Publications by authors named "Harald Lahner"

28 Publications

  • Page 1 of 1

Alpelisib in combination with everolimus ± exemestane in solid tumours: Phase Ib randomised, open-label, multicentre study.

Eur J Cancer 2021 May 5;151:49-62. Epub 2021 May 5.

Institut Gustave Roussy, Villejuif, France.

Background And Purpose: Combined mTORC1 inhibition with everolimus (EVE) and phosphatidylinositol 3-kinase catalytic subunit p110α blockade with alpelisib (ALP) has demonstrated synergistic efficacy in preclinical models and supports testing the combination of ALP and EVE in the clinical setting. The primary objective was to determine the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) of ALP in combination with EVE and in combination with EVE and exemestane (EXE) and subsequently assess safety, preliminary efficacy and effect of ALP on the pharmacokinetics of EVE and determine the magnitude of the drug-drug interaction.

Patients And Methods: Dose escalation phases were conducted in patients with advanced solid tumours and in postmenopausal women with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC). The dose expansion phase was conducted in patients with pancreatic neuroendocrine tumour and renal cell carcinoma (RCC) (both mechanistic target of rapamycin inhibitor [mTORi]-naive), in patients with mTORi-pretreated solid tumours and in postmenopausal women with HR+, HER2- ABC.

Results: During the doublet escalation phase, dose-limiting toxicities (DLTs) were reported in 5 of 10 (50%) patients: one patient had grade (Gr) 2 hyperglycemia and one patient had Gr 3 diarrhoea in the 300 mg dose group, one patient had Gr 2 hyperglycemia and one patient had Gr 4 hypocalcaemia in the 250 mg dose group, and one patient in the 200 mg dose group had Gr 3 diarrhoea and Gr 3 stomatitis. The combination of ALP 250 mg + EVE 2.5 mg was declared as the MTD/RDE in subjects with advanced solid tumours. In the triplet escalation phase, one patient who received ALP 200 mg + EVE 2.5 mg + EXE 25 mg had a DLT of Gr 3 acute kidney injury. This dose combination was declared as the MTD and RDE in subjects with advanced HR-positive HER2-negative BC. The common adverse events (≥30% patients), occurring across all phases, were hyperglycaemia, stomatitis, diarrhoea, nausea, asthenia, decreased appetite and fatigue. The sixteen-week progression-free survival rate was 52.4% (90% confidence interval [CI]: 32.8, 71.4) in the RCC cohort, 35.3% (90% CI: 16.6, 58.0) in the prior pNET cohort and 30.0% (90% CI: 8.7, 60.7) in the prior mTORi cohort. The pharmacokinetics of 2.5 mg of EVE was largely unchanged in the presence of ALP, independent of the dose (250 mg or 300 mg). There were no clinically relevant drug-drug interactions observed between ALP and EVE.

Conclusion: The overall safety profile of ALP with EVE and EXE is manageable and reversible; no unexpected safety signals were noted compared with the individual safety profiles. Pharmacokinetics of ALP, EVE and EXE was largely unchanged in combination with each other.
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http://dx.doi.org/10.1016/j.ejca.2021.03.042DOI Listing
May 2021

Correlation between contrast enhancement, standardized uptake value (SUV), and diffusion restriction (ADC) with tumor grading in patients with therapy-naive neuroendocrine neoplasms using hybrid Ga-DOTATOC PET/MRI.

Eur J Radiol 2021 Apr 19;137:109588. Epub 2021 Feb 19.

University Dusseldorf, Medical Faculty, Department of Diagnostic and Interventional Radiology, D-40225 Dusseldorf, Germany.

Objectives: To investigate a correlation between Ga-DOTATOC PET/MR imaging parameters such as arterial and venous contrast enhancement, diffusion restriction, and maximum standardized uptake value (SUVmax) with histopathological tumor grading in patients with neuroendocrine neoplasms (NEN).

Material And Methods: A total of 26 patients with newly diagnosed, therapy-naive neuroendocrine neoplasms (NEN) were enrolled in this prospective study and underwent Ga-DOTATOC PET/MRI. Images were evaluated regarding NEN lesion number and location, predominant tumor signal intensity on precontrast T1w and T2w images and on postcontrast arterial and portal venous phase T1w images, apparent diffusion coefficient (ADC) and SUVmax. Histopathological tumor grading was assessed and related to PET/MRI features using Pearson's correlation coefficient and Fisher's exact t-test. A binary logistic regression analysis was performed to evaluate a potential relation with an aggressive tumor biology and odds ratios (OR) were calculated.

Results: There was a moderate negative correlation between arterial contrast enhancement and tumor grading (r=-0.35, p = 0.005), while portal venous enhancement showed a weak positive correlation with the Ki-67 index (r = 0.28, p = 0.008) and a non-significant positive correlation with tumor grading (r = 0.19, p = 0.063). Features that were significantly associated with an aggressive tumor biology were the presence of liver metastases (OR 2.6, p = 0.042), T1w hyperintensity in comparison to muscle (OR 12.7, p = 0.0001), arterial phase hyperenhancement (OR 1.4, p = 0.001), diffusion restriction (OR 2.8, p = 0.02) and SUVmax above the hepatic level (OR 7.0, p = 0.001).

Conclusion: The study reveals that PET/MRI features might be useful for prediction of NEN grading and thus provide a preliminary assessment of tumor aggressiveness.
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http://dx.doi.org/10.1016/j.ejrad.2021.109588DOI Listing
April 2021

Durable Complete Response in a Melanoma Patient With Unknown Primary, Associated With Sequential and Severe Multi-Organ Toxicity After a Single Dose of CTLA-4 Plus PD-1 Blockade: A Case Report.

Front Oncol 2020 11;10:592609. Epub 2020 Nov 11.

Department of Dermatology, University of Duisburg-Essen, Essen, Germany.

Monoclonal antibodies blocking PD-1 and CTLA-4 immunological checkpoints lead to durable tumor responses in a considerable number of advanced melanoma patients. Besides their anti-neoplastic efficacy, these immune checkpoint inhibitors cause a wide range of immune-related adverse events (irAEs), often enforcing an early discontinuation of therapy. The value of irAEs as a predictive marker for better patient survival is still debated. We report here on a melanoma patient with intramuscular, pulmonary, and bone metastases who developed severe sequential irAEs involving multiple organ systems after single application of a combined immunotherapy with ipilimumab plus nivolumab, followed by a durable complete response despite an early discontinuation of therapy.
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http://dx.doi.org/10.3389/fonc.2020.592609DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686558PMC
November 2020

Treatment-related changes in neuroendocrine tumors as assessed by textural features derived from Ga-DOTATOC PET/MRI with simultaneous acquisition of apparent diffusion coefficient.

BMC Cancer 2020 Apr 16;20(1):326. Epub 2020 Apr 16.

Department of Nuclear Medicine, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.

Background: Neuroendocrine tumors (NETs) frequently overexpress somatostatin receptors (SSTRs), which is the molecular basis for Ga-DOTATOC positron-emission tomography (PET) and radiopeptide therapy (PRRT). However, SSTR expression fluctuates and can be subject to treatment-related changes. The aim of this retrospective study was to assess, which changes in PET and apparent diffusion coefficient (ADC) occur for different treatments and if pre-therapeutic Ga-DOTATOC-PET/MRI was able to predict treatment response to PRRT.

