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Contains fulltext : 282350.pdf (Publisher’s version ) (Open Access), BACKGROUND: Clinical pathways are care plans established to describe essential steps in the care of patients with a specific clinical problem. They translate (inter)national guidelines into local applicable protocols and clinical practice. The purpose of this article is to establish a multidisciplinary integrated care pathway for specialists and allied health care professionals in caring for individuals with von Hippel-Lindau (VHL) disease. METHODS: Using a modified Delphi consensus-making process, a multidisciplinary panel from 5 Dutch University Medical Centers produced an integrated care pathway relating to the provision of care for patients with VHL by medical specialists, specialized nurses, and associated health care professionals. Patient representatives cocreated the pathway and contributed quality criteria from the patients' perspective. RESULTS: The panel agreed on recommendations for the optimal quality of care for individuals with a VHL gene mutation. These items were the starting point for the development of a patient care pathway. With international medical guidelines addressing the different VHL-related disorders, this article presents a patient care pathway as a flowchart that can be incorporated into VHL expertise clinics or nonacademic treatment clinics. CONCLUSIONS: Medical specialists (internists, urologists, neurosurgeons, ophthalmologists, geneticists, medical oncologists, neurologists, gastroenterologists, pediatricians, and ear-nose-throat specialists) together with specialized nurses play a vital role alongside health care professionals in providing care to people affected by VHL and their families. This article presents a set of consensus recommendations, supported by organ-specific guidelines, for the roles of these practitioners in order to provide optimal VHL care. This care pathway can form the basis for the development of comprehensive, integrated pathways for multiple neoplasia syndromes.

Item does not contain fulltext, CONTEXT: Nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs) are highly prevalent and constitute an important cause of mortality in patients with multiple endocrine neoplasia type 1 (MEN1). Still, the optimal age to initiate screening for pNETs is under debate. OBJECTIVE: The aim of this work is to assess the age of occurrence of clinically relevant NF-pNETs in young MEN1 patients. METHODS: Pancreatic imaging data of MEN1 patients were retrieved from the DutchMEN Study Group database. Interval-censored survival methods were used to describe age-related penetrance, compare survival curves, and develop a parametric model for estimating the risk of having clinically relevant NF-pNET at various ages. The primary objective was to assess age at occurrence of clinically relevant NF-pNET (size ≥ 20 mm or rapid growth); secondary objectives were the age at occurrence of NF-pNET of any size and pNET-associated metastasized disease. RESULTS: Five of 350 patients developed clinically relevant NF-pNETs before age 18 years, 2 of whom subsequently developed lymph node metastases. No differences in clinically relevant NF-pNET-free survival were found for sex, time frame, and type of MEN1 diagnosis or genotype. The estimated ages (median, 95% CI) at a 1%, 2.5%, and 5% risk of having developed a clinically relevant tumor are 9.5 (6.5-12.7), 13.5 (10.2-16.9), and 17.8 years (14.3-21.4), respectively. CONCLUSION: Analyses from this population-based cohort indicate that start of surveillance for NF-pNETs with pancreatic imaging at age 13 to 14 years is justified. The psychological and medical burden of screening at a young age should be considered.

Item does not contain fulltext, INTRODUCTION: Multiple endocrine neoplasia type 1 (MEN1)-related neuroendocrine tumors (NETs) of the lung are mostly indolent, with a good prognosis. Nevertheless, cases of aggressive lung NET do occur, and therefore the management of individual patients is challenging. AIM: To assess tumor growth and the survival of patients with MEN1-related lung NETs at long-term follow-up. METHODS: The population-based Dutch MEN1 Study Group database (n = 446) was used to identify lung NETs by histopathological and radiological examinations. Tumor diameter was assessed. Linear mixed models and the Kaplan-Meier method were used for analyzing tumor growth and survival. Molecular analyses were performed on a lung NET showing particularly aggressive behavior. RESULTS: In 102 patients (22.9% of the total MEN1 cohort), 164 lesions suspected of lung NETs were identified and followed for a median of 6.6 years. Tumor diameter increased 6.0% per year. The overall 15-year survival rate was 78.0% (95% confidence interval: 64.6-94.2%) without lung NET-related death. No prognostic factors for tumor growth or survival could be identified. A somatic c.3127A > G (p.Met1043Val) PIK3CA driver mutation was found in a case of rapid growing lung NET after 6 years of indolent disease, presumably explaining the sudden change in course. CONCLUSION: MEN1-related lung NETs are slow growing and have a good prognosis. No accurate risk factors for tumor growth could be identified. Lung NET screening should therefore be based on well-informed, shared decision-making, balancing between the low absolute risk of an aggressive tumor in individuals and the potential harms of frequent thoracic imaging.

Contains fulltext : 238612.pdf (Publisher’s version ) (Closed access), Nuclear medicine plays an increasingly important role in the management neuroendocrine neoplasms (NEN). Somatostatin analogue (SSA)-based positron emission tomography/computed tomography (PET/CT) and peptide receptor radionuclide therapy (PRRT) have been used in clinical trials and approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). European Association of Nuclear Medicine (EANM) Focus 3 performed a multidisciplinary Delphi process to deliver a balanced perspective on molecular imaging and radionuclide therapy in well-differentiated neuroendocrine tumours (NETs). NETs form in cells that interact with the nervous system or in glands that produce hormones. These cells, called neuroendocrine cells, can be found throughout the body, but NETs are most often found in the abdomen, especially in the gastrointestinal tract. These tumours may also be found in the lungs, pancreas and adrenal glands. In addition to being rare, NETs are also complex and may be difficult to diagnose. Most NETs are non-functioning; however, a minority present with symptoms related to hypersecretion of bioactive compounds. NETs often do not cause symptoms early in the disease process. When diagnosed, substantial number of patients are already found to have metastatic disease. Several societies' guidelines address Neuroendocrine neoplasms (NENs) management; however, many issues are still debated, due to both the difficulty in acquiring strong clinical evidence in a rare and heterogeneous disease and the different availability of diagnostic and therapeutic options across countries. EANM Focus 3 reached consensus on employing (68)gallium-labelled somatostatin analogue ([(68)Ga]Ga-DOTA-SSA)-based PET/CT with diagnostic CT or magnetic resonance imaging (MRI) for unknown primary NET detection, metastatic NET, NET staging/restaging, suspected extra-adrenal pheochromocytoma/paraganglioma and suspected paraganglioma. Consensus was reached on employing (18)fluorine

