Publications by authors named "Stephan Petersenn"

102 Publications

International Multicenter Validation Study of the SAGIT ® Instrument in Acromegaly.

J Clin Endocrinol Metab 2021 Jul 27. Epub 2021 Jul 27.

Pituitary Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Context: The SAGIT ® instrument (SAGIT) has been developed to enable accurate characterization of acromegaly disease activity.

Objective: Evaluate the ability of SAGIT to discriminate between acromegaly disease control status.

Design: Multicenter, non-interventional, prospective and retrospective, longitudinal study.

Settings And Patients: Academic and private clinical practice sites; patients aged ≥18 years with diagnosis of controlled (n=109) or non-controlled (n=105) acromegaly, assessed by clinical global evaluation of disease control (CGE-DC) questionnaire, investigator therapeutic decision and international guidelines. Control status was not determined at baseline for 13 patients. As a limited number of patients were enrolled retrospectively (N=9), all presented analyses are based on the prospective population (N=227).

Methods: Patients were assessed over a two-year follow-up period. Classification and regression tree (CART) analyses were performed to investigate how the SAGIT components at baseline (signs/symptoms [S], associated comorbidities [A], GH levels [G], IGF-1 levels [I], tumor features [T]) discriminate between controlled and non-controlled acromegaly.

Results: Baseline mean subscores S, G, I and T, were significantly lower in patients with CGE-DC controlled acromegaly compared with CGE-DC non-controlled acromegaly. SAGIT components I and G for CGE-DC and S, A, G, I and T for the clinician's therapeutic decision were retained by CART analyses. For international guidelines, only SAGIT component I was retained. The risk for undergoing at least one treatment change during the study for patients with CGE-DC non-controlled acromegaly relative to CGEDC controlled acromegaly was 3.44 times greater.

Conclusion: The SAGIT instrument is a valid and sensitive tool to comprehensively and accurately assess acromegaly severity.
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http://dx.doi.org/10.1210/clinem/dgab536DOI Listing
July 2021

Multicenter, Observational Study of Lanreotide Autogel for the Treatment of Patients with Neuroendocrine Tumors in Routine Clinical Practice in Germany and Austria.

Exp Clin Endocrinol Diabetes 2021 Jul 22;129(7):500-509. Epub 2021 Jul 22.

ENDOC Center for Endocrine Tumors, Hamburg, Germany.

Background: The long-acting somatostatin analog lanreotide autogel is effective in the treatment of patients with neuroendocrine tumors.

Objective: To evaluate the long-term treatment response in patients with neuroendocrine tumors receiving lanreotide autogel in routine clinical practice.

Methods: Non-interventional, 24-month study in patients with neuroendocrine tumors treated with lanreotide autogel (NCT01840449).

Results: Patients (n=80) from 26 centers in Germany and Austria were enrolled. Neuroendocrine tumors were mainly grade 1/2, metastasized, intestinal, and associated with carcinoid syndrome; 88.9% had received previous neuroendocrine tumor treatment. Of those, 84.4% had previous surgery, 18.7% had received octreotide. The primary endpoint, defined by a <50% chromogranin A increase at month 12 compared with the lowest value between baseline and month 3 was achieved by 89.5% patients. Stable disease according to Response Evaluation Criteria in Solid Tumors 1.1 was observed in 76.9 and 75.0% patients at months 12 and 24 of lanreotide treatment, respectively. Mean change of chromogranin A levels from baseline to month 24 was -0.12 × upper limit of normal (95% CI, -0.22; -0.45). In a post hoc analysis, 38.5% of the subgroup of patients with carcinoid syndrome had daily diarrhea at baseline vs. 21.4% at month 24. At baseline, 27.8% of patients received lanreotide 120 mg every 4 weeks vs. 56.7% at month 24. Quality of life data were heterogeneous. No new safety issues arose and/or required further investigation.

Conclusions: Our study reflects routine lanreotide autogel use in patients with advanced/metastatic neuroendocrine tumors. This analysis shows effectiveness with stabilization of disease-related symptoms and good tolerability of lanreotide autogel in clinical practice.
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http://dx.doi.org/10.1055/a-1342-2755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8298132PMC
July 2021

Biochemical diagnosis of Cushing's disease: Screening and confirmatory testing.

Best Pract Res Clin Endocrinol Metab 2021 01 15;35(1):101519. Epub 2021 Mar 15.

ENDOC Center for Endocrine Tumors, Hamburg, Germany. Electronic address:

Due to the variable clinical features and its rarity diagnosis of Cushing's disease (CD) is often delayed. Clearly, awareness for CD needs to be raised, accompanied by the availability of simple and accurate screening tests. Late-night salivary cortisol (LNSC), 1 mg dexamethasone suppression test (DST), and urinary free cortisol (UFC) have all been extensively studied, demonstrating high sensitivity and specificity for the diagnosis of Cushing's syndrome. However, each of those well-established tests has its own distinctive features, making it preferable in specific clinical conditions and patient groups. To choose the most appropriate test in individual patients, an expert endocrinologist should be consulted. This review will discuss the pitfalls for each of those tests.
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http://dx.doi.org/10.1016/j.beem.2021.101519DOI Listing
January 2021

Medical Therapy of Aggressive Pituitary Tumors.

Exp Clin Endocrinol Diabetes 2021 Mar 9;129(3):186-193. Epub 2021 Mar 9.

ENDOC Center for Endocrine Tumors, Hamburg, Germany.

