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ABSTRACT: Pheochromocytomas are neuroendocrine tumors of the adrenal medulla which can occur either sporadically or in the context of hereditary tumor syndromes. Whereas the genetic background of hereditary pheochromocytomas is becoming rather well-defined, very little is known about the more common sporadic form of the disease which constitutes ∼70% of all cases. In this study, we elucidate some of the molecular mechanisms behind sporadic pheochromocytoma by performing a comprehensive analysis of copy number alterations, gene expression, promoter methylation and somatic mutations in the genes RET, VHL, NF1, SDHA, SDHB, SDHC, SDHD, SDHAF2, KIF1Bβ, TMEM127 and MAX, which have been associated with hereditary pheochromocytoma or paraganglioma. Our genomic and genetic analyses of 42 sporadic pheochromocytomas reveal that a large proportion (83%) has an altered copy number in at least one of the known susceptibility genes, often in association with an altered messenger RNA (mRNA) expression. Specifically, 11 sporadic tumors (26%) displayed a loss of one allele of the NF1 gene, which significantly correlated with a reduced NF1 mRNA expression. Subsequent sequencing of NF1 mRNA, followed by confirmation in the corresponding genomic DNA (gDNA), revealed somatic truncating mutations in 10 of the 11 tumors with NF1 loss. Our results thus suggest that the NF1 gene constitutes the most frequent (24%) target of somatic mutations so far known in sporadic pheochromocytomas.
Human Molecular Genetics 09/2012; · 7.64 Impact Factor
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ABSTRACT: Increased oxidative stress has been linked to thyroid carcinogenesis. In this paper, we investigate whether oxidative DNA damage and DNA repair differ in follicular adenoma (FA) and follicular thyroid carcinoma (FTC). 7,8-Dihydro-8-oxoguanine (8-OxoG) formation was analysed by immunohistochemistry in 46 FAs, 52 FTCs and 18 normal thyroid tissues (NTs). mRNA expression of DNA repair genes OGG1, Mut Y homologue (MUTYH) and endonuclease III (NTHL1) was analysed by real-time PCR in 19 FAs, 25 FTCs and 19 NTs. Induction and repair of oxidative DNA damage were studied in rat FRTL-5 cells after u.v. irradiation. Moreover, activation of DNA damage checkpoints (ataxia telangiectasia mutated (ATM) and H2A histone family, member X (H2AFX (H2AFX))) and proliferation index (MIB-1) were quantified in 28 non-oxyphilic and 24 oxyphilic FTCs. Increased nuclear and cytosolic 8-OxoG formation was detected in FTC compared with follicular adenoma, whereby cytosolic 8-OxoG formation was found to reflect RNA oxidation. Significant downregulation of DNA repair enzymes was detected in FTC compared with FA. In vitro experiments mirrored the findings in FTC with oxidative stress-induced DNA checkpoint activation and downregulation of OGG1, MUTYH and NTHL1 in FRTL-5 cells, an effect that, however, was reversible after 24 h. Further analysis of FTC variants showed decreased oxidative DNA damage, sustained checkpoint activation and decreased proliferation in oxyphilic vs non-oxyphilic FTC. Our data suggest a pathophysiological scenario of accumulating unrepaired DNA/RNA damage in FTC vs counterbalanced DNA/RNA damage and repair in FA. Furthermore, this study provides the first evidence for differences in oxidative stress defence in FTC variants with possible implications for therapeutic response and prognostic outcome.
Journal of Molecular Endocrinology 02/2012; 48(3):193-202. · 3.48 Impact Factor
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ABSTRACT: Selective venous sampling (SVS) helps to interpret imaging results in patients with persistent primary hyperparathyroidism (pHPT). However, one of the drawbacks of conventional SVS may be low "spatial resolution", depending on the sample size. We modified SVS in the following way: first, patients underwent conventional SVS with up to 11 parathyroid hormone (PTH) samples taken. The quickPTH assay was used to measure PTH levels. The patients subsequently underwent super-selective venous sampling (super-SVS) in the region with the highest quickPTH level in the same session. The subjects were five consecutive patients with persistent pHPT investigated by various imaging techniques, none of which was considered conclusive. Therefore, all five patients underwent super-SVS, which was done successfully in four. Re-evaluation of the imaging results of these four patients resulted in localization of the parathyroid adenoma. Curative surgery was performed successfully in all four patients during the study period. Super-SVS increases the "spatial resolution" of conventional SVS and may have advantages when imaging results of patients with persistent pHPT are interpreted. Its true value must be analyzed in larger studies.
