Design of the Growth hormone deficiency and Efficacy of Treatment (GET) score and non-interventional proof of concept study.

BACKGROUND: The adverse effects of growth hormone (GH) deficiency (GHD) in adults (AGHD) on metabolism and health-related quality of life (HRQoL) can be improved with GH substitution. This investigation aimed to design a score summarising the features of GHD and evaluate its ability to measure the effect of GH substitution in AGHD. METHODS: The Growth hormone deficiency and Efficacy of Treatment (GET) score (0-100 points) assessed (weighting): HRQoL (40%), disease-related days off work (10%), bone mineral density (20%), waist circumference (10%), low-density lipoprotein cholesterol (10%) and body fat mass (10%). A prospective, non-interventional, multicentre proof-of-concept study investigated whether the score could distinguish between untreated and GH-treated patients with AGHD. A 10-point difference in GET score during a 2-year study period was expected based on pre-existing knowledge of the effect of GH substitution in AGHD. RESULTS: Of 106 patients eligible for analysis, 22 were untreated GHD controls (9 females, mean ± SD age 52 ± 17 years; 13 males, 57 ± 13 years) and 84 were GH-treated (31 females, age 45 ± 13 years, GH dose 0.30 ± 0.16 mg/day; 53 males, age 49 ± 15 years, GH dose 0.25 ± 0.10 mg/day). Follow-up was 706 ± 258 days in females and 653 ± 242 days in males. The GET score differed between the untreated control and treated groups with a least squares mean difference of + 10.01 ± 4.01 (p = 0.0145). CONCLUSIONS: The GET score appeared to be a suitable integrative instrument to summarise the clinical features of GHD and measure the effects of GH substitution in adults. Exercise capacity and muscle strength/body muscle mass could be included in the GET score. TRIAL REGISTRATION: NCT number: NCT00934063 . Date of registration: 02 July 2009.

Endoscopic Ultrasound Features of Multiple Endocrine Neoplasia Type 1-Related versus Sporadic Pancreatic Neuroendocrine Tumors: A Single-Center Retrospective Study.

AIM: Pancreatic neuroendocrine tumors (pNETs) can occur in patients with a familial syndrome either as multiple endocrine neoplasia type 1 (MEN-1) or as sporadic tumors. Endoscopic ultrasound (EUS) has become one of the first-line investigations for pNET characterization. The ultrasonographic features of pNETs may differ depending on the familial versus sporadic pathogenesis of the tumor. Therefore, the EUS findings could help and direct the definition of a pNET with an impact on the most appropriate diagnostic and therapeutic patient management. METHODS: In this single-center retrospective study, we reviewed the EUS features of 94 pNETs from 37 MEN-1 patients and 15 pNETs from 11 sporadic disease patients at the time of their first EUS assessment. We analyzed the most relevant morphological and ultrasonographic characteristics of the tumors and compared the findings between the 2 patient groups. RESULTS: Patients with MEN-1 more likely present with multiple pNETs than patients with sporadic disease. Sporadic pNETs are usually much bigger than those due to MEN-1. Moreover, pNETs are more heterogeneous in patients with sporadic disease than in those with MEN-1. No statistical difference with regard to definition of the margins, morphology, and vascularization of the pNETs appears between the 2 groups. CONCLUSIONS: Patients with sporadic disease usually present with bigger and more heterogeneous pNETs than patients with MEN-1, who tend to present with a higher number of lesions. EUS can facilitate the precise characterization of a pNET, and the ultrasonographic features of the lesion can help and distinguish MEN-1-related versus sporadic disease.

Limited Value of Ga-68-DOTATOC-PET-CT in Routine Screening of Patients with Multiple Endocrine Neoplasia Type 1.

