI:10.1007/s00405-013-2384-5 · 1.55 Impact Factor
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    ABSTRACT: BACKGROUND:: Neurogenic polyglobulia occurs with CNS hemangioblastomas. Among the suggested mechanisms are extramedullary hematopoiesis in the tumor tissue and germline mutations of the VHL tumor suppressor gene. OBJECTIVE:: To determine the frequency and driving mechanisms of polyglobulia in CNS hemangioblastomas. METHODS:: We performed a retrospective analysis of pre- and postoperative (at 3 and 12 months) hemoglobin levels in a consecutive series of patients with hemangioblastomas operated in our institution from 1996 to 2009. We performed molecular genetic analyses for mutations of the VHL tumor suppressor gene. RESULTS:: Preoperative hemoglobin levels were available from 164 patients. The average hemoglobin level (15.2 g/dl in males and 13.1 g/dl in females) was within normal range according to our standards. Of 22 patients with increased preoperative hemoglobin levels (>17 g/dl in males and >15 g/dl in females), 8 presented with pathological hemoglobin (>18.5 g/dl in males and >16.5 g/dl in females) according to WHO criteria. Surgical removal of the hemangioblastoma resulted in a permanent cure of polyglobulia in all patients. 6 of the 8 patients with pathological hemoglobin elevation carried a germline mutation of the VHL tumor suppressor gene. CONCLUSION:: Neurogenic polyglobulia occurs in a subset of patients with hemangioblastomas. This phenomenon is mostly observed in VHL mutations-carriers, but also occurs in patients with sporadic hemangioblastomas. Removal of the tumor results in permanent cure of polyglobulia. Our observations suggest that polyglobulia is an effect by the tumor itself, either due to paraneoplasia or extramedullary hematopoiesis.
    Neurosurgery 02/2013; 72(6). DOI:10.1227/NEU.0b013e31828ba793 · 3.62 Impact Factor
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    ABSTRACT: Background As we emerge into the genomic medicine era, the epidemiology of diseases is taken for granted. Accurate prevalence figures, especially of rare diseases (RDs, ≤50/100 000), will become even more important for purposes of health care and societal planning. We noticed that the numbers of affected individuals in regionally established registries for mainly hereditary RDs do not align with published estimated and expected prevalence figures. We therefore hypothesized that such non-population-based means overestimate RDs and sought to address this by recalculating prevalence for an important 'common' hereditary disease, autosomal-dominant polycystic kidney disease (ADPKD) whereby presumed-prevalence is 100-250/100 000Methods The Else-Kroener-Fresenius-ADPKD-Study in south-west Germany with a population of 2 727 351 inhabitants was established with the cooperation of all nephrology centres. Furthermore, general practitioners, internists, urologists, human geneticists and neurosurgery centres were contacted with questionnaires for demographic, family and kidney function data. Germline-mutation screening of susceptibility genes PKD1 and PKD2 was offered. Official population data for 2010 were used for overall and kidney function-adjusted prevalence estimations.ResultsA total of 891 subjects, 658 index-cases and 233 relatives, aged 10-89 (mean 52), were registered, with >90% response rate, 398 by nephrologists and 493 by non-nephrologists. Molecular-genetic analyses contributed to confirmation of the diagnosis in 57%. The overall prevalence of ADPKD was 32.7/100 000 reaching a maximum of 57.3/100 000 in the 6th decade of life.Conclusions Prevalence of ADPKD is overestimated by 2- to 5-fold and close to the limit of RDs which may be of broad clinical, logistic and policy implications.
    Nephrology Dialysis Transplantation 01/2013; 28(6). DOI:10.1093/ndt/gfs551 · 3.58 Impact Factor
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    ABSTRACT: SDH genes, encoding succinate dehydrogenase, act as tumor suppressor, linking mitochondrial dysfunction with tumorigenesis. Heterozygous germline mutations in SDHA, SDHB, SDHC, SDHD and in the assembly factor encoding gene SDHAF2 have all been shown to predispose to heritable endocrine neoplasias such as Pheochromocytomas and Paragangliomas called "PHEO-PGL syndrome". SDH genes mutations, in addition to deletions or truncations which are most likely pathogenic, often include missense substitutions which can be of uncertain significance. Unclassified missense substitutions may be difficult to interpret unless the cause-effect link between mutation and the disease is established by functional and in silico studies or by the familial segregation with the phenotype.Using the yeast model, here we report functional investigations on several missense SDH mutations found in patients affected by Pheochromocytoma or Paraganglioma. The aim of this study was to evaluate whether and to which extent the yeast model may be useful for establishing the pathological significance of missense SDH mutations in humans. The results of our study demonstrate that the yeast is a good functional model to validate the pathogenic significance of SDHB missense mutations while, for missense mutations in SDHC and SDHD genes, the model can be informative only when the variation involves a conserved residue in a conserved domain.
    Human Molecular Genetics 11/2012; 22(4). DOI:10.1093/hmg/dds487 · 6.39 Impact Factor

Publication Stats

9k Citations
1,551.03 Total Impact Points


  • 1987–2015
    • University of Freiburg
      • Internal Medicine 4 - Nephrology and General Medicine
      Freiburg, Baden-Württemberg, Germany
  • 2005–2013
    • Universitätsklinikum Freiburg
      • • Department of Internal Medicine IV
      • • Preventive Medicine Unit
      Freiburg an der Elbe, Lower Saxony, Germany
  • 2011
    • Navy Environmental & Preventive Medicine Unit Five
      San Diego, California, United States
  • 2009
    • University Hospital München
      München, Bavaria, Germany
    • Universitätsklinikum Tübingen
      Tübingen, Baden-Württemberg, Germany
  • 2002–2008
    • Cardinal Wyszynski National Institute of Cardiology
      • Department of Heart Failure and Transplantology
      Warszawa, Masovian Voivodeship, Poland
    • King Faisal Specialist Hospital and Research Centre
      • Department of Surgery
      Jeddah, Mintaqat Makkah, Saudi Arabia
  • 2007
    • Ludwig-Maximilians-University of Munich
      • Department of Endocrinology and Diabetology
      München, Bavaria, Germany
  • 2006–2007
    • DRK Kliniken Berlin
      Berlín, Berlin, Germany
  • 2004
    • Evangelische Hochschule Freiburg, Germany
      Freiburg, Baden-Württemberg, Germany
    • Elisabethinen Hospital
      • Department of Urology
      Linz, Upper Austria, Austria
  • 2003
    • University of Michigan
      Ann Arbor, Michigan, United States
  • 1997
    • Dana-Farber Cancer Institute
      Boston, Massachusetts, United States
    • Otto-von-Guericke-Universität Magdeburg
      Magdeburg, Saxony-Anhalt, Germany
  • 1995
    • Technische Universität München
      München, Bavaria, Germany
  • 1991
    • Ospedale Centrale di Bolzano
      Bozen, Trentino-Alto Adige, Italy
  • 1990–1991
    • University of California, San Diego
      • Department of Medicine
      San Diego, CA, United States