What We Know about and What Is New in Primary Aldosteronism.

Primary aldosteronism (PA), a significant and curable cause of secondary hypertension, is seen in 5-10% of hypertensive patients, with its prevalence contingent upon the severity of the hypertension. The principal aetiologies of PA include bilateral idiopathic hypertrophy (BIH) and aldosterone-producing adenomas (APAs), while the less frequent causes include unilateral hyperplasia, familial hyperaldosteronism (FH) types I-IV, aldosterone-producing carcinoma, and ectopic aldosterone synthesis. This condition, characterised by excessive aldosterone secretion, leads to augmented sodium and water reabsorption alongside potassium loss, culminating in distinct clinical hallmarks: elevated aldosterone levels, suppressed renin levels, and hypertension. Notably, hypokalaemia is present in only 28% of patients with PA and is not a primary indicator. The association of PA with an escalated cardiovascular risk profile, independent of blood pressure levels, is notable. Patients with PA exhibit a heightened incidence of cardiovascular events compared to counterparts with essential hypertension, matched for age, sex, and blood pressure levels. Despite its prevalence, PA remains frequently undiagnosed, underscoring the imperative for enhanced screening protocols. The diagnostic process for PA entails a tripartite assessment: the aldosterone/renin ratio (ARR) as the initial screening tool, followed by confirmatory and subtyping tests. A positive ARR necessitates confirmatory testing to rule out false positives. Subtyping, achieved through computed tomography and adrenal vein sampling, aims to distinguish between unilateral and bilateral PA forms, guiding targeted therapeutic strategies. New radionuclide imaging may facilitate and accelerate such subtyping and localisation. For unilateral adrenal adenoma or hyperplasia, surgical intervention is optimal, whereas bilateral idiopathic hyperplasia warrants treatment with mineralocorticoid antagonists (MRAs). This review amalgamates established and emerging insights into the management of primary aldosteronism.

The tumour microenvironment of pituitary neuroendocrine tumours.

The tumour microenvironment (TME) includes a variety of non-neoplastic cells and non-cellular elements such as cytokines, growth factors and enzymes surrounding tumour cells. The TME emerged as a key modulator of tumour initiation, progression and invasion, with extensive data available in many cancers, but little is known in pituitary tumours. However, the understanding of the TME of pituitary tumours has advanced thanks to active research in this field over the last decade. Different immune and stromal cell subpopulations, and several cytokines, growth factors and matrix remodelling enzymes, have been characterised in pituitary tumours. Studying the TME in pituitary tumours may lead to a better understanding of tumourigenic mechanisms, identification of biomarkers useful to predict aggressive disease, and development of novel therapies. This review summarises the current knowledge on the different TME cellular/non-cellular elements in pituitary tumours and provides an overview of their role in tumourigenesis, biological behaviour and clinical outcomes.

Association of prolactin receptor (PRLR) variants with prolactinomas.

Prolactinomas are the most frequent type of pituitary tumors, which represent 10-20% of all intracranial neoplasms in humans. Prolactinomas develop in mice lacking the prolactin receptor (PRLR), which is a member of the cytokine receptor superfamily that signals via Janus kinase-2-signal transducer and activator of transcription-5 (JAK2-STAT5) or phosphoinositide 3-kinase-Akt (PI3K-Akt) pathways to mediate changes in transcription, differentiation and proliferation. To elucidate the role of the PRLR gene in human prolactinomas, we determined the PRLR sequence in 50 DNA samples (35 leucocytes, 15 tumors) from 46 prolactinoma patients (59% males, 41% females). This identified six germline PRLR variants, which comprised four rare variants (Gly57Ser, Glu376Gln, Arg453Trp and Asn492Ile) and two low-frequency variants (Ile76Val, Ile146Leu), but no somatic variants. The rare variants, Glu376Gln and Asn492Ile, which were in complete linkage disequilibrium, and are located in the PRLR intracellular domain, occurred with significantly higher frequencies (P < 0.0001) in prolactinoma patients than in 60 706 individuals of the Exome Aggregation Consortium cohort and 7045 individuals of the Oxford Biobank. In vitro analysis of the PRLR variants demonstrated that the Asn492Ile variant, but not Glu376Gln, when compared to wild-type (WT) PRLR, increased prolactin-induced pAkt signaling (>1.3-fold, P < 0.02) and proliferation (1.4-fold, P < 0.02), but did not affect pSTAT5 signaling. Treatment of cells with an Akt1/2 inhibitor or everolimus, which acts on the Akt pathway, reduced Asn492Ile signaling and proliferation to WT levels. Thus, our results identify an association between a gain-of-function PRLR variant and prolactinomas and reveal a new etiology and potential therapeutic approach for these neoplasms.