BACKGROUND: Routine screening is recommended for patients with multiple endocrine neoplasia type 1 (MEN1) to enable early detection and treatment of associated neuroendocrine neoplasms (NEN). Gallium68-DOTATOC-Positron emission tomography combined with computed tomography (Ga-68-DOTATOC-PET-CT) is a very sensitive and specific imaging technique for the detection of sporadic neuroendocrine tumors. The present study evaluated the value of Ga-68-DOTATOC-PET-CT in routine screening of patients with MEN1. METHODS: Between January 2014 and March 2016, all MEN1 patients underwent Ga-68-DOTATOC-PET-CT in addition to conventional imaging (computed tomography of the thorax, magnetic resonance imaging of the abdomen and pituitary, endoscopic ultrasonography). The diagnostic yield of conventional imaging and Ga-68-DOTATOC-PET-CT was prospectively documented and compared, and treatment changes caused by the addition of Ga-68-DOTATOC-PET-CT were recorded. RESULTS: Conventional imaging detected 145 NENs, mainly pancreaticoduodenal NENs (n = 117, 81%), in 31 of 33 MEN1 patients. Ga-68-DOTATOC-PET-CT detected 55 NENs in 23 of the 33 patients (p = 0.0001). Ninety (62%) NENs detected by conventional imaging were missed by DOTATOC-PET-CT. The majority of missed lesions were pNEN (n = 68; 74%). The sensitivity of Ga-68-DOTATOC-PET-CT for NENs <5, 5-9, 10-19 and ≥20 mm was 0, 29, 81 and 100%, respectively. However, Ga-68-DOTATOC-PET-CT detected more liver and lymph node metastases in patients with known metastatic disease, which did not lead to a change of patients' management. In one patient (3%), Ga-68-DOTATOC-PET-CT was the only imaging modality that detected a small intestine NEN and led to potentially curative surgery. CONCLUSION: Ga-68-DOTATOC-PET-CT cannot be recommended for routine screening of MEN1 patients. It might provide important additional information in patients with suspected or known metastatic disease.

Gender-, age- and time-dependent dosing of growth hormone in adults - real-world data from a decade of clinical practice in Germany.

We evaluated treatment patterns and gender-dependent dosing of growth hormone (GH) substitution in adults with GH deficiency (AGHD). Data on GH dose were collected (2003-2013) from 509 GH-treated patients (mean age: 48.9 years; 47% female) enroled in the observational German NordiWin study (NCT01543880). The impact of gender, age, treatment duration and calendar year on GH treatment patterns was evaluated by multiple regression analysis. Mean (SD) baseline GH dose (mg/day) was similar between females (0.25 [0.19] and males (0.24 [0.15]), but increased with treatment duration (at year 10, 0.55 [0.48] and 0.31 [0.09] in females and males, respectively), reflecting patient dose titration. GH dose increased more in females than males during treatment; this was statistically significant in years 2-6 (p < 0.05). Over the 10-year study period, a time trend of an overall estimated GH dose increase by 0.06 mg/day (females) and decrease by 0.07 mg/day (males) was shown; this interaction of gender and calendar year was significant (p < 0.0001). In both genders, overall GH dose decreased with increasing age (p < 0.0001). Our study confirms that females and younger patients require higher GH doses compared with males and older patients.

Partial pancreaticoduodenectomy can provide cure for duodenal gastrinoma associated with multiple endocrine neoplasia type 1.

OBJECTIVE: To evaluate the outcome of pancreaticoduodenectomy (PD) versus non-PD resections for the treatment of gastrinoma in multiple endocrine neoplasia type 1. BACKGROUND: Gastrinoma in MEN1 is considered a rarely curable disease and its management is highly controversial both for timing and extent of surgery. METHODS: Clinical characteristics, complications and outcomes of 27 prospectively collected MEN1 patients with biochemically proven gastrinoma, who underwent surgery, were analyzed with special regard to the gastrinoma type and the initial operative procedure. RESULTS: Twenty-two (81%) patients with gastrinoma in MEN1 had duodenal gastrinomas and 5 patients (19%) had pancreatic gastrinomas. At the time of diagnosis, 21 (77%) gastrinomas were malignant (18 duodenal, 3 pancreatic), but distant metastases were only present in 4 (15%) patients. Patients with pancreatic gastrinomas underwent either distal pancreatic resections or gastrinoma enucleation with lymphadenectomy, 2 patients also had synchronous resections of liver metastases. One of these patients was biochemically cured after a median of 136 (77-312) months. Thirteen patients with duodenal gastrinomas underwent PD resections (group 1, partial PD [n = 11], total PD [n = 2]), whereas 9 patients had no-PD resections (group 2) as initial operative procedure. Perioperative morbidity and mortality, including postoperative diabetes, differed not significantly between groups (P > 0.5). All patients of group 1 and 5 of 9 (55%) patients of group 2 had a negative secretin test at hospital discharge. However, after a median follow-up of 136 (3-276) months, 12 (92%) patients of group 1 were still normogastrinemic compared to only 3 of 9 (33%) patients of group 2 (P = 0.023). Three (33%) patients of group 2 had to undergo up to 3 reoperations for recurrent or metastatic disease compared to none of group 1. CONCLUSIONS: Duodenal gastrinoma in MEN1 should be considered a surgically curable disease. PD seems to be the adequate approach to this disease, providing a high cure rate and acceptable morbidity compared to non-PD resections.

