Volumetric evaluation of CT images of adrenal glands in primary aldosteronism.

OBJECTIVES: To investigate whether adrenal volumetry provides better agreement with adrenal vein sampling (AVS) than conventional CT for subtyping PA. Furthermore, we evaluated whether the size of this contralateral adrenal was a prognostic factor for clinical outcome after unilateral adrenalectomy. METHODS: We retrospectively analyzed volumes of both adrenal glands of the 180 CT-scans (88/180 with unilateral and 92/180 with bilateral disease) of the patients with PA included in the SPARTACUS trial of which 85 also had undergone an AVS. In addition, we examined CT-scans of 20 healthy individuals to compare adrenal volumes with published normal values. RESULTS: Adrenal volume was higher for the left than the right adrenal (mean and SD: 6.49 ± 2.77 ml versus 5.25 ± 1.87 ml for the right adrenal; p < 0.001). Concordance between volumetry and AVS in subtyping was 58.8%, versus 51.8% between conventional CT results and AVS (p = NS). The volumes of the contralateral adrenals in the patients with unilateral disease (right 4.78 ± 1.37 ml; left 6.00 ± 2.73 ml) were higher than those of healthy controls reported in the literature (right 3.62 ± 1.23 ml p < 0.001; left 4.84 ± 1.67 ml p = 0.02). In a multivariable analysis the contralateral volume was not associated with biochemical or clinical success, nor with the defined daily doses of antihypertensive agents at 1 year follow-up. CONCLUSIONS: Volumetry of the adrenal glands is not superior to current assessment of adrenal size by CT for subtyping patients with PA. Furthermore, in patients with unilateral disease the size of the contralateral adrenal is enlarged but its size is not associated with outcome.

Expression of p27Kip1 and p18Ink4c in human multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors.

PURPOSE: Pancreatic neuroendocrine tumors are a major manifestation of multiple endocrine neoplasia type 1 (MEN1). This tumor syndrome is caused by germline mutations in MEN1, encoding menin. Insight into pathogenesis of these tumors might lead to new biomarkers and therapeutic targets for these patients. Several lines of evidence point towards a role for p27Kip1 and p18Ink4c in MEN1-related tumor development in animal models for MEN1, but their contribution to human MEN1-related pancreatic neuroendocrine tumor development is not known. METHODS: In this study, we characterized protein expression of p27Kip1 and p18Ink4c in human MEN1-related PanNETs by immunohistochemistry. From the nationwide DutchMEN1 Study Group database including > 90% of the Dutch MEN1 population, MEN1-patients, who underwent pancreatic surgery, were selected. A tissue micro-array was constructed with available paraffin tissue blocks, and PanNETs from 61 MEN1 patients were eligible for analysis. RESULTS: Expression of p27Kip1 was high in 57 (93%) PanNETs and 67% of the tumors showed low expression of p18Ink4c (67.3%). No association was found between expression of either p27Kip1 or p18Ink4c and clinic-pathological characteristics. CONCLUSIONS: These findings indicate that loss of p18Ink4c, but not p27Kip1, is a common event in the development of MEN1-related PanNETs. Restoration of p18Ink4c function through CDK4/6 inhibitors could be a therapeutic option for MEN1-related PanNETs.

Long-term effects of oxandrolone treatment in childhood on neurocognition, quality of life and social-emotional functioning in young adults with Turner syndrome.

Turner syndrome (TS) is the result of (partial) absence of one X-chromosome. Besides short stature, gonadal dysgenesis and other physical aspects, TS women have typical psychological features. Since psychological effects of androgen exposure in childhood probably are long-lasting, we explored long-term psychological functioning after oxandrolone (Ox) therapy during childhood in adults with TS in terms of neurocognition, quality of life and social-emotional functioning. During the initial study, girls were treated with growth hormone (GH) combined with placebo (Pl), Ox 0.03 mg/kg/day, or Ox 0.06 mg/kg/day from the age of eight, and estrogen from the age of twelve. Sixty-eight women participated in the current double-blinded follow-up study (mean age 24.0 years, mean time since stopping GH/Ox 8.7 years). We found no effects on neurocognition. Concerning quality of life women treated with Ox had higher anxiety levels (STAI 37.4 ± 8.4 vs 31.8 ± 5.0, p=0.002) and higher scores on the depression subscale of the SCL-90-R (25.7 ± 10.7 vs 20.5 ± 4.7, p=0.01). Regarding social-emotional functioning, emotion perception for fearful faces was lower in the Ox-treated patients, without effect on interpersonal behavior. Our exploratory study is the first to suggest that androgen treatment in adolescence possibly has long-term effects on adult quality of life and social-emotional functioning. However, differences are small and clinical implications of our results seem limited. Therefore we would not recommend against the use of Ox in light of psychological consequences.