The rare aggressive pituitary adenoma presents a special challenge, due to the heterogenous presentation of the disease. The prognosis of aggressive pituitary adenomas has been improved due to recent studies demonstrating clinically-relevant efficacy of temozolomide, which is now considered first-line chemotherapy. However, there is limited data on second-line therapies in patients with treatment failure. This review presents a summary on the potential of medical therapies in aggressive pituitary tumors.
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http://dx.doi.org/10.1055/a-1331-6939DOI Listing
March 2021

Multicenter, Observational Study of Lanreotide Autogel for the Treatment of Patients with Acromegaly in Routine Clinical Practice in Germany, Austria and Switzerland.

Exp Clin Endocrinol Diabetes 2021 Mar 7;129(3):224-233. Epub 2020 Dec 7.

ENDOC Center for Endocrine Tumors, Hamburg.

Background: Evidence from controlled trials has shown that lanreotide autogel is effective in achieving biochemical and symptom control in patients with acromegaly. However, it is important to better understand the real-world patient population receiving lanreotide autogel treatment.

Methods: In this non-interventional study the long-term treatment response to lanreotide autogel in adult patients with acromegaly from office-based centers or clinics in Germany, Austria and Switzerland was studied. Assessments included growth hormone and insulin-like growth factor-I levels, symptoms, quality of life, lanreotide plasma levels and tumor somatostatin receptor subtype expression. The primary endpoint was achievement of full biochemical control, defined as growth hormone ≤2.5 µg/L and insulin-like growth factor I normalization at month 12.

Results: 76 patients were enrolled from 21 sites. 7/51 (13.7%) patients of the efficacy population had full biochemical control at baseline, 15/33 (45.5%) at month 12 and 10/26 (38.5%) at month 24 of treatment. At 12 months of treatment higher rates of biochemical control were observed in the following subgroups: older patients (>53 years [median]), females, treatment-naïve patients, and patients with a time since diagnosis of longer than 1.4 years (median). No clinically relevant differences in acromegaly symptoms or quality of life scores were observed. Median fasting blood glucose and glycated hemoglobin levels remained unchanged throughout the study. No new safety signals were observed. Overall tolerability of treatment with lanreotide autogel was judged by 80.8% of the enrolled patients at month 12 as 'very good' or 'good'.

Conclusion: Treatment with lanreotide autogel in a real-world setting showed long-term effectiveness and good tolerability in patients with acromegaly.
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http://dx.doi.org/10.1055/a-1247-4713DOI Listing
March 2021

Bevacizumab in Aggressive Pituitary Adenomas - Experience with 3 Patients.

Exp Clin Endocrinol Diabetes 2021 Mar 7;129(3):178-185. Epub 2020 Dec 7.

Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.

Objective: To investigate bevacizumab as alternative treatment of aggressive pituitary adenomas after exhaustion of standard therapies.

Design And Methods: Retrospectively, 3 patients undergoing microscopic transsphenoidal surgery of aggressive pituitary adenomas from 2008 till 2018 that were treated with bevacizumab were identified. Development of disease and treatment were evaluated.

Results: Two patients suffered from ACTH-secreting adenomas, one from a non-functioning adenoma. All patients underwent multiple surgical, chemo- and radiotherapeutical approaches including temozolomide, showing favorable results in one patient. Deterioration of clinical condition in all patients led to an individual, palliative attempt of bevacizumab. Patients 1 and 2 showed a decrease of ACTH after first administrations, but therapy had to be ended shortly after due to a further deterioration of their condition. Patient 3 showed a stabilization of the disease for 18 months. Patients died 8, 15 and 7 years after initial diagnosis, respectively, and 2, 4, and 24 months after initiation of bevacizumab therapy, respectively.

Conclusion: The demonstrated results suggest a considerable effect of bevacizumab in aggressive pituitary adenomas. The advanced stage of disease in all three patients, the overall short period of administration and just one patient showing a clinical benefit do not allow a general statement on the effectiveness. At the current stage of clinical experience, an approach with bevacizumab can be considered as an individual palliative attempt of treatment, when standard treatments are exhausted. Our results underline the need for further studies to evaluate this drug as potential player in therapy resistant aggressive pituitary tumors.
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http://dx.doi.org/10.1055/a-1260-3975DOI Listing
March 2021

Multidisciplinary management of acromegaly: A consensus.

Rev Endocr Metab Disord 2020 12 10;21(4):667-678. Epub 2020 Sep 10.

Medical Research Unit in Endcrine Diseases, Hospital de Especialidades, Centro Médico Nacional, Siglo XXI, IMSS, Facultad de Medicina, Universidad Nacional Autónoma de México, Mexico City, Mexico.

The 13th Acromegaly Consensus Conference was held in November 2019 in Fort Lauderdale, Florida, and comprised acromegaly experts including endocrinologists and neurosurgeons who considered optimal approaches for multidisciplinary acromegaly management. Focused discussions reviewed techniques, results, and side effects of surgery, radiotherapy, and medical therapy, and how advances in technology and novel techniques have changed the way these modalities are used alone or in combination. Effects of treatment on patient outcomes were considered, along with strategies for optimizing and personalizing therapeutic approaches. Expert consensus recommendations emphasize how best to implement available treatment options as part of a multidisciplinary approach at Pituitary Tumor Centers of Excellence.
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http://dx.doi.org/10.1007/s11154-020-09588-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7942783PMC
December 2020

Are aggressive pituitary tumors and carcinomas two sides of the same coin? Pathologists reply to clinician's questions.

Rev Endocr Metab Disord 2020 Jun;21(2):243-251

Pathology Department, Foch Hospital, 40 rue Worth, 92151, Suresnes, France.