Pituitary neuroendocrine tumors: a model for neuroendocrine tumor classification.

The classification of adenohypophysial neoplasms as "pituitary neuroendocrine tumors" (PitNETs) was proposed in 2017 to reflect their characteristics as epithelial neuroendocrine neoplasms with a spectrum of clinical behaviors ranging from small indolent lesions to large, locally invasive, unresectable tumors. Tumor growth and hormone hypersecretion cause significant morbidity and mortality in a subset of patients. The proposal was endorsed by a WHO working group that sought to provide a unified approach to neuroendocrine neoplasia in all body sites. We review the features that are characteristic of neuroendocrine cells, the epidemiology and prognosis of these tumors, as well as further refinements in terms used for other pituitary tumors to ensure consistency with the WHO framework. The intense study of PitNETs has provided information about the importance of cellular differentiation in tumor prognosis as a model for neuroendocrine tumors in different locations.

COVID-19-related thyroiditis: A novel disease entity?

The literature on COVID-19-related thyroid complications has accumulated over the past year or so as the pandemic has accelerated throughout the world. In particular, several recent case reports have been published describing a possible correlation between COVID-19 disease and subacute thyroiditis (SAT). In this review, we briefly present one of our own patients and review the current published literature in this area up to January 2021, including analyses of major series of thyroid function tests in patients with significant COVID-19 infection. We conclude that while the great majority of patients with severe COVID-19 infection may show manifestations of the sick euthyroid syndrome, clinicians should be aware of the possibility of SAT, especially in the early weeks and months following even mild COVID-19 infection.

Paediatric Cushing's disease: Epidemiology, pathogenesis, clinical management and outcome.

Cushing's disease (CD) is rare in paediatric practice but requires prompt investigation, diagnosis and therapy to prevent long-term complications. Key presenting features are a change in facial appearance, weight gain, growth failure, virilization, disturbed puberty and psychological disturbance. Close consultation with an adult endocrinology department is recommended regarding diagnosis and therapy. The incidence of CD, a form of ACTH-dependent Cushing's syndrome (CS), is equal to approximately 5% of that seen in adults. The majority of ACTH-secreting adenomas are monoclonal and sporadic, although recent studies of pituitary tumours have shown links to several deubiquitination gene defects. Diagnosis requires confirmation of hypercortisolism followed by demonstration of ACTH-dependence. Identification of the corticotroph adenoma by pituitary MRI and/or bilateral inferior petrosal sampling for ACTH may contribute to localisation before pituitary surgery. Transsphenoidal surgery (TSS) with selective microadenomectomy is first-line therapy, followed by external pituitary irradiation if surgery is not curative. Medical therapy to suppress adrenal steroid synthesis is effective in the short-term and bilateral adrenalectomy should be considered in cases unfit for TSS or radiotherapy or when urgent remission is needed after unsuccessful surgery. TSS induces remission of hypercortisolism and improvement of symptoms in 70-100% of cases, particularly when performed by a surgeon with experience in children. Post-TSS complications include pituitary hormone deficiencies, sub-optimal catch-up growth, and persisting excess of BMI. Recurrence of hypercortisolism following remission is recognised but infrequent, being less common than in adult CD patients. With experienced specialist medical and surgical care, the overall prognosis is good. Early referral to an experienced endocrine centre is advised.

Understanding the Treatment Algorithm of Patients with Metastatic Pancreatic Neuroendocrine Neoplasms: A Single-Institution Retrospective Analysis Comparing Outcomes of Chemotherapy, Molecular Targeted Therapy, and Peptide Receptor Radionuclide Therapy in 255 Patients.