Contains fulltext : 220617.pdf (Publisher’s version ) (Closed access), CONTEXT: Multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant hereditary disease caused by the loss of function of the MEN1 gene, a tumor-suppressor gene that encodes the protein menin. It is characterized by the occurrence of primary hyperparathyroidism (pHPT), duodenopancreatic neuroendocrine tumors (dpNET), pituitary tumors (PIT), adrenal adenomas, and bronchopulmonary (bp-NET), thymic, and gastric neuroendocrine tumors. More insight into factors influencing the age-related penetrance of MEN1 manifestations could provide clues for more personalized screening programs. OBJECTIVE: To investigate whether genetic anticipation plays a role in the largest known MEN1 families in the Netherlands. METHODS: All Dutch MEN1 families with >/= 10 affected members in >/= 2 successive generations were identified. Age at detection of the different MEN1-related manifestations were compared among generations using regression analyses adjusted for competing risks. To correct for the beneficial effect of being under surveillance, manifestations occurring during surveillance were also separately compared. RESULTS: A total of 152 MEN1 patients from 10 families were included. A significantly decreased age at detection of pHPT, dpNET, PIT, and bp-NET was found in successive generations (P < 0.0001). Adjusted analyses led to the same results. CONCLUSIONS: These results suggest the presence of genetic anticipation. However, due to a risk of residual bias, the results must be interpreted with caution. After independent validation in other cohorts and further translational research investigating the molecular mechanisms explaining this phenomenon in MEN1, the results might add to future, more personalized, screening protocols and earlier screening for future generations of MEN1 patients.

Contains fulltext : 215696.pdf (publisher's version ) (Open Access), BACKGROUND AND OBJECTIVES: Gastrinomas are the most prevalent functioning neuroendocrine tumors (NET) in multiple endocrine neoplasia type 1 (MEN1). Guidelines suggest medical therapy in most patients, but surgery may be considered in a subgroup. Currently, factors to guide management are necessary. This population-based cohort study assessed prognostic factors of survival in patients with MEN1-related gastrinomas. METHODS: Patients with MEN1 having gastrinomas were identified in the Dutch MEN1 database from 1990 to 2014 based on fasting serum gastrin (FSG) levels and/or pathology. Predictors of overall survival were assessed using Cox regression. RESULTS: Sixty-three patients with gastrinoma (16% of the MEN1 population) were identified. Five- and 10-year overall survival rates were 83% and 65%, respectively. Prognostic factors associated with overall survival were initial FSG levels >/=20x upper limit of normal (ULN) (hazard ratio [HR], 6.2 [95% confidence interval, 1.7-23.0]), pancreatic NET >/=2 cm (HR 4.5; [1.5-13.1]), synchronous liver metastases (HR 8.9; [2.1-36.7]), gastroduodenoscopy suspicious for gastric NETs (HR 12.7; [1.4-115.6]), and multiple concurrent NETs (HR 5.9; [1.2-27.7]). CONCLUSION: Life expectancy of patients with MEN1 gastrinoma is reduced. FSG levels and pancreatic NETs >/=2 cm are prognostic factors. FSG levels might guide surveillance intensity, step-up to additional diagnostics, or provide arguments in selecting patients who might benefit from surgery.

Contains fulltext : 196376.pdf (Publisher’s version ) (Closed access), BACKGROUND: Subclinical hypothyroidism is associated with dyslipidemia and atherosclerosis. Whether these effects are in part mediated via direct effects of thyrotropin (TSH) on peripheral thyroid hormone (TH) metabolism and/or concentrations of serum lipids is not clear. OBJECTIVE: This study examined whether TSH has direct effects on peripheral TH metabolism and serum lipids. METHODS: Eighty-two patients with differentiated thyroid cancer were retrospectively analyzed. All patients had undergone total thyroidectomy and (131)I remnant ablation. During follow-up, two successive injections of recombinant human TSH (rhTSH) were administered to patients on a stable dose of levothyroxine. In all patients, TSH, thyroxine (T4), free T4 (fT4), triiodothyronine (T3), reverse T3 (rT3), total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, apolipoprotein B, lipoprotein(a), and triglyceride levels were measured immediately before the first and approximately 72 hours after the second injection of rhTSH. RESULTS: After rhTSH stimulation, T3 values decreased (from 1.91 to 1.81 nmol/L; p < 0.001). T4, fT4, and rT3 did not change. After rhTSH, median apolipoprotein B increased from 0.90 to 0.92 g/L (p = 0.03), lipoprotein(a) from 0.21 to 0.24 g/L (p < 0.001), and triglycerides from 1.98 to 2.50 mmol/L (p < 0.001). Serum high-density lipoprotein cholesterol decreased from 0.98 to 0.81 mmol/L (p < 0.001). Multiple regression analysis showed that the changes in lipids were most closely associated with the decrease in T3 levels. CONCLUSIONS: TSH has direct effects on peripheral TH metabolism by decreasing T3 levels in levothyroxine-treated thyroidectomized patients. This decrease in T3 levels is accompanied by unfavorable changes in serum lipids.

Item does not contain fulltext, OBJECTIVE: To assess if surgery for Multiple Endocrine Neoplasia type 1 (MEN1) related nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs) is effective for improving overall survival and preventing liver metastasis. BACKGROUND: MEN1 leads to multiple early-onset NF-pNETs. The evidence base for guiding the difficult decision who and when to operate is meager. METHODS: MEN1 patients diagnosed with NF-pNETs between 1990 and 2014 were selected from the DutchMEN1 Study Group database, including > 90% of the Dutch MEN1 population. The effect of surgery was estimated using time-dependent Cox analysis with propensity score restriction and adjustment. RESULTS: Of the 152 patients, 53 underwent surgery and 99 were managed by watchful waiting. In the surgery group, tumors were larger and faster-growing, patients were younger, more often male, and were more often treated in centers that operated more frequently. Surgery for NF-pNETs was not associated with a significantly lower risk of liver metastases or death, [adjusted hazard ratio (HR) = 0.73 (0.25-2.11)]. Adjusted HR's after stratification by tumor size were: NF-pNETs <2 cm = 2.04 (0.31-13.59) and NF-pNETs 2-3 cm = 1.38 (0.09-20.31). Five out of the 6 patients with NF-pNETs >3 cm managed by watchful waiting developed liver metastases or died compared with 6 out of the 16 patients who underwent surgery. CONCLUSIONS: MEN1 patients with NF-pNETs <2 cm can be managed by watchful waiting, hereby avoiding major surgery without loss of oncological safety. The beneficial effect of a surgery in NF-pNETs 2 to 3 cm requires further research. In patients with NF-pNETs >3 cm, watchful waiting seems not advisable.

