Approach to the patient: Diagnosis of Cushing's syndrome
Savas, Mesut; Mehta, Sonal; Agrawal, Nidhi; van Rossum, Elisabeth F C; Feelders, Richard A
Cushing's syndrome results from supraphysiological exposure to glucocorticoids and is associated with significant morbidity and mortality. The pathogenesis includes administration of corticosteroids (exogenous Cushing's syndrome) or autonomous cortisol overproduction, whether or not adrenocorticotropin hormone (ACTH) dependent (endogenous Cushing's syndrome). An early diagnosis of Cushing's syndrome is warranted, however, in clinical practice very challenging partly due to resemblance with other common conditions (i.e. pseudo-Cushing's syndrome). Initial workup should start with excluding local and systemic corticosteroid use. First-line screening tests including the 1-mg dexamethasone suppression test, 24-hour urinary free cortisol excretion, and late-night salivary cortisol measurement should be performed to screen for endogenous Cushing's syndrome. Scalp-hair cortisol/cortisone analysis helps in the assessment of long-term glucocorticoid exposure as well as in detection of transient periods of hypercortisolism as observed in cyclical Cushing's syndrome. Interpretation of results can be difficult due to individual patient characteristics and hence requires awareness of test limitations. Once endogenous Cushing's syndrome is established, measurement of plasma ACTH concentrations differentiates between ACTH-dependent (80-85%) or ACTH-independent (15-20%) causes. Further assessment with different imaging modalities and dynamic biochemical testing including bilateral inferior petrosal sinus sampling helps further pinpoint the cause of Cushing's syndrome. In this issue of 'Approach to the patient' the diagnostic workup of Cushing's syndrome is discussed with answering the questions when to screen, how to screen and how to differentiate the different causes. In this respect, latest developments in biochemical and imaging techniques are discussed as well.
Determinants of surgical remission in prolactinomas: a systematic review and meta-analysis
Wright, Kyla; Chaker, Layal; Pacione, Donato; Sam, Keren; Feelders, Richard; Xia, Yuhe; Agrawal, Nidhi
OBJECTIVE:Prolactin secreting tumors respond well to medical management with a small fraction of patients requiring surgery. We conducted a systematic review and meta-analysis to study the determinants of surgical remission in these tumors. METHODS:We searched PubMed to identify eligible studies reporting postoperative remission in patients treated with transsphenoidal surgery for prolactinoma. Primary outcomes included postoperative remission, follow-up remission, and recurrence. Postoperative and follow-up remission were defined as normoprolactinemia at less than and greater than one-year post-operation respectively. Recurrence was defined as hyperprolactinemia after initial normalization of prolactin levels. Odds ratios (OR) were calculated, stratified by radiological size, tumor extension, and tumor invasion, and analyzed using a random-effects model meta-analysis. RESULTS:Thirty-five studies were included. Macroadenomas were associated with lower rates of postoperative remission OR 0.20, 95% confidence interval [CI] 0.16-0.24) and lower rates of remission at follow-up (OR 0.11, 95% CI 0.053-0.22). Postoperative remission was less likely in tumors with extra- or suprasellar extension (OR 0.16, 95% CI 0.06-0.43) and tumors with cavernous sinus invasion (OR 0.03, 95% CI 0.01-0.13). Female gender and absence of preoperative dopamine agonist (DA) treatment were also associated with higher remission rates. Across the included studies, there was considerable heterogeneity in each primary outcome (postoperative remission I2=94%, follow-up remission I2=86%, recurrence I2=68%). CONCLUSIONS:Transsphenoidal surgery for prolactinomas may be particularly effective in small, non-invasive, treatment naive tumors and may provide a viable first-line alternative to dopamine agonist therapy in such patients.