Unimpaired postprandial pancreatic polypeptide secretion in Parkinson's disease and REM sleep behavior disorder.

BACKGROUND: Pancreatic polypeptide is released immediately after food ingestion. The release is operated by vagal-abdominal projections and has therefore been suggested as a test for vagal nerve integrity. Pathoanatomical and clinical studies indicate vagal dysfunction in early Parkinson's disease (PD). METHODS: We assessed the postprandial secretion of pancreatic polypeptide and motilin in healthy controls (n = 18) and patients with idiopathic rapid-eye-movement sleep behavior disorder (iRBD, n = 10), a potential premotor stage of PD, as well as in drug-naive (n = 19) and treated (n = 19) PD patients. RESULTS: The postprandial pancreatic polypeptide secretion showed a physiological pattern in all groups and even an enhanced response in drug-naive PD and iRBD. Motilin concentrations correlated with pancreatic polypeptide concentrations. CONCLUSIONS: Postprandial pancreatic polypeptide secretion is not a suitable test for vagal nerve integrity in PD. The unimpaired pancreatic polypeptide response in iRBD and PD might be explained by partially intact vagal-abdominal projections or compensatory mechanisms substituting a defective neuronal brain-gut axis.

Enucleation and limited pancreatic resection provide long-term cure for insulinoma in multiple endocrine neoplasia type 1.

AIM: To assess the characteristics and long-term outcome after surgery in patients with multiple endocrine neoplasia type 1 (MEN1)-associated insulinoma. METHODS: Retrospective analysis of prospectively collected data of MEN1 patients with organic hyperinsulinism at a tertiary referral center. RESULTS: Thirteen (17%) of 74 patients with MEN1 had organic hyperinsulinism. The median age at diagnosis was 27 (range 9-48) years. In 7 patients insulinoma was the first manifestation of the syndrome. All patients had at least one pancreatic neuroendocrine neoplasm (pNEN) upon imaging, including CT, MRI or endoscopic ultrasonography. Seven patients had solitary lesions upon imaging, 4 patients had one dominant tumor with coexisting multiple small pNENs, and 2 patients had multiple lesions without dominance. Eight patients had limited resections (1 segmental resection, 7 enucleations), 4 subtotal distal pancreatectomies, and 1 patient a partial duodenopancreatectomy. There was no postoperative mortality. Six patients experienced complications, including pancreatic fistula in 5 patients. Pathological examination revealed median three (range 1-14) macro-pNENs sized between 6 and 40 mm, and a total of 14 potentially benign insulinomas were detected in the 13 patients. After median follow-up of 156 months, only 1 patient developed recurrent hyperinsulinism after initial enucleation. Twelve patients developed new pNENs in the pancreatic remnant and 4 patients underwent reoperations (3 for metastatic ZES, 1 for recurrent hyperinsulinism). One of 5 patients with an initial extended pancreatic resection developed insulin-dependent diabetes mellitus. CONCLUSION: Enucleation and limited resection provide long-term cure for MEN1 insulinoma in patients with solitary or dominant tumors. Subtotal distal pancreatectomy should thus be preserved for patients with multiple pNENs without dominance given the risk of exocrine and endocrine pancreas insufficiency in the mostly young patients.

Relation between bone quality values from ultrasound transmission velocity and implant stability parameters--an ex vivo study.