Surgery Today 01/2012; 42(6):570-6. · 1.22 Impact Factor
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Kerstin Krause,
Susanne Prawitt,
Markus Eszlinger,
Christian Ihling,
Andrea Sinz,
Katrin Schierle, Oliver Gimm,
Henning Dralle,
Frank Steinert,
Sien-Yi Sheu,
Kurt W Schmid,
Dagmar Fuhrer
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ABSTRACT: Benign hypofunctional cold thyroid nodules (CTNs) are a frequent scintiscan finding and need to be distinguished from thyroid carcinomas. The origin of CTNs with follicular morphologic features is unresolved. The DNA damage response might act as a physiologic barrier, inhibiting the progression of preneoplastic lesions to neoplasia. We investigated the following in hypofunctional follicular adenoma (FA) and follicular thyroid cancer (FTC): i) the mutation rate of frequently activated oncogenes, ii) the activation of DNA damage response checkpoints, and iii) the differential proteomic pattern between FA and FTC. Both FTC and FA, which did not harbor RAS, phosphoinositide-3-kinase, or PAX/peroxisome proliferator activated receptor-γ mutations, express various proteins in common and others that are more distinctly expressed in FTC rather than in FA or normal thyroid tissue. This finding is in line with the finding of constitutive DNA damage checkpoint activation (p-Chk2, γ-H2AX) and evidence for replicative stress causing genomic instability (increased cyclin E, retinoblastoma, or E2F1 mRNA expression) in FTC but not FA. We discuss the findings of the increased expression of translationally controlled tumor protein, phosphatase 2A inhibitor, and DJ-1 in FTC compared with FA identified by proteomics and their potential implication in follicular thyroid carcinogenesis. Our present findings argue for the definition of FA as a truly benign entity and against progressive development of FA to FTC.
American Journal Of Pathology 12/2011; 179(6):3066-74. · 4.89 Impact Factor
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ABSTRACT: Malignant pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare disorders arising from the adrenal gland, from the glomera along parasympathetic nerves or from paraganglia along the sympathetic trunk. According to the WHO classification, malignancy of PCCs and PGLs is defined by the presence of metastases at non-chromaffin sites distant from that of the primary tumor and not by local invasion. The overall prognosis of metastasized PCCs/PGLs is poor. Surgery offers currently the only change of cure. Preferably, the discrimination between malignant and benign PCCs/PGLs should be made preoperatively.
This review summarizes our current knowledge on how benign and malignant tumors can be distinguished.
Due to the rarity of malignant PCCs/PGLs and the obvious difficulties in distinguishing benign and malignant PCCs/PGLs, any patient with a PCC/PGL should be treated in a specialized center where a multidisciplinary setting with specialized teams consisting of radiologists, endocrinologist, oncologists, pathologists and surgeons is available. This would also facilitate future studies to address the existing diagnostic and/or therapeutic obstacles.