Methods: Patients with histopathologically confirmed NET, at least one liver metastasis > 1 cm and at least two Ga-DOTATOC-PET/MRI including ADC maps were eligible. Ga-DOTATOC-PET/MRI of up to 5 liver lesions per patients was subsequently analyzed. Extracted features comprise conventional PET parameters, such as maximum and mean standardized uptake value (SUVmax and SUVmean) and ADC values. Furthermore, textural features (TFs) from both modalities were extracted. In patients with multiple Ga-DOTATOC-PET/MRI a pair of 2 scans each was analyzed separately and the parameter changes between both scans calculated. The same image analysis was performed in patients with Ga-DOTATOC-PET/MRI before PRRT. Differences in PET and ADC maps parameters between PRRT-responders and non-responders were compared using Mann-Whitney test to test differences among groups for statistical significance.

Results: 29 pairs of Ga-DOTATOC-PET/MRI scans of 18 patients were eligible for the assessment of treatment-related changes. In 12 cases patients were treated with somatostatin analogues between scans, in 9 cases with PRRT and in 2 cases each patients received local treatment, chemotherapy and sunitinib. Treatment responders showed a statistically significant decrease in lesion volume and a borderline significant decrease in entropy on ADC maps when compared to non-responders. Patients treated with standalone SSA showed a borderline significant decrease in mean and maximum ADC, compared to patients treated with PRRT. No parameters were able to predict treatment response to PRRT on pre-therapeutic Ga-DOTATOC-PET/MRI.

Conclusions: Patients responding to current treatment showed a statistically significant decrease in lesion volume on ADC maps and a borderline significant decrease in entropy. No statistically significant changes in PET parameters were observed. No PET or ADC maps parameters predicted treatment response to PRRT. However, the sample size of this preliminary study is small and further research needed.
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http://dx.doi.org/10.1186/s12885-020-06836-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7161278PMC
April 2020

Textural analysis of hybrid DOTATOC-PET/MRI and its association with histological grading in patients with liver metastases from neuroendocrine tumors.

Nucl Med Commun 2020 Apr;41(4):363-369

Department of Nuclear Medicine, University Hospital Essen, University of Duisburg-Essen.

Aims: Neuroendocrine tumors (NETs) are known to overexpress somatostatin receptors (SSTR), which can be visualized by DOTATOC-PET. Reduced SSTR expression on the other hand may indicate dedifferentiation. The aim of this retrospective study was to assess, if conventional PET parameters and textural features (TF) derived from simultaneous PET and MRI including apparent diffusion coefficient (ADC) are associated with the proliferative activity of NETs, potentially allowing non-invasive tumor grading.

Methods: Our institutional database was screened for patients with NET and liver metastases >1 cm. We assessed conventional PET parameters, such as maximum and mean standardized uptake value and more elaborate TF parameters from PET and ADC-MRI (including entropy and homogeneity) from up to the five largest liver lesions per patient. The association of proliferative activity as measured by Ki67-/MIB1-index with the aforementioned parameters was analyzed.

Results: One hundred patients with NET/NECs were eligible with a Ki67-index ranging from <1% to 30%. Overall, 304 liver lesions were analyzed. Conventional PET parameters, entropy, homogeneity of PET and ADC maps differed significantly between G1 and G2 NETs. However, Spearman's test showed a weak association (r = -0.23 to 0.31).

Discussion: In our study cohort, conventional PET parameters and TF of PET and ADC-MRI showed only a weak correlation with Ki67. This indicates that in patients with a Ki67-index of up to 30% TF analysis of combined PET/MRI may not be reliably used for accurate non-invasive tumor grading. On the other hand, DOTATOC-PET might be a suitable staging tool in some higher grade NET/NECs.
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http://dx.doi.org/10.1097/MNM.0000000000001150DOI Listing
April 2020

Hedinger syndrome: first experience and two-year follow-up in patients with carcinoid heart disease.

J Thorac Dis 2019 Aug;11(8):3234-3240

Department of Thoracic and Cardiovascular Surgery, West-German Heart and Vascular Centre Essen, University Hospitals Duisburg-Essen, Essen, Germany.

Background: Carcinoid heart disease (CHD) (Hedinger syndrome) is a rare manifestation, it has been described in up to 60% of patients with both neuroendocrine tumors (NETs) and carcinoid syndrome (CS) which, typically inducing right heart-sided abnormalities.

Methods: Between 07/15 and 10/18, six patients (mean age 63±12 years; 3 females) presented with manifested (NYHA III-IV) Hedinger syndrome's related valvular(s) lesion and were operated at our center. Clinical data, adverse events and patient outcomes were recorded.

Results: The tricuspid valve was involved in all patients. Tricuspid valve repair was possible in four patients and two needed replacement. In two patients, operation was performed on beating heart without cross-clamping. Concomitant pulmonary valve replacement in two patients and aortic valve replacement in another two patients. A mean cross-clamp time of 61±50 minutes was observed. One patient with severely impaired right ventricular function needed ECMO support, and died 3 days later due to neuroendocrine enzyme storm. At 13 months, one patient developed severe tricuspid stenosis and underwent re-operation with replacement. Another patient died 18 months after surgery related to the underlying tumour. At mean of 30 months follow-up, four patients were alive and asymptotic.

Conclusions: Hedinger syndrome is a challenging entity in cardiac surgery characterized by aggressive valve lesions combined with metastatic neuroendocrine neoplasia affecting the systemic circulation. We advise a multidisciplinary collaboration to early diagnose cardiac involvement to offer an early and proper treatment regime.
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http://dx.doi.org/10.21037/jtd.2019.08.71DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753413PMC
August 2019

Octreotide SC depot in patients with acromegaly and functioning neuroendocrine tumors: a phase 2, multicenter study.

Cancer Chemother Pharmacol 2019 02 8;83(2):375-385. Epub 2018 Dec 8.

Endocrinology, DiMI and CEBR, University of Genoa, Genoa, Italy.

Purpose: Octreotide SC depot is a novel, ready-to-use formulation administered via a thin needle. In a phase 1 study in healthy volunteers, this formulation provided higher bioavailability of octreotide with faster onset and stronger suppression of IGF-1 in healthy volunteers versus long-acting intramuscular (IM) octreotide. This phase 2 study evaluated the pharmacokinetics, efficacy, and safety of octreotide SC depot in patients with acromegaly and functioning NETs, previously treated with octreotide IM.

Methods: Adult patients with acromegaly or functioning NETs treated for ≥ 2 months with octreotide IM [10/20/30 mg every 4 weeks (q4w)] received the last dose of octreotide IM treatment in study period 0 and were randomized 28 days later to receive octreotide SC depot 10 mg q2w, or 20 mg q4w for 3 months (period 1). The primary objective was to characterize the PK profile of octreotide SC depot after each injection vs PK for octreotide IM (period 0).

Results: Twelve patients were randomized to receive octreotide SC depot 10 mg q2w (acromegaly n = 3; NET n = 1) or 20 mg q4w (acromegaly n = 4; NET n = 4). Plasma levels of octreotide were higher with octreotide SC depot as compared to octreotide IM. Adverse events were reported in 6 and 8 patients during period 0 and period 1, respectively; most common in period 1 were gastrointestinal disorders.

Conclusion: Octreotide SC depot provided higher exposure (AUC) than octreotide IM, maintained biochemical control in patients with acromegaly and symptom control in patients with functioning NETs, and was well tolerated with a safety profile consistent with octreotide IM. CLINICALTRIALS.

