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Abstract Paragangliomas are rare tumours of the autonomic nervous system and occur in sporadic and hereditary forms. They are usually benign and have a low mortality. However, they cause significant morbidity related to their mass effect. Genetic predisposition can occur within the familial tumour syndromes multiple endocrine neoplasia type 2 (MEN 2), von Hippel-Lindau (VHL) and neurofibromatosis type 1 (NF-1), or be due to mutations in genes specific to the development of paraganglioma only. Compared to sporadic forms, familial paragangliomas tend to present at a younger age and at multiple sites. Tumours should be diagnosed and resected as early as possible, as it has been shown that morbidity is related to tumour size. This article gives an overview of the current literature on the origin of the different forms of paragangliomas, DNA diagnosis, as well as biochemical and radiological screening guidelines.

von Hippel-Lindau (VHL) mutation carriers develop benign and malignant tumors, requiring regular surveillance. The aim of this study was to calculate the optimal organ-specific age to initiate surveillance and optimal intervals to detect initial and subsequent VHL-related manifestations. In this study, we compare these results with the current VHL surveillance guidelines. We collected data from 82 VHL mutation carriers in the Dutch VHL surveillance program. The cumulative proportion of carriers diagnosed with a first VHL-related manifestation was estimated by the Kaplan-Meier method. The Poisson distribution model was used to calculate average time to detection of the first VHL-related manifestation and subsequent manifestations. We used this to calculate the optimal organ-specific age to initiate surveillance and the surveillance interval that results in a detection probability of 5%. The calculated organ-specific ages to initiate surveillance were 0 years (birth) for adrenal glands, 7 years for the retina, 14 years for the cerebellum, 15 years for the spinal cord, 16 years for pancreas, and 18 years for the kidneys. The calculated surveillance intervals were 4 years for the adrenal glands, biennially for the retina and pancreas, and annually for the cerebellum, spinal cord, and kidneys. Compared with current VHL guidelines, the calculated starting age of surveillance was 6 years later for the retina and 5 years earlier for adrenal glands. The surveillance intervals were two times longer for the retina and four times longer for the adrenal glands. To attain a 5% detection probability rate per organ, our mathematical model indicates that several modifications of current VHL surveillance guidelines should be considered.

Due to the variable expression of multiple endocrine neoplasia type 1 (MEN1), it is difficult to predict the course of the disease. However, knowledge about the normal function of the MEN1 gene product, together with the effects of cellular derangement by subsequent genetic events, has increased considerably. At first, the possible existence of a genotype-phenotype correlation is discussed. Thus, mild- and late-onset phenotypes may be distinguished from more malignant phenotypes depending on the character of the primary MEN1 disease gene mutation. Subsequently, tumor-promoting factors such as gender, additional genetic mutations and ecogenetic factors may contribute to the course of the disease. New developments in management are based on the knowledge and experience of the multidisciplinary teams involved. Finally, the metabolic effects of MEN1 mutations in aged patients are discussed. Early identification of predisposition to the disease, together with knowledge about the natural history of specific mutations, risks of additional mutations and periodic clinical monitoring, allow early treatment and may improve life expectancy and quality of life.

Objective: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary syndrome characterized by parathyroid, gastroenteropancreatic, pituitary and adrenal tumours. Cardiovascular disease has been identified as an important cause of death in MEN1 patients. Menin, the product of the MEN1 gene, is a co-activator for peroxisome proliferator-activated receptor-γ and the vitamin D receptor, which are involved in glucose metabolism. We aimed to compare insulin sensitivity and prevalence of impaired fasting glucose and diabetes mellitus between MEN1 patients and controls., Design: Cross-sectional study., Patients: Sixty-three MEN1 gene mutation carriers (44% men, mean age 41 years) from 22 kindreds and 126 unrelated controls matched for gender, age and BMI., Measurements: Fasting glucose levels were categorized and compared using WHO criteria. Homeostasis model assessment (HOMA) was used as a measure of insulin resistance., Results: Homeostasis model assessment was significantly increased in MEN1 patients compared with controls (3·0 ± 2·0 vs 2·0 ± 1·0, P < 0·05). In MEN1 patients, HOMA was associated with BMI, but not with age, calcium and gastrin levels. Using logistic regression analysis, the presence of hyperparathyroidism, pancreatic lesions and various other manifestations was not associated with HOMA. Impaired fasting glucose was more prevalent in MEN1 compared with controls (17%vs 6%, P < 0·05). Three MEN1 patients (5%) compared with four controls (3%) were diabetic (not significant)., Conclusions: Multiple endocrine neoplasia type 1 patients had decreased insulin sensitivity and higher prevalence of impaired fasting glucose compared with controls, which was unrelated to MEN1 manifestations. Impaired glucose metabolism may result in increased risk of cardiovascular disease in MEN1 patients., (© 2011 Blackwell Publishing Ltd.)

Multiple endocrine neoplasia type 1 (MEN1) is a heriditary syndrome characterised by the occurrence of parathyroid, gastroenteropancreatic and pituitary tumours. The MEN1 gene product, menin, co-activates gene transcription by recruiting histone methyltransferases for lysine 4 of histone H3 (H3K4). We investigated whether in MEN1 tumours global changes in H3K4 trimethylation (H3K4me3) occur or whether alterations in gene expression can be observed. By immunohistochemistry we found that global levels of H3K4me3 are not affected in MEN1-related parathyroid adenomas. Menin can interact directly with the vitamin D receptor (VDR) and enhance the transcriptional activity of VDR. Messenger RNA levels of VDR target genes CYP24 and KLK6 were significantly lower in MEN1 parathyroid adenomas compared to normal tissue. Thus, aberrant gene expression in MEN1 tumours is not caused by lower global H3K4me3, but rather by specific effects on genes that are regulated by menin-interacting proteins, such as VDR.

