Center for Endocrine Tumors

Hamburg, Germany

Center for Endocrine Tumors

Hamburg, Germany
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PubMed | Novartis, Center for Endocrine Tumors, University of Sheffield, University of Naples Federico II and 3 more.
Type: Journal Article | Journal: Endocrine | Year: 2016

Measuring salivary cortisol is a simple, convenient and accurate technique with potential value in monitoring patients with hypercortisolism. This analysis reports changes in late-night salivary cortisol (LNSC) during a 12-month, multicentre, Phase III study of patients with Cushings disease who were randomized to pasireotide 600 or 900g sc bid. LNSC assessment was an exploratory objective based on a single, optional measurement at midnight1h on the same day as one of the 24-h urinary free cortisol (UFC) measurements. Of 162 enrolled patients, baseline LNSC was measured in 93. Sixty-seven patients had levels above the upper limit of normal (ULN); median baseline levels were 19.7 and 20.7nmol/L in the groups subsequently randomized to 600g (n=40) and 900g (n=27), respectively. Median LNSC levels decreased from baseline to month 12; median changes in patients who had baseline LNSC>ULN in the 600 and 900g groups were -13.4nmol/L (-52.6%; n=19) and -11.8nmol/L (-56.1%; n=14), respectively. LNSC normalized at months 6 and 12 in 25/67 (37.3%) and 13/67 (19.4%) patients, respectively; 10/25 and 8/13 patients also had normalized UFC, and 7/25 and 4/13 had partial UFC control (UFC>ULN and 50% decrease from baseline). There was a moderate correlation (r=0.55) on the log scale between individual patient LNSC and UFC values when all time points were pooled. Pasireotide decreased LNSC levels during 12months of treatment. Salivary cortisol may be a simple, convenient biomarker for assessing treatment response in patients with Cushings disease.

Caron P.J.,Center Hospitalier University Larrey | Bevan J.S.,Royal Infirmary | Petersenn S.,Center for Endocrine Tumors | Flanagan D.,Derriford Hospital | And 4 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2014

Context: Methodological shortcomings often compromise investigations into the effects of primary somatostatin-analog treatment on tumor size in acromegaly. There are also limited data for the long-acting lanreotide formulation. Objective: The aim of the study was to better characterize the effects of primary lanreotide Autogel treatment on tumor size in patients with GH-secreting macroadenomas. Design: PRIMARYS was a 48-week, multicenter, open-label, single-arm study. Setting: The study was conducted at specialist endocrine centers. Patients: Treatment-nave acromegalic patients with GH-secretingmacroadenomas participated in the study. Intervention: Lanreotide Autogel 120 mg was administered sc every 28 days (without dose titration). Outcome Measures: The primary endpoint was the proportion of patients with clinically significant (20%) tumor volume reduction (TVR) at week 48/last post-baseline value available using central assessments from three readers. The null hypothesis (H0 ) for the primary endpoint was that the proportion with TVRwas-55%. Secondary endpointsincluded: TVR at other time points, GH andIGF-1, acromegalic symptoms, quality of life (QoL), and safety. Results: Sixty-four of 90 (71.1%) patients completed the study. Clinically significant TVR at 48 weeks/last post-baseline value available was achieved by 62.9% (95% confidence interval, 52.0, 72.9) of 89 patients in the primary analysis (intention-to-treat population; H0 not rejected) and 71.9 -75.3% in sensitivity (n89) and secondary analyses (n63) (H0 rejected). At 12 weeks, 54.1% had clinically significant TVR. Early and sustained improvements also occurred in GH and IGF-1, acromegalic symptoms, and QoL. No patients withdrew due to gastrointestinal intolerance. Conclusions: Primary treatment with lanreotide Autogel, administered at 120 mg (highest available dose) without dose titration, in patients with GH-secreting macroadenomas provides early and sustained reductions in tumor volume, GH and IGF-1, and acromegalic symptoms, and improves QoL. Copyright © 2014 by the Endocrine Society.

Fleseriu M.,Oregon Health And Science University | Petersenn S.,Center for Endocrine Tumors
Pituitary | Year: 2012