Gov Identifier: NCT02299089.
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http://dx.doi.org/10.1007/s00280-018-3734-1DOI Listing
February 2019

The Spectrum of Thyroid Gland Pathology in Carney Complex: The Importance of Follicular Carcinoma.

Am J Surg Pathol 2018 05;42(5):587-594

Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD.

The initial description of Carney complex (CNC) in 1985 included myxomas, spotty skin pigmentation, and endocrine overactivity (of the adrenal, the pituitary, and the testis). In 1997, thyroid neoplasms were found in 3 patients with CNC and involvement of the gland in the syndrome was apparent. Herein, we describe the clinical, pathologic, and follow-up findings in 26 patients with CNC and a disorder of the thyroid gland. The patients were predominantly middle-aged women with an asymptomatic thyroid mass. Four patients had hyperthyroidism, which was caused by follicular hyperplasia in 2 patients and by toxic adenoma in 2 others. Pathologic findings included benign lesions (follicular hyperplasia, nodular hyperplasia, and follicular adenoma) in 16 patients and carcinomas (follicular or papillary) in 10 patients. The follicular carcinomas had unusual features, multifocality, bilaterality, and lymph node metastasis. The tumor was fatal in 3 of 4 patients with a tumor ≥3 cm in diameter. One patient had an unusual multifocal microscopic follicular hyperplasia. Detection and treatment of the thyroid neoplasms in patients with CNC requires long-term follow-up of patients with the syndrome.
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http://dx.doi.org/10.1097/PAS.0000000000000975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5925749PMC
May 2018

Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

Lancet Oncol 2017 10 30;18(10):1411-1422. Epub 2017 Aug 30.

Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: In the phase 3 RADIANT-4 trial, everolimus increased progression-free survival compared with placebo in patients with advanced, progressive, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (NETs). We now report the health-related quality of life (HRQOL) secondary endpoint.

Methods: RADIANT-4 is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 97 centres in 25 countries worldwide. Adults (aged ≥18 years) were eligible for the study if they had pathologically confirmed, advanced (unresectable or metastatic), non-functional, well-differentiated (grade 1 or 2) NETs of lung or gastrointestinal origin. Patients were randomly allocated (2:1) using block randomisation (block size of three) by an interactive voice response system to receive oral everolimus (10 mg per day) or placebo, both with best supportive care, with stratification by tumour origin, WHO performance status, and previous somatostatin analogue treatment. HRQOL was assessed with the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at baseline (visit 2, day 1), every 8 weeks (± 1 week) during the study for the first 12 months after randomisation, and every 12 weeks thereafter until study drug discontinuation. The primary endpoint, reported previously, was progression-free survival assessed by central review; HRQOL was a prespecified secondary endpoint. The prespecified secondary outcome measure was time to definitive deterioration (≥7 points) in FACT-G total score. Analyses were done on the full analysis set, consisting of all randomised patients, by intention to treat. Only data obtained while receiving the randomly allocated treatment were included in this analysis. Enrolment for RADIANT-4 was completed on Aug 23, 2013, but the trial is ongoing pending final analysis of the key secondary endpoint of overall survival. This trial is registered with ClinicalTrials.gov, number NCT01524783.

Findings: Between April 3, 2012, and Aug 23, 2013, 302 patients were enrolled; 205 were randomly allocated everolimus and 97 were assigned placebo. At baseline, 193 (94%) of 205 patients assigned everolimus and 95 (98%) of 97 allocated placebo had completed either fully or partly the FACT-G questionnaire; at week 48, 70 (83%) of 84 patients assigned everolimus and 22 (85%) of 26 allocated placebo completed FACT-G. Median time to definitive deterioration in FACT-G total score was 11·27 months (95% CI 9·27-19·35) with everolimus and 9·23 months (5·52-not estimable) with placebo (adjusted hazard ratio 0·81, 95% CI 0·55-1·21; log-rank p=0·31).

Interpretation: HRQOL was maintained for patients with advanced, non-functional, gastrointestinal or lung NETs, with no relevant differences noted between the everolimus and placebo groups. In view of the previous RADIANT-4 findings of longer progression-free survival with everolimus, our findings suggest that everolimus delays disease progression while preserving overall HRQOL, even with the usual toxic effects related to active targeted drug treatment for cancer.

Funding: Novartis Pharmaceuticals.
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http://dx.doi.org/10.1016/S1470-2045(17)30471-0DOI Listing
October 2017

Everolimus in Neuroendocrine Tumors of the Gastrointestinal Tract and Unknown Primary.

Neuroendocrinology 2018 24;106(3):211-220. Epub 2017 May 24.

Sunnybrook Health Sciences Centre, Toronto, ON, Canada.

Purpose: The RADIANT-4 randomized phase 3 study demonstrated significant prolongation of median progression-free survival (PFS) with everolimus compared to placebo (11.0 [95% CI 9.2-13.3] vs. 3.9 [95% CI 3.6-7.4] months) in patients with advanced, progressive, nonfunctional gastrointestinal (GI) and lung neuroendocrine tumors (NET). This analysis specifically evaluated NET patients with GI and unknown primary origin.

Methods: Patients in the RADIANT-4 trial were randomized 2:1 to everolimus 10 mg/day or placebo. The effect of everolimus on PFS was evaluated in patients with NET of the GI tract or unknown primary site.

Results: Of the 302 patients enrolled, 175 had GI NET (everolimus, 118; placebo, 57) and 36 had unknown primary (everolimus, 23; placebo, 13). In the GI subset, the median PFS by central review was 13.1 months (95% CI 9.2-17.3) in the everolimus arm versus 5.4 months (95% CI 3.6-9.3) in the placebo arm; the hazard ratio (HR) was 0.56 (95% CI 0.37-0.84). In the unknown primary patients, the median PFS was 13.6 months (95% CI 4.1-not evaluable) for everolimus versus 7.5 months (95% CI 1.9-18.5) for placebo; the HR was 0.60 (95% CI 0.24-1.51). Everolimus efficacy was also demonstrated in both midgut and non-midgut populations; a 40-46% reduction in the risk of progression or death was reported for patients in the combined GI and unknown primary subgroup. Everolimus had a benefit regardless of prior somatostatin analog therapy.

Conclusions: Everolimus showed a clinically meaningful PFS benefit in patients with advanced progressive nonfunctional NET of GI and unknown primary, consistent with the overall RADIANT-4 results, providing an effective new standard treatment option in this patient population and filling an unmet treatment need for these patients.
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http://dx.doi.org/10.1159/000477585DOI Listing
January 2019

Evaluation of Ga-DOTATOC PET/MRI for whole-body staging of neuroendocrine tumours in comparison with Ga-DOTATOC PET/CT.

Eur Radiol 2017 Oct 24;27(10):4091-4099. Epub 2017 Apr 24.

Department of Diagnostic and Interventional Radiology and Neuroradiology, Medical Faculty, University Duisburg-Essen, 45122, Essen, Germany.

Objectives: To compare the diagnostic performance of Ga-DOTATOC PET/MRI and Ga-DOTATOC PET/CT in the whole-body staging of patients with neuroendocrine tumours (NET).