Menin, the product of the MEN1 (multiple endocrine neoplasia type 1) tumor suppressor gene, is involved in activation of gene transcription as part of an MLL1 (mixed-lineage leukemia 1)/MLL2 (KMT2A/B)-containing protein complex which harbors methyltransferase activity for lysine 4 of histone H3 (H3K4). As MEN1 patients frequently develop lipomas and peroxisome proliferator-activated receptor gamma (PPARgamma) is expressed in several MEN1-related tumor types, we investigated regulation of PPARgamma activity by menin. We found that menin is required for adipocyte differentiation of murine 3T3-L1 cells and PPARgamma-expressing mouse embryonic fibroblasts. Menin augments PPARgamma target gene expression through recruitment of H3K4 methyltransferase activity. Menin interacts directly with the activation function 2 transcription activation domain of PPARgamma in a ligand-independent fashion. Ligand-dependent coactivation, however, is dependent on the LXXLL motif of menin and the intact helix 12 of PPARgamma. We propose that menin is an important factor in PPARgamma-mediated adipogenesis and that loss of PPARgamma function may contribute to lipoma development in MEN1 patients.

Multiple endocrine neoplasia type 2 (MEN 2) is an autosomal dominantly inherited tumor syndrome subclassified into three distinct syndromes: MEN 2A, MEN 2B and familial medullary thyroid carcinoma. In MEN 2 families, medullary thyroid carcinoma, pheochromocytomas and parathyroid adenomas occur with a variable frequency, also depending on the specific genetic defect involved. In 1993, the responsible MEN2 gene was identified. The genetic defect in these disorders involves the RET proto-oncogene on chromosome 10. The germline RET mutations result in a gain-of-function of the RET protein. Extensive studies on large families revealed that there is a strong genotype-phenotype correlation. In this review, guidelines for early diagnosis, including MEN2 gene mutation analysis, and treatment, including preventive surgery, periodic and clinical monitoring, have been formulated, enabling improvement of life expectancy and quality of life. Identification of the RET protein has also provided new insights into its function, and the specific pathways it effects involved in cell proliferation, migration, differentiation and survival. In the near future, identification of biological tumor markers will enable target-directed intervention and may prevent and/or delay progression of both primary and residual tumor growth.

The phenotype of the multiple endocrine neoplasia type 1 (MEN1) syndrome cannot be explained solely by the expression pattern of the predisposing gene MEN1 and its encoded protein, menin. This review addresses putative factors determining MEN1-associated tissue-selective tumorigenesis. Menin's interaction with mixed-lineage leukemia protein-containing histone methyl transferase (MLL-HMT) complex mediates tissue-selective tumor-suppressing and tumor-promoting effects of menin, and as such could be decisive for the predisposition of individual tissues to MEN1-associated tumorigenesis. In tissues in which menin acts as a tumor suppressor, tumorigenesis could depend on the inability of such tissues to adequately compensate for MEN1 gene loss, whereas the variable clinical presentation of MEN1 in individual patients could be a reflection of additional epigenetic factors and/or modifier genes. Further research on this topic may facilitate development of novel therapeutic strategies that could prevent or delay the onset of MEN1-associated tumorigenesis.

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal-dominant inherited tumor syndrome characterized by hyperplasia and/or tumors in the parathyroid glands, the pancreatic islets, the anterior pituitary and adrenal glands, as well as neuroendocrine tumors in the thymus, lungs and stomach, and tumors in nonendocrine tissues. In 1997, the responsible MEN1 gene was identified as a tumor-suppressor gene and its product was named menin. In this review, guidelines for early diagnosis, including MEN1 gene mutation analysis, and treatment, including periodic clinical monitoring, have been formulated, enabling improvement of life expectancy and quality of life. Identification of menin-interacting proteins has provided new insights into the function of menin, notably involving regulation of gene transcription related to proliferation and apoptosis, genome stability and DNA repair, and endocrine/metabolic homeostasis. In the near future, target-directed intervention may prevent or delay the onset of MEN 1-related tumors.

Multiple endocrine neoplasia type 1 (MEN1) is caused by inactivating germ line mutations of the MEN1 tumour suppressor gene. The MEN1 gene product, menin, participates in many cellular processes, including regulation of gene transcription. As part of a protein complex that writes a trimethyl mark on lysine 4 of histone H3 (H3K4me3), menin is involved in activating gene transcription. Several functions of the menin histone methyltransferase complex have been discovered through protein interaction studies. Menin can interact with nuclear receptors and regulate transcription of hormone responsive target genes. Menin regulates transcription of cyclin-dependent kinase inhibitor and Hox genes via the chromatin-associated factor LEDGF. Aberrant expression of menin target genes in tumours in MEN1 patients suggests that loss of writing of the H3K4me3 mark contributes to MEN1 tumourigenesis. At present, drugs are being developed that target chromatin modifications. The identification of compounds that could restore H3K4me3 on menin target genes would provide new therapeutic strategies for MEN1 patients.

The clinical management of patients with persistent or recurrent medullary thyroid carcinoma (MTC) is still under debate, because these patients either have a long-term survival, due to an indolent course of the disease, or develop rapidly progressing disease leading to death from distant metastases. At this moment, it cannot be predicted what will happen within most individual cases. Biomarkers, indicators which can be measured objectively, can be helpful in MTC diagnosis, molecular imaging and treatment, and/or identification of MTC progression. Several MTC biomarkers are already implemented in the daily management of MTC patients. More research is being aimed at the improvement of molecular imaging techniques and the development of molecular systemic therapies. Recent discoveries, like the prognostic value of plasma calcitonin and carcino-embryonic antigen doubling-time and the presence of somatic RET mutations in MTC tissue, may be useful tools in clinical decision making in the future. In this review, we provide an overview of different MTC biomarkers and their applications in the clinical management of MTC patients.