Item does not contain fulltext, OBJECTIVE: Epigenetic changes contribute to pancreatic neuroendocrine tumor (PanNET) development. Hypermethylation of promoter DNA as a cause of tumor suppressor gene silencing is a well-established oncogenic mechanism that is potentially reversible and therefore an interesting therapeutic target. Multiple endocrine neoplasia type 1 (MEN1) is the most frequent cause of inherited PanNETs. The aim of this study was to determine promoter methylation profiles in MEN1-related PanNETs. DESIGN AND METHODS: Methylation-specific multiplex ligation-dependent probe amplification was used to assess promoter methylation of 56 tumor suppressor genes in MEN1-related (n = 61) and sporadic (n = 34) PanNETs. Differences in cumulative methylation index (CMI), individual methylation percentages and frequency of promoter hypermethylation between subgroups were analyzed. RESULTS: We found promoter methylation of a large number of potential tumor suppressor genes. CMI (median CMI: 912 vs 876, P = 0.207) was the same in MEN1-related and sporadic PanNETs. We found higher methylation percentages of CASP8 in MEN1-related PanNETs (median: 59% vs 16.5%, P = 0.002). In MEN1-related non-functioning PanNETs, the CMI was higher in larger PanNETs (>2 cm) (median: 969.5 vs 838.5; P = 0.021) and in PanNETs with liver metastases (median: 1036 vs 869; P = 0.013). Hypermethylation of MGMT2 was more frequent in non-functioning PanNETs compared to insulinomas (median: 44.7% vs 8.3%; P = 0.022). Hypermethylation of the Von Hippel-Lindau gene promoter was observed in one MEN1-related PanNET and was associated with loss of protein expression. CONCLUSION: Promoter hypermethylation is a frequent event in MEN1-related and sporadic PanNETs. Targeting DNA methylation could be of therapeutic value in MEN1 patients with advanced PanNETs.

Item does not contain fulltext, BACKGROUND: The prognostic value of WHO grade in pancreatic neuroendocrine tumors (PanNETs) in patients with Multiple Endocrine Neoplasia Type 1 (MEN1) is unknown. METHODS: We performed a cohort study using the Dutch National MEN1 database, which includes >90% of the Dutch MEN1 population with data collected between 1990 and 2014. Formalin-fixed paraffin embedded tissue blocks from the largest resected PanNET per patient were collected. MIB1 staining was performed and KI67 labeling index (LI) was determined by manual eye-counting under a microscope and by digital image analysis. Mitotic count was evaluated from hematoxylin & eosin stains. Association between WHO grade and (time until) development of liver metastases was calculated. RESULTS: Sixty-nine MEN1 patients who underwent pancreatic surgery were included. Ten patients (14%) developed liver metastases and all had PanNETs >/=3 cm. WHO G1, G2 and G3 PanNETs were seen in 83% (n = 57), 16% (n = 11) and 1% (n = 1) respectively. In non-functioning PanNETs >2 cm, liver metastases occurred in 80% of WHO G2 PanNETs (4/5) compared to 23% (5/22) in WHO G1 PanNETs (p = 0.03) when WHO grade was based on mitotic count only. This significant association was not seen for WHO grade based on Ki67 LI. After five years, liver metastases in non-functioning PanNETs were not seen in tumors

01 juni 2017, Item does not contain fulltext, OBJECTIVE: Duodenopancreatic neuroendocrine tumors (DP-NETs) develop in a majority of patients with multiple endocrine neoplasia type 1 (MEN1) and are the leading cause of death. Overall survival (OS) and prognostic factors for patients with liver metastases from DP-NETs are not known. METHODS: This was a cohort study using the Dutch National MEN1 database, which includes >90% of the Dutch MEN1 population treated between 1990 and 2014. OS was assessed with time to event analysis, and prognostic factors were evaluated. RESULTS: A total of 56% of the MEN1 patients (n = 220) were diagnosed with a DP-NET, of who 34 (15%) developed DP-NET liver metastases. Median age at liver metastases diagnosis was 53 years (range 31-74). Of those patients, 16 patients (47%) had died after a median follow-up of 4 years (range 0.3-12.3). OS at 2, 5, and 10 years were 91%, 65%, and 50%, respectively. A trend towards worse survival was seen in males compared to females (5-year OS 58% versus 75%, P = .07) and also in patients with multiple liver metastases compared to patients with solitary liver metastasis (59 versus 83%, P = .09). CONCLUSION: Despite the fairly indolent course of DP-NET liver metastases in MEN1 patients, half of the population was deceased after 10 years. Sex and tumor load at diagnosis of liver metastases are possible prognostic factors for worse survival. ABBREVIATIONS: DMSG = DutchMEN1 Study Group; D-NET = duodenal neuroendocrine tumor; DP-NET = duodenopancreatic neuroendocrine tumor; HPF = high-power field; Ki67 LI = Ki67 labeling index; MEN1 = multiple endocrine neoplasia type 1; NET = neuroendocrine tumor; OS = overall survival; P-NET = pancreatic neuroendocrine tumor; PPI = proton pump inhibitor; ULN = upper limit of normal; WHO = World Health Organization.