Cushing's disease (CD) is caused by a corticotroph, adrenocorticotropic- hormone (ACTH)-secreting pituitary adenoma resulting in significant morbidity and mortality. Transsphenoidal surgery is the initial treatment of choice in almost all cases. Remission rates for microadenomas are good at 65-90 % (with an experienced neurosurgeon) but remission rates are much lower for macroadenomas. However, even after postoperative remission, recurrence rates are high and can be seen up to decades after an initial diagnosis. Repeat surgery or radiation can be useful in these cases, although both have clear limitations with respect to efficacy and/or side effects. Hence, there is a clear unmet need for an effective medical treatment. Currently, most drugs act by inhibiting steroidogenesis in the adrenal glands. Most is known about the effects of ketoconazole and metyrapone. While effective, access to ketoconazole and metyrapone is limited in many countries, experience with long-term use is limited, and side effects can be significant. Recent studies have suggested a role for a pituitary-directed therapy with new multireceptor ligand somatostatin analogs (e.g., pasireotide, recently approved in Europe for treatment of CD), second-generation dopamine agonists, or a combination of both. Mifepristone (a glucocorticoid receptor antagonist) is another promising drug, recently approved by the FDA for treatment of hyperglycemia associated with Cushing's syndrome. We review available medical treatments for CD with a focus on the two most recent compounds referenced above. Our aim is to expand awareness of current research, and the possibilities afforded by available medical treatments for this mesmerizing, but often frightful disease. © The Author(s) 2012.

Colao A.,University of Naples Federico II | Petersenn S.,Center for Endocrine Tumors | Petersenn S.,University of Duisburg - Essen | Newell-Price J.,University of Sheffield | And 7 more authors.
New England Journal of Medicine | Year: 2012

BACKGROUND: Cushing's disease is associated with high morbidity and mortality. Pasireotide, a potential therapy, has a unique, broad somatostatin-receptor-binding profile, with high binding affinity for somatostatin-receptor subtype 5. METHODS: In this double-blind, phase 3 study, we randomly assigned 162 adults with Cushing's disease and a urinary free cortisol level of at least 1.5 times the upper limit of the normal range to receive subcutaneous pasireotide at a dose of 600 μg (82 patients) or 900 μg (80 patients) twice daily. Patients with urinary free cortisol not exceeding 2 times the upper limit of the normal range and not exceeding the baseline level at month 3 continued to receive their randomly assigned dose; all others received an additional 300 μg twice daily. The primary end point was a urinary free cortisol level at or below the upper limit of the normal range at month 6 without an increased dose. Open-label treatment continued through month 12. RESULTS: Twelve of the 82 patients in the 600-μg group and 21 of the 80 patients in the 900-μg group met the primary end point. The median urinary free cortisol level decreased by approximately 50% by month 2 and remained stable in both groups. A normal urinary free cortisol level was achieved more frequently in patients with baseline levels not exceeding 5 times the upper limit of the normal range than in patients with higher baseline levels. Serum and salivary cortisol and plasma corticotropin levels decreased, and clinical signs and symptoms of Cushing's disease diminished. Pasireotide was associated with hyperglycemia-related adverse events in 118 of 162 patients; other adverse events were similar to those associated with other somatostatin analogues. Despite declines in cortisol levels, blood glucose and glycated hemoglobin levels increased soon after treatment initiation and then stabilized; treatment with a glucose-lowering medication was initiated in 74 of 162 patients. CONCLUSIONS: The significant decrease in cortisol levels in patients with Cushing's disease who received pasireotide supports its potential use as a targeted treatment for corticotropin-secreting pituitary adenomas. (Funded by Novartis Pharma; number, NCT00434148.) Copyright © 2012 Massachusetts Medical Society.

Petersenn S.,Center for Endocrine Tumors | Newell-Price J.,University of Sheffield | Findling J.W.,Medical College of Wisconsin | Gu F.,Peking Union Medical College | And 5 more authors.
Clinical Endocrinology | Year: 2014

Objective Twenty-four-hour urinary free cortisol (UFC) sampling is commonly used to evaluate Cushing's syndrome. Because there are few data on UFC variability in patients with active Cushing's disease, we analysed baseline UFC in a large patient cohort with moderate-to-severe Cushing's disease and assessed whether variability correlates with hypercortisolism severity. These data will help clinicians establish the minimum number of UFC samples required to obtain reliable data. Design Observational study (enrolment phase of Phase III study). Methods Patients (n = 152) with persistent/recurrent or de novo Cushing's disease and mean UFC (mUFC) ≥1·5×ULN (normal: 30-145 nmol/24 h) were included. Mean UFC level was calculated from four 24-h urine samples collected over 2 weeks. Results Over 600 24-h UFC samples were analysed. The mUFC levels of samples 1 and 2 and samples 3 and 4 were 1000 nmol/24 h (SD 1872) and 940 nmol/24 h (SD 2148), respectively; intrapatient coefficient of variation (CV) was 38% for mUFC. The intrapatient CV using all four samples was 52% (95% CI: 48-56). The intrapatient CV was 51% (95% CI: 44-58) for samples 1 and 2, 49% (95% CI: 43-56) for samples 3 and 4 and 54% (95% CI: 49-59) for samples 1, 2 and 3. Variability in mUFC increased as UFC levels increased. There were no correlations between UFC and clinical features of hypercortisolism. Conclusions There is intrapatient variability of approximately 50% in 24-h UFC measurements, which is relevant to targets set to estimate any treatment effect. Analysing more than two 24-h collection periods in individual patients does not result in a relevant decrease in variability. Interestingly, UFC levels did not correlate with hypercortisolism severity. © 2013 The Authors. Clinical Endocrinology published by John Wiley & Sons Ltd.