Objectives/methods: The intracellular serine protease inhibitor 8 (SERPINB8) is expressed by squamous epithelium, monocytes, and a subset of neuroendocrine cells. Using immunohistochemistry, we now have further investigated the expression of SERPINB8 in normal neuroendocrine cells and its potential use as a marker to identify neuroendocrine tumors of the pancreas., Results: In normal neuroendocrine tissues, strongest SERPINB8 expression was detected in islets of Langerhans of the pancreas. Moderate SERPINB8 expression was observed in neuroendocrine cells of the thyroid, adrenal cortex, colon, and pituitary gland. Fluorescent double staining revealed that in the pancreas, SERPINB8 is specifically expressed by insulin-producing beta cells. In a panel of 20 patients with pancreatic islet cell tumors, however, SERPINB8 was broadly expressed and not restricted to insulinomas. In islet cell tumors, SERPINB8 had a similar diagnostic sensitivity as compared with the widely used neuroendocrine markers chromogranin A and synaptophysin. When SERPINB8 was combined with these 2 markers, an even higher diagnostic sensitivity was reached. In contrast, exocrine adenocarcinomas of the pancreas showed no SERPINB8 expression., Conclusions: The SERPINB8 is expressed in normal neuroendocrine cells of several organs as well as in neuroendocrine tumors of the pancreas, where it can be used as an additional diagnostic immunohistochemical marker.

In multiple endocrine neoplasia syndrome Type 2 (MEN2), medullary thyroid carcinoma (MTC) and pheochromocytoma (PC) are associated with hereditary activating germ-line mutations in the RET proto-oncogene. Also in a large percentage of sporadic MTCs and PCs, somatic RET mutations appear to be involved in tumor formation. In one single MEN2 family an extensive variety in disease expression may be observed, indicating that additional genetic events are responsible for progression of the disease towards a more aggressive phenotype. However, these additional mutations in both hereditary and sporadic MTC and PC development are largely unknown. Here, we show for the first time the presence of somatic mutations in the cell cycle regulator P18 in human RET-associated MTCs and PCs. Each of these mutations causes an amino acid substitution in the cyclin dependent kinase-interacting region of P18(INK4C). Since these mutations partly inhibited P18(INK4C) function and reduced its stability, our findings implicate P18 as a tumor suppressor gene involved in human MTC and PC development., (Copyright (c) 2008 Wiley-Liss, Inc.)

Unlabelled: Measurements of thyroglobulin (Tg) levels 72 h after administration of recombinant human thyrotropin (rhTSH) are recommended by the manufacturer in the follow-up of patients with differentiated thyroid carcinoma (DTC). In our department, Tg measurements are performed both 24 h and 72 h after administration of rhTSH, together with 72 h post rhTSH 131I whole body scintigraphy (WBS). The OBJECTIVE of this study is to compare the diagnostic usefulness of Tg measurements 24 and 72 h after rhTSH administration, and 131I WBS., Patients and Methods: 181 patients were included who had been referred to our Nuclear Medicine Department for follow-up after 131I ablation of DTC. Tg measurements 24 h (Tg24) and 72 h (Tg72) after rhTSH, and 131I WBS, were done in all patients. The lower detection limit of Tg was 0,2 microg/l., Results: 47 patients (26%) had detectable Tg levels: in 4/47 cases (8%) only Tg24 was detectable (always <1 microg/l), and in 6/47 cases (11%), only Tg72 was detectable. In 10/47 patients with detectable Tg-levels, Tg24 and Tg72 tested equally. In 27/47 cases, Tg24 was lower, and in 10/47 higher, than Tg72. Two patients with one or two positive Tg-test results also had a positive 131I WBS. In 8 patients (14%) only the 131I WBS was positive; an anatomical substrate for such a Tg-negative positive WBS was confirmed in only 2 patients., Conclusion: Tg-measurement 72 hours after rhTSH injection reveals all clinically relevant detectable Tg-levels. Diagnostic 131I scintigraphy may be omitted, even in high-risk patients.

Introduction: The aim of the study was to compare the success rate of an uptake-related ablation protocol in which the dose depends on an I-131 24-h neck uptake measurement and a fixed-dose ablation protocol in which the dose depends on tumour stage., Methods: All differentiated thyroid carcinoma patients with M0 disease who had undergone (near-) total thyroidectomy followed by I-131 ablation were included. In the uptake-related ablation protocol, 1100 (uptake >10%), 1850 (uptake 5-10%) and 2800 MBq (uptake <5%) were used. In the fixed-dosage ablation strategy, 3700 (T1-3, N0 stage) and 5550 MBq (N1 and/or T4 stage) were applied. We used I-131 uptake on whole-body scintigraphy and thyroglobulin-off values to evaluate the ablation 6-12 months after treatment., Results: In the uptake-related ablation protocol, 60 out of 139 (43%) patients were successfully treated versus 111 out of 199 for the fixed-dose ablation protocol (56%) (P=0.022). The differences were not statistically significant for patients with T4 (P=0.581) and/or N1 (P=0.08) disease or for patients with T4N1 tumour stage (P=0.937)., Conclusion: The fixed-dose I-131 ablation protocol is more effective in ablation of the thyroid remnant in differentiated thyroid carcinoma patients than an uptake-related ablation protocol. This difference is not observed in patients with a N1 and/or T4 tumour stage.

Activating mutations in the RET proto-oncogene are associated with both familial and sporadic medullary thyroid carcinoma (MTC) development; however, the genetic mechanisms underlying MTC tumorigenesis remain largely unknown. Recently, we have identified somatic inactivating mutations in the cell cycle inhibitor gene P18 in human MTC, which coincided with activating RET mutations, suggesting a role for loss of P18 in combination with oncogenic RET in the multistep process of MTC development. Therefore, we crossed transgenic mice expressing oncogenic RET (RET2B) with mice lacking p18 (and p27, another cell cycle inhibitor) and monitored MTC development. RET2B;p18(+/-) mice and RET2B;p18(-/-) mice developed MTC with a highly increased incidence compared with their corresponding single mutant littermates. In addition, expression of oncogenic RET causes an earlier age of onset and larger MTCs in p18(-/-);p27(+/-) mice. In a subset of MTCs of RET2B;p18(+/-)(;p27(+/-)) mice, p18(Ink4c) expression was completely lost. This loss of p18(Ink4c) expression correlated with higher proliferation rates as well as with larger MTCs, indicating that loss of p18 in combination with oncogenic RET not only increases the risk for MTC development but also enhances MTC progression. Our data strongly indicate that oncogenic RET and loss of p18 cooperate in the multistep tumorigenesis of MTC.