Langenbeck s Archives of Surgery 11/2011; 397(2):155-77. · 1.81 Impact Factor
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ABSTRACT: Multiple endocrine neoplasia type 1 (MEN 1) and type 2 (MEN 2) are autosomal-dominantly inherited syndromes where highly penetrant germline mutations predispose patients to the development of tumours in hormone-secreting cells. In the case of MEN 1, loss-of-function germline mutations in the tumour suppressor gene MEN1 increase the risk of developing pituitary, parathyroid and pancreatic islet tumours, and less commonly thymic carcinoids, lipomas and benign adrenocortical tumours. In the case of MEN 2, gain-of-function germline mutations clustered in specific codons of the RET proto-oncogene increase the risk of developing medullary thyroid carcinoma (MTC), phaeochromocytoma and parathyroid tumours. Offering RET testing is best practice for the clinical management of patients at-risk of MEN 2, and MEN 2 has become a classic model for the integration of molecular medicine into patient care. Prophylactic thyroidectomy in an asymptomatic RET mutation carrier to address the risk of developing MTC can prevent or cure this malignancy. No similar preventative strategies can be employed to prevent or cure MEN 1-associated tumours. Genetic testing for MEN 1 is therefore both more complex due to a general lack of mutational hotspots, and the benefit to patients is less straight forward. While a number of genotype-phenotype correlations exist in MEN 2, providing further rationale for performing genetic testing in this condition, these correlations are absent in MEN 1. This review summarises our current knowledge of these two syndromes with emphasis on those aspects with specific relevance to the otorhinolaryngologist.
Advances in oto-rhino-laryngology 01/2011; 70:84-90.
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Journal of thyroid research. 01/2011; 2011:631593.
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Michael A Hahn,
Viive M Howell,
Anthony J Gill,
Adele Clarkson,
Graham Weaire-Buchanan,
Bruce G Robinson,
Leigh Delbridge, Oliver Gimm,
Wolfgang D Schmitt,
Bin T Teh,
Deborah J Marsh
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ABSTRACT: The tumor suppressor HRPT2/CDC73 is mutated in constitutive DNA from patients with the familial disorder hyperparathyroidism-jaw tumor syndrome and in approximately 70% of all parathyroid carcinomas. In a number of HRPT2 mutant tumors however, expression of the encoded protein parafibromin is lost in the absence of a clear second event such as HRPT2 allelic loss or the presence of a second mutation in this tumor suppressor gene. We sought to determine whether hypermethylation of a 713 bp CpG island extending 648 nucleotides upstream of the HRPT2 translational start site and 65 nucleotides into exon 1 might be a mechanism contributing to the loss of expression of parafibromin in parathyroid tumors. Furthermore, we asked whether mutations might be present in the 5'-untranslated region (5'-UTR) of HRPT2. We investigated a pool of tissue from 3 normal parathyroid glands, as well as 15 individual parathyroid tumor samples including 6 tumors with known HRPT2 mutations, for hypermethylation of the HRPT2 CpG island. Methylation was not identified in any specimens despite complete loss of parafibromin expression in two parathyroid carcinomas with a single detectable HRPT2 mutation and retention of the wild-type HRPT2 allele. Furthermore, no mutations of a likely pathogenic nature were identified in the 5'-UTR of HRPT2. These data strongly suggest that alternative mechanisms such as mutation in HRPT2 intronic regions, additional epigenetic regulation such as histone modifications, or other regulatory inactivation mechanisms such as targeting by microRNAs may play a role in the loss of parafibromin expression.
Endocrine Related Cancer 12/2009; 17(1):273-82. · 4.36 Impact Factor
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Thyroid: official journal of the American Thyroid Association 07/2009; 19(6):555-7. · 2.60 Impact Factor
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ABSTRACT: More than 90% of M918T carriers with multiple endocrine neoplasia type 2B (MEN 2B) harbor de novo mutations in the REarranged during Transfection (RET) protooncogene. DNA-based screening for RET germline mutations is rarely useful for early diagnosis, which thus is contingent on the clinical ascertainment of MEN 2B-specific symptoms as soon as they emerge. Little information exists about the presence of these symptoms in infancy.
Detailed information was gathered regarding the development of MEN 2B-associated symptoms from the parents of 25 M918T RET carriers and 50 age- and sex-matched controls with the use of a disease-specific questionnaire.
