Explore the vast range of titles available.

Chronic exposure to excess glucorticoids results in diverse manifestations of Cushing's syndrome, including debilitating morbidities and increased mortality. Genetic and molecular mechanisms responsible for excess cortisol secretion by primary adrenal lesions and adrenocorticotropic hormone (ACTH) secretion from corticotroph or ectopic tumours have been identified. New biochemical and imaging diagnostic approaches and progress in surgical and radiotherapy techniques have improved the management of patients. The therapeutic goal is to normalise tissue exposure to cortisol to reverse increased morbidity and mortality. Optimum treatment consisting of selective and complete resection of the causative tumour is necessay to allow eventual normalisation of the hypothalamic-pituitary-adrenal axis, maintenance of pituitary function, and avoidance of tumour recurrence. The development of new drugs offers clinicians several choices to treat patients with residual cortisol excess. However, for patients affected by this challenging syndrome, the long-term effects and comorbidities associated with hypercortisolism need ongoing care.

Abstract Purpose Peptide receptor radionuclide therapy (PRRT) with the radiolabeled somatostatin analogue [Lutetium-177-DOTA0-Tyr3]octreotate (177Lu-DOTATATE) is widely applied for inoperable metastatic small intestinal and nonfunctioning pancreatic neuroendocrine tumors (pNETs). The aim of this study is to describe the safety and efficacy of the treatment of functioning pNETs. Methods Patients were treated with up to four cycles of 177Lu-DOTATATE with an intended dose of 7.4 Gbq per cycle. Radiological (Response Evaluation Criteria in Solid Tumors 1.1), symptomatic, and biochemical response were analyzed retrospectively for all patients with a functioning pNET (insulinoma, gastrinoma, VIPoma, and glucagonoma) treated with 177Lu-DOTATATE. Quality of life (QOL) was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire–Core Module questionnaire. Results Thirty-four patients with a metastatic functioning pNET (European Neuroendocrine Tumor Society grade 1 or 2) were included: 14 insulinomas, 5 VIPomas, 7 gastrinomas, and 8 glucagonomas. Subacute hematological toxicity, grade 3 or 4 occurred in 4 patients (12%) and a hormonal crisis in 3 patients (9%). PRRT resulted in partial or complete response in 59% of patients and the disease control rate was 78% in patients with baseline progression. 71% of patients with uncontrolled symptoms had a reduction of symptoms and a more than 80% decrease of circulating hormone levels was measured during follow-up. After PRRT, median progression-free survival was 18.1 months (interquartile range: 3.3 to 35.7) with a concurrent increase in QOL. Conclusion Treatment with 177Lu-DOTATATE is a safe and effective therapy resulting in radiological, symptomatic and biochemical response in a high percentage of patients with metastatic functioning pNETs. Hormonal crises occur relatively frequent and preventive therapy should be considered before and/or during PRRT. Treatment of metastatic functioning pancreatic neuroendocrine tumors with 177Lu-DOTATATE results in symptomatic, radiological, and response in a high percentage of patients.

ContextThe disease course of adrenocortical carcinoma (ACC) patients is heterogeneous. A marker for prognosis and treatment response would facilitate choices for diagnosis and therapy. In other cancer types, circulating cell-free tumor DNA predicted tumor dynamics.Case DescriptionsThe present pilot study included six patients. Next-generation sequencing (NGS) showed mutations in three ACC cases. From these patients, blood was drawn before (1 to 2 weeks) and after surgery and cell-free circulating DNA (cfDNA) was isolated. Tumor-specific mutations were found in the cfDNA of one of the three patients, with metastasized ACC at diagnosis. NGS of the tumor showed an NRAS mutation (c.182A>G:p.Q61R) in 78%, a TP53 mutation (c.856G>A:p.E286K) in 60%, and a TERT gene mutation (1295250C>T) in 28% of the reads. The preoperative cfDNA showed the same mutations at a frequency of 64%, 32%, and 2%, respectively. The postoperative cfDNA showed the same mutations but at lower frequencies (52%, 16%, and 3%, respectively). The patient was postoperatively treated with mitotane and chemotherapy. No mutations were detected in the corresponding leukocyte DNA or in the cfDNA from the two other patients.ConclusionsTo the best of our knowledge, we report for the first time mutations occurring at high levels in cfDNA collected before and after surgery from one of three patients, after previous identification in the tumor. However, in the cfDNA from two patients with known mutations, we were unable to reliably detect mutations in the cfDNA. Our results indicate that mutation detection in cfDNA can vary among ACC patients, and other approaches might be required to detect the tumor response and monitor progressive disease.We report the presence of circulating cell-free tumor DNA in the plasma of a patient with metastatic ACC after previous mutation identification in the primary tumor.

