Faculty Bibliography

INTRODUCTION/BACKGROUND:Endogenous Cushing's syndrome (CS) is characterized by chronic overproduction of cortisol and is associated with increased mortality and morbidity. It can be caused by a pituitary adenoma, ectopic adrenocorticotropic hormone (ACTH) production or primary adrenal disease. Successful tumor-directed surgery is the keystone treatment. When surgery is unsuccessful, contraindicated or in case of acute disease, pharmacotherapy is indicated to treat hypercortisolism. AREAS COVERED/METHODS:In this review, pharmacotherapeutic options for CS will be covered discussing the different possible targets, that is: i) inhibition of ACTH secretion; ii) suppression of steroidogenesis; and iii) blockade of cortisol effects at tissue level. Preclinical and clinical studies will be discussed considering mono- and combination therapy, taking into account efficacy, toxicity and mechanism of action. Per CS entity, future directions of pharmacotherapies will be addressed. EXPERT OPINION/CONCLUSIONS:The number of medical treatment options for CS has increased in the past years. In contrast to decades ago, prospective trials are now being performed focusing on pituitary-directed drugs like pasireotide, the glucocorticoid receptor blocker mifepristone and 'new generation' steroid synthesis inhibitors. Future studies will focus on tumor-shrinking effects of neuromodulatory drugs, the optimal order and combination of pharmacotherapy, long-term efficacy and safety and new targets for medical treatment of CS.

BACKGROUND:Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occurs frequently. OBJECTIVE:The aim of this study was to identify markers with prognostic value for patients in this clinical setting. DESIGN, SETTING, AND PARTICIPANTS/METHODS:From the German ACC registry, 319 patients with the European Network for the Study of Adrenal Tumors stage I-III were identified. As an independent validation cohort, 250 patients from three European countries were included. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS/METHODS:Clinical, histological, and immunohistochemical markers were correlated with recurrence-free (RFS) and overall survival (OS). RESULTS:Although univariable analysis within the German cohort suggested several factors with potential prognostic power, upon multivariable adjustment only a few including age, tumor size, venous tumor thrombus (VTT), and the proliferation marker Ki67 retained significance. Among these, Ki67 provided the single best prognostic value for RFS (hazard ratio [HR] for recurrence, 1.042 per 1% increase; P < .0001) and OS (HR for death, 1.051; P < .0001) which was confirmed in the validation cohort. Accordingly, clinical outcome differed significantly between patients with Ki67 <10%, 10-19%, and ≥20% (for the German cohort: median RFS, 53.2 vs 31.6 vs 9.4 mo; median OS, 180.5 vs 113.5 vs 42.0 mo). Using the combined cohort prognostic scores including tumor size, VTT, and Ki67 were established. Although these scores discriminated slightly better between subgroups, there was no clinically meaningful advantage in comparison with Ki67 alone. CONCLUSION/CONCLUSIONS:This largest study on prognostic markers in localized ACC identified Ki67 as the single most important factor predicting recurrence in patients following R0 resection. Thus, evaluation of Ki67 indices should be introduced as standard grading in all pathology reports of patients with ACC.

BACKGROUND:In multiple endocrine neoplasia type 1 (MEN1), pancreatic neuroendocrine tumors (pNETs) are the leading MEN1-related cause of death. OBJECTIVE:To evaluate EUS and (11)C-5-hydroxytryptophan positron emission tomography ((11)C-5-HTP PET), compared with the recommended screening techniques in MEN1 patients for early detection of pNETs. DESIGN/METHODS:Cross-sectional study. SETTING/METHODS:Tertiary-care university medical center. PATIENTS/METHODS:This study involved 41 patients with a proven MEN1 mutation or with one MEN1 manifestation and a mutation carrier as a first-degree family member, with recent screening by abdominal CT or magnetic resonance imaging (MRI) and somatostatin receptor scintigraphy (SRS). INTERVENTIONS/METHODS:EUS by using a linear Pentax echoendoscope and Hitachi EUB-525 and (11)C-5-HTP PET. MAIN OUTCOME MEASUREMENTS/METHODS:Patient-based and lesion-based positivity for pNET was calculated for all imaging techniques. The McNemar test was used to compare the yield of the 4 imaging techniques. RESULTS:In 35 of 41 patients, 107 pancreatic lesions were detected in total. EUS detected 101 pancreatic lesions in 34 patients, (11)C-5-HTP PET detected 35 lesions in 19 patients, and CT/MRI + SRS detected 32 lesions in 18 patients (P < .001). (11)C-5-HTP PET performed similarly to CT/MRI + SRS and better compared with SRS only (13 lesions in 12 patients), both at a patient-based and lesion-based level (P < .05). LIMITATIONS/CONCLUSIONS:Single-center study. CONCLUSION/CONCLUSIONS:EUS is superior to CT/MRI + SRS for pancreatic lesion detection in patients with MEN1. In this setting, (11)C-5-HTP PET is not useful. We recommend EUS as the first-choice pancreas imaging technique in patients with MEN1. ( CLINICAL TRIAL REGISTRATION NUMBER/BACKGROUND:NTR1668.).