Peptide receptor radionuclide therapy with 177Lu-DOTATATE for symptomatic control of refractory carcinoid syndrome
Zandee, Wouter T; Brabander, Tessa; BlaÅ¾eviÄ‡, Anela; Minczeles, Noémie S; Feelders, Richard A; de Herder, Wouter W; Hofland, Johannes
CONTEXT/BACKGROUND:Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE results in an increase of progression-free survival and quality of life in patients with progressive well-differentiated neuroendocrine neoplasms (NENs). OBJECTIVE:To study the effect of 177Lu-DOTATATE in patients with carcinoid syndrome and radiologically stable or newly diagnosed disease treated solely for the purpose of symptom reduction. DESIGN/METHODS:Retrospective cohort study. SETTING/METHODS:Tertiary care hospital. PATIENTS/METHODS:22 patients with a metastatic midgut NEN, elevated urinary 5-hydroxyindolacetic acid excretion and flushing and/or diarrhea despite treatment with a somatostatin analog, without documented disease progression. INTERVENTION/METHODS:PRRT with 177Lu-DOTATATE (intended cumulative dose: 29.6 GBq) with a primary aim to reduce symptoms. RESULTS:After PRRT, mean bowel movement frequency (BMF) decreased from 6.1 Â± 3.4 to 4.6 Â± 3.6 per day (p=0.009). Flushes decreased from 4.3 Â± 2.9 to 2.4 Â± 2.7 flushes per day (p=0.002). A decrease of BMF of more than 30% occurred in 47% of patients with baseline BMF of 4 or more (n=17). In patients with â‰¥2 episodes of flushing a day (n=15), 67% of patients had more than 50% decrease of daily flushing. A decrease in urinary 5-hydroxyindolacetic acid excretion of more than 30% was seen in 56% of patients. The EORTC-C30 diarrhea subscale score showed a trend towards improvement by an average of 16.7 Â± 33.3 points (p=0.11). CONCLUSION/CONCLUSIONS:PRRT with 177Lu-DOTATATE effectively reduced diarrhea and flushing in patients with carcinoid syndrome and can be considered for symptomatic treatment of carcinoid syndrome insufficiently controlled with somatostatin analogs.
Efficacy of the tryptophan hydroxylase inhibitor telotristat on growth and serotonin secretion in 2D and 3D cultured pancreatic neuroendocrine tumor cells
Herrera-Martínez, Aura D; Feelders, Richard A; Van den Dungen, Rosanna; Dogan-Oruc, Fadime; van Koetsveld, Peter M; Castaño, Justo P; de Herder, Wouter; Hofland, Leo J
<br>Serotonin, a biologically active amine, is related to carcinoid syndrome in functioning neuroendocrine tumors (NETs). Telotristat ethyl is a novel inhibitor of the tryptophan hydroxylase (TPH), a key enzyme in the production of serotonin. While its use in patients with carcinoid syndrome and uncontrolled diarrhea under somatostatin analogs (SSAs) has been recently approved, in vitro data evaluating it effectiveness are lacking. For this reason, we aimed to evaluate the effect of telotristat as monotherapy, and in combination with SSAs, on proliferation and secretion in a NET cell line model. The human pancreatic NET cell lines BON-1/QGP-1 were used as 2D and 3D cultured models; somatostatin receptor and TPH mRNA expression, as well as the potential autocrine effect of serotonin on tumor cell proliferation using a 3D culture system were evaluated. Telotristat decreased serotonin production in a dose-dependent manner at a clinically feasible concentration, without affecting cell proliferation. Its combination with pasireotide, but not with octreotide, had an additive inhibitory effect on serotonin secretion. The effect of telotristat was slightly less potent, when BON-1 cells were co-treated with octreotide. Octreotide and pasireotide had no effect on the expression of TPH. Telotristat did not have an effect on mRNA expression of somatostatin receptor subtypes. Finally, we showed that serotonin did not have an autocrine effect on NET cell proliferation on the 3D cell model. These results suggest that telotristat is an effective drug for serotonin inhibition, but the effectiveness of its combination with SST2-preferring SSA should be evaluated in more detail.<br>.
Osilodrostat Is a Potential Novel Steroidogenesis Inhibitor for the Treatment of Cushing Syndrome: An In Vitro Study
Creemers, Sara G; Feelders, Richard A; de Jong, Frank H; Franssen, Gaston J H; de Rijke, Yolanda B; van Koetsveld, Peter M; Hofland, Leo J
CONTEXT/BACKGROUND:Metyrapone and ketoconazole, frequently used steroidogenesis inhibitors for treatment of Cushing syndrome, can be associated with side effects and limited efficacy. Osilodrostat is a CYP11B1 and CYP11B2 inhibitor, with unknown effects on other steroidogenic enzymes. OBJECTIVE:To compare the effects of osilodrostat, metyrapone, and ketoconazole on adrenal steroidogenesis, and pituitary adenoma cells in vitro. METHODS:HAC15 cells, 17 primary human adrenocortical cell cultures, and pituitary adenoma cells were incubated with osilodrostat, metyrapone, or ketoconazole (0.01 to 10 ÂµM). Cortisol and ACTH were measured using chemiluminescence immunoassays, and steroid profiles by liquid chromatography-mass spectrometry. RESULTS:In HAC15 cells, osilodrostat inhibited cortisol production more potently (IC50: 0.035 ÂµM) than metyrapone (0.068 ÂµM; P < 0.0001), and ketoconazole (0.621 ÂµM; P < 0.0001). IC50 values of osilodrostat and metyrapone for basal cortisol production varied with a 25- and 18-fold difference, respectively, with comparable potency. Aldosterone production was inhibited more potently by osilodrostat vs metyrapone and ketoconazole. Osilodrostat and metyrapone treatment resulted in strong inhibition of corticosterone and cortisol, 11-deoxycortisol accumulation, and modest effects on adrenal androgens. No pituitary-directed effects of osilodrostat were observed. CONCLUSIONS:Under our study conditions, osilodrostat is a potent cortisol production inhibitor in human adrenocortical cells, comparable with metyrapone. All steroidogenesis inhibitors showed large variability in sensitivity between primary adrenocortical cultures. Osilodrostat might inhibit CYP11B1 and CYP11B2, in some conditions to a lesser extent CYP17A1 activity, and a proximal step in the steroidogenesis. Osilodrostat is a promising treatment option for Cushing syndrome, and in vivo differences with metyrapone are potentially driven by pharmacokinetic differences.