Pituitary adenohypophyseal tumors are considered as benign and termed "adenomas". However, many tumors are invasive and a proportion of these exhibit an "aggressive behavior" with premature death due to progressive growth. Only very rare (0.2%) tumors with metastases are considered malignant and termed "carcinomas". Taking into account this variability in behavior and the oncological definition, pathologists have proposed changing the term adenoma to tumor. Here we explain why use the term tumor instead of adenoma and identify tumor characteristics, associated with a high risk for poor prognosis. In a cohort of 125 tumors with aggressive behavior (APT) and 40 carcinomas with metastases (PC), clinical and pathological features were very similar. The comparison of this cohort (APT+PC) with a reference surgical cohort of 374 unselected patients clearly shows that the two cohorts differ greatly, especially the percentage of tumors with Ki67 ≥ 10% (35%vs3%; p < 0.001). A five-tiered prognostic classification, associating invasion and proliferation, identified grade 2b tumors (invasive and proliferative), with a high risk of recurrence/progression. Because half of the APT+ PC tumors have a Ki67 index ≥10%, and 80% of them show 2 or 3 positive markers of proliferation, we suggest that tumors that are clinically aggressive, invasive and highly proliferative with a Ki67 ≥ 10%, represent tumors with malignant potential. The percentage of grade 2b tumors, suspected of malignancy, which will become aggressive tumors or carcinomas is unknown. It is probably very low, but higher than 0.2% in surgical series. Early identification and active treatment of these aggressive tumors is needed to decrease morbidity and prolong survival.
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http://dx.doi.org/10.1007/s11154-020-09562-9DOI Listing
June 2020

Targeted systemic and peptide radio-ligand therapy for aggressive pituitary tumors and carcinomas.

Rev Endocr Metab Disord 2020 Jun;21(2):277-286

Departments of Medicine & Neurosurgery (1&2), University of California, Los Angeles, USA.

Aggressive pituitary tumors comprise a rare but challenging subset of pituitary tumors. A major issue currently is the absence of a holistic definition that reliably identifies these tumors in a prospective manner. Although comprehensive evaluation of patient gender, age, local invasiveness, treatment responses, radiological and histopathological features may be informative to assess the potential for aggressiveness, a definitive diagnosis of this entity cannot be confidently made until disease progression is actually observed despite standard medical and surgical therapy. Failure to diagnose these aggressive pituitary tumors early may impede initiation of suitable intensive stepwise multimodal treatments, and lessen their ultimate therapeutic success. Even though current therapeutic options for aggressive pituitary tumors are suboptimal in many cases, large-scale randomized prospective clinic trials are impractical and will likely never be conducted due to the rarity of this disease entity. Therefore, the majority of novel therapies in this subset of tumors derive from case reports or small case series, which greatly reduces their validity to make strong recommendations. This chapter, as part of this series on aggressive pituitary tumors, focuses on the role of systemic targeted medical and peptide radio-receptor therapy in treatment of aggressive pituitary tumors and carcinomas, and discusses future directions in these fields.
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http://dx.doi.org/10.1007/s11154-020-09554-9DOI Listing
June 2020

Diagnosis and management of prolactinomas: current challenges.

Pituitary 2020 02;23(1):1-2

Endocrinology Unit, Ospedale San Raffaele and Università Vita-Salute San Raffaele, Milan, Italy.

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http://dx.doi.org/10.1007/s11102-019-01025-yDOI Listing
February 2020

Predictive factors for responses to primary medical treatment with lanreotide autogel 120 mg in acromegaly: post hoc analyses from the PRIMARYS study.

Pituitary 2020 Apr;23(2):171-181

Department of Endocrinology and Metabolic Diseases, CHU Larrey, Toulouse, France.

Purpose: PRIMARYS (NCT00690898) was a 48-week, open-label, phase 3b study, evaluating treatment with the somatostatin receptor ligand lanreotide autogel (stable dose: 120 mg/28 days) in treatment-naïve patients with growth hormone (GH)-secreting pituitary macroadenoma. This post hoc analysis aimed to evaluate factors predictive of long-term responses.

Methods: Potential predictive factors evaluated were: sex, age, and body mass index at baseline; and GH, insulin-like growth factor-1 (IGF-1), and tumor volume (TV) at baseline and week 12, using univariate regression analyses. Treatment responses were defined as hormonal control (GH ≤ 2.5 µg/L and age- and sex-normalized IGF-1), tight hormonal control (GH < 1.0 µg/L and normalized IGF-1), or ≥ 20% TV reduction (TVR). Receiver-operating-characteristic (ROC) curves were constructed using predictive factors significant in univariate analyses. Cut-off values for predicting treatment responses at 12 months were derived by maximizing the Youden index (J).

Results: At baseline, older age, female sex, and lower IGF-1 levels were associated with an increased probability of achieving long-term hormonal control. ROC area-under-the curve (AUC) values for hormonal control were high for week-12 GH and IGF-1 levels (0.87 and 0.93, respectively); associated cut-off values were 1.19 μg/L and 110% of the upper limit of normal (ULN), respectively. Results were similar for tight hormonal control (AUC values: 0.92 [GH] and 0.87 [IGF-1]; cut-off values: 1.11 μg/L and 125% ULN, respectively). AUC and J values associated with TVR were low.

Conclusions: The use of predictive factors at baseline and week 12 of treatment could inform clinical expectations of the long-term efficacy of lanreotide autogel.
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http://dx.doi.org/10.1007/s11102-019-01020-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066297PMC
April 2020

Biochemical diagnosis in prolactinomas: some caveats.

Pituitary 2020 Feb;23(1):9-15

ENDOC Center for Endocrine Tumors, Erik-Blumenfeld-Platz 27a, 22587, Hamburg, Germany.