Methods: Thirty patients with histopathologically confirmed NET underwent PET/CT and PET/MRI in a single-injection protocol. PET/CT and PET/MRI scans were prospectively evaluated with regard to lesion count, localization, nature (NET/non-NET), and conspicuity (four-point scale). Histopathology and follow-up imaging served as the reference standards. The proportions of NET and non-NET lesions rated correctly were compared using McNemar's chi-squared test. The Wilcoxon test was used to assess differences in SUVmax and lesion conspicuity. The correlation between the SUVmax for the same lesions from each modality was analysed using Pearson's correlation coefficient (r).

Results: According to the reference standard, there were 197 lesions (142 NET, 55 non-NET). Lesion-based analysis showed a higher proportion of correctly rated NET lesions on PET/MRI than on PET/CT (90.8% vs. 86.7%, p = 0.031), whereas on PET/CT there was a higher proportion of correctly rated non-NET lesions (94.5% vs. 83.6%, p = 0.031). SUVmax was strongly correlated (r = 0.86; p < 0.001) and did not differ significantly (p = 0.35) between the modalities. Overall conspicuity and NET lesion conspicuity were higher on PET/MRI (both p < 0.01).

Conclusions: Ga-DOTATOC PET/MRI yielded a higher proportion of correctly rated NET lesions and should be regarded as a valuable alternative to Ga-DOTATOC PET/CT in whole-body staging of NET patients.

Key Points: • Ga-DOTATOC PET/MRI correctly identified more NET lesions than Ga-DOTATOC PET/CT. • Ga-DOTATOC PET/MRI provides better NET lesion conspicuity than Ga-DOTATOC PET/CT. • SUVmax values from the two modalities are strongly correlated and do not differ significantly.
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http://dx.doi.org/10.1007/s00330-017-4803-2DOI Listing
October 2017

Impact of season and different vitamin D thresholds on prevalence of vitamin D deficiency in epidemiological cohorts-a note of caution.

Endocrine 2017 Jun 17;56(3):658-666. Epub 2017 Apr 17.

Institute of Medical Informatics, Biometry and Epidemiology, University Hospital Essen, Essen, Germany.

Purpose: We investigated the impact of different cut-offs on the prevalence of 25-hydroxyvitamin D [25-(OH)D] deficiency.

Methods: We used baseline data of 4149 participants (45-75 years, 50% women) of the population-based Heinz Nixdorf Recall study. Serum 25-(OH)D was measured with the Roche Cobas assay. Quartiles (p25, p50, and p75) were calculated. Data were stratified by months, sex, and age. According to the recommendations of 'Dachverband Osteologie', Endocrine Society and National Institute of Health we used 25-(OH)D thresholds of 12, 20, and 30 ng/ml to estimate vitamin D deficiency.

Results: Overall the median of 25-(OH)D was 19.8 ng/ml (p25 = 14.4 ng/ml, p75 = 26.6 ng/ml), with highest concentrations in July (p50 = 23.8 ng/ml, p25 = 18.2 ng/ml, and p75 = 31.2 ng/ml) and lowest in March (p50 = 15.8 ng/ml, p25 = 11.5 ng/ml, and p75 = 20.6 ng/ml). Prevalence of vitamin D deficiency rose from 16, 51 up to 83% using the cut-offs of <12, <20 ng/ml, and <30 ng/ml, respectively. With respect to seasonal variance, prevalence of vitamin D deficiency rose to 92% in February/March using the cut-off <30 ng/ml (<12: 28%, <20 ng/ml: 71%) whereas in June/July prevalence of vitamin D deficiency decreased to 71% (<12: 6%, <20 ng/ml: 30%). The chance to attest the diagnosis of vitamin D deficiency for cut-off 12 ng/ml in March is 6.4-fold higher than in June, for cut-off 20 ng/ml, 5.5-fold higher and for cut-off 30 ng/ml, 3.1-fold higher.

Conclusions: Guidelines to define vitamin D deficiency revealed extremely different prevalence rates ranging between 6 and 92%. Accounting for collection time and antecedent sun exposure are important to reduce bias in research studies and improve decision-making in clinical care. Vitamin D thresholds have to be rethought.
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http://dx.doi.org/10.1007/s12020-017-1292-7DOI Listing
June 2017

A Piece of the Puzzle: The Bone Health Index of the BoneXpert Software Reflects Cortical Bone Mineral Density in Pediatric and Adolescent Patients.

PLoS One 2016 25;11(3):e0151936. Epub 2016 Mar 25.

Pediatric Endocrinology and Diabetology, Kinderklinik II, Universitätsklinikum-Essen and the University of Duisburg-Essen, Essen, Germany.

Introduction: Suspected osteopathology in chronically ill children often necessitates the assessment of bone mineral density. The most frequently used methods are dual-energy X-ray-absorption (DXA) and peripheral quantitative computed tomography (pQCT). The BoneXpert software provides an automated radiogrammatic method to assess skeletal age from digitalized X-rays of the left hand. Furthermore, the program calculates the Bone Health Index (BHI), a measure of cortical thickness and mineralization, which is obtained from indices of three metacarpal bones. In our study, we analyzed the manner in which BHI information provided by BoneXpert compares with DXA or pQCT measurements in youths.

Study Design: The BHI was retrospectively obtained using digitalized X-rays of the left hand and compared with the results of 203 corresponding DXA readings (Lunar Prodigy, GE Healthcare) of the lumbar vertebrae and femur as well as 117 pQCT readings (XCT 900, Stratec) of the distal radius.

Results: The BHI values showed a strong positive correlation with the DXA readings at each and all lumbar vertebrae (L1 -L4: r = 0.73; P < 0.0001). The age-adjusted Z-score of L1 -L4 and the height-adjusted score showed a positive correlation with the BHI-SDS (standard deviation score, r = 0.23; P < 0.002 and r = 0.27; P < 0.001, respectively). Total bone mineral density, as assessed via pQCT, also positively correlated with the BHI (r = 0.39; P < 0.0001), but the trabecular values displayed only a weak correlation.

Conclusions: The BHI obtained using BoneXpert can be a useful parameter in the assessment of bone health in children in most cases. This technique provides observer-independent information on cortical thickness and mineralization based on X-ray imaging of the hands.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0151936PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4807844PMC
August 2016

A Phase II Study of BEZ235 in Patients with Everolimus-resistant, Advanced Pancreatic Neuroendocrine Tumours.

Anticancer Res 2016 Feb;36(2):713-9

University Hospitals Leuven, Leuven, Belgium.

Background: This was a two-stage, phase II trial of the dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor BEZ235 in patients with everolimus-resistant pancreatic neuroendocrine tumours (pNETs) (NCT01658436).

Patients And Methods: In stage 1, 11 patients received 400 mg BEZ235 orally twice daily (bid). Due to tolerability concerns, a further 20 patients received BEZ235 300 mg bid. Stage 2 would be triggered by a 16-week progression-free survival (PFS) rate of ≥60% in stage 1.

Results: As of 30 June, 2014, 29/31 patients had discontinued treatment. Treatment-related grade 3/4 adverse events were reported in eight (72.7%) patients at 400 mg and eight (40.0%) patients at 300 mg, including hyperglycaemia, diarrhoea, nausea, and vomiting. The estimated 16-week PFS rate was 51.6% (90% confidence interval=35.7-67.3%).

Conclusion: BEZ235 was poorly tolerated by patients with everolimus-resistant pNETs at 400 and 300 mg bid doses. Although evidence of disease stability was observed, the study did not proceed to stage 2.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5076549PMC
February 2016

Everolimus for the treatment of advanced, non-functional neuroendocrine tumours of the lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled, phase 3 study.