BACKGROUND: The number of therapeutic options for patients with pancreatic neuroendocrine neoplasms (PNEN) has increased, but the optimal therapeutic algorithm has not been defined due to lack of randomised trials comparing different modalities. METHODS: We performed a retrospective study in patients with metastatic PNEN treated with ≥1 line of systemic therapy. The relationship between baseline characteristics, treatment type, and time to treatment failure (TTF), time to progression (TTP), and overall survival (OS) was analysed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model. RESULTS: Two hundred and fifty-five patients with metastatic PNEN had 491 evaluable lines of therapy. Independent predictors of TTF included treatment type, Ki-67, tumour grade, and chromogranin A. To reduce selection bias, a subgroup of 114 patients with grade 2 (G2) metastatic pancreatic neuroendocrine tumours (PNET) was analysed separately. These patients had received 234 lines of treatment (105 chemotherapy, 82 molecular targeted therapy, and 47 peptide receptor radionuclide therapy [PRRT]). In the G2 cohort, TTF and TTP were superior for PRRT compared with both chemotherapy and molecular targeted therapy. OS in the G2 cohort was also superior for those that had received PRRT compared with those that had not (median 84 vs. 56 months; HR 0.55, 95% CI: 0.31-0.98, p = 0.04). CONCLUSIONS: This study suggests that PRRT is associated with superior clinical outcomes relative to other systemic therapies for G2 metastatic PNET. Prospective studies are required to confirm these observations.

Mechanisms of Central Hypogonadism.

Reproductive function depends upon an operational hypothalamo-pituitary-gonadal (HPG) axis. Due to its role in determining survival versus reproductive strategies, the HPG axis is vulnerable to a diverse plethora of signals that ultimately manifest with Central Hypogonadism (CH) in all its many guises. Acquired CH can result from any pituitary or hypothalamic lesion, including its treatment (such as surgical resection and/or radiotherapy). The HPG axis is particularly sensitive to the suppressive effects of hyperprolactinaemia that can occur for many reasons, including prolactinomas, and as a side effect of certain drug therapies. Physiologically, prolactin (combined with the suppressive effects of autonomic neural signals from suckling) plays a key role in suppressing the gonadal axis and establishing temporary CH during lactation. Leptin is a further key endocrine regulator of the HPG axis. During starvation, hypoleptinaemia (from diminished fat stores) results in activation of hypothalamic agouti-related peptide neurons that have a dual purpose to enhance appetite (important for survival) and concomitantly suppresses GnRH neurons via effects on neural kisspeptin release. Obesity is associated with hyperleptinaemia and leptin resistance that may also suppress the HPG axis. The suppressibility of the HPG axis also leaves it vulnerable to the effects of external signals that include morphine, anabolic-androgenic steroids, physical trauma and stress, all of which are relatively common causes of CH. Finally, the HPG axis is susceptible to congenital malformations, with reports of mutations within >50 genes that manifest with congenital CH, including Kallmann Syndrome associated with hyposmia or anosmia (reduction or loss of the sense of smell due to the closely associated migration of GnRH with olfactory neurons during embryogenesis). Analogous to the HPG axis itself, patients with CH are often vulnerable, and their clinical management requires both sensitivity and empathy.

GH deficiency in cancer survivors in the transition age: diagnosis and therapy.

BACKGROUND: Survival rates among childhood cancer survivors (CCSs) have significantly risen in the last 40 years due to substantial improvements in treatment protocols. However, this improvement has brought with it serious late effects that frequently involve the endocrine system. Of the endocrine disorders, GH deficiency (GHD) is the most common among CCSs as a consequence of a history of cancers, surgery, and/or radiotherapy involving the hypothalamo-pituitary region. METHODS: A comprehensive search of English language articles regardless of age was conducted in the MEDLINE database between December 2018 and October 2019. We selected all studies on GH therapy in CCSs during the transition age regarding the most challenging topics: when to retest; which diagnostic tests and cut-offs to use; when to start GH replacement therapy (GHRT); what GH dose to use; safety; quality of life, compliance and adherence to GHRT; interactions between GH and other hormonal replacement treatments. RESULTS: In the present review, we provide an overview of the current clinical management of challenges in GHD in cancer survivors in the transition age. CONCLUSIONS: Endocrine dysfunction among CCSs has a high prevalence in the transition age and increase with time. Many endocrine disorders, including GHD, are often not diagnosed or under-diagnosed, probably due to the lack of specialized centers for the long-term follow-up. Therefore, it is crucial that transition specialized clinics should be increased in terms of number and specific skills in order to manage endocrine disorders in adolescence, a delicate and complex period of life. A multidisciplinary approach, also including psychological counseling, is essential in the follow-up and management of these patients in order to minimize their disabilities and maximize their quality of life.