Fleseriu M.,Oregon Health And Science University | Petersenn S.,Center for Endocrine Tumors
Journal of Neuro-Oncology | Year: 2013

Cushing's disease (CD) is a condition of chronic hypercortisolism caused by an adrenocorticotropic hormone-secreting pituitary adenoma. First-line transsphenoidal surgery is not always curative and disease sometimes recurs. Radiotherapy often requires months or years to be effective, and is also not curative in many cases. Consequently, effective medical therapies for patients with CD are needed. Corticotroph adenomas frequently express both dopamine (D2) and somatostatin receptors (predominantly sstr5). Pasireotide, a somatostatin analog with high sstr5 binding affinity, has shown urinary free cortisol (UFC) reductions in most patients with CD in a large phase 3 trial, with UFC normalization and tumor shrinkage in a subset of patients. Adverse events were similar to other somatostatin analogs, with the exception of the degree and severity of hyperglycemia. Two small trials (one prospective and one retrospective) have suggested that cabergoline, a D2 receptor agonist, could be effective in normalizing UFC, but current long-term data results are conflicting. Combination treatment with pasireotide plus cabergoline and the adrenal steroidogenesis inhibitor ketoconazole has been successful, but further investigation in larger trials is necessary. Retinoic acid also showed interesting results in a recent very small prospective study. Glucocorticoid receptor blockade with mifepristone has recently demonstrated improvement in signs and symptoms of Cushing's and glycemic control; however, this modality does not address the etiology of the disease and has inherent adverse events related to its mechanism of action. Pituitary-targeted medical therapies will soon play a more prominent role in treating CD, and may potentially become first-line medical therapy when surgery fails or is contraindicated. © 2013 The Author(s).

Pivonello R.,University of Naples Federico II | Petersenn S.,Center for Endocrine Tumors | Newell-Price J.,University of Sheffield | Findling J.W.,Medical College of Wisconsin | And 8 more authors.
Clinical Endocrinology | Year: 2014

Objective Signs and symptoms of Cushing's disease are associated with high burden of illness. In this analysis, we evaluated the effect of pasireotide treatment on signs and symptoms in patients with Cushing's disease. Design Phase III study with double-blind randomization of two pasireotide doses. Methods Patients (n = 162) with persistent/recurrent or de novo Cushing's disease and urinary free cortisol (UFC) levels ≥1·5× upper limit of normal (ULN) were randomized to receive subcutaneous pasireotide (600/900 μg bid). At month 3, patients with UFC ≤2 × ULN and not exceeding the baseline value continued their randomized dose; all others received 300 μg bid uptitration. At month 6, patients could enter an open-label phase until month 12 with a maximal dose of 1200 μg bid. Changes in signs and symptoms of hypercortisolism over 12 months' treatment in patients still enroled in the study and with evaluable measurements were assessed in relation to degree of UFC control. Results Reductions in blood pressure were observed even without full UFC control and were greatest in patients who did not receive antihypertensive medications during the study. Significant reductions in total cholesterol and low-density lipoprotein (LDL)-cholesterol were observed in patients who achieved UFC control. Reductions in BMI, weight and waist circumference occurred during the study even without full UFC control. Adverse effects were typical of somatostatin analogues except for hyperglycaemia-related events, which were experienced by 72·8% of patients. Conclusions In the largest Phase III study of medical therapy in Cushing's disease, significant improvements in signs and symptoms were seen during 12 months of pasireotide treatment, as UFC levels decreased. © 2014 John Wiley & Sons Ltd.

Manolopoulou J.,Ludwig Maximilians University of Munich | Alami Y.,IDS Ltd. | Petersenn S.,Center for Endocrine Tumors | Petersenn S.,University of Duisburg - Essen | And 4 more authors.
Clinical Chemistry | Year: 2012