Lancet 2016 Mar 17;387(10022):968-977. Epub 2015 Dec 17.

Charité Universitätsmedizin Berlin, Campus Virchow-Klinikum, Berlin, Germany.

Background: Effective systemic therapies for patients with advanced, progressive neuroendocrine tumours of the lung or gastrointestinal tract are scarce. We aimed to assess the efficacy and safety of everolimus compared with placebo in this patient population.

Methods: In the randomised, double-blind, placebo-controlled, phase 3 RADIANT-4 trial, adult patients (aged ≥18 years) with advanced, progressive, well-differentiated, non-functional neuroendocrine tumours of lung or gastrointestinal origin were enrolled from 97 centres in 25 countries worldwide. Eligible patients were randomly assigned in a 2:1 ratio by an interactive voice response system to receive everolimus 10 mg per day orally or identical placebo, both with supportive care. Patients were stratified by tumour origin, performance status, and previous somatostatin analogue treatment. Patients, investigators, and the study sponsor were masked to treatment assignment. The primary endpoint was progression-free survival assessed by central radiology review, analysed by intention to treat. Overall survival was a key secondary endpoint. This trial is registered with ClinicalTrials.gov, number NCT01524783.

Findings: Between April 3, 2012, and Aug 23, 2013, a total of 302 patients were enrolled, of whom 205 were allocated to everolimus 10 mg per day and 97 to placebo. Median progression-free survival was 11·0 months (95% CI 9·2-13·3) in the everolimus group and 3·9 months (3·6-7·4) in the placebo group. Everolimus was associated with a 52% reduction in the estimated risk of progression or death (hazard ratio [HR] 0·48 [95% CI 0·35-0·67], p<0·00001). Although not statistically significant, the results of the first pre-planned interim overall survival analysis indicated that everolimus might be associated with a reduction in the risk of death (HR 0·64 [95% CI 0·40-1·05], one-sided p=0·037, whereas the boundary for statistical significance was 0·0002). Grade 3 or 4 drug-related adverse events were infrequent and included stomatitis (in 18 [9%] of 202 patients in the everolimus group vs 0 of 98 in the placebo group), diarrhoea (15 [7%] vs 2 [2%]), infections (14 [7%] vs 0), anaemia (8 [4%] vs 1 [1%]), fatigue (7 [3%] vs 1 [1%]), and hyperglycaemia (7 [3%] vs 0).

Interpretation: Treatment with everolimus was associated with significant improvement in progression-free survival in patients with progressive lung or gastrointestinal neuroendocrine tumours. The safety findings were consistent with the known side-effect profile of everolimus. Everolimus is the first targeted agent to show robust anti-tumour activity with acceptable tolerability across a broad range of neuroendocrine tumours, including those arising from the pancreas, lung, and gastrointestinal tract.

Funding: Novartis Pharmaceuticals Corporation.
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http://dx.doi.org/10.1016/S0140-6736(15)00817-XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6063317PMC
March 2016

Artificial Hyperparathyroidism--Think Twice Before Taking Your Blood Sample.

Am J Med 2015 Dec 30;128(12):e21-2. Epub 2015 Jul 30.

Department of Endocrinology and Metabolism, University-Hospital of Essen, Essen, Germany.

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http://dx.doi.org/10.1016/j.amjmed.2015.06.052DOI Listing
December 2015

Differential uptake of (68)Ga-DOTATOC and (68)Ga-DOTATATE in PET/CT of gastroenteropancreatic neuroendocrine tumors.

Recent Results Cancer Res 2013 ;194:353-71

Department of Nuclear Medicine, University Hospital Essen, Essen, Germany.

Purpose: Abundant expression of somatostatin receptors (sst) is a characteristic of neuroendocrine tumors (NET). Thus, radiolabeled somatostatin analogs have emerged as important tools for both in vivo diagnosis and therapy of NET. The two compounds most often used in functional imaging with positron emission tomography (PET) are (68)Ga-DOTATATE and (68)Ga-DOTATOC. Both analogs share a quite similar sst binding profile. However, the in vitro affinity of (68)Ga-DOTATATE in binding the sst subtype 2 (sst2) is approximately tenfold higher than that of (68)Ga-DOTATOC. This difference may affect their efficiency in detection of NET lesions, as sst2 is the predominant receptor subtype on gastroenteropancreatic NET. We thus compared the diagnostic value of PET/CT with both radiolabeled somatostatin analogs ((68)Ga-DOTATATE and (68)Ga-DOTATOC) in the same patients with gastroenteropancreatic NET.

Patients And Methods: Twenty-seven patients with metastatic gastroenteropancreatic NET underwent (68)Ga-DOTATOC and (68)Ga-DOTATATE PET/CT as part of the workup before prospective peptide receptor radionuclide therapy (PRRT). The performance of both imaging methods was analyzed and compared for detection of individual lesions per patient and for eight defined body regions. A region was regarded as positive if at least one lesion was detected in that region. In addition, radiopeptide uptake in terms of the maximal standardized uptake value (SUV(max)) was compared for concordant lesions and renal parenchyma.

Results: Fifty-one regions were found positive with both (68)Ga-DOTATATE and (68)Ga-DOTATOC. Overall, however, significantly fewer lesions were detected with (68)Ga-DOTATATE in comparison with (68)Ga-DOTATOC (174 versus 179, p < 0.05). Mean (68)Ga-DOTATATE SUV(max) across all lesions was significantly lower compared with (68)Ga-DOTATOC (16.9 ± 6.8 versus 22.1 ± 12.0, p < 0.01). Mean SUV(max) for renal parenchyma was not significantly different between (68)Ga-DOTATATE and (68)Ga-DOTATOC (12.6 ± 2.6 versus 12.6 ± 2.7).

Conclusions: (68)Ga-DOTATOC and (68)Ga-DOTATATE possess similar diagnostic accuracy for detection of gastroenteropancreatic NET lesions (with a potential advantage of (68)Ga-DOTATOC) despite their evident difference in affinity for sst2. Quite unexpectedly, maximal uptake of (68)Ga-DOTATOC tended to be higher than its (68)Ga-DOTATATE counterpart. However, tumor uptake shows high inter- and intraindividual variance with unpredictable preference of one radiopeptide. Thus, our data encourage the application of different sst ligands to enable personalized imaging and therapy of gastroenteropancreatic NET with optimal targeting of tumor receptors.
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http://dx.doi.org/10.1007/978-3-642-27994-2_18DOI Listing
June 2013

68Ga-DOTATOC versus 68Ga-DOTATATE PET/CT in functional imaging of neuroendocrine tumors.

J Nucl Med 2011 Dec 9;52(12):1864-70. Epub 2011 Nov 9.

Department of Nuclear Medicine, University Essen, Essen, Germany.

Unlabelled: Radiolabeled somatostatin analogs represent valuable tools for both in vivo diagnosis and therapy of neuroendocrine tumors (NETs) because of the frequent tumoral overexpression of somatostatin receptors (sst). The 2 compounds most often used in functional imaging with PET are (68)Ga-DOTATATE and (68)Ga-DOTATOC. Both ligands share a quite similar sst binding profile. However, the in vitro affinity of (68)Ga-DOTATATE in binding the sst subtype 2 (sst2) is approximately 10-fold higher than that of (68)Ga-DOTATOC. This difference may affect their efficiency in the detection of NET lesions because it is the sst2 that is predominantly overexpressed in NET. We thus compared the diagnostic value of PET/CT with both radiolabeled somatostatin analogs ((68)Ga-DOTATATE and (68)Ga-DOTATOC) in the same NET patients.