Item does not contain fulltext, Background: Pancreatic neuroendocrine tumors (pNETs) are highly prevalent in patients with multiple endocrine neoplasia type 1 (MEN1), and metastatic disease is an important cause of MEN1-related mortality. Especially small nonfunctional (NF) pNETs pose a challenge to the treating physician and more information is needed regarding their natural course. We assessed long-term natural history of small NF-pNETs and its modifiers in the Dutch MEN1 population. Patients and Methods: Retrospective longitudinal observational cohort study of patients with small (<2 cm) NF-pNETs from the Dutch national MEN1 database, which includes >90% of the Dutch MEN1 population. Modifiers of long-term natural course were analyzed using linear mixed-models analysis. Results: Growth rate of the 115 included small NF-pNETs from 99 patients was slow (0.4 mm/y; 95% confidence interval, 0.15 to 0.59). Seventy percent of the tumors was stable and a subgroup of 30% of the tumors was growing (1.6 mm/y; 95% confidence interval, 1.1 to 2.0). No differences in clinical characteristics were identified between growing and stable tumors. Within the subgroup of growing tumors, germline missense mutations were significantly associated with accelerated growth compared with nonsense and frameshift mutations. Conclusion: The majority of small NF-pNETs are stable at long-term follow-up, irrespective of the underlying MEN1 genotype. A subgroup of tumors is slowly growing but cannot be identified on clinical grounds. In this subgroup, tumors with missense mutations exhibited faster growth. Additional events appear necessary for pNETs to progress. Future studies should be aimed at identifying these molecular driving events, which could be used as potential biomarkers.

Item does not contain fulltext, OBJECTIVE: Identifying a germline mutation in the multiple endocrine neoplasia type 1 (MEN1) gene in an index case has consequences for a whole family. Eligible family members should be offered genetic counseling and MEN1 mutation testing. Subsequently, clinical screening of mutation carriers according to the guidelines should be initiated. We assessed whether there is a lag time from MEN1 diagnosis of the index case to MEN1 diagnosis of family members. In addition, we determined whether this lag time was associated with an increased morbidity and mortality risk. DESIGN: A cohort study was performed using the Dutch MEN1 database, including >90% of the Dutch MEN1 population >16 years of age (n = 393). RESULTS: Fifty-eight MEN1 families were identified, of whom 57 were index cases and 247 were non-index cases (n = 304). The median lag time in MEN1 diagnosis of family members was 3.5 (range, 0-30) years. At the time of MEN1 diagnosis, 30 (12.1%) non-index cases had a duodenopancreatic neuroendocrine tumor, of whom 20% had metastases with a mean lag time of 10.9 years, in comparison with 7.1 years without metastases. Twenty-five (10.1%) non-index cases had a pituitary tumor, of whom 80% had a microadenoma and 20% had a macroadenoma, with mean lag times of 7.2 and 10.6 years, respectively. Ninety-five (38.4%) non-index cases had a primary hyperparathyroidism with a mean lag time of 9.5 years in comparison with seven patients without a primary hyperparathyroidism with a mean lag time of 3 years (P = .005). Ten non-index cases died because of a MEN1-related cause that developed during or before the lag time. CONCLUSION: There is a clinically relevant delay in MEN1 diagnosis in families because of a lag time between the diagnosis of an index case and the rest of the family. More emphasis should be placed on the conduct of proper counseling and genetic testing in all eligible family members.

Item does not contain fulltext, BACKGROUND: Patients with von Hippel-Lindau (VHL) disease are prone to develop pancreatic neuroendocrine tumors (pNETs). However, the best imaging technique for early detection of pNETs in VHL is currently unknown. In a head-to-head comparison, we evaluated endoscopic ultrasound (EUS) and (11)C-5-hydroxytryptophan positron emission tomography ((11)C-5-HTP PET) compared with conventional screening techniques for early detection of pancreatic solid lesions in VHL patients. METHODS: We conducted a cross-sectional, prospective study in 22 patients at a tertiary care university medical center. Patients with VHL mutation or with one VHL manifestation and a mutation carrier as first-degree family member, with recent screening by abdominal computed tomography (CT) or magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS), were eligible. Patients underwent EUS by linear Pentax echoendoscope and Hitachi EUB-525, and (11)C-5-HTP PET. Patient-based and lesion-based positivity for pancreatic solid lesions were calculated for all imaging techniques with a composite reference standard. RESULTS: In 10 of the 22 patients, 20 pancreatic solid lesions were detected: 17 with EUS (P < 0.05 vs CT/MRI+ SRS), 3 with (11)C-5-HTP PET, 3 with SRS, 9 with CT/MRI, and 9 with CT/MRI + SRS. EUS evaluations showed solid lesions with a median size of 9.7 mm (range 2.9-55 mm) and most of them were homogeneous, hypoechoic, isoelastic, and hypervascular. Moreover, EUS detected multiple pancreatic cysts in 18 patients with a median of 4 cysts (range 1-30). CONCLUSIONS: EUS is superior to CT/MRI + SRS for detecting pancreatic solid lesions in VHL disease.(11)C-5-HTP PET has no value as a screening method in this setting. EUS performs well in early detection of pNETs, but its role in VHL surveillance is unclear.

Contains fulltext : 170909.pdf (publisher's version ) (Open Access), BACKGROUND: Multiple Endocrine Neoplasia type 1 (MEN1) is diagnosed when two out of the three primary MEN1-associated endocrine tumors occur in a patient. Up to 10-30 % of those patients have no mutation in the MEN1 gene. It is unclear if the phenotype and course of the disease of mutation-negative patients is comparable with mutation-positive patients and if these patients have true MEN1. The present study aims to describe and compare the clinical course of MEN1 mutation-negative patients with two out of the three main MEN1 manifestations and mutation-positive patients during long-term follow-up. METHODS: This is a cohort study performed using the Dutch MEN1 database, including > 90 % of the Dutch MEN1 population. RESULTS: A total of 293 (90.7 %) mutation-positive and 30 (9.3 %) mutation-negative MEN1 patients were included. Median age of developing the first main MEN1 manifestation was higher in mutation-negative patients (46 vs. 33 years) (P = 0.007). Mutation-negative patients did not develop a third main MEN1 manifestation in the course of follow-up compared to 48.3 % of mutation-positive patients (P < 0.001). Median survival in mutation-positive patients was estimated at 73.0 years (95 % CI, 69.5-76.5) compared to 87.0 years (95 % CI not available) in mutation-negative patients (P = 0.001). CONCLUSIONS: Mutation-positive and mutation-negative MEN1 patients have a different phenotype and clinical course. Mutation-negative patients develop MEN1 manifestations at higher age and have a life expectancy comparable with the general population. The apparent differences in clinical course suggest that MEN1 mutation-negative patients do not have true MEN1, but another MEN1-like syndrome or sporadic co-incidence of two neuro-endocrine tumors.