Adrenocortical carcinoma (ACC) is a rare cancer with a poor prognosis. Adrenal incidentalomas are, however, commonly identified in clinical practice. Discrimination between benign and malignant adrenal tumors is of great importance considering the large differences in clinical behavior requiring different strategies. Diagnosis of ACC starts with a thorough physical examination, biochemical evaluation, and imaging. Computed tomography is the first-level imaging modality in adrenal tumors, with tumor size and Hounsfield units being important features for determining malignancy. New developments include the use of urine metabolomics, also enabling discrimination of ACC from adenomas preoperatively. Postoperatively, the Weiss score is used for diagnosis of ACC, consisting of nine histopathological criteria. Due to known limitations as interobserver variability and lack of accuracy in borderline cases, much effort has been put into new tools to diagnose ACC. Novel developments vary from immunohistochemical markers and pathological scores, to markers at the level of DNA, methylome, chromosome, or microRNA. Molecular studies have provided insights into the most promising and most frequent alterations in ACC. The use of liquid biopsies for diagnosis of ACC is studied, although in a small number of patients, requiring further investigation. In this review, current diagnostic modalities and challenges in ACC will be addressed.

Abstract Insulinomas are hormone-producing pancreatic neuroendocrine neoplasms with an estimated incidence of 1 to 4 cases per million per year. Extrapancreatic insulinomas are extremely rare. Most insulinomas present with the Whipple triad: (1) symptoms, signs, or both consistent with hypoglycemia; (2) a low plasma glucose measured at the time of the symptoms and signs; and (3) relief of symptoms and signs when the glucose is raised to normal. Nonmetastatic insulinomas are nowadays referred to as “indolent” and metastatic insulinomas as “aggressive.” The 5-year survival of patients with an indolent insulinoma has been reported to be 94% to 100%; for patients with an aggressive insulinoma, this amounts to 24% to 67%. Five percent to 10% of insulinomas are associated with the multiple endocrine neoplasia type 1 syndrome. Localization of the insulinoma and exclusion or confirmation of metastatic disease by computed tomography is followed by endoscopic ultrasound or magnetic resonance imaging for indolent, localized insulinomas. Glucagon-like peptide 1 receptor positron emission tomography/computed tomography or positron emission tomography/magnetic resonance imaging is a highly sensitive localization technique for seemingly occult, indolent, localized insulinomas. Supportive measures and somatostatin receptor ligands can be used for to control hypoglycemia. For single solitary insulinomas, curative surgical excision remains the treatment of choice. In aggressive malignant cases, debulking procedures, somatostatin receptor ligands, peptide receptor radionuclide therapy, everolimus, sunitinib, and cytotoxic chemotherapy can be valuable options.

Abstract In Cushing syndrome (CS), prolonged exposure to high cortisol levels results in a wide range of devastating effects causing multisystem morbidity. Despite the efficacy of treatment leading to disease remission and clinical improvement, hypercortisolism-induced complications may persist. Since glucocorticoids use the epigenetic machinery as a mechanism of action to modulate gene expression, the persistence of some comorbidities may be mediated by hypercortisolism-induced long-lasting epigenetic changes. Additionally, glucocorticoids influence microRNA expression, which is an important epigenetic regulator as it modulates gene expression without changing the DNA sequence. Evidence suggests that chronically elevated glucocorticoid levels may induce aberrant microRNA expression which may impact several cellular processes resulting in cardiometabolic disorders. The present article reviews the evidence on epigenetic changes induced by (long-term) glucocorticoid exposure. Key aspects of some glucocorticoid-target genes and their implications in the context of CS are described. Lastly, the effects of epigenetic drugs influencing glucocorticoid effects are discussed for their ability to be potentially used as adjunctive therapy in CS.