Methods: Forty patients with metastatic NETs underwent (68)Ga-DOTATOC and (68)Ga-DOTATATE PET/CT as part of the work-up before prospective peptide receptor radionuclide therapy. The performance of both imaging methods was analyzed and compared for the detection of individual lesions per patient and for 8 defined body regions. A region was regarded positive if at least 1 lesion was detected in that region. In addition, radiopeptide uptake in terms of the maximal standardized uptake value (SUVmax) was compared for concordant lesions and renal parenchyma.

Results: Seventy-eight regions were found positive with (68)Ga-DOTATATE versus 79 regions with (68)Ga-DOTATOC (not significant). Overall, however, significantly fewer lesions were detected with (68)Ga-DOTATATE than with (68)Ga-DOTATOC (254 vs. 262, P < 0.05). Mean (68)Ga-DOTATATE SUVmax across all lesions was significantly lower than (68)Ga-DOTATOC (16.0 ± 10.8 vs. 20.4 ± 14.7, P < 0.01). Mean SUVmax for renal parenchyma was not significantly different between (68)Ga-DOTATATE and (68)Ga-DOTATOC (12.7 ± 3.0 vs. 13.2 ± 3.3).

Conclusion: (68)Ga-DOTATOC and (68)Ga-DOTATATE possess a comparable diagnostic accuracy for the detection of NET lesions, with (68)Ga-DOTATOC having a potential advantage. The approximately 10-fold higher affinity for the sst2 of (68)Ga-DOTATATE does not prove to be clinically relevant. Quite unexpectedly, SUVmax of (68)Ga-DOTATOC scans tended to be higher than their (68)Ga-DOTATATE counterparts.
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http://dx.doi.org/10.2967/jnumed.111.091165DOI Listing
December 2011

Is minimally invasive, video-assisted thyroidectomy feasible in Graves' disease?

Surgery 2011 Apr 5;149(4):556-60. Epub 2011 Feb 5.

Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Kliniken Essen-Mitte, Akademisches Lehrkrankenhaus der Universität Duisburg-Essen, Essen, Germany.

Background: Although the safety and advantages of minimally invasive, video-assisted thyroidectomy (MIVAT) are well documented in nodular thyroid disease, its role in Graves' disease is controversial. We compared the outcomes of patients undergoing MIVAT with those undergoing conventional thyroidectomy for Graves' disease.

Methods: Of the 497 patients with Graves' disease referred for surgery (1999-2009), 157 (31.6%) patients underwent the MIVAT procedure (video-assisted group). As a control group, 340 patients undergoing conventional thyroidectomy (conventional thyroidectomy group) were included in the current analysis. MIVAT was proposed if the thyroid volume was ≤ 30 mL. The data were obtained through a prospectively maintained surgical database.

Results: Most patients in both groups underwent total thyroidectomy (98% in the MIVAT group and 96.5% in the conventional group). Three (1.9%) conversions to open surgery occurred in the video-assisted group. Hospital stay was significantly shorter (P = .008) in the video-assisted group (2.1 ± 0.4 days) compared with the conventional thyroidectomy group (2.4 ± 1.4 days). The mean operative time was shorter (84 ± 29 min; range, 15-240) for the video-assisted group compared with the conventional thyroidectomy group (94 ± 43 min; range, 20-360), although this difference was not statistically significant (P = .05). Postoperative transient hypocalcemia occurred in 14 (8.9%), transient recurrent laryngeal nerve palsy occurred in 2 (1.3%), and postoperative hematoma occurred in 5 (3.2%) patients in the video-assisted group compared with 23 (6.8%), 11 (3.2%), and 8 (2.3%) patients in the conventional thyroidectomy group, respectively (P = ns).

Conclusion: In selected patients with Graves' disease, MIVAT is feasible and can be performed safely with results comparable with open surgery.
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http://dx.doi.org/10.1016/j.surg.2010.11.018DOI Listing
April 2011

Cardiovascular risk factors in patients with uncontrolled and long-term acromegaly: comparison with matched data from the general population and the effect of disease control.

J Clin Endocrinol Metab 2010 Aug 12;95(8):3648-56. Epub 2010 May 12.

Department of Endocrinology, Institute for Medical Informatics, Biometry, and Epidemiology, West-German Heart Centre Essen, University Hospital of Essen, University of Duisburg-Essen, Department of Endocrinology, Hufelandstrasse 55, 45122 Essen, Germany.

Context: Data on cardiovascular risk in acromegaly are scanty and lack a clear correlation to epidemiological data.

Objective: Our aim was an evaluation of cardiovascular risk factors in patients with active acromegaly, a calculation of the Framingham risk score (FRS) compared with age- and gender-matched controls of the general population, and an evaluation of the effect of IGF-I normalization.

Design And Setting: We conducted a retrospective, comparative study at a university referral center.

Patients: A total of 133 patients with acromegaly (65 men, aged 45-74 yr) from the German Pegvisomant Observational Study were matched to 665 controls from the general population.

Main Outcome Measures: Risk factors were measured at baseline and after 12 months of treatment with pegvisomant (n=62).

Results: Patients with acromegaly had increased prevalence of hypertension, mean systolic and diastolic blood pressure (BP), history of diabetes mellitus and glycosylated hemoglobin (all P<0.001) and decreased high-density lipoprotein, low-density lipoprotein, and total cholesterol (all P<0.001). FRS was significantly higher in patients with acromegaly compared with controls (P<0.001). At 12 months, systolic BP (P=0.04) and glycosylated hemoglobin (P=0.02) as well as FRS (P=0.005) decreased significantly. IGF-I was normalized in 62% (41 of 62). In these patients, glucose and systolic and diastolic BP was significantly lower than in partially controlled patients.

Summary: We found an increased prevalence of cardiovascular risk factors in acromegalic patients compared with controls. Control of acromegaly led to a significant decrease of FRS, implying a reduced risk for coronary heart disease. This was most significant in those patients who completely normalized their IGF-I levels.

Conclusion: Disease control is important to reduce the likelihood for development of coronary heart disease.
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http://dx.doi.org/10.1210/jc.2009-2570DOI Listing
August 2010

Posterior retroperitoneoscopic adrenalectomy for clinical and subclinical Cushing's syndrome.

World J Surg 2010 Jun;34(6):1391-7

Klinik für Chirurgie und Zentrum für Minimal Invasive Chirurgie, Kliniken Essen-Mitte, Akademisches Lehrkrankenhaus der Universität Duisburg-Essen, Henricistrasse 92, 45136, Essen, Germany.

Background: Because of co-morbidity, adrenalectomy for adrenal Cushing's syndrome may be associated with an increased complication rate and long operating times. In the present study we report our experience with the posterior retroperitoneoscopic adrenalectomy in a large group of patients with clinical or subclinical Cushing's syndrome.