Prolactinomas are the most frequently seen pituitary adenomas in clinical practice. A correct biochemical diagnosis of hyperprolactinemia is a prerequisite for further investigation but may be hampered by analytical difficulties as well as a large number of potentially overlapping conditions associated with increased prolactin levels. Suspicion should rise in patients whose symptoms and biochemical results do not match. Assay problems, macroprolactinemia, and high-dose hook effect are discussed as possible reasons for false positive or false negative prolactin levels. Physiological and pathological causes of hyperprolactinemia and their implications for interpreting prolactin results are reviewed.
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http://dx.doi.org/10.1007/s11102-019-01024-zDOI Listing
February 2020

[Hypoparathyroidism - un underestimated problem?]

MMW Fortschr Med 2019 12;161(Suppl 7):12-20

MVZ Endokrinologikum Göttingen, Zentrum für Hormon- und Stoffwechselerkrankungen, Nuklearmedizin und Humangenetik, Göttingen, Deutschland.

Background: Hypoparathyroidism is a rare and disabilitating disorder characterized by hypocalcemia and low parathyroid hormone levels. Most of the cases occur as a result of the removal of parathyroid glands or damage to the glands during neck surgery. More rare causes include nonsurgical causes such as autoimmune or genetic diseases.

Method: In this review, a panel of experts presents the current state of diagnosis and therapy of hypoparathyroidism and explains practical aspects of caring for the affected patients.

Results: Common signs and symptoms are abnormal sensations and increased excitability in the lower limbs, paresthesia of perioral areas and nocturnal leg cramps. Renal complications frequently occur, but also basal ganglia calcification. Treatment consists of administration of vitamin D analogs in combination with 0.5-1.0 g calcium daily. An adjunctive treatment with the in April 2017 approved recombinant human parathyroid hormone (1-84) is an option for patients whose hypoparathyroidism is difficult to control by conventional treatment alone. Initially and after dose changes follow-up controls should be performed at least every 2 weeks, in well-controlled patients or in the case of chronic progression every 3-6 months.
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http://dx.doi.org/10.1007/s15006-019-1174-4DOI Listing
December 2019

Management of Aggressive Pituitary Tumors - A 2019 Update.

Horm Metab Res 2019 Dec 11;51(12):755-764. Epub 2019 Dec 11.

ENDOC, Center for Endocrine Tumors, Hamburg, Germany.

With a prevalence of 80-100/100000, pituitary adenomas are more frequent than thought. The rare aggressive pituitary adenoma presents a special challenge, due to the heterogenous presentation of the disease. The prognosis of aggressive pituitary adenomas has been improved due to recent studies demonstrating some efficacy of chemotherapy with temozolomide. However, there is very limited data on second-line therapies in patients with treatment failure. This review presents an update on the diagnostic and therapeutic management of aggressive pituitary tumors. Patients should be treated by a team consisting of an expert endocrinologist, neurosurgeon, radiation oncologist, and pathologist, and according to the recently published ESE guideline.
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http://dx.doi.org/10.1055/a-1060-1883DOI Listing
December 2019

Use of late-night salivary cortisol to monitor response to medical treatment in Cushing's disease.

Eur J Endocrinol 2020 Feb;182(2):207-217

Neuroendocrine Clinical Center, Massachusetts General Hospital, Boston, Massachusetts, USA.

Objective: Monitoring of patients with Cushing's disease on cortisol-lowering drugs is usually performed with urinary free cortisol (UFC). Late-night salivary cortisol (LNSC) has an established role in screening for hypercortisolism and can help to detect the loss of cortisol circadian rhythm. Less evidence exists regarding the usefulness of LNSC in monitoring pharmacological response in Cushing's disease.

Design: Exploratory analysis evaluating LNSC during a Phase III study of long-acting pasireotide in Cushing's disease (clinicaltrials.gov: NCT01374906).

Methods: Mean LNSC (mLNSC) was calculated from two samples, collected on the same days as the first two of three 24-h urine samples (used to calculate mean UFC [mUFC]). Clinical signs of hypercortisolism were evaluated over time.

Results: At baseline, 137 patients had evaluable mLNSC measurements; 91.2% had mLNSC exceeding the upper limit of normal (ULN; 3.2 nmol/L). Of patients with evaluable assessments at month 12 (n = 92), 17.4% had both mLNSC ≤ULN and mUFC ≤ULN; 22.8% had mLNSC ≤ULN, and 45.7% had mUFC ≤ULN. There was high variability in LNSC (intra-patient coefficient of variation (CV): 49.4%) and UFC (intra-patient CV: 39.2%). mLNSC levels decreased over 12 months of treatment and paralleled changes in mUFC. Moderate correlation was seen between mLNSC and mUFC (Spearman's correlation: ρ = 0.50 [all time points pooled]). Greater improvements in systolic/diastolic blood pressure and weight were seen in patients with both mLNSC ≤ULN and mUFC ≤ULN.

Conclusion: mUFC and mLNSC are complementary measurements for monitoring treatment response in Cushing's disease, with better clinical outcomes seen for patients in whom both mUFC and mLNSC are controlled.
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http://dx.doi.org/10.1530/EJE-19-0695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7003692PMC
February 2020

Efficacy of Temozolomide Therapy in Patients With Aggressive Pituitary Adenomas and Carcinomas-A German Survey.

J Clin Endocrinol Metab 2020 03;105(3)

Department of Neurosurgery, University of Tuebingen, Tuebingen, Germany.

Context: Despite growing evidence that temozolomide (TMZ) therapy is effective for the treatment of aggressive pituitary tumors (APTs) or carcinomas (PCs), individual therapy decisions remain challenging.

Objective: We therefore aimed to report on clinical characteristics leading to initiation of TMZ therapy and to add evidence on TMZ long-term effectiveness.