Aim: The aim of this study was to assess the efficacy of treatment of patients with papillary thyroid carcinoma (PTC) and lymph node metastases at the time of diagnosis and its influence on the course of the disease., Methods: It is a retrospective review of all 51 patients with PTC and histologically proven lymph node metastases treated with I-131 ablation in our center between January 1990 and January 2003. Patients were considered disease-free if during follow-up thyroglobulin levels were undetectable and scintigraphy with 370 MBq (131)I was negative during thyroid-stimulating hormone stimulation. Staging of patients was in accordance with the 5th edition of the TNM system., Results: After a median follow-up of 84 months, 33 (65%) patients were never free of detectable disease; and 3 of these patients had died of the PTC. In total, 22 patients still showed persistent activity in the neck outside the thyroid bed, which was suspect to be cervical lymph node metastasis on postablation scintigraphy; it was not related to the initial clinical presentation (lymph node metastasis or a thyroid nodule without suspicion of metastatic disease) or to the extent of surgery. Altogether, 34 patients required additional treatment. Patients presenting with clinically overt lymph node metastasis showed a significantly (p = 0.022) lower rate of becoming disease-free than those in whom microscopic lymph node involvement was unexpectedly found upon pathologic examination. There was no significant association of the eventual outcome with the extent of surgical treatment, TNM staging, or age., Conclusions: Patients with lymph node metastasis are considerably less likely to become disease-free. If the initial treatment does not result in a disease-free status, chances are low that additional treatment will succeed in achieving it.

Background: Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited disease. It is relatively recent that type 2C was identified as a separate group solely presenting with pheochromocytomas. As an illustration, an interesting case is presented of a pregnant woman with refractory hypertension. It proved to be the first manifestation of bilateral pheochromocytomas. The family history may indicate the diagnosis, but only identification of a germ line mutation in the DNA of a patient will confirm carriership., Case Presentation: A 27 year pregnant patient with intra uterine growth retardation presented with hypertension and pre-eclampsia. Magnetic resonance imaging revealed bilateral adrenal pheochromocytoma. She underwent laparoscopic adrenelectomy and a missense mutation (Gly93Ser) in exon 1 of the VHL gene on chromosome 3 (p25 - p26) was shown in the patient, her father and her daughter confirming the diagnosis of VHL., Conclusion: In almost all VHL families molecular genetic analysis of DNA will demonstrate an inherited mutation. Because of the involvement in several organs, periodic clinical evaluation should take place in a well coordinated, multidisciplinary setting. VHL disease can be classified into several subtypes. VHL type 2C patients present with pheochromocytomas without evidence of haemangioblastomas in the central nervous system and/or retina and a low risk of renal cell carcinoma. Therefore, in such families, periodic clinical screening can be focussed on pheochromocytomas.

Context: Medullary thyroid carcinoma (MTC) metastasizes early in its clinical course. No effective systemic therapy is available. Generally (somatic or germline), mutations in the rearranged during transfection gene are considered essential in the pathogenesis of MTC., Objective: We investigated imatinib, a tyrosine kinase inhibitor, as a potential treatment in patients with disseminated MTC., Design: A phase II study was initiated using 600 mg imatinib daily with a possible dose increase to 800 mg in case of progression. Standard Response Evaluation Criteria in Solid Tumors were used using computed tomography or magnetic resonance imaging every 2 months., Results: There were 15 patients with disseminated MTC treated for up to 12 months. No objective responses were observed. Four patients had stable disease over 24 months. Three patients stopped treatment due to toxic effects [fatigue (n = 2) and nausea (n = 1)]. In four cases the dose of imatinib was decreased because of toxicity [rash and malaise (n = 2) and laryngeal swelling (n = 2)]. Emergency tracheotomy was performed in two cases due to mucosal swelling of the larynx in patients with recurrent nerve palsy and a narrow vocal cleft. In nine patients with a history of a thyroidectomy, the dose of supplemental thyroid hormone was increased because of serious hypothyroidism., Conclusions: Imatinib therapy yielded no objective responses and induced considerable toxicity in patients with MTC. A minority of patients had stable disease. Patients with supplemented hypothyroidism or with recurrent nerve palsy are specifically at risk for serious adverse events and need special attention when treated with imatinib.

The current clinical diagnosis of Von Hippel-Lindau (VHL) disease demands at least one specific [corrected] VHL manifestation in a patient with familial VHL disease, or, in a [corrected] sporadic patient, at least two or more hemangioblastomas or a single hemangioblastoma in combination with a typical visceral lesion. To evaluate this definition, we studied the frequency of germline VHL mutation in three patients groups: (i) multi-organ involvement (classic VHL), (ii) limited VHL manifestations meeting criteria (non-classic VHL) and (iii) patients with VHL-associated tumors not meeting current diagnostic VHL criteria. In addition, we validated multiplex ligation-dependent probe amplification (MLPA) as a rapid and reliable quantitative method for the identification of germline VHL deletions. The frequency of germline VHL mutations was very high in classic VHL cases with multi-organ involvement (95%), lower in non-classic cases that meet current diagnostic criteria but have limited VHL manifestations or single-organ involvement (24%) and low (3.3%), but tangible in cases not meeting current diagnostic VHL criteria. The detection of germline VHL mutations in patients or families with limited VHL manifestations, or single-organ involvement is relevant for follow-up of probands and early identification of at-risk relatives.

Multiple endocrine neoplasia type 1 (MEN1) is a hereditary tumor syndrome characterized by tumors of the parathyroid glands, the pancreatic islets, the pituitary gland, the adrenal glands, as well as by neuroendocrine carcinoid tumors, often at a young age. Causal to the syndrome are germline mutations of the MEN1 tumor-suppressor gene. Identification of gene-mutation carriers has enabled presymptomatic diagnosis and treatment of MEN1-related lesions. The product of the MEN1 gene is the nuclear protein menin. Recent observations indicate several functions for menin in the regulation of transcription, serving either as a repressor or as an activator: menin interacts with the activator-protein-1-family transcription factor JunD, changing it from an oncoprotein into a tumor-suppressor protein, putatively by recruitment of histone deacetylase complexes; menin maintains transforming growth factor beta mediated signal transduction involved in parathyroid hormone and prolactin gene expression; and menin is an integral component of histone methyltransferase complexes. In this capacity menin is a regulator of expression of the cyclin-dependent-kinase inhibitors p18INK4C and p27Kip1; furthermore, menin serves as a co-activator of estrogen receptor mediated transcription, by recruiting methyltransferase activity to lysine 4 of histone 3 at the estrogen responsive TFF1(pS2) gene promoter. We propose that menin links transcription-factor function to histone-modification pathways and that this is crucial for MEN1 tumorigenesis. Understanding the molecular pathology of MEN1 tumorigenesis will lead to new therapeutic strategies.