Item does not contain fulltext, CONTEXT: Guidelines advise lifelong radiological followup for asymptomatic pituitary adenomas (PITs) because of the risk for growth and subsequent visual field defects. In the context of multiple endocrine neoplasia type 1 (MEN1) an even more comprehensive screening is advised because PITs are presumed to manifest more aggressive behavior. We studied the long-term course of MEN1-related PITs, which may be used as a model for sporadically occurring PITs. OBJECTIVE: The aim of our study is to assess the results of systematic pre-symptomatic PIT screening and subsequent long-term followup of PITs with emphasis on nonfunctioning microadenomas diagnosed by screening. PATIENTS AND METHODS: A cohort study was performed using the Dutch national MEN1 database, including greater than 90% of the Dutch MEN1 population older than 16 years (n = 323). MAIN OUTCOME MEASURES: Screening results, natural course, and effects of treatment of PIT were assessed. RESULTS: PIT was diagnosed in 123 patients with MEN1 (38.1 %), of whom 66 were diagnosed by MEN1-related screening. Ninety-one percent of the nonfunctioning PIT detected during screening (n = 35), did not require intervention during followup (median, 6.0 y). Three microadenomas showed limited growth but did not progress toward macroadenomas. Both screening-detected and prevalent prolactinomas (n = 52) responded well to treatment with dopamine agonists. CONCLUSION: Systematic presymptomatic screening for PIT in patients with MEN1 predominantly results in detection of nonfunctioning microadenomas. Prolactinoma in patients with MEN1 responded well to medical treatment. Microadenomas grew only occasionally and after many years without clinical consequences. Frequent magnetic resonance imaging followup of nonfunctioning microadenomas in the context of MEN1 and sporadically occurring PITs therefore seems debatable.

Item does not contain fulltext, CONTEXT: An association between ABO blood type and the development of cancer, in particular, pancreatic cancer, has been reported in the literature. An association between blood type O and neuroendocrine tumors in multiple endocrine neoplasia type 1 (MEN1) patients was recently suggested. Therefore, blood type O was proposed as an additional factor to personalize screening criteria for neuroendocrine tumors in MEN1 patients. OBJECTIVE: The aim of this study was to assess the association between blood type O and the occurrence of neuroendocrine tumors in the national Dutch MEN1 cohort. DESIGN: This is a cohort study using the Dutch National MEN1 database, which includes more than 90% of the Dutch MEN1 population. Demographic and clinical data were analyzed by blood type. Chi-square tests and Fisher exact tests were used to determine the association between blood type O and occurrence of neuroendocrine tumors. A cumulative incidence analysis (Gray's test) was performed to assess the equality of cumulative incidence of neuroendocrine tumors in blood type groups, taking death into account as a competing risk. RESULTS: The ABO blood type of 200 of 322 MEN1 patients was known. Demographic and clinical characteristics were similar among blood type O and non-O type cohorts. The occurrence of neuroendocrine tumors of the lung, thymus, pancreas, and gastrointestinal tract was equally distributed across the blood type O and non-O type cohorts (Grays's test for equality; P = 0.72). Furthermore, we found no association between blood type O and the occurrence of metastatic disease or survival. CONCLUSIONS: An association between blood type O and the occurrence of neuroendocrine tumors in MEN1 patients was not confirmed. For this reason, the addition of the blood type to screening and surveillance practice seems not to be of additional value for identifying MEN1 patients at risk for the development of neuroendocrine tumors, metastatic disease, or a shortened survival.

Item does not contain fulltext, OBJECTIVE: Currently, little is known about the prevalence of thyroid tumors in multiple endocrine neoplasia type 1 (MEN1) patients and it is unclear whether tumorigenesis of these thyroid tumors is MEN1-related. The aim of the study was to assess the prevalence of thyroid incidentalomas in MEN1 patients compared with nonMEN1 patients and to verify whether thyroid tumorigenesis is MEN1-related. DESIGN: A cross-sectional study. METHODS: The study included two groups: patients with MEN1 and a matched non-MEN1 control group without known thyroid disease, who underwent an ultrasound of the neck for the localization of parathyroid adenoma. Ninety-five MEN1 patients underwent ultrasound of the neck and were matched on gender and age with non-MEN1 patients. The prevalence of thyroid incidentalomas described in the ultrasound report was scored. Multinodular goiters, solitary nodes, and cysts were scored as incidentalomas. Presence of nuclear menin expression was evaluated by menin immunostaining of the thyroid tumors. RESULTS: In the MEN1 group, 43 (45%) patients had a thyroid incidentaloma compared with 48 (51%) in the non-MEN1 group, of which 14 (15%) and 16 (17%), respectively, were solitary nodes. Menin was expressed in the nuclei of all evaluated thyroid tumors. CONCLUSIONS: MEN1 patients do not have a higher prevalence of thyroid incidentalomas compared with primary hyperparathyroidism patients without the diagnosis of MEN1. Menin was expressed in the thyroid tumors of MEN1 patients.

Item does not contain fulltext, BACKGROUND: In multiple endocrine neoplasia type 1 (MEN1), pancreatic neuroendocrine tumors (pNETs) are the leading MEN1-related cause of death. OBJECTIVE: To evaluate EUS and (11)C-5-hydroxytryptophan positron emission tomography ((11)C-5-HTP PET), compared with the recommended screening techniques in MEN1 patients for early detection of pNETs. DESIGN: Cross-sectional study. SETTING: Tertiary-care university medical center. PATIENTS: This study involved 41 patients with a proven MEN1 mutation or with one MEN1 manifestation and a mutation carrier as a first-degree family member, with recent screening by abdominal CT or magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS). INTERVENTIONS: EUS by using a linear Pentax echoendoscope and Hitachi EUB-525 and (11)C-5-HTP PET. MAIN OUTCOME MEASUREMENTS: Patient-based and lesion-based positivity for pNET was calculated for all imaging techniques. The McNemar test was used to compare the yield of the 4 imaging techniques. RESULTS: In 35 of 41 patients, 107 pancreatic lesions were detected in total. EUS detected 101 pancreatic lesions in 34 patients, (11)C-5-HTP PET detected 35 lesions in 19 patients, and CT/MRI + SRS detected 32 lesions in 18 patients (P < .001). (11)C-5-HTP PET performed similarly to CT/MRI + SRS and better compared with SRS only (13 lesions in 12 patients), both at a patient-based and lesion-based level (P < .05). LIMITATIONS: Single-center study. CONCLUSION: EUS is superior to CT/MRI + SRS for pancreatic lesion detection in patients with MEN1. In this setting, (11)C-5-HTP PET is not useful. We recommend EUS as the first-choice pancreas imaging technique in patients with MEN1. ( CLINICAL TRIAL REGISTRATION NUMBER: NTR1668.).