The Effect of Perioperative Music on the Stress Response to Surgery: A Meta-analysis
Fu, Victor X; Oomens, Pim; Sneiders, Dimitri; van den Berg, Sjoerd A A; Feelders, Richard A; Wijnhoven, Bas P L; Jeekel, Johannes
BACKGROUND:Current perioperative patient care aims to maintain homeostasis by attenuation of the stress response to surgery, as a more vigorous stress response can have detrimental effects on postoperative recovery. This systematic review and meta-analysis aims to assess the effect of perioperative music on the physiological stress response to surgery. METHODS:The Embase, Medline Ovid, Cochrane Central, Web of Science, and Google Scholar databases were searched from inception date until February 5, 2019, using a systematic literature search following the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines for randomized controlled trials investigating the effect of music before, during, and/or after surgery in adult surgical patients on the stress response to surgery. Meta-analysis was performed using a random effects model and pooled standardized mean differences were calculated with 95% confidence intervals. This study was registered in the PROSPERO database (CRD42018097060). RESULTS:Â =Â 0). CONCLUSIONS:Perioperative music can attenuate the neuroendocrine stress response to surgery.
Treatment of inoperable or metastatic paragangliomas and pheochromocytomas with peptide receptor radionuclide therapy using 177Lu-DOTATATE
Zandee, Wouter Thomas; Feelders, Richard A; Smit Duijzentkunst, Daan; Hofland, Johannes; Metselaar, R Mick; Oldenburg, Rogier A; van Linge, Anne; Kam, Boen L R; Teunissen, Jaap; Korpershoek, Esther; Hendriks, Johanna; Abusaris, Huda; Slagter, Cleo; Franssen, Gaston J H; Brabander, Tessa; de Herder, Wouter
Objectives - Inoperable or metastatic paragangliomas (PGL) and malignant pheochromocytomas (PCC) are rare tumours with limited options for systemic treatment. Aim of this study was to assess the safety and efficacy of the radiolabelled somatostatin analogue [177LutetiumDOTA0-Tyr3]octreotate (177Lu-DOTATATE) for the treatment of PGLs and PCCs. Methods - Patients with histologically proven inoperable or malignant PGLs and PCCs treated with 177Lu-DOTATATE at our centre were retrospectively analysed. Patients were treated with up to four cycles of 177Lu-DOTATATE with an intended dose of 7.4 Gb per cycle. Response was assessed with use of RECIST 1.1 Results - Thirty patients were included: 17 with parasympathetic, 10 with sympathetic PGLs and 3 with PCCs. Grade 3/4 subacute haematotoxicity occurred in 6 (20%) of patients. A reversible subacute adverse event due to cardiac failure following possible catecholamine release occurred in two patients. Best tumour response was partial response in 7 (23%) and stable disease in 20 (67%), whereas 3 (10%) patients had progressive disease. In 20 patients with baseline disease progression, tumour control was observed in 17 (85%); the median progression free survival was 91 months in patients with parasympathetic PGLs, 13 months in patients with sympathetic PGLs and 10 months in patients with metastatic PCCs. Conclusion - This study suggests that PRRT with 177Lu-DOTATATE is a safe and effective treatment option for patients with inoperable or malignant PGL and PCC.