An important role is reserved for nuclear imaging techniques in the imaging of neuroendocrine tumors (NETs). Somatostatin receptor scintigraphy (SRS) with (111)In-DTPA-octreotide is currently the most important tracer in the diagnosis, staging and selection for peptide receptor radionuclide therapy (PRRT). In the past decade, different positron-emitting tomography (PET) tracers have been developed. The largest group is the (68)Gallium-labeled somatostatin analogs ((68)Ga-SSA). Several studies have demonstrated their superiority compared to SRS in sensitivity and specificity. Furthermore, patient comfort and effective dose are favorable for (68)Ga-SSA. Other PET targets like β-[(11)C]-5-hydroxy-L-tryptophan ((11)C-5-HTP) and 6-(18)F-L-3,4-dihydroxyphenylalanine ((18)F-DOPA) were developed recently. For insulinomas, glucagon-like peptide-1 receptor imaging is a promising new technique. The evaluation of response after PRRT and other therapies is a challenge. Currently, the official follow-up is performed with radiological imaging techniques. The role of nuclear medicine may increase with the newest tracers for PET. In this review, the different nuclear imaging techniques and tracers for the imaging of NETs will be discussed.

UNLABELLED:Pancreatic neuroendocrine tumors (NETs) are rare neoplasms for which surgery has almost the only potential for cure. When surgery is not possible because of tumor size and vascular involvement, neoadjuvant treatment with [(177)Lu-DOTA(0),Tyr(3)]octreotate ((177)Lu-octreotate) may be an option. METHODS:We studied 29 Dutch patients with a pathology-proven nonfunctioning pancreatic NET treated with (177)Lu-octreotate. All patients had a borderline or unresectable pancreatic tumor (group 1) or oligometastatic disease (defined as ≤3 liver metastases) (group 2). Progression-free survival (PFS) was analyzed using the Kaplan-Meier method and Cox proportional hazards modeling. RESULTS:After the treatment with (177)Lu-octreotate, successful surgery was performed in 9 of 29 patients (31%). Six patients had a Whipple procedure, 2 patients had a pylorus-preserving pancreaticoduodenectomy, and 1 patient had a distal pancreatectomy and splenectomy. The median PFS was 69 mo for patients with successful surgery and 49 mo for the other patients. For comparison, the median PFS in 90 other patients with a nonfunctioning pancreatic NET with more than 3 liver metastases or other metastases was 25 mo. CONCLUSION/CONCLUSIONS:Neoadjuvant treatment with (177)Lu-octreotate is a valuable option for patients with initially unresectable pancreatic NETs.

Pituitary adenomas (PA) represent in the majority of cases, benign tumors whose treatment currently associate surgery, medical therapies and radiotherapy in a multidisciplinary approach. While trans-sphenoidal surgery remains, except for prolactin-secreting adenomas, the first-line treatment of PA, it can considerably be hampered by the existence of an invasive and/or aggressive tumor for which medical therapies are often requested. In this review, we extensively discuss, both at molecular and clinical levels, the medical therapies currently used and in development in the different phenotypes of pituitary adenomas.

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.

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.

The mTOR pathway has recently been suggested as a new potential target for therapy in adrenocortical carcinomas (ACCs). The aim of the current study is to describe the expression of the mTOR pathway in normal adrenals (NAs) and pathological adrenals and to explore whether there are correlation between the expression of these proteins and the in vitro response to sirolimus. For this purpose, the MTOR, S6K1 (RPS6KB1), and 4EBP1 (EIF4EBP1) mRNA expression were evaluated in ten NAs, ten adrenal hyperplasias (AHs), 17 adrenocortical adenomas (ACAs), and 17 ACCs by qPCR, whereas total(t)/phospho(p)-MTOR, t/p-S6K, and t/p-4EBP1 protein expression were assessed in three NAs, three AHs, six ACAs, and 20 ACCs by immunohistochemistry. The effects of sirolimus on cell survival and/or cortisol secretion in 12 human primary cultures of adrenocortical tumors (ATs) were also evaluated. In NAs and AHs, layer-specific expression of evaluated proteins was observed. S6K1 mRNA levels were lower in ACCs compared with NAs, AHs, and ACAs (P<0.01). A subset of ATs presented a moderate to high staining of the evaluated proteins. Median t-S6K1 protein expression in ACCs was lower than that in ACAs (P<0.01). Moderate to high staining of p-S6K1 and/or p-4EBP1 was observed in most ATs. A subset of ACCs not having moderate to high staining had a higher Weiss score than others (P<0.029). In primary AT cultures, sirolimus significantly reduced cell survival or cortisol secretion only in sporadic cases. In conclusion, these data suggest the presence of an activated mTOR pathway in a subset of ATs and a possible response to sirolimus only in certain ACC cases.