Cushing’s syndrome is associated with serious morbidity and increased mortality. Irrespective of its cause, i.e. a pituitary adenoma, ectopic ACTH production or an adrenal neoplasia, Cushing’s syndrome is primarily treated surgically. However, when surgery is unsuccessful or contraindicated, medical therapy is needed to treat hypercortisolism. The spectrum of available drugs includes adrenal-blocking agents, neuromodulatory drugs and glucocorticoid receptor antagonists. Adrenal blocking drugs suppress adrenal cortisol production via inhibition of steroidogenic enzymes. Ketoconazole and metyrapone are most frequently used for this purpose, but chronic treatment with these drugs can be limited by side effects like hepatotoxicity (ketoconazole) and increased androgen and mineralocorticoid production (metyrapone). Etomidate can be used to rapidly reverse cortisol excess in patients with acute complications of (severe) hypercortisolism like psychosis. In Cushing’s disease, combination therapy with drugs that target the corticotropic adenoma, i.e. the universal somatostatin analogue pasireotide and/or the dopamine agonist cabergoline, and low-dose ketoconazole seems a rational approach to achieve biochemical control.

In Cushing syndrome (CS), prolonged exposure to high Cortisol levels results in a wide range of devastating effects causing multisystem morbidity. Despite the efficacy of treatment leading to disease remission and clinical improvement, hypercortisolism-induced complications may persist. Since glucocorticoids use the epigenetic machinery as a mechanism of action to modulate gene expression, the persistence of some comorbidities may be mediated by hypercortisolism-induced long-lasting epigenetic changes. Additionally, glucocorticoids influence microRNA expression, which is an important epigenetic regulator as it modulates gene expression without changing the DNA sequence. Evidence suggests that chronically elevated glucocorticoid levels may induce aberrant microRNA expression which may impact several cellular processes resulting in cardiometabolic disorders.