The RET gene encodes a receptor tyrosine kinase that is expressed in neural crest-derived cell lineages. The RET receptor plays a crucial role in regulating cell proliferation, migration, differentiation, and survival through embryogenesis. Activating mutations in RET lead to the development of several inherited and noninherited diseases. Germline point mutations are found in the cancer syndromes multiple endocrine neoplasia (MEN) type 2, including MEN 2A and 2B, and familial medullary thyroid carcinoma. These syndromes are autosomal dominantly inherited. The identification of mutations associated with these syndromes has led to genetic testing to identify patients at risk for MEN 2 and familial medullary thyroid carcinoma and subsequent implementation of prophylactic thyroidectomy in mutation carriers. In addition, more than 10 somatic rearrangements of RET have been identified from papillary thyroid carcinomas. These mutations, as those found in MEN 2, induce oncogenic activation of the RET tyrosine kinase domain via different mechanisms, making RET an excellent candidate for the design of molecular targeted therapy. Recently, various kinds of therapeutic approaches, such as tyrosine kinase inhibition, gene therapy with dominant negative RET mutants, monoclonal antibodies against oncogene products, and nuclease-resistant aptamers that recognize and inhibit RET have been developed. The use of these strategies in preclinical models has provided evidence that RET is indeed a potential target for selective cancer therapy. However, a clinically useful therapeutic option for treating patients with RET-associated cancer is still not available.

Background: Neuroendocrine tumours frequently metastasize to the liver. Although generally slowly progressing, hepatic metastases are the major cause of carcinoid syndrome and ultimately lead to liver dysfunction, cardiac insufficiency and finally death., Methods: A literature review was performed to define the optimal treatment strategy and work-up in patients with neuroendocrine hepatic metastases. Based on this, an algorithm for the management of these patients was established., Results: Platelet serotonin and chromogranin A are useful biomarkers for detection and follow-up of neuroendocrine tumour. Helical computed tomography and somatostatin receptor scintigraphy are the most sensitive diagnostic modalities. Surgical debulking is an accepted approach for reducing hormonal symptoms and to establish better conditions for medical treatment, but is frequently impossible due to the extent of disease. A novel approach is the local ablation of tumour by thermal coagulation using therapies such as radiofrequency ablation (RFA) or laser induced thermotherapy (LITT). These techniques preserve normal liver tissue. There is a tendency to destroy metastases early in the course of disease, thereby postponing or eliminating the surgically untreatable stage. This can be combined with postoperative radioactive octreotide to eliminate small multiple metastases. In patients with extensive metastases who are not suitable for local destruction, systemic therapy by octreotide, 131I-MIBG treatment or targeted chemo- and radiotherapy should be attempted. A final option for selective patients is orthotopic liver transplantation., Conclusion: Treatment for patients with neuroendocrine hepatic metastases must be tailored for each individual patient. When local ablative therapies are used early in the course of the disease, the occurrence of carcinoid syndrome with end stage hepatic disease can be postponed or prevented.

The product of the multiple endocrine neoplasia type 1 (MEN1) tumor suppressor gene, menin, is an integral component of MLL1/MLL2 histone methyltransferase complexes specific for Lys4 of histone H3 (H3K4). We show that menin is a transcriptional coactivator of the nuclear receptors for estrogen and vitamin D. Activation of the endogenous estrogen-responsive TFF1 (pS2) gene results in promoter recruitment of menin and in elevated trimethylation of H3K4. Knockdown of menin reduces both activated TFF1 (pS2) transcription and H3K4 trimethylation. In addition, menin can directly interact with the estrogen receptor-alpha (ERalpha) in a hormone-dependent manner. The majority of disease-related MEN1 mutations prevent menin-ERalpha interaction. Importantly, ERalpha-interacting mutants are also defective in coactivator function. Our results indicate that menin is a critical link between recruitment of histone methyltransferase complexes and nuclear receptor-mediated transcription.

Diabetes mellitus is one of the most common metabolic diseases worldwide and its prevalence is rapidly increasing. Due to its chronic nature (diabetes mellitus can be treated but as yet not cured) and its serious complications, it is one of the most expensive diseases with regard to total health care costs per patient. The elevated blood glucose levels in diabetes mellitus are caused by a defect in production and/or secretion of the polypeptide hormone insulin, which normally promotes glucose-uptake in cells. Insulin is produced by the pancreatic 'beta-cells' in the 'islets of Langerhans', which lie distributed within the exocrine pancreatic tissue. In type 2 diabetes mellitus, the initial defect in the pathogenesis of the disease in most of the patients is believed to be 'insulin resistance'. Hyperglycemia (clinically overt diabetes mellitus) will not develop as long as the body is able to produce enough insulin to compensate for the reduced insulin action. When this compensation fails ('beta-cell failure') blood glucose levels will become too high. In this review, we discuss one of the mechanisms that have been implicated in the development of beta-cell failure, i.e. amyloid formation in the pancreatic islets. This islet amyloid is a characteristic histopathological feature of type 2 diabetes mellitus and both in vitro and in vivo studies have revealed that its formation causes death of islet beta-cells. Being a common pathogenic factor in an otherwise heterogeneous disease, islet amyloidosis is an attractive novel target for therapeutic intervention in type 2 diabetes mellitus.