Until the end of the study, at a median age of 16.2 (range, 0.5-34.9 years), all 25 M918T RET carriers had developed medullary thyroid cancer. By that time, 96%, 91%, 71%, 75%, and 28% of carriers displayed oral manifestations, ocular abnormalities, intestinal symptoms, musculoskeletal malformations, and pheochromocytoma, respectively. During the first year of life, fewer than 20% of carriers were found to express the typical MEN 2B phenotype, whereas 86% and 61% of these children, but none of the controls, were noted for their inability to cry tears and for constipation.
Because the classic MEN 2B phenotype is rare during the first year of life, more emphasis should be placed on the more subtle features of the syndrome. Additional studies are needed to validate the usefulness of the symptoms "inability to cry" and "constipation" for earlier diagnosis of MEN 2B.
Surgery 01/2009; 144(6):1044-50; discussion 1050-3. · 3.10 Impact Factor
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ABSTRACT: Parafibromin, encoded by HRPT2, is the first marker with significant benefit in the diagnosis of parathyroid carcinoma. However, because parafibromin is only involved in up to 70% of parathyroid carcinomas and loss of parafibromin immunoreactivity may not be observed in all cases of HRPT2 mutation, a complementary marker is needed.
We sought to determine the efficacy of increased expression of protein gene product 9.5 (PGP9.5), encoded by ubiquitin carboxyl-terminal esterase L1 (UCHL1) as an additional marker to loss of parafibromin immunoreactivity for the diagnosis of parathyroid carcinoma.
In total, 146 parathyroid tumors and nine normal tissues were analyzed for the expression of parafibromin and PGP9.5 by immunohistochemistry and for UCHL1 by quantitative RT-PCR. These samples included six hyperparathyroidism-jaw tumor syndrome-related tumors and 24 sporadic carcinomas.
In tumors with evidence of malignancy, strong staining for PGP9.5 had a sensitivity of 78% for the detection of parathyroid carcinoma and/or HRPT2 mutation and a specificity of 100%. Complete lack of nuclear parafibromin staining had a sensitivity of 67% and a specificity of 100%. PGP9.5 was positive in a tumor with the HRPT2 mutation L64P that expressed parafibromin. Furthermore, UCHL1 was highly expressed in the carcinoma/hyperparathyroidism-jaw tumor syndrome group compared to normal (P < 0.05) and benign specimens (P < 0.001).
These results suggest that positive staining for PGP9.5 has utility as a marker for parathyroid malignancy, with a slightly superior sensitivity (P = 0.03) and similar high specificity to that of parafibromin.
Journal of Clinical Endocrinology & Metabolism 11/2008; 94(2):434-41. · 6.50 Impact Factor
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ABSTRACT: The forkhead box transcription factor FOXO3a has recently been identified as central mediator of the cellular response to oxidative stress inducing cell cycle arrest or apoptosis. The aim of our study was to investigate the regulation of FOXO3a in the thyroid and to determine whether alterations in FOXO3a activity occur in thyroid carcinogenesis. In vitro, we demonstrate that FOXO3a activity is negatively regulated by the PI3K/Akt cascade promoting increased phosphorylation and cytoplasmatic accumulation of FOXO3a with decreased transcription of the target genes p27kip (CDKN1B) and Bim (BCL2L11), but increased expression of GADD45A. By contrast, we show that H(2)O(2) exposure activates FOXO3a in thyrocytes with JNK (MAPK8)-mediated nuclear accumulation of FOXO3a and increased expression of the cell cycle arrest genes p27kip and GADD45A. In vivo, we observed a marked cytoplasmatic accumulation of FOXO3a in differentiated thyroid cancers versus an exclusive nuclear accumulation in follicular adenoma and normal thyroid tissue. Moreover, this cytosolic accumulation of FOXO3a correlated with an increased phospho-Akt expression in thyroid malignancies and was accompanied by decreased expression of the FOXO targets p27kip and Bim and an increase in GADD45A mRNA expression in the thyroid cancers. Our data suggest FOXO3a as a novel player of cellular stress response in the thyroid, mediating the thyrocyte's fate either to survive or to undergo apoptosis. Furthermore, PI3K-dependent FOXO3a inactivation may be a novel pathomechanism for the escape from apoptosis in thyroid cancer cells, in particular in follicular thyroid carcinoma.