In a prospective clinical proof-of-concept trial involving nine advanced NET patients with low SST expression, we were able to show that epigenetic treatment with the histone deacetylase (HDAC) inhibitor valproic acid and the DNA methyltransferase (DNMT) inhibitor hydralazine did not lead to an increase in tumour-uptake of 68Ga-DOTATATE, contradicting the in vitro data. A prerequisite for the treatment of advanced NETs with (radiolabelled) somatostatin analogues (SSA) is the expression of SST2 on the tumour cell surface, providing rationale for the inferior outcome in patients with low uptake on functional SST imaging.3 Several previous in vitro studies and one in vivo study achieved stimulation of SST2 expression levels and binding of SSAs by increasing histone acetylation levels and reducing DNA methylation of the SST2 gene promoter region in NET cells by epigenetic drugs.1,2,4 Despite these promising results, there are only data from one study showing limited increase of 68Ga-DOTATOC uptake by HDAC inhibitor vorinostat in five NET patients already expressing SST at baseline.5 In the present study, which was approved by the Ethics Committee of the Erasmus Medical Center Rotterdam and registered at the Netherlands Trial Register (NL7726), nine patients with advanced NETs (Table 1) and low SST expression at baseline on 68Ga-DOTATATE/PET (Table 2), defined as tumour uptake below or equal to the physiological uptake in the liver, were included and provided written informed consent. Values are shown as median (interquartile range [IQR]) or number (%) Patient characteristics Total (n = 9) Age, years (IQR) 67 (54, 75) Sex (male), n (%) 5 (56) Origin Pancreas NET, n (%) 2 (22) Small intestinal NET, n (%) 1 (11) Lung NET, n (%) 4 (44) Rectum NET, n (%) 1 (11) Thymus NET, n (%) 1 (11) Metastases Lymph nodes, n (%) 9 (100) Liver, n (%) 5 (56) Mesenterial, n (%) 1 (11) Bone, n (%) 3 (33) Lung, n (%) 1 (11) Other, n (%) 4 (44) Ki67 index 0%–2%, n (%) 3 (33) 5%–10%, n (%) 4 (44) 30% 1 (11) Unknown 1 (11) Grading G1, n (%) 4 (44) G2, n (%) 4 (44) G3, n (%) 1 (11) Previous treatments Surgery, n (%) 3 (33) Somatostatin analogue, n (%) 2 (22) Chemotherapy, n (%) 1 (11) Other, n (%) 3 (33) Abbreviations: Bpm, beats per minute; n, number; NET, neuroendocrine tumour; IQR, interquartile range; SUV, standard uptake values. TABLE 2 Change in study parameters of neuroendocrine tumour patients at baseline and after 1 and 2 weeks of epigenetic treatment Clinical parameters Baseline Week 1 Week 2 p Value Weight, kg (IQR) 76 (68, 86) 77 (68, 88) 77 (69, 88) .05 Blood pressure systolic, mmHg (IQR) 147 (130, 155) 139 (129, 151) 135 (126, 148) .14 Heart rate, bpm (IQR) 69 (62, 81) 77 (67, 109) 76 (65, 96) .34 Laboratory parameters Haemoglobin, mmol/L (IQR) 8.5 (8.1, 9.2) 8.5 (7.7, 9.2) 8.1 (7.6, 8.6) .05 Thrombocytes, ×109/L (IQR) 247 (195, 282) 233 (173, 255) 177 (148, 271) .11 Creatinine, umol/L (IQR) 73 (58, 90) 74 (54, 86) 76 (56, 89) .72 ASAT, U/L (IQR) 27 (23, 32) 23 (21, 30) 28 (24, 36) 1 ALAT, U/L (IQR) 26 (17, 35) 17 (16, 25) 21 (13, 26) .09 GGT, U/L (IQR) 65 (19, 98) 46 (19, 82) 48 (18, 115) .16 Valproic acid drug level, μg/ml (IQR) NA 102 (84, 126) 95 (90, 117) NA Study medication Valproic acid dosage, mg/day (IQR) (n = 9) NA 2300 (1900, 2500) 1900 (1763, 2000) NA Hydralazine dosage, mg/day (IQR) (n = 7) NA 150 (150, 150) 150 (100, 150) NA Tumour uptake of 68Ga-DOTATATE None, n (%) 6 (67) 6 (67) 1 Below liver, n (%) 3 (33) 3 (33) 1 Peak uptake Primary tumour, SUV (IQR)(n = 6) 8.1 (3.0, 11.4) 6.8 (2.8, 9.9) .17 Lymph node metastases, SUV (IQR) (n = 5) 4.8 (3.1, 9.0) 5.8 (2.6, 7.8) .35 Liver metastases, SUV (IQR) (n = 5) 7.5 (5.0, 7.9) 7.3 (4.5, 8.4) .29 Bone metastases, SUV (IQR) (n = 4) 4.1 (2.6, 5.1) 4.2 (2.7, 5.2) .47 Intestinal metastases, SUV (IQR) (n = 2) 9 (7.5, 10.5) 8.7 (6.7, 10.6) .67 Skin metastases, SUV (IQR) (n = 1) 3.5 3.7 NA Liver, SUV (IQR) 10.5 (8.3, 12.6) 10.7 (8.3, 12.3) .95 Kidneys, SUV (IQR) 16.3 (14.3, 19.2) 20.7 (16.1, 26.0) .02 Spleen, SUV (IQR) 25.9 (22.7, 32.7) 27.8 (22.0, 31.9) .68 Note: Values are shown as median (IQR) or number (%) in nine patients, unless otherwise indicated.

Cushing's syndrome is a rare disorder resulting from prolonged exposure to excess glucocorticoids. Early diagnosis and treatment of Cushing's syndrome is associated with a decrease in morbidity and mortality. Clinical presentation can be highly variable, and establishing the diagnosis can often be difficult. Surgery (resection of the pituitary or ectopic source of adrenocorticotropic hormone, or unilateral or bilateral adrenalectomy) remains the optimal treatment in all forms of Cushing's syndrome, but may not always lead to remission. Medical therapy (steroidogenesis inhibitors, agents that decrease adrenocorticotropic hormone levels or glucocorticoid receptor antagonists) and pituitary radiotherapy may be needed as an adjunct. A multidisciplinary approach, long-term follow-up, and treatment modalities customized to each individual are essential for optimal control of hypercortisolemia and management of comorbidities.