AIM: The objective of this study was to determine the relationship between bone qualities measured by ultrasound transmission velocity (UTV) and primary implant stability parameters measured by radiofrequency analysis (RFA) and push-out test (POT) in an ex-vivo model. MATERIALS AND METHODS: Three blocks of fresh porcine bone samples were obtained from different anatomic regions, correlating to cortical, mixed and cancellous bone. Mechanical bone qualities of these samples were measured using UTV (expressed in m/s) prior to implantation. Three similar implants (4.1 × 11 mm, AstraTech OS) were inserted into each of the procured bone blocks. The evaluation of implant-bone interface stability was evaluated by RFA expressed as implant stability quotient (ISQ), and POT measured in Newton (N). RESULTS: For cortical, mixed and cancellous bone samples UTV values showed a mean of 2049.33, 1728.67 and 1427.67 m/s, respectively. For the implants inserted into cortical, mixed and cancellous bone samples the mean RFA (ISQ) values were 94.33, 81.33 and 63.11, whereas the POT values were >2000, 680 and 290 N, respectively. There was a strong correlation between UTV values and implant stability parameters that was shown descriptively by scatter box plots. CONCLUSION: The bone quality measurements obtained by UTV values significantly correlated to primary implant stability values measured by RFA and push-out test. Moreover, UTV was able to significantly differentiate between the different bone types. This suggested that UTV may be considered as a reasonable instrument to measure bone quality preoperatively and would help clinicians predict primary implant stability before implant insertion.

Outcome of surgery for primary hyperaldosteronism.

BACKGROUND: Primary hyperaldosteronism (PHA) frequently causes secondary hypertension and is a surgically amenable disease if associated with unilateral adenoma. Patients who underwent laparoscopic adrenalectomy at the authors' department were followed to identify clinical parameters that predict resolution of hypertension. METHODS: All patients with PHA and adrenalectomy from 1993 to 2009 were identified. Charts and follow-up data were reviewed for clinical parameters and hormone levels. Univariate and multivariate analysis were performed with SPSS 15.0. RESULTS: A cohort of 30 female and 24 male patients underwent laparoscopic adrenalectomy. Hypokalemia was observed in 47/54 (87%) patients. Twenty patients (37%) were cured without any further need of antihypertensive medication, 20 (37%) patients experienced an improvement in hypertension, and 14 (26%) patients remain unaffected. Consequently, hypertension was resolved or improved in 40/54 (74%) patients. A shorter duration of hypertension (<6 years), the number of antihypertensive drugs (<3), and the serum creatinine level (<1.3 mmol/l) were independent predictors of resolution of hypertension in a multivariate analysis. At final follow-up after a mean of 49 ± 40 months, resolution of hypertension was observed in 17/30 (57%) patients. Interestingly, in 10/17 patients a period longer than 12 months was required before a resolution of hypertension was observed. Coexistent hyperplasia, which was observed in 30% of patients, did not correlate with outcome. CONCLUSIONS: In 50% of patients with PHA, hypertension resolves after laparoscopic adrenalectomy, but the process may require more than 12 months. Patients with a duration of hypertension of more than 6 years, more than 3 antihypertensive drugs, and elevated serum creatinine have a higher risk of persistent hypertension after surgery. Coexistent hyperplasia in the resected adrenal gland is not associated with persistent hypertension.

Long-term results of surgery for pancreatic neuroendocrine neoplasms in patients with MEN1.

PURPOSE: This study was made to evaluate long-term results of an aggressive surgical approach for pancreaticoduodenal neuroendocrine neoplasms (pNENs) in patients with multiple endocrine neoplasia type 1 (MEN1). METHODS: MEN1 patients with either biochemical evidence of functioning or non-functioning pNENs larger than 1 cm in size on imaging underwent duodenopancreatic surgery. Since 1997, patients were followed annually by biochemical testing and imaging studies. RESULTS: Thirty-eight genetically confirmed MEN1 patients underwent duodenopancreatic resection for functioning (n = 22) or non-functioning (n = 16) pNENs, nine patients were yet not operated. Malignant disease occurred in 12 (35%) patients defined by either lymph node (12 patients) and/or distant metastases (2 patients). Six patients with Zollinger-Ellison syndrome (ZES) required pylorus-preserving pancreaticoduodenectomy (PPPD) as initial or redo procedure and 32 patients underwent other duodenopancreatic resections. Ten (26%) patients underwent up to four reoperations for either recurrent or metastatic disease that resulted in completion pancreatectomy in four patients. After median 109 months, 44 patients were alive and three patients died, one due to thymic carcinoid and two of unrelated causes. All eight patients with organic hyperinsulinism and 7 of 13 patients with ZES were biochemically cured. However, 24 of 38 (78%) patients developed new pNENs in the pancreatic remnant, but none developed distant metastases. CONCLUSIONS: Early resection of pNENs in MEN1 may prevent the development of distant metastases. However, the majority of patients develop new pNENs in the duodenopancreatic remnant which may require completion pancreatectomy in the long term.