Multiple endocrine neoplasia type 1 (MEN1) is an inherited syndrome that is characterised by the occurrence of tumours in the parathyroid glands, the endocrine pancreas, the pituitary gland and the adrenal glands and by neuroendocrine carcinoid tumours, often at a young age. The penetrance of MEN1 among gene carriers is reported to be high; 82-99% at age 50. We present a patient with a history of parathyroid adenomas also showing signs of acromegaly. He turned out to be a carrier of a MEN1 germ-line mutation in intron 3 (IVS3-6C > G). This germ-line mutation was also found in nine of his family members. However, none of these relatives have developed any MEN1-related lesion yet, although several are older than 60 years. To our knowledge, a MEN1 family with as few clinical features as this family has not been reported to date. Because MEN1 patients have an increased risk of developing acromegaly, insulin-like growth factor (IGF-I) levels are monitored periodically. We investigated whether IGF-I levels might serve as a presymptomatic marker for acromegaly; 9% (3/33) of MEN1 patients showed temporary IGF-I elevations. One patient (1/3) later developed clinical signs of acromegaly. Possibly, acromegaly in MEN1 is preceded by a transient preacromegalic state.

A germline mutation in the Von-Hippel Lindau (VHL) gene predisposes carriers to development of abundantly vascularised tumours in the retina, cerebellum, spine, kidney, adrenal gland and pancreas. Most VHL patients die from the consequences of cerebellar haemangioblastoma or renal cell carcinoma. The VHL gene is a tumour suppressor gene and is involved in angiogenesis by regulation of the activity of hypoxia-inducible factor 1-alpha (HIF1-alpha). Clinical diagnosis of VHL can be confirmed by molecular genetic analysis of the VHL gene, which is informative in virtually all VHL families. A patient with (suspicion for) VHL is an indication for genetic counselling and periodical examination.

Context: Approximately 10% of pheochromocytomas are malignant with a 5-yr survival rate of less than 40%. Promising results have been published on single high-dosage [131I]metaiodobenzylguanidine ([131I]MIBG) treatment for malignant pheochromocytoma. We present our experience with multiple intermediate-dosage [131I]MIBG therapy instead of single high-dosage therapy., Setting and Patients: The study took place at University Medical Centers and included two patients (one male, 36 yr of age, and one female, 43 yr of age) with widely spread metastatic pheochromocytoma and bad prognosis because of liver and lung metastases., Interventions: Instead of a single high dosage, these two patients were treated with multiple intermediate dosages of [131I]MIBG. The first patient received 37 GBq (1 Ci) [131I]MIBG in five sessions [7400 MBq (200 mCi) each; interval range, 2-11 months]; the second patient received 66.6 GBq (1.8 Ci) [131I]MIBG in 12 sessions [5550 MBq (150 mCi) each; interval range, 2-14 months]., Outcome Measures: We measured efficacy, toxicity, and survival., Results: Both patients had a complete symptomatic response and a partial tumor volume response. The first patient had a partial biochemical response, the second a complete biochemical response. In both cases, toxicity has been confined to nausea during treatment. Hematological toxicity was minimal, and both patients stayed euthyroid. The survival (so far) of these patients was 5 yr (clinical case 1) and 16 yr (clinical case 2) after initial diagnosis., Conclusions: Repeated intermediate-dosage [131I]MIBG treatment appears to be a reliable and well-tolerated radionuclide therapy and might be a useful adjunct in patients with malignant pheochromocytoma, providing longstanding palliation and prolonged survival.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominantly inherited disorder, characterised by the occurrence of tumours of the parathyroid glands, the pancreatic islets, the pituitary gland, the adrenal glands and neuroendocrine carcinoid tumours. Carcinoid tumours of the thymus and pancreatic-duodenal gastrinomas are the most harmful tumour types, since these tumours have malignant potential and curative treatment is difficult to achieve.MEN1 is caused by germline mutations of the MEN1 tumour suppressor gene. Mutation analysis enables mutation carriers to be identified. MEN1 patients and their family members, family members of mutation carriers and patients who are clinically suspected to be carriers of a MEN1 gene mutation are eligible for mutation analysis. MEN1-associated tumours can be detected and treated at an early stage through periodical clinical monitoring of mutation carriers.

Objectives: Currently, little is known about the prognostic significance of achieving successful ablation with the first dosage of I-131 in patients with differentiated thyroid cancer. This study aimed to assess the following: (i) whether successful or unsuccessful ablation at post-ablation follow-up has prognostic consequences; (ii) possible factors predicting success of ablation in a patient., Methods: In order to do this, we retrospectively studied 180 patients with a median follow-up of 55 months. Ablation was considered to be successful if 1 year after the initial dosage of I-131 patients fulfilled all of the following criteria: not dead from thyroid cancer, no additional therapy needed for any kind for thyroid cancer within the first year, undetectable thyroglobulin (Tg) levels under TSH stimulation, and negative I-131 scintigraphy. Tg levels at the time of ablation (P < 0.001), lymph node metastasis (P = 0.04) and distant metastasis (P < 0.001) have a significant influence on the success of ablation. P values were calculated by Mann-Whitney U test and Chi-square test, respectively., Results: Patients with successful ablation had a better prognosis than those with unsuccessful ablation: disease-free survival was 87% versus 49% after 10 years; additionally, thyroid-cancer related survival was 93% versus 78%., Conclusion: We conclude that the extent of the remaining normal or neoplastic thyroid tissue influences the outcome of ablation, and that successful ablation leads to a better prognosis. It seems that it is very important to achieve complete ablation as soon as possible in order to ensure the best possible prognosis for a patient.