Item does not contain fulltext, OBJECTIVE: Pheochromocytomas and paragangliomas (PPGL) are relatively rare and mostly benign tumours. Approximately 10% of PPGL are malignant, as defined by the presence of metastases, i.e chromaffin tissue at a location that usually does not contain chromaffin cells. However, up to 35% of tumours in patients carrying an SDHB mutation appears to be malignant. Nowadays, no reliable marker allows to predict whether a PPGL is, or will become malignant. In addition, there are no curative treatments if metastases occur. The aim of the present study was to dentify genetic markers allowing to distinguish benign from malignant tumours. DESIGN AND METHOD: An mRNA expression array was performed on benign and malignant PPGL. The genes showing a different expression between the benign and malignant tumours were selected to be confirmed and validated by qRT-PCR. Finally, the remaining genes were stained by immunohistochemistry on Tissue MicroArray including a large series of PPGL. RESULTS: Forty benign and 12 malignant PPGL were investigated for differences in mRNA expression with Affymetrix arrays. Expression data were normalized according to Affymetrix recommendations. Then, using Pomelo II (http://pomelo2.bioinfo.cnio.es/), a Limma t-test was performed, to assess which genes were differentially expressed between benign and malignant PPGL. First, a non-clustered analysis was performed and 10 genes with a False Discovery Rate (FDR) below 0.05 and a relative overexpression ratio of at least 4 were found, including Interleukin 13 Receptor alpha 2 (IL13RA2) and Monooxygenase DBH-like 1 (MOXD1). Secondly, a supervised cluster analysis was performed (based on HIF target genes), resulting in 2 groups, which were both investigated for differences in mRNA expression between benign and malignant tumours. Five genes showed an FDR below 0.01 and were overexpressed in malignant tumours with a ratio higher than 4, including Contactin 4 (CNTN4), Iroquois Homeobox 3 (IRX3), and Sulfatase 2 (S

Item does not contain fulltext, CONTEXT: The natural course and survival of neuroendocrine tumors (NETs) of thymus (Th) and lung in multiple endocrine neoplasia type 1 (MEN1) patients are still unknown. OBJECTIVE: Our objective was to assess prevalence, tumor growth, and survival of Th and lung NETs in an unselected MEN1 population with long-term follow-up. DESIGN: This was an observational study. PATIENTS AND METHODS: A longitudinal study was performed using the Dutch national MEN1 database, including >90% of the Dutch MEN1 population >16 years of age. Patients under care of the Dutch University Medical Centers (1990-2011) (n = 323) were included. MAIN OUTCOME MEASURES: The prevalence and survival of Th and lung NETs were assessed. Linear mixed-models analysis was applied to assess tumor growth with age as a possible confounder and gender, genotype and baseline tumor size as possible effect modifiers. RESULTS: Th NETs occurred in 3.4% of patients, almost exclusively in males with a 10-year survival of 25% (95% confidence interval = 8%-80%). A thoracic computed tomography scan was available in 188 patients (58.2%). A lung NET was identified in 42 patients (13.0%) with a 10-year survival of 71.1% (95% confidence interval = 51%-100%). Tumor volume of lung NETs increased 17% per year (P < .001) (tumor doubling time 4.5 years). Tumor doubling time in males was 2.5 vs 5.5 years in females (P = .05). Lung NET growth was not associated with genotype or with baseline tumor size (<1 vs >/=1 cm). CONCLUSION: In MEN1 patients, Th NETs almost exclusively occurred in males and had a very low prevalence and a high mortality. Lung NETs occurred more often than previously thought, had an indolent course, and occurred equally in both sexes. Tumor growth in males was double compared with female patients.

Item does not contain fulltext, Hotspot mutations in the promoter of the telomerase reverse transcriptase (TERT) gene have been recently reported in human cancers and proposed as a novel mechanism of telomerase activation. To explore TERT promoter mutations in tumors originating from the adrenal gland and extra-adrenal paraganglia, a set of 253 tumors (38 adrenocortical carcinomas (ACCs), 127 pheochromocytomas (PCCs), 18 extra-adrenal paragangliomas (ea PGLs), 37 head and neck PGLs (HN PGLs), and 33 peripheral neuroblastic tumors) was selected along with 16 human neuroblastoma (NBL) and two ACC cell lines to assess TERT promoter mutations by the Sanger sequencing method. All mutations detected were confirmed by a SNaPshot assay. Additionally, 36 gastrointestinal stromal tumors (GISTs) were added to explore an association between TERT promoter mutations and SDH deficiency. TERT promoter mutations were found in seven out of 289 tumors and in three out of 18 human cell lines; four C228T mutations in 38 ACCs (10.5%), two C228T mutations in 18 ea PGLs (11.1%), one C250T mutation in 36 GISTs (2.8%), and three C228T mutations in 16 human NBL cell lines (18.75%). No mutation was detected in PCCs, HN PGLs, neuroblastic tumors as well as ACC cell lines. TERT promoter mutations preferentially occurred in a SDH-deficient setting (P=0.01) being present in three out of 47 (6.4%) SDH-deficient tumors vs zero out of 171 (0%) SDH-intact tumors. We conclude that TERT promoter mutations occur in ACCs and ea PGLs. In addition, preliminary evidence indicates a potential association with the acquisition of TERT promoter mutations in SDH-deficient tumors.

Item does not contain fulltext, BACKGROUND: Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and limited therapeutic options. Mitotane is considered the standard first-line therapy with only 30% of the patients showing objective tumour response. Defining predictive factors for response is therefore of clinical importance. The epidermal growth factor receptor (EGFR) has been implicated in the development of one-third of all malignancies. EGFR pathway members in ACC have been investigated, however, without available clinical data and relation to survival. METHODS: In this study, mutation status of EGFR and downstream signalling pathways was evaluated in 47 ACC patients on mitotane using direct sequencing, a TaqMan allele-specific assay and immunohistochemistry. Archival formalin-fixed paraffin-embedded tumour tissue was used for all analyses. Patient data were obtained anonymously, after coupling with the collected tumour tissue. RESULTS: One BRAF, two EGFR TK domain (c.2590G>A, p.864A>T) and 11 TP53, but no PIK3CA or KRAS, mutations were found. No relationship was found between mutation status, immunostaining and mitotane response or survival. CONCLUSION: In conclusion, our data suggest that the role of EGFR tyrosine kinase inhibitors in ACC is limited. Treatment with EGFR monoclonal antibodies on the other hand might be beneficial for a larger group of patients. The possible efficacy of this therapy in ACC should be evaluated in future trials.