The Effect of Obstructive Sleep Apnea and Continuous Positive Airway Pressure Therapy on Skeletal Muscle Lipid Content in Obese and Nonobese Men.

Obstructive sleep apnea (OSA), independently of obesity (OBS), predisposes to insulin resistance (IR) for largely unknown reasons. Because OSA-related intermittent hypoxia triggers lipolysis, overnight increases in circulating free fatty acids (FFAs) including palmitic acid (PA) may lead to ectopic intramuscular lipid accumulation potentially contributing to IR. Using 3-T-1H-magnetic resonance spectroscopy, we therefore compared intramyocellular and extramyocellular lipid (IMCL and EMCL) in the vastus lateralis muscle at approximately 7 am between 26 male patients with moderate-to-severe OSA (17 obese, 9 nonobese) and 23 healthy male controls (12 obese, 11 nonobese). Fiber type composition was evaluated by muscle biopsies. Moreover, we measured fasted FFAs including PA, glycated hemoglobin A1c, thigh subcutaneous fat volume (ScFAT, 1.5-T magnetic resonance tomography), and maximal oxygen uptake (VO2max). Fourteen patients were reassessed after continuous positive airway pressure (CPAP) therapy. Total FFAs and PA were significantly (by 178% and 166%) higher in OSA patients vs controls and correlated with the apnea-hypopnea index (AHI) (r ≥ 0.45, P < .01). Moreover, IMCL and EMCL were 55% (P < .05) and 40% (P < .05) higher in OSA patients, that is, 114% and 103% in nonobese, 24.4% and 8.4% in obese participants (with higher control levels). Overall, PA, FFAs (minus PA), and ScFAT significantly contributed to IMCL (multiple r = 0.568, P = .002). CPAP significantly decreased EMCL (-26%) and, by trend only, IMCL, total FFAs, and PA. Muscle fiber composition was unaffected by OSA or CPAP. Increases in IMCL and EMCL are detectable at approximately 7 am in OSA patients and are partly attributable to overnight FFA excesses and high ScFAT or body mass index. CPAP decreases FFAs and IMCL by trend but significantly reduces EMCL.

Screening of patients with multiple endocrine neoplasia type 1 (MEN-1): a critical analysis of its value.

BACKGROUND: Screening of multiple endocrine neoplasia type 1 (MEN-1) patients is widely recommended because one-fifth succumb to malignant neoplasms. However, recommendations for screening modalities and intervals are based mostly on nonprospective data. METHODS: Thirty-five of 48 MEN-1 patients were evaluated at least twice by an annual screening program in a single-center, prospective, nonrandomized study between 1997 and 2006. The screening program comprised anamnesis, clinical examination, imaging procedures, and extensive biochemical evaluations. Prospectively diagnosed lesions were evaluated separately from nonprospectively diagnosed lesions at first evaluation. RESULTS: The median age of the patients was 45 years (range = 15-70) at initial assessment. They were followed for a median of 72 months (range = 24-108) by a median of 6 (range = 2-10) evaluations. The vast majority of lesions were nonprospectively diagnosed at initial evaluation: 13 of 17 patients had primary hyperparathyroidism (pHPT), 24 of 29 had pancreatic endocrine tumors (PETs), and 4 of 4 had carcinoids. Vice versa adrenal lesions were mostly prospectively detected (18/23). Malignancy was observed in 10 patients (28%) in the initial assessment and without symptoms in 5 patients (9 PETs, 3 carcinoids). Endoscopic ultrasound (EUS) of 29 patients detected 88 PETs which were followed for 157 patient years. The mean annual growing rate was 13.28 +/- 28.23 mm with respect to the baseline tumor diameter of 9 mm. In 35 patients the mean incidence of newly diagnosed PETs was 0.52/year. Adrenal lesions were invariably nonfunctional. A mean change in diameter of 6.7 +/- 23.44% was monitored and malignant transformation was absent. CONCLUSIONS: Most lesions are detected at initial screening, particularly malignant tumors. Computed tomography of the abdomen and chest did not identify additional lesions. The interval between screenings could be extended to 3 years based on annually calculated growth rates and the incidence of MEN-1-associated lesions. The assessment of calcium, gastrin, and prolactin is sufficient for biochemical screening in MEN-1.