Three-dimensional facial analysis in acromegaly: a novel tool to quantify craniofacial characteristics after long-term remission.

PURPOSE: The exact quantification of craniofacial characteristics in patients with acromegaly is important because it provides insight in the pathophysiology of the disease and offers a tool to evaluate the effects of treatment on tissue specific endpoints. However, until recently this was not feasible due to limitations of available cephalometric methods. The new technique of three-dimensional (3D) cephalometry enables the accurate quantification of facial anatomical characteristics of both soft tissue and bone. This is the first study that uses 3D cephalometry to analyze craniofacial disproportions in patients in long-term remission of acromegaly. METHODS: Sixteen patients in remission of acromegaly for over 24 months (50% male, mean age 56.0 ± 10.7 years, mean body mass index 29.3 ± 5.5 kg/m(2)) were compared to 16 matched control subjects. A 3D cone beam computed tomography scan and 3D stereophotograph of each individual were acquired and analyzed using 3D cephalometry. RESULTS: In addition to an accurate quantification of the classical craniofacial characteristics, 3D cephalometry, shows that many typical soft tissue deformities persist, even after long-term remission. Furthermore, we found that, compared to controls, the patients in remission of acromegaly have a wider face at the level of the zygoma and longer maxilla (p < 0.05). CONCLUSIONS: 3D cephalometry is an attractive novel imaging modality to accurately investigate craniofacial disproportions of both soft tissue and bony parts of the face in patients with acromegaly, which makes it a promising technique for future research purposes and clinical practice.

Persistent self-consciousness about facial appearance, measured with the Derriford appearance scale 59, in patients after long-term biochemical remission of acromegaly.

CONTEXT: Acromegaly is associated with impaired quality of life (QoL) and causes anatomical disproportions, which may contribute to the decreased QoL after successful treatment. The Derriford appearance scale 59 (DAS59) is a questionnaire measuring psychological distress and disruptions to everyday life associated with self-consciousness of appearance. OBJECTIVE: Investigate the psychological distress and dysfunction related to self-consciousness about appearance and its effect on QoL in patients in long-term remission of acromegaly. PATIENTS, DESIGN AND METHODS: Patients (>18 years old) treated for acromegaly at the Department of Endocrinology of the Radboud University Medical Center Nijmegen were invited to participate. A gender-, age- and body mass index matched control group was provided by the patients themselves. Participants were asked to complete the modified DAS59-, research and development 36- (RAND-36), acromegaly quality of life questionnaire (AcroQoL) and a sociodemographic questionnaire. Differences between patient- and control groups and correlations between questionnaire scores and clinical characteristics collected from medical records were analyzed. MAIN OUTCOME MEASURES: Questionnaire scores. RESULTS: Of the 120 respondents, 73 agreed to participate [all cured or under biochemical control, median remission time 10.5 years (range 2.3-43.6 years)]. Of these, 34 (46.6%) reported self-consciousness about their appearance. Twenty-nine of these patients (85.3%) pointed out their face to be a prominent source of self-consciousness. Fifty-seven matched control subjects were included as well. Significant correlations were found between the scores of the DAS59 and the AcroQoL, RAND-36 and VAS in patients. CONCLUSIONS: Even after long-term remission of acromegaly, a large number of patients are self-conscious about their appearance, leading to psychological distress and disruptions to everyday life and decreased QoL. Facial features were the most important source of self-consciousness. This stresses the importance of addressing self-consciousness of appearance and the need for additional support in this regard during follow-up in these patients.

Cortisol diurnal rhythm and quality of life after successful medical treatment of Cushing's disease.

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.

Association between thyroid function, thyroid autoimmunity, and state and trait factors of depression.