Endocrine Related Cancer 11/2008; 16(1):189-99. · 4.36 Impact Factor
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Martin Anlauf,
Tetsuji Enosawa,
Tobias Henopp,
Anja Schmitt, Oliver Gimm,
Michael Brauckhoff,
Henning Dralle,
Anette Musil,
Steffen Hauptmann,
Aurel Perren,
Günter Klöppel
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ABSTRACT: Gastrinoma tissue has been found frequently in lymph nodes located near the duodenum without a known primary tumor. Therefore, it has been suggested that a primary lymph node gastrinoma exists. We report on a 38-year-old woman suffering from multiple endocrine neoplasia type 1 (MEN1) confirmed by menin gene mutation analysis. MEN1 disease started with primary hyperparathyroidism followed by Cushing disease, the detection of tumors of the pituitary, adrenal cortex, and the pancreas and also an elevated serum gastrin level. An octreotide scan revealed 4 tumors in the upper abdomen. A selective arterial calcium stimulation test located the source of the hypergastrinemia to the area of the gastroduodenal and the superior mesenteric arteries. Total pancreatoduodenectomy was performed and conventional histopathologic examination revealed a well-differentiated cystic neuroendocrine tumor of the pancreas expressing glucagon and accompanied by several microadenomas. In addition, 3 suprapancreatic lymph nodes with gastrin-positive endocrine tissue were found. None of the pancreatic microadenomas expressed gastrin and no duodenal endocrine tumor was found despite careful macroscopic examination. Only after complete embedding of the duodenal and pancreatic tissue in 65 paraffin blocks, 2 microgastrinomas (0.45 and 0.8 mm in diameter) were identified in the duodenum. It is concluded that duodenal gastrinomas that give rise to lymph node metastases may be so tiny that they are easily overlooked in a routine examination and that systematic tissue monitoring is required to identify them.
The American journal of surgical pathology 07/2008; 32(7):1101-5. · 4.06 Impact Factor
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ABSTRACT: We have recently found an increased expression of amyloid precursor protein (APP) in cold thyroid nodules that are difficult to classify as a truly benign thyroid neoplasm or a lesion with the potential for further dedifferentiation. Since differences in APP activity have been found in other human cancers, we asked whether thyroid carcinogenesis might be associated with an altered APP expression and function. APP regulation was studied in vitro in differentiated (FRTL-5) and dedifferentiated follicular thyroid carcinomas (FTC-133) thyroid cells after specific inhibition or activation of the cAMP-PKA, the PI3K/AKT or the protein kinase c (PKC) cascades. In vivo analysis of APP expression and downstream signalling was performed in benign and malignant thyroid tissues. We found that upregulation of APP expression and sAPP secretion is induced by TSH in differentiated thyroid cells and by insulin in thyroid cancer cells. PKC is a strong activator of APP cleavage and in FTC-133 confers prolonged release of the APP ectodomain. FTC-133 but not FRTL-5 cells show a prominent cell surface expression of the APP ectodomain, which has been suggested to function as an autocrine growth factor. Thyroid cancers are characterized by APP upregulation, increased membrane targeting of the APP ectodomain and significantly increased mRNA levels of the APP scaffold proteins JIP1, ShcA and Fe65.
Journal of Endocrinology 06/2008; 198(2):291-9. · 3.55 Impact Factor
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ABSTRACT: Recent studies have shown that a minimum of approximately one-third of one normal adrenal gland is required for sufficient adrenocortical stress capacity. Correlation between intraoperative measurement, determination of remnant size by computed tomography (CT), and adrenocortical stress capacity has not been examined so far.
Twenty-two patients with familial pheochromocytoma (n=13), sporadic pheochromocytoma (n=3), and adrenocortical tumors (n=6) who underwent unilateral or bilateral subtotal adrenalectomy (STAE, 28 adrenal remnants) were prospectively studied. Patients were examined in a multi-slice CT to determine residual adrenal tissue and by ACTH test 4 days and 3 months postoperatively.