Design And Subjects: Retrospective survey on TMZ treatment in patients with APTs or PCs. TMZ therapy was initiated in 47 patients (22 females) with APTs (n = 34) or PCs (n = 13). Mean age at diagnosis was 45 ± 15 years. The immunohistochemical subtypes were corticotroph (n = 20), lactotroph (n = 18), and nonfunctioning (n = 9) tumors. TMZ therapy started 8 years after initial diagnosis using a standard regimen (median 6 cycles) for the majority of patients.

Results: Long-term radiological response to TMZ after a median follow-up of 32 months with 4 patients still on TMZ therapy was tumor regression for 9 (20%), stable disease for 8 (17%), and tumor progression for 29 patients (63%) (outcome data available for 46 patients). Progression occurred 16 months after initiation of TMZ. Median estimated progression-free survival was 23 months. Disease stabilization and median progression-free survival did not differ between patients with APTs or PCs. Predictors of tumor response were not identified. Overall, TMZ was well tolerated.

Conclusion: We performed a nationwide survey on TMZ therapy in patients with APTs and PCs. While early response rates to TMZ are promising, long-term outcome is less favorable. Prolonged TMZ administration should be considered. We were not able to confirm previously reported predictors of tumor response to TMZ.
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http://dx.doi.org/10.1210/clinem/dgz211DOI Listing
March 2020

A Consensus on the Diagnosis and Treatment of Acromegaly Comorbidities: An Update.

J Clin Endocrinol Metab 2020 04;105(4)

Department of Medicine, CIBERER, Universidad Autónoma de Madrid, Madrid, Spain.

Objective: The aim of the Acromegaly Consensus Group was to revise and update the consensus on diagnosis and treatment of acromegaly comorbidities last published in 2013.

Participants: The Consensus Group, convened by 11 Steering Committee members, consisted of 45 experts in the medical and surgical management of acromegaly. The authors received no corporate funding or remuneration.

Evidence: This evidence-based consensus was developed using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system to describe both the strength of recommendations and the quality of evidence following critical discussion of the current literature on the diagnosis and treatment of acromegaly comorbidities.

Consensus Process: Acromegaly Consensus Group participants conducted comprehensive literature searches for English-language papers on selected topics, reviewed brief presentations on each topic, and discussed current practice and recommendations in breakout groups. Consensus recommendations were developed based on all presentations and discussions. Members of the Scientific Committee graded the quality of the supporting evidence and the consensus recommendations using the GRADE system.

Conclusions: Evidence-based approach consensus recommendations address important clinical issues regarding multidisciplinary management of acromegaly-related cardiovascular, endocrine, metabolic, and oncologic comorbidities, sleep apnea, and bone and joint disorders and their sequelae, as well as their effects on quality of life and mortality.
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http://dx.doi.org/10.1210/clinem/dgz096DOI Listing
April 2020

Clinical Situation, Therapy, and Follow-Up of Adult Craniopharyngioma.

J Clin Endocrinol Metab 2020 01;105(1)

Department of Neurosurgery, Hamburg University Medical Center, Hamburg, Germany.

Context: Craniopharyngioma is a rare neoplastic entity of the central nervous system. Childhood-onset craniopharyngioma is the subject of frequent research whereas the information on adult-onset craniopharyngioma is scarce.

Objective: The objective of this study was to examine the level of daily impairment in adult patients suffering from craniopharyngioma.

Design: Noninterventional patient registry indexed as PV4842 with the local ethics committee.

Setting: The study is set in a hospitalized and ambulatory setting.

Patients: 148 patients with adult-onset craniopharyngioma were recruited from 8 centers, 22 prospectively and 126 retrospectively. Mean follow-up was 31 months.

Interventions: No interventions performed.

Main Outcome Measures: Complications, symptoms, body mass index (BMI), and quality of life (QoL; EORTC QLQ C30 and BN20) were recorded preoperatively and at follow-up. The hypotheses tested were generated after data collection.

Results: Complications were more frequent after transcranial than transsphenoidal approaches (31 % vs. 11%; P < 0.01). Preoperative obesity was present in 0% papillary and in 38% of all adamantinomatous craniopharyngiomas (P = 0.05), and diabetes insipidus was more frequent for papillary craniopharyngioma (36.8% vs. 16,7%; P < 0.05). Hormone deficits at follow-up were reduced in 16.9%, equal in 31.4%, and increased in 63.6% (P < 0.001). BMI increased from 28.7 ± 7.4 kg/m2 before surgery to 30.2 ± 7.4 kg/m2 at follow-up (P < 0.001). In QoL, a decrease of future uncertainty (62.5 vs. 36.8; P = 0.02) and visual disorders (38.9 vs. 12.0; P = 0.01) were observed in the prospective collective after surgery.

Conclusions: Adult craniopharyngioma is associated with a complex sociological and psychological burden and hypothalamic dysfunction, warranting further investigation and emphasizing the need for a wider treatment approach.
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http://dx.doi.org/10.1210/clinem/dgz043DOI Listing
January 2020

Long-term efficacy and safety of once-monthly pasireotide in Cushing's disease: A Phase III extension study.

Clin Endocrinol (Oxf) 2019 12 1;91(6):776-785. Epub 2019 Oct 1.

University of Sheffield, Sheffield, UK.

Objectives: Many patients with Cushing's disease (CD) require chronic pharmacotherapy to control their hypercortisolism. We evaluated the efficacy and safety of long-acting pasireotide during a long-term extension study in patients with CD.

Design: Open-label extension to a 12-month Phase III study of long-acting pasireotide in CD (N = 150; NCT01374906).

Patients: Patients with mean urinary free cortisol (mUFC) ≤ upper limit of normal (ULN) or receiving clinical benefit at core study end could continue long-acting pasireotide during the extension.