BACKGROUND: Large variability exists among different growth hormone (GH) assays owing to differences in calibration, antibody specificity, isoform recognition, and interference from GH binding protein (GHBP). The GH receptor antagonist Pegvisomant presents a new challenge because Pegvisomant interferes with many GH assays. A recent consensus conference established criteria for standardization and evaluation of GH assays. Following consensus recommendations, we developed a new GH assay on an automated analyzer (IDS-iSYS, Immunodiagnostic Systems). METHODS: A monoclonal antibody not cross-reacting with Pegvisomant was combined with a monoclonal antibody specific for 22-kD GH. Isoform specificity and interference from GHBP was tested and compared to that seen in 2 existing automated GH assays (Siemens Immulite, Diasorin Liaison). We also compared GH concentrations measured by the 3 assays for healthy volunteers and patients with acromegaly receiving different treatments. Using the iSYS assay, we also established nadir GH values during oral glucose load and analyzed changes in endogenous GH during Pegvisomant treatment. RESULTS: Analytical and functional sensitivities were 0.01 μg/L and 0.04 μg/L, with a dynamic range from 0.04 to 100 μg/L. Intraassay CVs were 2%-4%, whereas interassay CVs were 5%-7% at GH concentrations between 1.7 and 27.5 μg/L. The assay was specific for 22-kD GH and not affected by GHBP. The presence of Pegvisomant, which leads to a negative bias on the Immulite and dramatic overestimation of GH on the Liaison, had no impact on the iSYS GH assay. CONCLUSIONS: The new assay fulfils recent consensus recommendations and presents a useful new tool for reliable measurement of GH. © 2012 American Association for Clinical Chemistry.

Deutschbein T.,University of Würzburg | Mann K.,University of Duisburg - Essen | Petersenn S.,Center for Endocrine Tumors
Hormone and Metabolic Research | Year: 2015

Measurement of sex steroids is required to evaluate gonadal function, but normative data are lacking (especially for estimates of physiologically active testosterone). Using modern immunoassays, this study established sex-specific reference ranges (2.5% and 97.5% percentiles) for total testosterone (TOT), bioactive testosterone Vermeulen (BTV), free androgen index (FAI), free testosterone Sartorius (FTS), free testosterone Vermeulen (FTV), and sex hormone binding globulin (SHBG). In the comparative study, subjects were grouped by age (18-30; 31-50; >50 years), BMI (<25; 25-30; >30 kg/m2), and sex. Study participants were selected in such a way that each group comprised 12 subjects (e. g., 12 males between 18 and 30 years with a BMI of <25 kg/m2, and so on), resulting in a total of 216 controls (108 males, 108 females; age: 40.3±1.0; BMI: 27.8±0.4). Multiple stepwise regression analyses were performed (covariates: age, BMI, sex), and sex-specific reference ranges were applied to 50 males (age: 46.1±2.3; BMI: 27.4±0.7) with suspected hypogonadism. Regression analysis identified the strongest predictor of each parameter apart from sex, resulting in age-specific (males: FAI, SHBG, BTV, FTV; females: TOT, FTS, SHBG), BMI-specific (males: TOT, FTS; females: FAI, BTV, FTV) and overall cutoffs for both sexes. In male patients, overall agreement between the results derived from the estimates (i. e., BTV, FTS, FTV) was high (with discordant results in only 4%). In summary, if both the endocrine workup and the clinical presentation were taken into account, the newly established reference ranges allowed reliable identification of hypogonadal males. © Georg Thieme Verlag KG Stuttgart New York.

Deutschbein T.,University of Würzburg | Petersenn S.,Center for Endocrine Tumors
Hormone and Metabolic Research | Year: 2013

Cushing's syndrome results from chronic inappropriate exposure to excessive glucocorticoid concentrations. Low-dose dexamethasone suppression, late-night salivary cortisol, and 24-h urinary free cortisol are regarded as screening tests of first choice. Consequently, measurement of circulating cortisol (e. g., in serum, saliva, and urine) is mandatory in the diagnostic workup of suspected patients. The particular analytical procedure needs to be chosen carefully. Antibody-based immunoassays offer several potential advantages: they require small volumes and are widely available, relatively cheap, and easy to handle. Modern (ideally automated) systems also have a rapid turnaround time on a large number of samples and demonstrate high analytical accuracy. However, there are some important pitfalls. Inadequate standardization and poor interlaboratory performance remain problematic and precise reference ranges are lacking for some of the newer assays. Immunoassays are also susceptible to error due to cross-reactivity with cortisol metabolites or exogenous glucocorticoids. In contrast, steroid analysis by modern chromatographic and mass spectrometric techniques is largely independent from such interference and is therefore regarded as diagnostic gold standard. To date, however, these procedures are costly, time-consuming, and at least at present restricted to a limited number of specialized centers. This review puts special emphasis on the potential advantages of salivary cortisol analysis by immunoassays. It has been shown in numerous studies that such an approach allows excellent identification of hypercortisolemic states. In this context, use of automated systems may allow for broader use of this diagnostic tool. © Georg Thieme Verlag KG Stuttgart - New York.

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