OBJECTIVE: The aim of this study was to investigate whether thyroid function and thyroid peroxidase antibodies (TPOAb) are associated with depression, when using both state and trait parameters of depression. METHOD: In 1125 participants of the Nijmegen Biomedical Study, thyroid-stimulating hormone (TSH), free thyroxine (FT4), and TPOAb were measured twice. The Beck Depression Inventory (BDI), a self-reported lifetime diagnosis of depression, and the neuroticism scale of the Eysenck Personality Questionnaire Revised Short Scale (EPQ-RSS) were used to evaluate the presence of state and trait features of depression. RESULTS: We found no association between TSH and FT4 levels and BDI score, current depression, lifetime diagnosis of depression, and EPQ-RSS neuroticism score. Subjects with TPOAb had higher EPQ-RSS neuroticism scores in comparison with subjects without TPOAb, mean score 4.1 vs. 3.2 (regression coefficient 0.70; 95% CI 0.1-1.3; P-value 0.02 after adjustment for confounders). The prevalence of a lifetime diagnosis of depression was higher in subjects with positive TPOAb in comparison with participants without TPOAb: 24.2% vs. 16.7% (relative risk 1.4; 95% CI 1.0-2.1; P-value 0.04 after adjustment for confounders). CONCLUSION: Thyroid peroxidase antibodies are positively associated with trait markers of depression. The presence of TPOAb may be a vulnerability marker for depression.

Effects of naproxen and sulphasalazine or methotrexate on hypothalamic-pituitary-adrenal axis activity in patients with rheumatoid arthritis.

OBJECTIVES: To study the effects of antirheumatic drugs on hypothalamic-pituitary-adrenal (HPA) axis activity in patients with rheumatoid arthritis (RA). METHODS: Twenty patients with recent-onset active RA were studied before antirheumatic treatment, after 2 weeks of naproxen, and after 5½ months of additional treatment with sulphasalazine or methotrexate. The results before treatment were compared with those obtained in 20 age and sex-matched healthy controls (HC). Activity of the HPA-axis was assessed under basal conditions and during insulin tolerance tests (ITT). The ex-vivo production of interleukin (IL)-1ß, tumour necrosis factor-α (TNF-α) and IL-6 in whole blood samples was measured with and without stimulation by LPS. RESULTS: At baseline, plasma ACTH and cortisol levels were not different between patients with RA and HC. The unstimulated production of IL-6 was significantly higher in RA patients than in HC. After 2 weeks of treatment with naproxen, urinary cortisol excretion decreased significantly (p=0.03), and the area under the curve for plasma cortisol during the ITT was significantly lower (p=0.015). The LPS stimulated production of IL-1ß was significantly lower compared with baseline. After 6 months, basal plasma, salivary and urinary cortisol levels, and plasma cortisol and ACTH levels during the ITT, were all unchanged in comparison to the pre-treatment period. The unstimulated ex-vivo production of IL-1ß was significantly lower than before treatment. CONCLUSIONS: Our results suggest that the non-steroidal anti-inflammatory drug naproxen suppresses the HPA-axis in the first weeks of treatment. After 6 months, this suppressive effect is no longer present, suggesting the existence of adaptive mechanisms.

The effect of treatment on quality of life in patients with acromegaly: a prospective study.

OBJECTIVE: Acromegaly has a negative influence on health-related quality of life (HRQoL). Previous studies provide limited information on the course of HRQoL during treatment. This study aims to assess the effect of treatment on the course of HRQoL at six predefined time points. DESIGN: This prospective study examines HRQoL in treatment-naive patients before and during the first 2.5 years of acromegaly treatment. METHODS: Therapy-naive acromegaly patients completed three validated questionnaires (RAND-36, AcroQoL, and the Appearance Self-Esteem (ASE)) at six predetermined time points before, during, and after treatment. Outcomes were correlated to IGF1 levels and disease control status. RESULTS: Twenty-seven acromegaly patients completed the questionnaires at all time points. After treatment, all patients had controlled acromegaly. Scores of RAND-36 domains General health, Vitality and Health change, and all AcroQoL dimensions (except for Relations) improved during treatment (P ≤ 0.003); the largest changes were detected during the first year. Gender influenced HRQoL scores, since AcroQoL scores significantly improved in males but not in females. Over time, IGF1 levels were negatively correlated with HRQoL. After 2.5 years of follow-up, HRQoL of controlled patients was still lower than in the general population. CONCLUSION: HRQoL of acromegaly patients was considerably reduced at diagnosis. Disease control was associated with an improvement of HRQoL scores. Males showed a more pronounced improvement than females. The largest changes were detected in the first year of treatment. However, HRQoL during and after treatment remained impaired in acromegaly patients, emphasizing the need of additional support.