Results: Eighty-one of 150 (54.0%) enrolled patients entered the extension. Median overall exposure to pasireotide at study end was 23.9 months; 39/81 (48.1%) patients completed the extension (received ≥ 12 months' treatment during the extension and could transit to a separate pasireotide safety study). mUFC was ≤ULN in 42/81 (51.9%), 13/81 (16.0%) and 43/81 (53.1%) patients at extension baseline, month (M) 36 and last assessment. Median mUFC remained within normal limits. Median late-night salivary cortisol was 2.6 × ULN at core baseline and 1.3 × ULN at M36. Clinical improvements were sustained over time. Forty-two (51.9%) patients discontinued during the extension: 25 (30.9%) before M24 and 17 (21.0%) after M24. Hyperglycaemia-related AEs occurred in 39.5% of patients. Mean fasting glucose (FPG) and glycated haemoglobin (HbA ) were stable during the extension, with antidiabetic medication initiated/escalated in some patients. Sixty-six (81.5%) and 71 (88.9%) patients were classified as having diabetes (HbA  ≥ 6.5%, FPG ≥ 7.0 mmol/L, antidiabetic medication use, or history of diabetes) at extension baseline and last assessment.

Conclusions: Long-acting pasireotide provided sustained biochemical and clinical improvements, with no new safety signals emerging, supporting its use as an effective long-term therapy for CD.
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http://dx.doi.org/10.1111/cen.14081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899900PMC
December 2019

Staging and managing patients with acromegaly in clinical practice: baseline data from the SAGIT® validation study.

Pituitary 2019 Oct;22(5):476-487

Cedars-Sinai Medical Center, Los Angeles, CA, USA.

Purpose: The SAGIT® instrument, designed to assist clinicians to stage acromegaly, assess treatment response and adapt patient management, was well received by endocrinologists in a pilot study. We report an interim analysis of baseline data from the validation phase.

Methods: The SAGIT® validation study (ClinicalTrials.gov NCT02539927) is an international, non-interventional study. Data collection included: demographic/disease characteristics; medical/surgical histories; concomitant acromegaly treatments; investigators' subjective evaluation of disease-control status (clinical global evaluation of disease control [CGE-DC]; controlled/not controlled/yet to be clarified) and clinical disease activity (active/not active); growth hormone (GH) and insulin-like growth factor-1 (IGF-1) levels; investigators' therapeutic decision.

Results: Of 228 patients enrolled, investigators considered disease to be controlled in 110 (48.2%), not controlled in 105 (46.1%), and yet to be clarified in 13 (5.7%) according to CGE-DC. Thirty-three patients were treatment-naïve (not controlled, n = 31; yet to be clarified, n = 2). Investigators considered 48.2% patients in the controlled and 95.2% in the not-controlled groups to have clinically active disease. In the controlled group, 29.7% of patients did not exhibit hormonal control (GH ≤ 2.5 µg/L; normalized IGF-1) and 47.3% did not have rigorous hormonal control (GH < 1.0 µg/L; normalized IGF-1) by contemporary consensus. Current acromegaly treatment was continued with no change for 91.8% of patients in the controlled and 40.0% in the not-controlled groups.

Conclusions: These data highlight discrepancies between investigator-evaluated disease-control status, disease activity, hormonal control, and treatment decisions in acromegaly. Once validated, the SAGIT® instrument may assist clinicians in making active management decisions for patients with acromegaly.
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http://dx.doi.org/10.1007/s11102-019-00977-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728296PMC
October 2019

Pituitary Disease in Pregnancy: Special Aspects of Diagnosis and Treatment?

Geburtshilfe Frauenheilkd 2019 Apr 6;79(4):365-374. Epub 2019 Mar 6.

Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München, Germany.

The diagnosis and treatment of pituitary disease in pregnancy represents a special clinical challenge. Not least because there is very little data on the treatment of pregnant patients with pituitary disorders. A selective search of the literature was carried out with the aim of compiling evidence about the diagnosis and treatment of pituitary disease in pregnancy. The search covered the databases PubMed/MEDLINE including PubMed Central and also used the Livivo (ZB MED) search engine. Recent studies were evaluated for recommendations about the care of pregnant patients with hormone-inactive and hormone-active pituitary adenomas (prolactinoma, acromegaly and Cushing's disease), pituitary insufficiency, pituitary apoplexy and hypophysitis. The most well-established forms of treatment are for prolactinoma, due to the incidence of this disease and its impact on fertility. When pregnancy has been confirmed, prolactinoma treatment with dopamine agonists should be paused. Although microprolactinomas rarely increase significantly in size after the administration of dopamine agonists is discontinued, symptomatic tumor growth of macroprolactinomas can occur. In such cases, treatment with dopamine agonists can be resumed. If the primary tumor is large and the risk that it will continue to grow is high, it may be necessary to continue medical treatment from the start of pregnancy. If one of the partners has a pituitary disorder, it is often still possible for many couples to achieve their wish of having children if they receive medical support to plan and the pregnancy is carefully monitored. Given the complexity of pituitary disease, pregnant patients with pituitary disorders should be cared for and treated by a multidisciplinary team in centers specializing in the diagnosis and treatment of pituitary disease.
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http://dx.doi.org/10.1055/a-0794-7587DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461462PMC
April 2019

MRI T2 signal intensity and tumor response in patients with GH-secreting pituitary macroadenoma: PRIMARYS post-hoc analysis.

Eur J Endocrinol 2018 12 1. Epub 2018 Dec 1.

P Caron, Department of Endocrinology and Metabolic Diseases, Centre Hospitalier Universitaire Larrey, Toulouse, France.