Surgical Management, Preoperative Tumor Localization, and Histopathology of 80 Patients Operated on for Insulinoma.

INTRODUCTION: Diagnosis and pathological classification of insulinomas are challenging. AIM: To characterize localization of tumors, surgery outcomes, and histopathology in patients with insulinoma. METHODS: Patients with surgically resected sporadic insulinoma were included. RESULTS: Eighty patients were included. Seven had a malignant tumor. A total of 312 diagnostic examinations were performed: endoscopic ultrasonography (EUS; n = 59; sensitivity, 70%), MRI (n = 33; sensitivity, 58%), CT (n = 55; sensitivity, 47%), transabdominal ultrasonography (US; n = 45; sensitivity, 40%), somatostatin receptor imaging (n = 17; sensitivity, 29%), 18F-fluorodeoxyglucose positron emission tomography/CT (n = 1; negative), percutaneous transhepatic venous sampling (n = 10; sensitivity, 90%), arterial stimulation venous sampling (n = 20; sensitivity, 65%), and intraoperative US (n = 72; sensitivity, 89%). Fourteen tumors could not be visualized. Invasive methods were used in 7 of these 14 patients and localized the tumor in all cases. Median tumor size was 15 mm (range, 7 to 80 mm). Tumors with malignant vs benign behavior showed less staining for insulin (3 of 7 vs 66 of 73; P = 0.015) and for proinsulin (3 of 6 vs 58 of 59; P < 0.001). Staining for glucagon was seen in 2 of 6 malignant tumors and in no benign tumors (P < 0.001). Forty-three insulinomas stained negative for somatostatin receptor subtype 2a. CONCLUSION: Localization of insulinomas requires many different diagnostic procedures. Most tumors can be localized by conventional imaging, including EUS. For nonvisible tumors, invasive methods may be a useful diagnostic tool. Malignant tumors showed reduced staining for insulin and proinsulin and increased staining for glucagon.

Clinical and Laboratory Evaluation of a New Specific Point-of-Care Test for Intact Proinsulin.

BACKGROUND: Intact proinsulin is a biomarker for pancreatic ß-cell dysfunction. In large prospective studies in nondiabetic subjects, elevated intact proinsulin predicted development of type 2 diabetes and/or macrovascular events up to 7 years in advance. This study was performed to evaluate a new semiquantitative lateral flow-based point-of-care rapid test (POCT) for elevated intact proinsulin (cutoff: 15 pmol/L). The test requires 10 µL of capillary whole blood, with visual readout after 5 minutes. It is best applied at 2 hours after a glucose challenge or a meal. METHODS: POCT results were obtained by health care professionals from 60 patients and healthy subject (33 female, 27 male, 28 type 2 diabetes, age: 53.6 ± 12.3 years). An additional venous blood sample was obtained from all participants for measurement of intact proinsulin by means of a quantitative ELISA reference method (TecoMedical, Sissach, Switzerland). RESULTS: Elevated intact proinsulin levels (>15 pmol/L) were determined by the reference method in 26 participants, of whom 22 were also positive with the POCT (sensitivity: 85%). All 34 subjects with low intact proinsulin levels were tested negative by the POCT (specificity: 100%). CONCLUSIONS: The test successfully detected elevated postprandial intact proinsulin levels in 85% of the tested subjects and no false positive test result occurred. This POCT can therefore serve as a simple screening tool for identification of patients with prevalent ß-cell dysfunction, who are at high risk for development of type 2 diabetes and/or macrovascular events within the next 5-7 years.

Healthcare utilization, quality of life and patient-reported outcomes during two years of GH replacement therapy in GH-deficient adults--comparison between Sweden, The Netherlands and Germany.