Repeated transsphenoidal pituitary surgery (TS) via the endoscopic technique: a good therapeutic option for recurrent or persistent Cushing's disease (CD).

BACKGROUND: No data on results of repeated transsphenoidal surgery via the endoscopic technique for patients with persistent or recurrent Cushing's disease are available. DESIGN AND PATIENTS: We retrospectively evaluated the remission rates and complications of repeated transsphenoidal surgery via the endoscopic technique in 14 patients with persistent (N = 6) or recurrent (N = 8) Cushing's disease treated in our centre between 1999 and 2007. MAIN OUTCOMES: Remission was defined as the disappearance of symptoms of hypercortisolism with basal plasma cortisol level < or = 50 nmol/l 24-48 h after glucocorticoid withdrawal and/or suppression of plasma cortisol level < or = 50 nmol/l after 1 mg dexamethasone overnight within the first 3 months after transsphenoidal surgery. RESULTS: With repeated endoscopic transsphenoidal surgery a remission rate of 10/14 (71%) was achieved. No patient had a relapse during a median follow-up of 24 months. Cerebrospinal fluid leakage was the most frequent complication (6 patients) and 11 patients required hormonal substitution after surgery. The success of repeated transsphenoidal surgery could not be predicted by visualization of an adenoma on MRI before first or second surgery, histopathological confirmation of an ACTH secreting adenoma after first or second surgery, treatment with cortisol lowering agents before first or second surgery, the operation technique used during the first surgery, persistent vs. recurrent disease after the first surgery, age, gender and interval between the two surgeries. CONCLUSION: Repeated transsphenoidal surgery via the endoscopic technique is a good treatment option for selected patients with recurrent or persistent Cushing's disease following primary pituitary surgery.

Conditioning cortisol in humans: design and pilot study of a randomized controlled trial.

BACKGROUND: Conditioning of physiological responses can be achieved by repeatedly pairing a previously neutral conditioned stimulus with the administration of a pharmacologically salient unconditioned stimulus. This type of conditioning has been effective for specific immune and endocrine responses, but results with regard to conditioning of cortisol, a key stress-regulatory parameter, are currently unclear. This paper describes a pharmacological conditioning design, optimized for the examination of effects of cortisol conditioning under both basal conditions and in response to stress. METHODS: A double-blind randomized controlled conditioning paradigm aimed at conditioning of cortisol is conducted in 48 healthy female volunteers. During the acquisition phase, a gustatory stimulus (conditioned stimulus) is paired with hydrocortisone (100 mg, capsulated, unconditioned stimulus) three times before being administered together with placebo during three evocation sessions. To investigate possible effects of cortisol conditioning in response to stress, participants are exposed to the Trier Social Stress Test during the third evocation session. Primary outcome measure of this study is the mean area under the curve of salivary cortisol during the first two evocation sessions. As secondary outcomes, self-reported affect and stress as well as alpha-amylase are investigated. A pilot study was conducted to ensure that this design is feasible to be used in a larger study. DISCUSSION: This study design provides an innovative opportunity to examine the conditioning of cortisol under basal conditions and in response to stress. Also, the possible effect of cortisol conditioning on secondary outcomes of self-reported affect and alpha-amylase can be investigated. If cortisol could successfully be conditioned, this would be of conceptual relevance, showing that hypothalamic pituitary adrenal (HPA) axis regulation can be influenced by associative learning processes. Eventually, this could also have important clinical implications for understanding and treating stress-related disorders in which HPA axis dysregulation might play a role. TRIAL REGISTRATION: Nederlands Trial Register, NTR4651. Registered on 29 July 2014.

Metastases but not cardiovascular mortality reduces life expectancy following surgical resection of apparently benign pheochromocytoma.