There was a slight significant correlation between intraoperative and CT calculated volumes (r=0.77; p<0.001). However, volumes assessed by CT were almost doubled compared with intraoperative determination (p<0.001). Although recovery of adrenal function could be observed, no significant changes of remnant volumes could be detected within 3 months. In patients with familial pheochromocytoma, there was a significant correlation between residual adrenal volume and stimulated cortisol levels (P<0.001). A distinct minimum of adrenal volume for intact adrenocortical stress capacity could not be exactly determined; however, in one patient with only 10% residual adrenal tissue intact stress capacity was found.
Residual adrenal tissue of approximately 10-15% offers intact stress capacity. However, an exact determination of the size of an adrenal remnant after STAE has limitations. CT gives larger volumes compared with intraoperative determination. For calculation of a volume-function correlation of residual adrenal tissue, in clinical practice, the determination of relative adrenal residual volume is acceptable.
World Journal of Surgery 06/2008; 32(5):863-72. · 2.36 Impact Factor
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ABSTRACT: With the advent of microarray technology, increasing numbers of marker genes are proposed to distinguish benign and malignant thyroid lesions. However, most markers await confirmation through independent studies. In this paper, we re-evaluate the diagnostic potential of 10 proposed candidate genes in benign and malignant thyroid pathologies in a region with borderline iodine deficiency.
Quantitative real-time PCR was performed for CCND2, PLAB, PCSK2, HGD1, TFF3, B4GALT, LGALS3, ETS1, ADM3, and TG in 150 thyroid specimens, including 52 benign thyroid nodules (28 follicular adenoma and 24 adenomatous nodules), 52 corresponding normal thyroid tissues, 20 follicular carcinomas, 20 papillary carcinomas, and six undifferentiated carcinomas.
On a single-gene basis, significant differences in mRNA expression were found for TFF3, PLAB, and ADM3 in benign thyroid nodules and thyroid malignancy. Using two-marker gene sets, we identified 11 combinations, which allowed both a distinction of benign and malignant thyroid nodules and a discrimination of follicular adenoma and carcinoma. However, for cancer prediction, analysis of a minimum of six genes per sample was necessary and allowed correct prediction of a benign thyroid lesion and thyroid cancer with 94% accuracy in the most discriminative set (TFF3/PLAB/TG/ADM3/HGD1/LGALS3).
We confirm the applicability of a number of recently proposed marker genes for the distinction of benign and malignant thyroid tumor and suggest that their diagnostic usefulness is independent of the iodide supply. We propose that the most discriminative marker set identified in our validation study together with marker combinations proposed by other investigators should now be evaluated in multicenter trials.
Journal of Clinical Endocrinology & Metabolism 05/2008; 93(4):1390-3. · 6.50 Impact Factor
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ABSTRACT: Insulinomas are rare endocrine disorders. Pre-operatively, conventional imaging techniques often fail to localise the tumor. In addition, due to the lack of quick insulin assays, intra-operative confirmation of complete resection was impossible until recently.
Six patients with biochemical evidence of an insulinoma underwent pre-operative localisation studies and selective arterial calcium injection (SACI). In addition, insulin was measured before surgery and every 10-15 min after resection of the tumor using a quick insulin assay.
Pre-operative localisation studies identified the tumor correctly as follows: endosonography: three of four, magnetic resonance imaging: two of four and SACI: six of six. Tumors in the head and body were enucleated while those in the tail were resected (n = 2, each). Those three patients, in whom magnetic resonance imaging and/or endosonography could localise the tumors pre-operatively, underwent laparoscopic surgery while the remaining three patients underwent open surgery. Intra-operatively, insulin dropped to normal levels within 20 min in all cases. After a follow-up of 0.8-3 years, all patients remained biochemically cured.
Pre-operatively, SACI appears to be a very sensitive localisation technique and may be most helpful in guiding the surgeon if conventional imaging techniques fail to localise the tumor. Complete removal of an insulinoma can be reliably predicted using a quick insulin assay.