Objective Pituitary adenoma MRI T2 signal intensity associates with tumor characteristics including responsiveness to somatostatin analogs (SSAs). These analyses determined whether baseline T2 signal intensity predicts response to primary medical treatment with long-acting SSA. Design Post-hoc analyses of the prospective multicenter, open-label, single-arm PRIMARYS study in which patients with treatment-naïve GH-secreting pituitary macroadenomas received fixed-dose lanreotide autogel (120mg) every 4-weeks for 48-weeks. Methods Associations were investigated between adenoma T2-signal hypo/iso/hyperintensity and treatment responses at week 48/last visit: hormonal control (GH ≤2.5μg/L and IGF-1 normalization); tumor response (tumor volume reduction [TVR] ≥20%); separate GH/IGF-1 control; and change-from-baseline in GH/IGF-1 and tumor volume. Results Adenomas were hypointense at baseline in 50/85 (59%) patients using visual assessment. Of these, 40% achieved hormonal control and 76% achieved a tumor response. Significant univariate associations arose for hypo- vs isointensity with tumor response and achievement of GH ≤2.5 μg/L, but not IGF-1 normalization or overall hormonal control. In multivariate analysis, tumor response was 6-times more likely for hypo- vs isointense tumors (=6.15; 95% CI [1.36;27.88]). In univariate change-from-baseline analyses, hypo- vs isointensity was associated with greater TVR and IGF-1 reduction but not change in GH. In multivariate analysis, IGF-1 decreased by an estimated additional 65 μg/L [P=0.0026]) for hypo- vs isointense. Conclusions Patients with hypointense vs isointense GH-secreting macroadenomas had greater reductions in IGF-1 following primary treatment with lanreotide autogel, and were more likely to achieve tumor response. Assessment of T2 signal intensity at baseline may help to predict long-term responses to primary treatment with SSAs.
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http://dx.doi.org/10.1530/EJE-18-0254DOI Listing
December 2018

Aggressive pituitary tumours and carcinomas: two sides of the same coin?

Eur J Endocrinol 2018 Jun 27;178(6):C7-C9. Epub 2018 Mar 27.

Faculté de Médecine Lyon Est, Université Lyon 1, Lyon, France.

The European Society of Endocrinology (ESE) survey reported on the largest cohort of 125 aggressive pituitary tumours (APT) and 40 pituitary carcinomas (PC). Whilst the survey focused on treatment effectiveness, all pathological data were not explored in detail. Here, we comment on some interesting pathological findings, notably the difference between APT and PC.
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http://dx.doi.org/10.1530/EJE-18-0250DOI Listing
June 2018

Secondary adrenal insufficiency in pregnancy: any differences?

Minerva Endocrinol 2018 Dec 15;43(4):446-450. Epub 2018 Mar 15.

ENDOC Center for Endocrine Tumors, Hamburg, Germany -

Secondary adrenal insufficiency may pose specific challenges during pregnancy. The interpretation of diagnostic tests is hindered by physiological adaptations of the hypothalamic-pituitary-adrenal axis. Due the relevant increases in cortisol-binding globulin, measurement of salivary cortisol may be preferable, but lacks sufficiently established cut-offs both for early-morning evaluation and during dynamic testing. Hydrocortisone should be used for replacement to avoid overexposure of the fetus, with dose adjustments according to clinical judgement. To account for increased free cortisol levels during the course of pregnancy, hydrocortisone may be increased by 5-7.5 mg in the third trimester. Patients should be seen at least once every trimester. Counseling of patients is of special importance to manage hyperemesis and infections. For labor, sufficient stress doses need to be applied.
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http://dx.doi.org/10.23736/S0391-1977.18.02840-7DOI Listing
December 2018

Pituitary disease management during pregnancy: an overview.

Minerva Endocrinol 2018 Dec 15;43(4):420-422. Epub 2018 Mar 15.

ENDOC Center for Endocrine Tumors, Hamburg, Germany -

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http://dx.doi.org/10.23736/S0391-1977.18.02835-3DOI Listing
December 2018

Editorial : Neuroendocrine neoplasms.

Rev Endocr Metab Disord 2017 Dec;18(4):379-380

ENDOC Center, Hamburg, Germany.

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http://dx.doi.org/10.1007/s11154-018-9441-8DOI Listing
December 2017

Treatment of aggressive pituitary tumours and carcinomas: results of a European Society of Endocrinology (ESE) survey 2016.

Eur J Endocrinol 2018 03 12;178(3):265-276. Epub 2018 Jan 12.

Department of Endocrinology, Skåne University Hospital Malmö, University of Lund, Lund, Sweden.

Objective: To collect outcome data in a large cohort of patients with aggressive pituitary tumours (APT)/carcinomas (PC) and specifically report effects of temozolomide (TMZ) treatment.

Design: Electronic survey to ESE members Dec 2015-Nov 2016.

Results: Reports on 166 patients (40 PC, 125 APT, 1 unclassified) were obtained. Median age at diagnosis was 43 (range 4-79) years. 69% of the tumours were clinically functioning, and the most frequent immunohistochemical subtype were corticotroph tumours (45%). Ki-67 index did not distinguish APT from PC, median 7% and 10% respectively. TMZ was first-line chemotherapy in 157 patients. At the end of the treatment (median 9 cycles), radiological evaluation showed complete response (CR) in 6%, partial response (PR) in 31%, stable disease (SD) in 33% and progressive disease in 30%. Response was more frequent in patients receiving concomitant radiotherapy and TMZ. CR was seen only in patients with low MGMT expression. Clinically functioning tumours were more likely to respond than non-functioning tumours, independent of MGMT status. Of patients with CR, PR and SD, 25, 40 and 48% respectively progressed after a median of 12-month follow-up. Other oncological drugs given as primary treatment and to TMZ failures resulted in PR in 20%.