OBJECTIVE: This study set out to determine the change in quality of life (QoL) and healthcare utilization during 2 years of growth hormone (GH) replacement therapy in adults with GH deficiency. Data were compared from three European countries. DESIGN: Analysis was made from KIMS, the Pfizer International Metabolic Database on adult GH deficiency. METHODS: QoL and healthcare utilization were measured at baseline and after 1 and 2 years of GH replacement in patient cohorts from Sweden (n = 302), The Netherlands (n = 103) and Germany (n = 98). QoL was assessed by the QoL-Assessment in Growth Hormone Deficient Adults (QoL-AGHDA) questionnaire, and the KIMS Patient Life Situation Form was used to evaluate healthcare utilization. RESULTS: QoL improved significantly (P < 0.0001) and comparably in all three cohorts. The improvement was seen during the first year of treatment and QoL remained improved during the second year. The number of days in hospital was reduced by 83% (P < 0.0001) during GH replacement. There were no country-specific differences either at baseline or during follow-up. The same was true for the number of days of sick leave (reduction of 63%; P = 0.0004). Significant reductions were recorded in the number of doctor visits in each of the three cohorts after 2 years of GH replacement (P < 0.05). CONCLUSIONS: This study provides a detailed comparative analysis of GH replacement therapy in GHD patients in three European countries. Despite some differences in treatment strategies, the beneficial effects on QoL, patient-reported outcomes and healthcare utilization are essentially similar in the healthcare environment of Western European countries.

The switch from sulfonylurea to preprandial short- acting insulin analog substitution has an immediate and comprehensive beta-cell protective effect in patients with type 2 diabetes mellitus.

BACKGROUND: Supplementary insulin therapy provides assistance to meal-time insulin secretion in patients with type 2 diabetes and may have protective effects on beta-cell function. METHODS: This study explored the immediate effect of supplementary insulin therapy on beta- cell function in patients with glimepiride monotherapy (five women, 15 men; 61.8 +/- 6.4 years old; body mass index, 31.1 +/- 4.4 kg/m(2); hemoglobin A1c, 7.0 +/- 1.3%). After 1 week of continued glimiperide therapy, the patients were randomized either to continue with their oral treatment or to switch to a fixed-dose supplementary insulin therapy (8 U of insulin aspart subcutaneously before each meal) for another week. Oral glucose tolerance tests (OGTTs) after drug uptake were performed at days 7 and 14, with measurement of glucose, insulin, C-peptide, intact and total proinsulin, glucagon, lactate, free fatty acids, and adiponectin. RESULTS: Significant reductions from baseline were seen in the supplementary insulin therapy group for the fasting values of insulin (from 13.1 +/- 5.1 microU/mL to 10.6 +/- 5.2 microU/mL, P < 0.01), intact proinsulin (from 18.3 +/- 11.2 pmol/L to 10.3 +/- 4.6 pmol/L, P micro 0.05), total proinsulin (from 43.3 +/- 22.7 pmol/L to 29.7 +/- 14.5 pmol/L, P < 0.01), split proinsulin (from 24.9 +/- 13.8 pmol/L to 19.4 +/- 10.8 pmol/L, P micro 0.01), and the degree of beta-cell dysfunction (P < 0.05). Also, lower values for intact and total proinsulin and split proinsulin in the OGTT were observed in this group during the OGTT at the end point, while no changes at all occurred in the glimepiride group. CONCLUSIONS: A fixed low-dose preprandial insulin aspart therapy resulted in an overall beta-cell protection with an improved fasting beta-cell secretion profile already within 1 week. Our study indicates that supplementary insulin therapy might be a reasonable alternative to bedtime basal insulin injections for initiation of insulin therapy in patients with type 2 diabetes.

[Endosonography -- an additional diagnostic possibility in the differentiation between the two common types of primary hyperaldosteronism]. / Endosonographie -- eine zusätzliche diagnostische Möglichkeit bei der Differenzierung der beiden häufigsten Formen des primären Hyperaldosteronismus.

BACKGROUND: Primary aldosteronism is an important and one of the few potentially curable forms of secondary hypertension. The distinction between aldosterone-producing adenoma (APA) and idiopathic adrenal hyperplasia (IHA) may be difficult, but establishing the correct diagnosis is essential because surgery is only effective in patients with adrenal adenoma. CASE REPORT: The case of a 65-year-old man with long-term hypertension due to an APA is reported. The routine laboratory tests displayed an elevated plasma aldosterone/renin quotient as well as an elevated 24-h urinary excretion of aldosterone and its metabolites. The serum aldosterone concentration did not decrease normally in the saline suppression test. The posture testing demonstrated an increase in aldosterone. These facts might lead to the conclusion of an IHA. Magnetic resonance imaging (MRI) of the adrenal glands revealed no abnormalities. Because of the unusual combination of laboratory findings and radiologic results an endosonographic examination of the adrenal glands was performed which yielded a unilateral adrenal adenoma. With establishing this diagnosis, curative surgery became possible. CONCLUSION: This case demonstrates that in the differential diagnosis of primary aldosteronism, endosonography is more important than previously discussed. It may be helpful in the differentiation of an unusual constellation of laboratory and radiologic findings.