Primary Ovarian Carcinoid: Extensive Clinical Experience With an Underrecognized Uncommon Entity.

PURPOSE: Primary ovarian neuroendocrine tumors (NETs) develop in pure form or in association with other tumors, mainly teratomas. The available data regarding this rare condition are limited. Much of the literature focuses on single case reports, previously dismissed as a totally benign disorder, and thus long-term considerations and evidence-based management guidelines are lacking. The objective of the current study was to describe the clinical and pathologic characteristics and the effect of various therapeutic modalities on patient morbidity and mortality from 2 major centers. A secondary objective was to highlight that carcinoid syndrome may be manifest in the absence of metastatic disease. METHODS: The authors retrospectively studied a cohort of 34 consecutive patients with primary ovarian NETs who attended either the Oxford University Hospitals or Beatson Oncology Centre, Glasgow, between 1984 and 2014, and had their ovarian carcinoid data (eg, tumor growth, chemotherapy regimen) and mortality outcomes assessed. RESULTS: All patients were women, with an average age of 53 years (range, 23-87 years) at diagnosis. Of the 34 patients, 8 patients (23.5%) presented with carcinoid symptoms. Carcinoid heart disease was evident in 2 of the 34 patients (6%). All patients had a primary ovarian carcinoid tumor on histopathology, and 2 patients had bilateral ovarian carcinoids. Teratoma associations could be assessed in 29 tumors, with 20 (69%) of 29 showing a pathological association. The mean tumor size was 48 mm (range, 4-120 mm; SD, 40 mm). The mean follow-up was 4.5 years, ranging up to 17 years. The disease has been quiescent with no evidence of relapse in 22 of 34 patients; in 12 of 34 patients, it was metastatic. There were 5 patients who received treatment with somatostatin analogs or chemotherapy, whereas 8 patients (23.5%) died of disease. Metastatic disease was found up to 11 years from initial diagnosis. CONCLUSIONS: Primary ovarian NET is rare and likely underrepresented in the literature. It can no longer be simply dismissed as a generally benign entity and may present with both the carcinoid syndrome and carcinoid heart disease. It requires careful evaluation and long-term review.

A prospective longitudinal study of Pasireotide in Nelson's syndrome.

PURPOSE: Nelson's syndrome is a challenging condition that can develop following bilateral adrenalectomy for Cushing's disease, with high circulating ACTH levels, pigmentation and an invasive pituitary tumor. There is no established medical therapy. The aim of the study was to assess the effects of pasireotide on plasma ACTH and tumor volume in Nelson's syndrome. METHODS: Open labeled multicenter longitudinal trial in three steps: (1) a placebo-controlled acute response test; (2) 1 month pasireotide 300-600 µg s.c. twice-daily; (3) 6 months pasireotide long-acting-release (LAR) 40-60 mg monthly. RESULTS: Seven patients had s.c. treatment and 5 proceeded to LAR treatment. There was a significant reduction in morning plasma ACTH during treatment (mean ± SD; 1823 ± 1286 ng/l vs. 888.0 ± 812.8 ng/l during the s.c. phase vs. 829.0 ± 1171 ng/l during the LAR phase, p < 0.0001). Analysis of ACTH levels using a random intercept linear mixed-random effects longitudinal model showed that ACTH (before the morning dose of glucocorticoids) declined significantly by 26.1 ng/l per week during the 28-week of treatment (95% CI - 45.2 to - 7.1, p < 0.01). An acute response to a test dose predicted outcome in 4/5 patients. Overall, there was no significant change in tumor volumes (1.4 ± 0.9 vs. 1.3 ± 1.0, p = 0.86). Four patients withdrew during the study. Hyperglycemia occurred in 6 patients. CONCLUSIONS: Pasireotide lowers plasma ACTH levels in patients with Nelson's syndrome. A longer period of treatment may be needed to assess the effects of pasireotide on tumor volume. TRIAL REGISTRATION: Clinical Trials.gov ID, NCT01617733.

INITIATION OF PATIENTS ONTO LONG-ACTING SOMATOSTATIN ANALOGUE THERAPY FOR NEUROENDOCRINE TUMORS: A SINGLE-CENTER REVIEW OF PRACTICE.