Langenbeck s Archives of Surgery 12/2007; 392(6):679-84. · 1.81 Impact Factor
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Melanoma Research 11/2007; 17(5):335-8. · 2.19 Impact Factor
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Marianthi Georgitsi,
Anniina Raitila,
Auli Karhu,
Rob B van der Luijt,
Cora M Aalfs,
Timo Sane,
Outi Vierimaa,
Markus J Mäkinen,
Karoliina Tuppurainen,
Ralph Paschke, [......],
Anneke Lucassen,
Marc Tischkowitz,
Louise Izatt,
Simon Aylwin,
Gul Bano,
Shirley Hodgson,
Ernesto De Menis,
Virpi Launonen,
Pia Vahteristo,
Lauri A Aaltonen
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ABSTRACT: Germline mutations in the MEN1 gene predispose to multiple endocrine neoplasia type 1 (MEN1) syndrome, but in up to 20-25% of clinical MEN1 cases, no MEN1 mutations can be found. Recently, a germline mutation in the CDKN1B gene, encoding p27(Kip1), was reported in one suspected MEN1 family with two acromegalic patients.
Our objective was to evaluate the role of CDKN1B/p27(Kip1) in human tumor predisposition in patients clinically suspected of MEN1 but testing negative for MEN1 germline mutation as well as in familial and sporadic acromegaly/pituitary adenoma patients.
Genomic DNA was analyzed for germline mutations in the CDKN1B/p27(Kip1) gene by PCR amplification and direct sequencing.
The study was conducted at nonprofit academic research and medical centers.
Thirty-six Dutch and one German suspected MEN1 patient, who previously tested negative for germline MEN1 gene mutations, were analyzed. In addition, 19 familial and 50 sporadic acromegaly/pituitary adenoma patients from Europe and the United States were included in the study.
We analyzed germline CDKN1B/p27(Kip1) mutations in individuals with pituitary adenoma and MEN1-like features.
A heterozygous 19-bp duplication (c.59_77dup19) leading to a truncated protein product was identified in one Dutch patient with suspected MEN1 phenotype, pituitary adenoma, carcinoid tumor, and hyperparathyroidism (one of 36, 2.8%). No mutations were detected in either familial or sporadic acromegaly/pituitary adenoma patients.
Our results support the previous finding that germline CDKN1B/p27(Kip1) mutations predispose to a human MEN1-like condition. However, such mutations appear uncommon in suspected MEN1 cases and rare or nonexistent in familial or sporadic acromegaly/pituitary adenoma patients.
Journal of Clinical Endocrinology & Metabolism 09/2007; 92(8):3321-5. · 6.50 Impact Factor
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ABSTRACT: No surgical standard for Riedel's thyroiditis (RT) is established. Salvage surgery follows severe cervical and compressive airway symptoms or strong suspicion of malignancy. Obscured planes and multi-infiltrative extension prevent sufficient surgery with considerate complications. No alternative definitive treatment is available. In failing conservative treatment, the role of surgery in RT remains unclear.
Clinical manifestation, treatment, outcome and follow-up in a unique series of eight consecutive patients with RT are presented.
Seven female patients and one male patient with cervical tumor growth or thyroiditis underwent four total and three sub-total thyroidectomies, respectively, one patient declined remedial surgery. Complications were one bilateral laryngeal nerve palsy and one transient hypoparathyroidism. Histology confirmed RT with perithyroidal extension and excluded malignancy in all. Symptomatic relief of cervical and airway obstruction was achieved in all. Follow-up revealed two extensive mediastinal RT recurrences 1 and 6 years after surgery.
Favourable symptomatic outcome and alleviation of steroids in the majority render surgery for RT valuable when conservative treatment fails. However, more radical procedures show no advantages and recurrences are not prevented. The demanding technique in RT requires special surgical expertise and highly recommends intra-operative neuromonitoring.
Langenbeck s Archives of Surgery 07/2007; 392(4):405-12. · 1.81 Impact Factor