Patients And Methods: Between July 1994 and June 2009, 170 patients (17 males, 153 females age 50 +/- 13 years; range: 12-78 years) affected by Cushing's syndrome underwent operation via posterior retroperitoneoscopic access. Patients were divided into two groups, those with manifest Cushing's syndrome (mCS) [99 patients: 6 male, 93 female; age 45 +/- 13 years] and those with subclinical Cushing's syndrome (sCS) [71 patients: 11 male, 60 female; age: 56 +/- 11 years]. The sCS classification was assumed in cases without typical clinical symptoms but with a pathological dexamethasone suppression test. Partial adrenalectomy was performed in 35 cases (24 in the mCS-group and 11 in the sCS-group).

Results: Mortality was zero; major complications did not occur. The incidence of postoperative minor complications was 5.3%. Mean operating time was 58 +/- 36 min (range: 20-230 min) and did not differ between mCS and sCS patients (58 versus 59 min; p = ns). Postoperative oral steroids supplementation (POSS) was administered in 136 patients (99 mCS, 37 sCS). If POSS was started, mean duration of therapy was 12.3 months (mCS) and 10.3 months (sCS) [p = 0.08], respectively. After a mean follow-up of 70.9 +/- 46.5 months the cure rate was 99.4%.

Conclusions: The posterior retroperitoneoscopic approach is fast and safe even in patients with Cushing's syndrome. Partial adrenalectomy represents a new option in the treatment of cortisol-producing adenomas.
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http://dx.doi.org/10.1007/s00268-010-0453-0DOI Listing
June 2010

Large effects on body mass index and insulin resistance of fat mass and obesity associated gene (FTO) variants in patients with polycystic ovary syndrome (PCOS).

BMC Med Genet 2010 Jan 21;11:12. Epub 2010 Jan 21.

Department of Child and Adolescent Psychiatry, University of Duisburg-Essen, Essen, Germany.

Background: The polycystic ovary syndrome (PCOS), a common endocrine disorder in women of child-bearing age, mainly characterised by chronic anovulation and hyperandrogenism, is often associated with insulin resistance (IR) and obesity. Its etiology and the role of IR and obesity in PCOS are not fully understood. We examined the influence of validated genetic variants conferring susceptibility to obesity and/or type 2 diabetes mellitus (T2DM) on metabolic and PCOS-specific traits in patients with PCOS.

Methods: We conducted an association study in 386 patients with PCOS (defined by the Rotterdam-criteria) using single nucleotide polymorphisms (SNPs) in or in proximity to the fat mass and obesity associated gene (FTO), insulin-induced gene-2 (INSIG2), transcription factor 7-like 2 gene (TCF7L2) and melanocortin 4 receptor gene (MC4R). To compare the effect of FTO obesity risk alleles on BMI in patients with PCOS to unselected females of the same age range we genotyped 1,971 females from the population-based KORA-S4 study (Kooperative Gesundheitsforschung im Raum Augsburg, Survey 4).

Results: The FTO risk allele was associated with IR traits and measures of increased body weight. In addition, the TCF7L2 SNP was associated with body weight traits. For the SNPs in the vicinity of INSIG2 and MC4R and for the other examined phenotypes there was no evidence for an association. In PCOS the observed per risk allele effect of FTO intron 1 SNP rs9939609 on BMI was +1.56 kg/m2, whereas it was +0.46 kg/m2 in females of the same age range from the general population as shown previously.

Conclusion: The stronger effect on body weight of the FTO SNP in PCOS might well have implications for the etiology of the disease.
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http://dx.doi.org/10.1186/1471-2350-11-12DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824654PMC
January 2010

Diagnostic utility of the glucagon stimulation test in comparison to the insulin tolerance test in patients following pituitary surgery.

Eur J Endocrinol 2010 Mar 8;162(3):477-82. Epub 2009 Dec 8.

Department of Endocrinology, University of Duisburg-Essen, Hufelandstrasse 55, 45122 Essen, Germany.

Objective: The glucagon stimulation test (GST) like the insulin tolerance test (ITT) stimulates both ACTH and GH secretion. However, there are limited data with modern assays on sensitivity and specificity for GST in comparison to ITT. The aim of this study was to evaluate the diagnostic utility of the GST for GH deficiency (GHD) and adrenal insufficiency (AI) in patients following pituitary surgery.

Design And Patients: ITT and GST were performed within 7 days in 49 patients at least 3 months after transsphenoidal surgery. Serum GH and cortisol were measured by Immulite 2000 assay (Siemens AG). Receiver-operating characteristic (ROC) analysis was performed to identify the thresholds for GST.

Results: In ITT, 18/49 cases were classified as AI. ROC analysis revealed a peak cortisol value >599 nmol/l in GST for adrenal sufficiency with 100% specificity and 32% sensitivity, and a peak cortisol <277 nmol/l with >95% specificity and 72% sensitivity for AI. Of the 49 subjects, 25 (51%) demonstrated levels between these cut-offs and could not be diagnosed by GST alone with sufficient accuracy. Regarding GHD, 21/49 cases were classified as insufficient by ITT. ROC analysis revealed a cut-off of 2.5 ng/ml with 95% sensitivity and 79% specificity. Of the 49 cases, seven (14%) were discordant in terms of defining GHD, with six subjects being treated for GHD according to GST although being sufficient in ITT.

Conclusion: In our prospective series of patients with pituitary disease, GST is a potential alternative test for the assessment of GH reserve, but is a poor test for ACTH reserve. Test-specific cut-offs should be applied to avoid misinterpretation.
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http://dx.doi.org/10.1530/EJE-09-0824DOI Listing
March 2010

Apoptotic markers indicate nonalcoholic steatohepatitis in polycystic ovary syndrome.

J Clin Endocrinol Metab 2010 Jan 11;95(1):343-8. Epub 2009 Nov 11.

Department of Endocrinology and Division of Laboratory Research, University of Duisburg-Essen, 45122 Essen, Germany.

Background: Polycystic ovary syndrome (PCOS) characterized by chronic anovulation and hyperandrogenism is highly associated with obesity and insulin resistance (IR), two key features of nonalcoholic steatohepatitis (NASH). NASH often leads to cirrhosis, including portal hypertension, liver failure, and hepatocellular carcinoma as long-term complications. The caspase 3-cleaved fragment of cytokeratin 18 (CK18) emerging from ongoing cell death during apoptosis process has been established as a serum marker for NASH. This study was conducted to evaluate the prevalence of NASH in PCOS patients by caspase-cleaved CK18 measurement.

Methods: In 192 PCOS patients [age, 29.0 +/- 6.7 yr; body mass index (BMI), 31.5 +/- 8.2 kg/m(2)] and 73 age-matched controls (age, 28.6 +/- 8.0 yr; BMI, 24.1 +/- 4.6 kg/m(2)), obesity and IR were determined by BMI and area under the curve of insulin response (AUCI), respectively. Apoptotic cell death was measured by M30 ELISA detecting caspase-cleaved CK18 only.

Results: M30 levels were significantly elevated in PCOS patients after correction for BMI (304.7 +/- 223.1 vs. 86.3 +/- 165.6 U/liter; P < 0.001). M30 correlated significantly with BMI, AUCI, glucose secretion, low-density lipoprotein, low high-density lipoprotein, and free androgen index. AUCI turned out to be the only independent M30-determining factor in the multiple regression analysis with an effect size of 7.9%. Fifty-one of 186 (27.4%) PCOS patients showed M30 levels of at least 395 U/liter, indicating NASH.