The treatment of choice for non-metastatic pheochromocytoma is surgical resection. Its goals are to abolish catecholamine hypersecretion, normalize blood pressure, and prevent further tumor growth or progression to metastatic disease. Data on long-term mortality and morbidity after pheochromocytoma surgery are limited. We here report a retrospective study on the long-term outcome after surgery for apparently benign pheochromocytoma at the Radboud University Nijmegen Medical Centre. Data on clinical presentation, treatment, post-surgical blood pressure and recurrence, metastasis and death were collected of 69 consecutive patients (January 1966-December 2000; follow-up: until death or January 2006). Survival was compared with survival of a matched reference population. Two patients died of surgical complications. All ten patients with metastatic disease (including three diagnosed at first surgery) died. At follow-up, 40 patients were alive and recurrence free and three patients were lost to follow up. Two patients experienced a benign recurrence. Mean+/-s.d. follow-up was 10.2+/-7.5 (median 9, range 1-38) years. Kaplan-Meier estimates for 5- and 10-year survival since surgery were 85.8% (95% CI: 77.2-94.4%) and 74.2% (95% CI: 62.0-86.4%) for patients versus 95.5 and 89.4% in the reference population (P<0.05). Sixty-four percent of all patients with hypertension prior to surgery showed a significant decrease in blood pressure, but remained hypertensive after surgery. In conclusion, compared with the general population patients have a reduced life expectancy following pheochromocytoma surgery, due to their risk of developing metastatic disease. Only one-third becomes normotensive without antihypertensive medication. Therefore, lifelong follow-up is warranted.

Treatment of adrenocorticotropin-dependent Cushing's syndrome: a consensus statement.

OBJECTIVE: Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushing's syndrome, because there is no recent consensus on the management of this rare disorder. PARTICIPANTS: Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushing's syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushing's disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushing's disease, and 5) management of ectopic ACTH syndrome, Nelson's syndrome, and special patient populations. EVIDENCE: Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking. CONSENSUS PROCESS: Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority. CONCLUSIONS: ACTH-dependent Cushing's syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushing's syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushing's disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushing's syndrome, early diagnosis and prompt therapy are warranted.

Thyroid function disorders--Guidelines of the Netherlands Association of Internal Medicine.

Thyroid function disorders are common with a female to male ratio of 4 to 1. In adult women primary hypothyroidism and thyrotoxicosis have a prevalence of 3.5/1000 and 0.8/1000, respectively. This guideline is aimed at secondary care providers especially internists, but also contains relevant information for interested general practitioners and gynaecologists. A multidisciplinary working group, containing delegates of professional and patient organisations, prepared the guideline. According to principles of 'evidence-based medicine' available literature was studied and discussed. Considering the availability and quality of published studies a practical advice was formulated. For a full overview of the literature and considerations the reader is referred to the original version of the guideline (accessible through NIV-net). In this manuscript we have aimed to provide the practicing internist with practical and 'as evidence-based as possible' treatment guidelines with respect to thyroid function disorders.

Thyroid function in patients with proteinuria.

BACKGROUND: Patients with proteinuria may suffer from substantial losses of functional proteins such as hormones and hormone-binding proteins. A limited number of studies have reported urinary losses of thyroid hormones and thyroxin-binding globulin. Overt hypothyroidism attributable to these urinary losses has been described. However, the impact of proteinuria on thyroid function parameters has not been studied in a large patient cohort. METHODS: We evaluated thyroid function parameters in patients with proteinurea who are negative to thyroxine peroxidase antibodies (TPOAbs). Values of free thyroxin and thyroid-stimulating hormone (TSH) were compared with data from age- and gender-matched controls derived from the Nijmegen Biomedical Study, a population-based survey conducted in our hospital. RESULTS: We evaluated 159 patients. There were 111 males and 48 females. Median (IQR) age was 52 (40 to 62) years, serum creatinine concentration 99 (82 to 134) micromol/l, serum albumin concentration 29 (22 to 35) g/l, and proteinuria 6.6 (3.1 to 10.9) g/10 mmol creatinine. Median TSH was significantly higher in the patients than the controls (1.81 mU/l vs 1.34 mU/l, p.<0.001); however, overt hypothyroidism was observed in only one patient. CONCLUSION: Patients with proteinuria have higher TSH levels, consistent with urinary loss of thyroid hormones. However, these urinary losses do not result in overt, clinically relevant, hypothyroidism. The role of subclinical hypothyroidism in these patients needs further evaluation.