Counselling of patients and closely related family members has to take a central place in management of hereditary diseases, like multiple endocrine neoplasia (MEN) syndromes including von Hippel-Lindau (VHL) disease. In the strategy of health care, preventive medicine such as periodic clinical examination of families at-risk needs a high priority, because in general it is assumed that continuity in attendance is cost-effective. Counselling has to be based on individual medical experience of the doctor, adjusted to common guidelines and the findings in the family. Information leaflets, appropriate outpatient departments and an extensive network of specialists will facilitate continuity in care. Flow diagrams involving practical guidelines for diagnosis, treatment and follow up need to be applicable and after adjustment, should be accepted generally. Specially trained paramedics for counselling are required as a network that will guarantee periodic clinical examination and secure optimal prevention. Such paramedics will coordinate nationwide multidisciplinary guidance, and organize preventive and emergency cure for these patients. They will be supervised by expert clinicians in the field, and collaborate with specialists for social and psychological issues, patient organizations and clinical genetic centres. All of these professionals are responsible together for providing patients with up to date clinical information (via newsletters, Internet, etc.). Recently, in the Netherlands, a project was initiated to guarantee continuity in care and study the delivery of care. In order to realize this plan, funding has to be provided in the current research programme. In a future system support has to be obtained on a continuous base, preferably by the government and health care insurers and supervised by the national institute for health care.

Unlabelled: Recombinant human thyroid-stimulating hormone (rhTSH) recently was introduced as a radioiodine administration adjunct that avoids levothyroxine (LT-4) withdrawal and resultant hypothyroidism. The pharmacokinetics of 131I after rhTSH administration are known to differ from those after LT-4 withdrawal but are largely nondelineated in the radioiodine therapy setting. We therefore sought to calculate the red marrow absorbed dose of high therapeutic activities of 131I given after rhTSH administration to patients with metastatic or inoperable locally recurrent differentiated thyroid cancer. We also sought to evaluate the clinical and laboratory effects of this therapy on the bone marrow., Methods: Fourteen consecutive patients received in total 17 131I treatments (7.4 GBq). Blood and urine samples were obtained at fixed intervals, and their activities were measured in a well counter. Based on blood activity, renal clearance of the activity, and residence times in red marrow and the remainder of the body, the red marrow absorbed dose was calculated using the MIRD schema. Additionally, we monitored for potential hematologic toxicity and compared platelet counts before and 3 mo after treatment., Results: The mean +/- SD absorbed dose per unit of administered (131)I in the red marrow was 0.16 +/- 0.07 mGy/MBq. The corresponding total red marrow absorbed dose was 1.15 +/- 0.52 Gy (range, 0.28-1.91 Gy). In none of the patients was hematologic toxicity observed. The mean +/- SD platelet count (n = 13 treatments) was 243 +/- 62 x 10(9)/L before treatment and 233 +/- 87 x 10(9)/L 3 mo later, a slight and statistically insignificant decrease. After rhTSH-aided administration of high activities of 131I, the bone marrow absorbed dose remained under 2 Gy, the level long considered the safety threshold for all radioiodine therapy., Conclusion: Our specific findings imply that when clinically warranted, rhTSH should allow an increase in the therapeutic radioiodine activity. Such an increase might improve efficacy while preserving safety and tolerability; this possibility should be assessed in further studies.

To investigate the usefulness of thyroglobulin mRNA (Tg-mRNA) detection in peripheral blood in the follow-up of papillary and follicular (differentiated) thyroid cancer, a literature study was performed. Both evidence for and evidence against the usefulness of Tg-mRNA detection were found. Also, evidence for the expression of Tg-mRNA in cells other than normal or neoplastic thyroid follicular cells was found. It is concluded that currently Tg-mRNA detection is not a useful tool in the follow-up of differentiated thyroid carcinoma, but that the concept of using RT-PCR measurements during follow-up still warrants further research.

Carcinoids are neuroendocrine tumours of the gut which may also be found in the bronchus, pancreatic islets and retroperitoneum. They probably arise from gastrointestinal or bronchopulmonary pluripotential stem cells. Carcinoid tumours derived from these cells are potentially malignant; the strength of the tendency for aggressive growth correlates with the site of origin, depth of local penetration and the size of the tumour. Carcinoids occur sporadically or result from specific hereditary tumour syndromes. Mutations and/or aberrant expression of specific genes induce and promote tumour growth. Clinical features include local symptoms due to angulation or obstruction and hepatomegaly due to liver metastases. The carcinoid syndrome commonly involves flushing, diarrhoea, bronchospasm and hypotension. Other distinct syndromes may be caused by tumour release of products that may also be used as biochemical markers in diagnosis and follow-up. Scanning using radiolabelled octreotide, an analogue of somatostatin, sensitively identifies occult primary and metastatic deposits. Localized carcinoid tumours should be resected. Some patients benefit from hepatic resection. Palliation of symptoms is best achieved with octreotide. Hepatic artery chemoembolization may produce long-acting palliation. Further genetic characterization of the different types and stages of carcinoid development as well as assessment of gene expression profiles may improve differential diagnosis, prognosis and treatment.

Objective: Islet amyloid polypeptide (IAPP)/amylin is produced by the pancreatic islet beta-cells, which also produce insulin. To study potential functions of IAPP, we have generated transgenic mice overexpressing human IAPP (hIAPP) in the beta-cells. These mice show a diabetic phenotype when challenged with an oral glucose load. In this study, we examined the islet cytoarchitecture in the hIAPP mice by examining islet cell distribution in the neonatal period, as well as 1, 3 and 6 months after birth., Results: Neonatal transgenic mice exhibited normal islet cell distribution with beta-cells constituting the central islet portion, whereas glucagon and somatostatin-producing cells constituted the peripheral zone. In contrast, in hIAPP transgenic mice at the age of 1 month, the glucagon-immunoreactive (IR) cells were dispersed throughout the islets. Furthermore, at the age of 3 and 6 months, the islet organisation was similarly severely disturbed as at 1 month. Expression of both endogenous mouse IAPP and transgenic hIAPP was clearly higher in 6-month-old mice as compared to newborns, as revealed by mRNA in situ hybridisation., Conclusions: Mice transgenic for hIAPP have islets with disrupted islet cytoarchitecture in the postnatal period, particularly affecting the distribution of glucagon-IR cells. This islet cellular phenotype of hIAPP transgenic mice is similar to that of other mouse models of experimental diabetes and might contribute to the impaired glucose homeostasis.