Conclusion: These data demonstrate elevation of apoptotic cell death, its correlation with IR, and a high prevalence of NASH in PCOS patients. Given this high prevalence, PCOS may be a risk factor for progressive hepatic sequelae. Incidence data are of strong interest.
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http://dx.doi.org/10.1210/jc.2009-1834DOI Listing
January 2010

Metformin improves polycystic ovary syndrome symptoms irrespective of pre-treatment insulin resistance.

Eur J Endocrinol 2007 Nov;157(5):669-76

Division of Endocrinology, Department of Medicine, University Hospital of Essen Medical School, Hufelandstr. 55, 45122 Essen, Germany.

Objective: Insulin resistance (IR) and obesity are common features of the polycystic ovary syndrome (PCOS). Insulin-sensitizing agents have been shown to improve both reproductive and metabolic aspects of PCOS, but it remains unclear whether it is also beneficial in lean patients without pre-treatment IR. The aim of this study was to determine the influence of metformin on the clinical and biochemical parameters of PCOS irrespective of the presence of basal obesity and IR.

Design: The effect of 6 months of metformin treatment was prospectively assessed in 188 PCOS patients, divided into three groups according to body mass index (BMI; lean: BMI<25 kg/m2, overweight: BMI 25-29 kg/m2, and obese: BMI30 kg/m2). Outcome parameters, which were also assessed in 102 healthy controls, included body weight, homeostasis model assessment for IR (HOMA-IR), fasting glucose and insulin levels, area under the curve of insulin response (AUCI), hyperandrogenism, and menstrual irregularities.

Results: In comparison with the respective BMI-appropriate control groups, only obese but not lean and overweight PCOS patients showed differences in fasting insulin and HOMA-IR. Metformin therapy significantly improved all outcome parameters except fasting glucose levels. Subgroup analyses revealed that in the group of lean PCOS patients without pre-treatment IR, metformin significantly improved HOMA-IR (1.7+/-1.0 vs 1.1+/-0.7 micromol/lxmmol/l2) and fasting insulin levels (7.7+/-4.2 vs 5.4+/-3.9 mU/l), in addition to testosterone levels (2.6+/-0.9 vs 1.8+/-0.7 nmol/l), anovulation rate (2.3 vs 59.5%), and acne (31.8 vs 11.6%; all P<0.017). In the overweight and obese PCOS groups, metformin also showed the expected beneficial effects.

Conclusion: Metformin improves parameters of IR, hyperandrogenemia, anovulation, and acne in PCOS irrespective of pre-treatment IR or obesity.
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http://dx.doi.org/10.1530/EJE-07-0294DOI Listing
November 2007

[Leydig cell tumor as a cause of hirsutism in a postmenopausal woman].

Med Klin (Munich) 2007 Mar;102(3):259-62

Klinik für Endokrinologie, Universitätsklinikum Essen, Essen, Deutschland.

Background: Hirsutism or virilization in postmenopausal women may be due to increased testosterone levels caused by an androgen-secreting tumor. The preoperative localization of small ovarian or adrenal androgen-secreting tumors is difficult.

Case Report: A 61-year-old, postmenopausal woman presented with progressive hirsutism and deepening of voice over the last 9 years. Serum testosterone was very high (almost 30 nmol/l). Computed tomographic (CT) scans of the adrenals and ultrasonography of the pelvis were negative. Selective catheterization and [(18)F]FDG-PET/CT investigation raised the suspicion of an androgen-secreting tumor of the right ovary. Oophorectomy was performed, and a Leydig cell tumor of the right ovary was confirmed on histological examination.

Conclusion: Selective catheterization and [(18)F]FDG-PET investigation may aid the detection of androgen-secreting tumors.
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http://dx.doi.org/10.1007/s00063-007-1032-5DOI Listing
March 2007

C-terminal amino acid alteration rather than late termination causes complete deficiency of thyroxine-binding globulin CD-NeuIsenburg.

J Clin Endocrinol Metab 2006 Aug 30;91(8):3215-8. Epub 2006 May 30.

Division of Endocrinology, Department of Medicine, University Hospital of Essen Medical School, Hufelandstrasse 55, 45122 Essen, Germany.

Context: T(4)-binding globulin (TBG) is the main transport protein for T(4) in blood and a member of the superfamily of serine proteinase inhibitors. So far, 14 mutations leading to familial complete TBG deficiency have been reported. Eleven of these are caused by mutations leading to truncation of the molecule, and three are caused by single amino acid substitutions.

Objective: We report and study the complete deficiency TBG variant found in a patient from NeuIsenburg, Germany (TBG-CDNI).

Methods: Direct DNA sequencing was used to identify the TBG-CDNI mutation in the propositus, which was confirmed by allele-specific amplification. Site-directed mutagenesis and expression in Xenopus oocytes was used to study the secretion defect of TBG-CDNI and several variants by Western blot and T(4)-binding assay.

Results: The deletion of two nucleotides in codon 384 (1211_1212delTC) causes a frameshift altering the last 11 residues, introduces a new glycosylation site, and elongates the molecule by seven new amino acids. In contrast to normal TBG, TBG-CDNI was not secreted by Xenopus oocytes. Elongation of normal TBG by seven alanines did not affect its secretion or binding properties. On the other hand, neither disruption of its new glycosylation site nor termination of TBG-CDNI at the normal length repaired its secretion defect.

Conclusions: In this first late termination variant of complete TBG deficiency, alteration of beta-strand 5B, located in the core of the molecule, rather than elongation of the molecule or introduction of a new glycosylation site, suffices to disrupt secretion of TBG-CDNI.
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http://dx.doi.org/10.1210/jc.2005-2261DOI Listing
August 2006

Characterization and primary structures of bovine and porcine thyroxine-binding globulin.

Mol Cell Endocrinol 2002 Jan;186(1):27-35

Department of Medicine, Division of Endocrinology, Universitatsklinikum Essen, Hufelandstrasse 55, D-45122, Essen, Germany.

Thyroxine-binding globulin (TBG) is the major serum transport protein for iodothyronines in most of the large, omni- or herbivorous mammals. Characterization of human TBG (hTBG), including its 20 known natural variants, allowed the identification of the ligand-binding site and a correlation of diminished synthesis or loss of function with mutations in the TBG gene. Further refinement of the structure-function correlation, especially the high binding affinity and heat stability, requires characterization of other mammalian TBGs, of which only rat and sheep TBG were available. We now present some of the chemical and physical properties of bovine TBG (bTBG) and porcine TBG (pTBG) and their primary structures deduced from their cDNA sequences. The serum concentrations of bTBG and pTBG estimated by Scatchard analysis of T(4)-binding were similar to hTBG. The T(4)-binding affinity of human, bovine and porcine TBGs were all similar, at 1.2x10(10) M(-1). However, heat stability of the animal TBGs was reduced, with a half life of denaturation of 7 min (bTBG) and 5 min (pTBG) at 55 degreeC, compared with 21 min for hTBG. Nucleotide alignment revealed identity with hTBG of 85.5% (bTBG) and 83.7% (pTBG) and amino acid identity of 82.8% (bTBG) and 82.6% (pTBG). As expected, the relevant parts of the ligand-binding domain (amino acids 215-291, and 363-395) were highly conserved at more than 95% similarity. Comparison of the five known mammalian TBGs allows focusing of future mutagenesis experiments to further characterize the properties of the molecule.
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http://dx.doi.org/10.1016/s0303-7207(01)00679-7DOI Listing
January 2002