[Addisonian crisis in patients with known adrenal insufficiency: the importance of early intervention]. / Addison-crisis bij patiënten bekend wegens bijnierschorsinsufficiëntie: het belang van vroegtijdig ingrijpen.

In patients known to have adrenal insufficiency, inadequate adjustment of the glucocorticoid dosage during intercurrent illness can be life threatening. We describe two patients with adrenal insufficiency who died after their glucocorticoid dosage was insufficiently increased during an episode of gastroenteritis and pneumonia, respectively. Another patient died after a few days of fever and vomiting of unknown origin, after a period of refusing her medication. To prevent unnecessary death from Addisonian crisis, we have developed a protocol. Patients with known adrenal insufficiency, as well as their relatives and general practitioners, should repeatedly receive verbal and written instructions on how to deal with physical and severe psychic stress. We teach the patients and their relatives how to use an emergency injection of hydrocortisone, and the patients can consult the on-call endocrinologist by telephone 24 hours a day.

[Intraoperative parathyroid hormone measurement in patients with primary hyperparathyroidism; particularly valuable for suspected solitary parathyroid adenoma and re-operation]. / Intraoperatieve bepaling van parathormoon bij primaire hyperparathyreoïdie; vooral waardevol bij vermoeden van solitair bijschildklieradenoom en bij heroperatie.

OBJECTIVE: Analysis of the value of intraoperative parathormone (PTH) measurement in patients with primary hyperparathyroidism. DESIGN: Prospective study. METHOD: Evaluation of the value of intraoperative measurement ofPTH in 75 patients (including 19 patients with multiple endocrine neoplasia(MEN)-1 syndrome) who underwent parathyroidectomy in 2001-2005. RESULTS: The so-called Miami-criterion (PTH concentration 10 min after excision at least 50% below the value measured prior to the first incision) correctly predicted the success of the operation in 91% of the subjects. The success rate was correctly predicted as follows: in subgroups of patients with MEN-1 syndrome, 85%, patients after exclusion of MEN-1, 94%, and patients in whom a solitary adenoma was likely after preoperative localization studies, 97%. In 13% of the total number of operations, PTH-measurements led to further exploration, removal of additional parathyroid tissue and normocalcemia postoperatively. In patients without MEN-1 syndrome, in whom a solitary adenoma was likely on the basis of preoperative investigations, it was possible to limit the operation to a unilateral procedure in 87%. CONCLUSION: In the majority of patients with primary hyperparathyroidism, intraoperative PTH-measurement in combination with preoperative imaging studies leads to patients being cured with a unilateral instead of a bilateral operation.

DNA methylation profiling in MEN1-related pancreatic neuroendocrine tumors reveals a potential epigenetic target for treatment.

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.

DNA copy number status is a powerful predictor of poor survival in endocrine pancreatic tumor patients.

The clinical behavior of endocrine pancreatic tumors (EPTs) is difficult to predict in the absence of metastases or invasion to adjacent organs. Several markers have been indicated as potential predictors of metastatic disease, such as tumor size > or =2 cm, Ki67 proliferative index > or =2%, cytokeratin (CK) 19 status, and recently in insulinomas, chromosomal instability (CIN). The goal of this study was to evaluate the value of these markers, and in particular of the CIN, to predict tumor recurrence or progression and tumor-specific death, using a series of 47 insulinomas and 24 non-insulinoma EPTs. From these EPT cases, a genomic profile has been generated and follow-up data have been obtained. The proliferative index has been determined in 68 tumors and a CK19 expression pattern in 50 tumors. Results are statistically analyzed using Kaplan-Meier plots and the log-rank statistic. General CIN, as well as specific chromosomal alterations such as 3p and 6q loss and 12q gain, turned out to be the most powerful indicators for poor tumor-free survival (P< or =0.0004) and tumor-specific death (P< or =0.0113) in insulinomas. The CIN, chromosome 7q gain, and a proliferative index > or =2% were reliable in predicting a poor tumor-free survival in non-insulinoma EPTs (P< or =0.0181, whereas CK19 expression was the most optimal predictor of tumor-specific death in these tumors. In conclusion, DNA copy number status is the most sensitive and efficient marker of adverse clinical outcome in insulinomas and of potential interest in non-insulinoma EPTs. As a consequence, this marker should be considered as a prognosticator to improve clinical diagnosis, most practically as a simple multi-target test.