The development of recombinant human thyrotropin (rhTSH) has given clinicians new options for diagnostic follow-up and treatment of patients with differentiated thyroid cancer (DTC). This paper evaluates the tumour dosimetry and response following -iodine-131 treatment of metastatic thyroid cancer patients after rhTSH stimulation instead of classical hormone withdrawal-induced hypothyroidism. Nineteen consecutive (131)I treatments in 16 patients were performed after rhTSH stimulation. All patients had undergone a near-total thyroidectomy followed by an ablative dosage of (131)I. They all suffered from metastatic or recurrent disease showing tumoral (131)I uptake on previous post-treatment scintigraphy. Dosimetric calculations were performed using (131)I tumour uptake measurements from post-treatment (131)I scintigrams and tumour volume estimations from radiological images. Response was assessed by comparing pre-treatment serum thyroglobulin (Tg) level with the Tg level 3 months post treatment. In 18 out of 19 treatments, uptake of (131)I in metastatic or recurrent lesions was seen. The median tumour radiation dose was 26.3 Gy (range 1.3-368 Gy), and the median effective half-life was 2.7 days (range 0.5-6.5 days). Eleven of 19 treatments (10/16 patients) were evaluable for response after 3 months. (131)I therapy with rhTSH resulted in a biochemical partial response in 3/11 or 27% of treatments (two patients), biochemical stable disease in 2/11 or 18% of treatments and biochemical progressive disease in 6/11 or 55% of treatments. Our study showed that although tumour doses in DTC patients treated with (131)I after rhTSH were highly variable, 45% of treatments led to disease stabilisation or partial remission when using rhTSH in conjunction with (131)I therapy, without serious side-effects and with minimal impact on quality of life. RhTSH is therefore adequately satisfactory as an adjuvant tool in therapeutic settings and is especially suitable in advanced recurrent or metastatic DTC patients who may be intolerant to TSH stimulation by levothyroxine withdrawal.

Type 2 diabetes mellitus (DM2) is characterized metabolically by defects in both insulin secretion and insulin action, resulting in hyperglycemia. Histopathologically, DM2 is characterized by depositions of protein in the pancreatic islets. This 'islet amyloid' is present in >90% of patients with DM2, as well as in monkeys and cats with DM2. The pathogenesis of DM2 is heterogeneous and multifactorial, although insulin resistance seems to be the predominant initiating factor for development of the disease. In the longer term, an insulin secretion defect is also revealed (referred to as 'beta-cell failure'), resulting in clinically manifest diabetes. Recent data, particularly from transgenic mouse studies, indicate that islet amyloidosis is a diabetogenic factor, which is both consequence (of insulin resistance) and cause (of beta-cell failure) of DM2. Available transgenic mouse models with islet amyloid formation in vivo will provide the opportunity to assess the effectiveness of novel anti-amyloidogenic therapies, for which promising results are emerging.

Amyloid deposits are formed as a result of uncontrolled aggregation of (poly)peptides or proteins. Today several diseases are known, for example Alzheimer's disease, Creutzfeldt-Jakob disease, mad cow disease, in which amyloid formation is involved. Amyloid fibrils are large aggregates of beta-pleated sheets and here a general method is described to introduce molecular mutations in order to achieve disruption of beta-sheet formation. Eight backbone-modified amylin derivatives, an amyloidogenic peptide involved in maturity onset diabetes, were synthesized. Their beta-sheet forming properties were studied by IR spectroscopy and electron microscopy. Modification of a crucial amide NH by an alkyl chain led to a complete loss of the beta-sheet forming capacity of amylin. The resulting molecular mutated amylin derivative could be used to break the beta-sheet thus retarding beta-sheet formation of unmodified amylin. Moreover, it was found that the replacement of this amide bond by an ester moiety suppressed fibrillogenesis significantly. Introduction of N-alkylated amino acids and/or ester functionalities-leading to depsipeptides-into amyloidogenic peptides opens new avenues towards novel peptidic beta-sheet breakers for inhibition of beta-amyloid aggregation.

In this study, the ob/ob mouse model was used to investigate epidemiological evidence linking fish intake to relative reduction in incidence of Type 2 diabetes mellitus and glucose. We have investigated, in comparison to low and high fat diets, the effect of a fish oil diet on basal and stimulated plasma glucose and insulin levels in male and female ob/ob mice. Mice were fed for 12 months with a saturated fat diet containing 25% lard, with a low fat diet containing 5% soybean oil, with a polyunsaturated fat diet containing 25% safflower seed oil (n-6) or with polyunsaturated fat diet containing 23% fish oil (n-3). Total body weight increased to approximately 100 g at the end of the experiment, with the highest increase in the order of lard > safflower oil > fish oil > soybean oil diet. Intercurrent deaths were found especially in the fish oil diet group. Compared to the other diet groups, plasma insulin levels of the fish oil diet group were significantly increased 3 months after the start of the diet and remained higher for another 3 months. Thereafter, the level declined to those of the other diet groups. Glucose-tolerance tests at 3, 6, 8 and 10 months showed a tendency of more efficient tissue glucose uptake in the fish oil group compared to the other groups, which was in accordance with a higher plasma insulin levels. At 12 months, microscopy revealed an increased severity of hepatic brown pigment accumulation and extramedullary haematopoiesis in the spleen of mice fed with fish oil. We conclude that fish oil diet in ob/ob mice reduced the body weight gain and increased the glucose-induced insulin secretion. Fish oil diet also increased intercurrent mortality. However, a consistent course of death could not be established using morphological parameters.

A kindred was diagnosed with atypical MEN type 2B characterized by medullary thyroid cancer and mucosal neurilemmomas in multiple family members. Mutation analysis revealed a double RET germline mutation, Val804Met and Ser904Cys, in affected individuals. The clinical phenotype, the functional effect of the mutations, and the clinical implications of our findings are discussed.

This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.

The RET gene encodes a receptor tyrosine kinase involved in normal and neoplastic development of neural crest cell lineages. Activating RET mutations are present in patients with multiple endocrine neoplasia types 2A and 2B (MEN2A, 2B) and in familial medullary thyroid carcinoma (FMTC) patients, whereas inactivating RET mutations are found in patients with Hirschsprung (HSCR) disease. In particular for MEN2A and FMTC, the clinical management largely depends on the specific mutation found.