Conclusion: This survey confirms that TMZ is established as first-line chemotherapeutic treatment of APT/PC. Clinically functioning tumours, low MGMT and concurrent radiotherapy were associated with a better response. The limited long-term effect of TMZ and the poor efficacy of other drugs highlight the need to identify additional effective therapies.
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http://dx.doi.org/10.1530/EJE-17-0933DOI Listing
March 2018

Targeting CXCR4 (CXC Chemokine Receptor Type 4) for Molecular Imaging of Aldosterone-Producing Adenoma.

Hypertension 2018 02 26;71(2):317-325. Epub 2017 Dec 26.

From the Department of Internal Medicine I, Endocrinology and Diabetes Unit (B.H., C.T.F., M.F., K.L., S.H.), Department of Nuclear Medicine (A.S., K.H., A.K.B., C.B.), and Comprehensive Cancer Center Wuerzburg (T.D., M.F.), University Hospital of Wuerzburg, University of Wuerzburg, Germany; Division of Internal Medicine and Hypertension, Department of Medical Sciences, University of Torino, Italy (P.M., T.A.W., S.M.); Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, Germany (F.B., M.R., T.A.W., Y.R.); Department of Nuclear Medicine, Klinikum rechts der Isar der Technischen Universität München, Germany (M.M.); Endocrinology in Charlottenburg, Berlin, Germany (M.Q.); Department of General, Visceral, and Transplant Surgery, Campus Virchow Klinikum, Charité-Universitätsmedizin Berlin, Germany (N.R.); Department of Pathology, University of Würzburg, Germany (V.W.); Division of Endocrinology, G.V. (Sonny) Montgomery VA Medical Center, MS (C.E.G.-S.); Institute of Pathology, University Hospital Essen, University of Duisburg-Essen, Germany (A.-C.R.); ENDOC, Center for Endocrine Tumors, Hamburg, Germany (S.P.); Pharmaceutical Radiochemistry, Technische Universität München, Garching bei München, Germany (H.-J.W.); and Scintomics GmbH, Fürstenfeldbruck, Germany (S.K.).

Primary aldosteronism is the most frequent cause of secondary hypertension and is associated with increased morbidity and mortality compared with hypertensive controls. The central diagnostic challenge is the differentiation between bilateral and unilateral disease, which determines treatment options. Bilateral adrenal venous sampling, currently recommended for differential diagnosis, is an invasive procedure with several drawbacks, making it desirable to develop novel noninvasive diagnostic tools. When investigating the expression pattern of chemokine receptors by quantitative real-time polymerase chain reaction and immunohistochemistry, we observed high expression of CXCR4 (CXC chemokine receptor type 4) in aldosterone-producing tissue in normal adrenals, adjacent adrenal cortex from adrenocortical adenomas, and in aldosterone-producing adenomas (APA), correlating strongly with the expression of CYP11B2 (aldosterone synthase). In contrast, CXCR4 was not detected in the majority of nonfunctioning adenomas that are frequently found coincidently. The specific CXCR4 ligand 68Ga-pentixafor has recently been established as radiotracer for molecular imaging of CXCR4 expression and showed strong and specific binding to cryosections of APAs in our study. We further investigated 9 patients with primary aldosteronism because of APA by 68Ga-pentixafor-positron emission tomography. The tracer uptake was significantly higher on the side of increased adrenocortical aldosterone secretion in patients with APAs compared with patients investigated by 68Ga-pentixafor-positron emission tomography for other causes. Molecular imaging of aldosterone-producing tissue by a CXCR4-specific ligand may, therefore, be a highly promising tool for noninvasive characterization of patients with APAs.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.117.09975DOI Listing
February 2018

European Society of Endocrinology Clinical Practice Guidelines for the management of aggressive pituitary tumours and carcinomas.

Eur J Endocrinol 2018 Jan 18;178(1):G1-G24. Epub 2017 Oct 18.

Departments of Internal Medicine (Section Endocrinology) & Clinical Epidemiology, Leiden University Medical Centre, Leiden, The Netherlands.

Background: Pituitary tumours are common and easily treated by surgery or medical treatment in most cases. However, a small subset of pituitary tumours does not respond to standard medical treatment and presents with multiple local recurrences (aggressive pituitary tumours) and in rare occasion with metastases (pituitary carcinoma). The present European Society of Endocrinology (ESE) guideline aims to provide clinical guidance on diagnosis, treatment and follow-up in aggressive pituitary tumours and carcinomas.

Methods: We decided upfront, while acknowledging that literature on aggressive pituitary tumours and carcinomas is scarce, to systematically review the literature according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system. The review focused primarily on first- and second-line treatment in aggressive pituitary tumours and carcinomas. We included 14 single-arm cohort studies (total number of patients = 116) most on temozolomide treatment ( = 11 studies, total number of patients = 106). A positive treatment effect was seen in 47% (95% CI: 36-58%) of temozolomide treated. Data from the recently performed ESE survey on aggressive pituitary tumours and carcinomas (165 patients) were also used as backbone for the guideline. SELECTED RECOMMENDATION: (i) Patients with aggressive pituitary tumours should be managed by a multidisciplinary expert team. (ii) Histopathological analyses including pituitary hormones and proliferative markers are needed for correct tumour classification. (iii) Temozolomide monotherapy is the first-line chemotherapy for aggressive pituitary tumours and pituitary carcinomas after failure of standard therapies; treatment evaluation after 3 cycles allows identification of responder and non-responder patients. (iv) In patients responding to first-line temozolomide, we suggest continuing treatment for at least 6 months in total. Furthermore, the guideline offers recommendations for patients who recurred after temozolomide treatment, for those who did not respond to temozolomide and for patients with systemic metastasis.
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http://dx.doi.org/10.1530/EJE-17-0796DOI Listing
January 2018
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