An unusual phenotype of MEN1 syndrome with a SI-NEN associated with a deletion of the MEN1 gene.

UNLABELLED: We report about a young female who developed an unusual and an aggressive phenotype of the MEN1 syndrome characterized by the development of a pHPT, malignant non-functioning pancreatic and duodenal neuroendocrine neoplasias, a pituitary adenoma, a non-functioning adrenal adenoma and also a malignant jejunal NET at the age of 37 years. Initial Sanger sequencing could not detect a germline mutation of the MEN1 gene, but next generation sequencing and MPLA revealed a deletion of the MEN1 gene ranging between 7.6 and 25.9 kb. Small intestine neuroendocrine neoplasias (SI-NENs) are currently not considered to be a part of the phenotype of the MEN1-syndrome. In our patient the SI-NENs were detected during follow-up imaging on Ga68-Dotatoc PET/CT and could be completely resected. Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients. Whether an aggressive phenotype or the occurrence of SI-NENs in MEN1 are more likely associated with large deletions of the gene warrants further investigation. LEARNING POINTS: Our patient presents an extraordinary course of disease.Although SI-NENs are extremely rare, these tumors should also be considered in MEN1 patients, besides the typical MEN1 associated tumors.This case reports indicate that in some cases conventional mutation analysis of MEN1 patients should be supplemented by the search for larger gene deletions with modern techniques, if no germline mutation could be identified by Sanger sequencing.

Applicability of recently established reference values for serum insulin-like growth factor 1: A comparison of two assays--an (automated) chemiluminescence immunoassay and an enzyme-linked immunosorbent assay.

Analysis and interpretation of insulin-like growth factor 1 in serum (IGF-1) is a principal diagnostic and follow-up tool in growth hormone-related disorders and is becoming of interest for many other disorders. Only for the automated chemiluminescence immunoassay Nichols Advantage have age- and sex-specific reference values based on a large population and valid for different laboratories been established. The aim of the present study was to compare two different assays (the automated chemiluminescence immunoassay and the enzyme-linked immunosorbent assay DSL-10-2800) in order to prove applicability of recently published reference values. The study included 95 serum samples from 88 patients, adults as well as children, with different or no endocrine disorders, and acromegalic as well as growth hormone-deficient patients. IGF-1 measurements were performed with both methods. The results have shown a very high correlation between the IGF-1 values obtained with the two assays (r=0.971, p<0.0001). In conclusion, the reference values established for the chemiluminescence assay are applicable also for the enzyme-linked immunosorbent assay.

Proposal of a clinical response score and predictors of clinical response to 2 years of GH replacement therapy in adult GH deficiency.

OBJECTIVE: There is no single clinical marker to reliably assess the clinical response to growth hormone replacement therapy (GHRT) in adults with growth hormone deficiency (GHD). The objective of this study was to propose a clinical response score to GHRT in adult GHD and to establish clinical factors that predict clinical response. DESIGN: This was a prospective observational cohort study from the international KIMS database (Pfizer International Metabolic Database). METHODS: We included 3612 adult patients with GHD for proposing the response score and 844 patients for assessing predictors of response. We propose a clinical response score based on changes in total cholesterol, waist circumference and QoL-AGHDA quality of life measurements after 2 years of GHRT. A score point was added for each quintile of change in each variable, resulting in a sum score ranging from 3 to 15. For clinical response at 2 years, we analysed predictors at baseline and after 6 months using logistic regression analyses. RESULTS: In a baseline prediction model, IGF1, QoL-AGHDA, total cholesterol and waist circumference predicted response, with worse baseline parameters being associated with a favourable response (AUC 0.736). In a combined baseline and 6-month prediction model, baseline QoL-AGHDA, total cholesterol and waist circumference, and 6-month change in waist circumference were significant predictors of response (AUC 0.815). CONCLUSIONS: A simple clinical response score might be helpful in evaluating the success of GHRT. The baseline prediction model may aid in the decision to initiate GHRT and the combined prediction model may be helpful in the decision to continue GHRT.