Effects of novel somatostatin-dopamine chimeric drugs in 2D and 3D cell culture models of neuroendocrine tumors
Herrera Martínez, Aura D; van den Dungen, Rosanna; Dogan, Fadime; van Koetsveld, P M; Culler, Michael; de Herder, Wouter W; Luque, Raul M; Feelders, R A; Hofland, Leo
Control of symptoms related to hormonal hypersecretion by functioning neuroendocrine tumors (NETs) is challenging. New therapeutic options are required. Since novel in vitro tumor models seem to better mimic the tumor in vivo conditions, we aimed to study the effect of somatostatin and dopamine receptor agonists (octreotide and cabergoline, respectively) and novel somatostatin-dopamine chimeric multi-receptor drugs (BIM-065, BIM-23A760) using 2D (monolayer) and 3D (spheroids) cultures.
IGF and mTOR pathway expression and in vitro effects of linsitinib and mTOR inhibitors in adrenocortical cancer
De Martino, Maria Cristina; van Koetsveld, Peter M; Feelders, Richard A; de Herder, Wouter W; Dogan, Fadime; Janssen, Joseph A M J L; Hofste Op Bruinink, Davine; Pivonello, Claudia; Waaijers, A Marlijn; Colao, Annamaria; de Krijger, Ronald R; Pivonello, Rosario; Hofland, Leo J
PURPOSE/OBJECTIVE:The IGF and mTOR-pathways are considered as potential targets for therapy in patients with adrenocortical carcinoma (ACC). This study aims to describe the IGF pathway in ACC and to explore the response to the combined treatment with the IGF1R/IR inhibitor linsitinib, and mTOR inhibitors (sirolimus and everolimus) in in vitro models of ACC. METHODS:The protein expression level of IGF2, IGF1R and IGF2R was evaluated by immunohistochemistry in 17 human ACCs and the mRNA expression level of IGF1, IGF2, IGF1R, IR isoforms A and B, IGF2R, IGF-Binding-Proteins[IGFBP]-1, 2, 3 and 6 was evaluated by RT-qPCR in 12 samples. In H295R and HAC15 ACC cell lines the combined effects of linsitinib and sirolimus or everolimus on cell survival were evaluated. RESULTS:A high protein expression of IGF2, IGF1R and IGF2R was observed in 82, 65 and 100% of samples, respectively. A high relative expression of IGF2 mRNA was found in the majority of samples. The mRNA levels of the IRA were higher than that of IRB and IGF1R in the majority of samples (75%). Linsitinib inhibits cell growth in the H295R and HAC15 cell lines and, combined with sirolimus or everolimus, linsitinib showed a significant additive effect. CONCLUSIONS:In addition to IGF2 and IGF1R, ACC express IGF2R, IRA and several IGFBPs, suggesting that the interplay between the different components of the IGF pathway in ACC could be more complex than previously considered. The addition of mTOR inhibitors to linsitinib may have stronger antiproliferative effects than linsitinib alone.
Effects of Ketoconazole on ACTH-Producing and Non-ACTH-Producing Neuroendocrine Tumor Cells
Herrera-Martínez, Aura D; Feelders, Richard A; de Herder, Wouter W; Castaño, Justo P; GÃ¡lvez Moreno, María Ãngeles; Dogan, Fadime; van Dungen, Rosanna; van Koetsveld, Peter; Hofland, Leo J
Prolonged remission of hypercortisolism with steroidogenesis inhibitors has been described in patients with ectopic adrenocorticotropic hormone (ACTH) syndrome. The anti-proliferative and pro-apoptotic effect of ketoconazole in human cancer cells was previously suggested. The aim of this study was to explore the effects of ketoconazole on ACTH-producing and non-ACTH-producing neuroendocrine tumor (NET) cell lines. The effects of ketoconazole alone, and in combination with somatostatin analogs, were evaluated in two human cell lines: DMS-79 (ectopic ACTH-producing small cell lung carcinoma) and BON-1 (human pancreatic NET). Total DNA measurement, apoptosis, cell cycle, chromogranin A (CgA)/proopiomelanocortin (POMC) expression by qRT-PCR, serotonin, CgA, and ACTH secretion assays were performed. In both cell lines, ketoconazole significantly suppressed cell growth and colony formation in a dose and time-dependent manner. The effect in DMS-79 was primarily cytotoxic, while it was more apoptotic in BON-1 cells. Ketoconazole also induced increase in G0/G1 phase in both cell lines and arrest in phase G2/M of BON-1 cells. Ketoconazole did not affect the secretion of serotonin, CgA, ACTH, or the mRNA expression of CgA and POMC. Decreased serotonin secretion was observed after the combination treatment with pasireotide. These results suggest a direct effect of ketoconazole on cell proliferation, apoptosis, and cell cycle in both ACTH- and non-ACTH-producing NET cells.