1 december 2013, Item does not contain fulltext, Cushing's disease (CD) is associated with severely impaired quality of life (QoL). Moreover, the physiological cortisol diurnal rhythm (CDR) is disturbed in CD. QoL can improve after successful surgery, the primary treatment for CD. We evaluated the effects of medical treatment on QoL and CDR. In 17 patients, stepwise medical treatment was applied with the somatostatin analog pasireotide, the dopamine agonist cabergoline and the adrenal-blocking agent ketoconazole. After 80 days, 15/17 (88%) patients had reached normal urinary free cortisol excretion (UFC). Subsequently, patients continued medical therapy or underwent surgery. UFC, plasma and salivary CDR and QoL-related parameters (assessed using 5 questionnaires: Nottingham Health Profile, Hospital Anxiety and Depression Scale, Multidimensional Fatigue Index-20, RAND-36, CushingQoL) were measured. At baseline, 5/17 patients had preserved CDR. In 6/12 patients with disturbed baseline CDR, recovery was observed, but without any correlation with QoL. QoL was significantly impaired according to 18/20 subscales in CD patients compared to literature-derived controls. According to the RAND-36 questionnaire, patients reported more pain at day 80 (p < 0.05), which might reflect steroid-withdrawal. Generally, QoL did not improve or deteriorate after 80 days. CushingQoL scores seemed to improve after 1 year of remission in three patients that continued medical therapy (p = 0.11). CDR can recover during successful pituitary- and adrenal-targeted medical therapy. Patients with CD have impaired QoL compared to controls. Despite the occurrence of side-effects, QoL does not deteriorate after short-term biochemical remission induced by medical therapy, but might improve after sustained control of hypercortisolism.

Item does not contain fulltext, CONTEXT: The assessment of tumor markers for diagnosing pancreatic neuroendocrine tumors (pNET) in multiple endocrine neoplasia type 1 (MEN1) patients is advised in the current guidelines but has never been validated for this purpose. OBJECTIVE: The objective of the study was to assess the diagnostic accuracy of chromogranin A (CgA), pancreatic polypeptide (PP), and glucagon for pNET in MEN1. DESIGN: This was a diagnostic study. SETTING: The study was conducted at Dutch university medical centers from 2008 to 2011, representing 90% of the total Dutch MEN1 population. PATIENTS AND METHODS: Patients for whom data on tumor markers in combination with the reference standard (ie, radiological imaging) were available between 2008 and 2011 were included. The reference standard for the presence of pNET was pathology or detection on magnetic resonance imaging, computed tomography, or endoscopic ultrasound confirmed on subsequent imaging, irrespective of modality at follow-up. MAIN OUTCOME MEASURES: The area under the receiver-operating characteristic curve (AUC), positive predictive value, negative predictive value, positive likelihood ratio, negative likelihood ratio, sensitivity, and specificity were calculated for each marker. RESULTS: For the analysis of PP, CgA, and glucagon, 73, 81, and 94 patients were available, respectively. The AUC for CgA was 0.48 [95% confidence interval (CI) 0.35-0.61] with a sensitivity 0.33 and a specificity 0.73; the AUC for glucagon was 0.58 (95% CI 0.46-0.70) with a sensitivity 0.43 and a specificity 0.73; and the AUC for PP was 0.64 (95% CI 0.50-0.77) with a sensitivity 0.36 and a specificity 0.74. Age, imaging modality, tumor size, and number did not influence the outcomes. CONCLUSION: The diagnostic accuracy of the tumor markers CgA, PP, and glucagon for pNET in MEN1 is low.

Item does not contain fulltext, OBJECTIVE: Radioactive iodine (RAI) therapy in medullary thyroid carcinoma (MTC) is applied in some centers, based on the assumption that cross-irradiation from thyroid follicular cells may be beneficial. However, no systematic studies on the effect of RAI treatment in MTC have been performed. The aim of this study was to analyze the effect of RAI treatment on survival in MTC patients. DESIGN: Retrospective multicenter study in eight University Medical Centers in The Netherlands. METHODS: Two hundred and ninety three MTC patients without distant metastases who had undergone a total thyroidectomy were included between 1980 and 2007. Patients were stratified by clinical appearance, hereditary stage, screening status, and localization. All patients underwent regular surgical treatment with additional RAI treatment in 61 patients. Main outcome measures were disease-free survival (DFS) and disease-specific survival (DSS). Cure was defined as biochemical and radiological absence of disease. RESULTS: In multivariate analysis, stratification according to clinical appearance (P=0.72), hereditary stage (P=0.96), localization (P=0.69), and screening status (P=0.31) revealed no significant effects of RAI treatment on DFS. Multivariate analysis showed no significant difference in DSS for the two groups stratified according to clinical appearance (P=0.14). Owing to limited number of events, multivariate analysis was not possible for DSS in the other groups of stratification. CONCLUSIONS: Based on the results of the present analysis, we conclude that RAI has no place in the treatment of MTC.

Item does not contain fulltext, OBJECTIVE: We studied the reciprocal effect of pregnancy and von Hippel-Lindau (VHL) disease by analyzing the influence of pregnancy on VHL disease-related lesions and VHL disease on pregnancy outcome. METHODS: Medical charts and imaging reports from the VHL disease expertise centers in the Netherlands were used to retrospectively assess lesion progression score before and after pregnancy and to obtain data on pregnancy outcome and VHL disease-related lesions. The Friedman test was used for analysis (p

1 april 2012, Item does not contain fulltext, CONTEXT: Cushing's disease (CD) is accompanied by an increased risk of venous thromboembolism. Surgery is the primary treatment of CD. OBJECTIVE: The aim of the study was to compare hemostatic parameters between patients with CD and controls and to evaluate the effect of medical treatment of CD on hemostasis. DESIGN AND SETTING: During 80 d, stepwise medical treatment was applied with the somatostatin analog pasireotide, the dopamine agonist cabergoline, and ketoconazole, which suppresses adrenocortical steroidogenesis, at four university medical centers in The Netherlands. PATIENTS: Seventeen patients with de novo, residual, or recurrent CD were included. MAIN OUTCOME MEASURES: We measured urinary free cortisol and parameters of coagulation and fibrinolysis. RESULTS: Patients with CD had significantly higher body mass index (P < 0.001), shortened activated partial thromboplastin time (P < 0.01), and higher levels of fibrinogen, Factor VIII, and protein S activity (P < 0.05) compared to healthy control subjects. In addition, fibrinolytic capacity was impaired in patients with CD as reflected by prolonged clot lysis time (P < 0.001) and higher levels of plasminogen activator inhibitor type 1, thrombin-activatable fibrinolysis inhibitor, and alpha2-antiplasmin (P < 0.01). There were no statistically significant differences in von Willebrand factor:antigen, antithrombin, and protein C activity. After 80 d, 15 of 17 patients had normalized urinary free cortisol excretion. Despite biochemical remission, only slight decreases in antithrombin (P < 0.01) and thrombin-activatable fibrinolysis inhibitor (P < 0.05) levels were observed. Other parameters of coagulation and fibrinolysis did not change significantly. CONCLUSIONS: The hypercoagulable state in patients with CD, which is explained by both increased production of procoagulant factors and impaired fibrinolysis, is not reversible upon short-term biochemical remission after successful medical therapy. This may have impl

1 februari 2012, Item does not contain fulltext, CONTEXT: Two patients presented with Cushing's syndrome due to ectopic ACTH secretion. Initial localization studies included computed tomography, magnetic resonance imaging, and octreoscans ((111)In-pentreotide scintigraphy), which were negative in both patients. They were treated with the glucocorticoid receptor antagonist mifepristone, with improvement in their clinical symptoms. Follow-up octreoscans after, respectively, 6 and 12 months showed the unequivocal presence of a bronchial carcinoid in both patients. OBJECTIVE: The objective of the study was to correlate in vivo and in vitro findings in patients with ectopic ACTH-producing syndrome. METHODS: We determined the expression of somatostatin and dopamine receptors by immunohistochemistry (patients 1 and 2), quantitative PCR, and in vitro culturing of tumor cells (patient 1 only). IN VITRO RESULTS: Both tumors were strongly positive for somatostatin receptor type 2 (sst(2)) on immunohistochemistry, whereas one of the tumors (patient 1) was also dopamine receptor subtype 2 (D(2)) positive on both immunohistochemistry and quantitative PCR. Octreotide (a sst(2) preferring analog) and cabergoline (D(2) agonist) both decreased the ACTH levels in the cultured tumor cells of patient 1. CONCLUSION: We describe two patients with ACTH-producing bronchial carcinoids, in whom a direct down-regulatory effect of glucocorticoid levels on tumoral sst(2) receptor expression is suggested by a remarkable change in octreoscan status after successful mifepristone therapy. Further studies will have to demonstrate whether glucocorticoid lowering or antagonizing therapy may be used to improve the diagnostic accuracy of somatostatin receptor scintigraphy in patients with ectopic ACTH production of unknown primary origin.

Contains fulltext : 97999.pdf (publisher's version ) (Closed access), Context: Venous thrombosis has frequently been reported in patients with endogenous Cushing's syndrome (CS). Objective: The aim of this study was to evaluate the incidence of venous thromboembolism (VTE) in patients with CS prior to treatment and after surgery. Design and Setting: We conducted a multicenter cohort study at all university medical centers in The Netherlands. Patients: Consecutive patients diagnosed with endogenous CS of benign origin between January 1990 and June 2010 were eligible for inclusion. Patients surgically treated for nonfunctioning pituitary adenoma served as controls for the incidence of postoperative VTE in ACTH-dependent CS. Main Outcome Measures: We documented all objectively confirmed VTE during 3 yr prior to, and 3 yr after treatment onset. The incidences of VTE were expressed as incidence rates. Results: A total of 473 patients (mean age 42 yr, 363 women) were included (360 ACTH-dependent pituitary CS). The total number of person-years was 2526. Thirty-seven patients experienced VTE during the study period, resulting in an incidence rate of 14.6 [95% confidence interval (CI) 10.3-20.1] per 1000 person-years. The incidence rate for first-ever VTE prior to treatment was 12.9 (95% CI 7.5-12.6) per 1000 person-years (17 events). The risk of postoperative VTE, defined as risk within 3 months after surgery, was 0% for ACTH-independent and 3.4% (95% CI 2.0-5.9) for ACTH-dependent CS (12 events in 350 patients); most events occurred between 1 wk and 2 months after surgery. Compared with the controls, the risk of postoperative VTE in patients undergoing transsphenoidal surgery was significantly greater (P = 0.01). Conclusions: Patients with CS are at high risk of VTE, especially during active disease and after pituitary surgery. Guidelines on thromboprophylaxis are urgently needed.

Item does not contain fulltext, PURPOSE: To assess compliance with a periodic surveillance regimen for Von Hippel-Lindau disease. METHODS: In this nationwide study, Von Hippel-Lindau disease mutation carriers and those at 50% risk were invited to complete a questionnaire assessing (compliance with) advice given for periodic surveillance. Medical record data on compliance with recommended radiologic surveillance examinations were also collected. RESULTS: Of the 84 (77%) participants, 78 indicated having received advice to undergo periodic surveillance. Of these, 71 reported being fully compliant with that advice. In 64% of the cases, this advice was only partially consistent with published guidelines. Based on medical record data, between one quarter and one third of individuals did not undergo surveillance as recommended in the guidelines for central nervous system lesions and one half for visceral lesions. Screening delay for central nervous system lesions was significantly higher in one hospital and in those cases where "the advice given" deviated from the guidelines. CONCLUSIONS: The majority of those with or at risk of Von Hippel-Lindau disease reported having received and being fully compliant with screening advice. However, in many cases, the advice given was only partially consistent with published guidelines, and screening delays were observed. Efforts should be undertaken to stimulate guideline-based surveillance advice and to minimize screening delay.

Contains fulltext : 89845.pdf (publisher's version ) (Open Access)

Udgivelsesdato: 2008