OBJECTIVE: Neuroendocrine tumors (NETs) are being seen increasingly frequently, and recent data show that long-acting somatostatin analogues have become a major initial treatment, regardless of whether the tumors are functioning or not. However, test dosing with subcutaneous (sc) octreotide is usually advised to assess longer-term tolerability, although this advice is mainly based on results with functioning tumors. The aim of the study was to assess the value of an initiating test dose of sc octreotide on the prediction of subsequent adverse events after treatment with the long-acting analogue. METHODS: In a single, large Centre of Excellence for NETs, a first cohort of patients (n = 24) was admitted overnight after an sc injection of octreotide, and then administered the analogue; a subsequent group (n = 53) had the test dose performed on an outpatient basis. Side effects were recorded after the test dose and subsequent treatment with the long-acting analogue. RESULTS: The test dose injection was of little value in predicting adverse events following the long-acting somatostatin analogue. CONCLUSION: Unless there are serious symptoms associated with a functioning NET, it is unnecessary to carry out a test dose; a change to this procedure will improve resource allocation and should enhance early initiation onto maintenance therapy. ABBREVIATIONS: CLARINET = Controlled study of lanreotide antiproliferative response in neuroendocrine tumors LAR = long-acting repeatable NET = neuroendocrine tumor PROMID = Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with meta-static neuroendocrine midgut tumors.

Baseline morning cortisol level as a predictor of pituitary-adrenal reserve: a comparison across three assays.

CONTEXT: The short ACTH stimulation test (250 µg) is the dynamic test most frequently used to assess adrenal function. It is possible that a single basal cortisol could be used to predict the dynamic response, but research has been hampered by the use of different assays and thresholds. OBJECTIVE: To propose a morning baseline cortisol criterion of three of the most commonly used modern cortisol immunoassays - Advia Centaur (Siemens), Architect (Abbott) and the Roche Modular System (Roche) - that could predict adrenal sufficiency. DESIGN: Observational, retrospective cross-sectional study at two centres. PATIENTS AND MEASUREMENTS: Retrospective analysis of the results of 1019 Short Synacthen tests (SSTs) with the Advia Centaur, 449 SSTs with the Architect and 2050 SSTs with the Roche Modular System assay. Serum cortisol levels were measured prior to injection of 250 µg Synacthen and after 30 min. Overall, we were able to collate data from a total of 3518 SSTs in 3571 patients. RESULTS: Using receiver-operator curve analysis, baseline cortisol levels for predicting passing the SST with 100% specificity were 358 nmol/l for Siemens, 336 nmol/l for Abbott and 506 nmol/l for Roche. Utilizing these criteria, 589, 158 and 578 SSTs, respectively, for Siemens, Abbott and Roche immunoassays could have been avoided. CONCLUSIONS: We have defined assay-specific morning cortisol levels that are able to predict the integrity of the hypothalamo-pituitary-adrenal axis. We propose that this represents a valid tool for the initial assessment of adrenal function and has the potential to obviate the need for dynamic testing in a significant number of patients.

Changes in the Epidemiology of Neuroendocrine Tumours.

BACKGROUND: The reviewing and assessment of epidemiological characteristics of neuroendocrine tumours (NETs) remains a challenge. Despite the fact that it is an uncommon family of neoplasms, several worldwide series have revealed an increasing incidence of this rare condition. However, the data are difficult to compare over time due to changes in classification. METHODS: We compared the data related to incidence, prevalence, stage of the disease at diagnosis and survival reported in several series, focusing on the differences and trying to examine some of the probable reasons that may explain the variations in the results between studies. RESULTS AND CONCLUSIONS: The incidence of NETs is increasing over time, and their incidental discovery due to improved and more frequent imaging does not seem to be enough to explain this rise. Significant differences can be found between geographic regions and races, suggesting that environmental or genetic factors may contribute to the clinical and biological behaviour of these tumours; increasing our knowledge of oncogenesis will be necessary to explain them. As with other rare diseases, creating specific databases and multidisciplinary working groups would improve the accuracy of the information gained.

Thymic Neuroendocrine Neoplasms: Biological Behaviour and Therapy.

Thymic neuroendocrine neoplasms are rare tumours, but their management can often be highly problematic. While previously assumed to be essentially variants of bronchopulmonary (lung) carcinoids, they are generally more aggressive and more difficult to treat. Some 25% are associated with multiple endocrine neoplasia-1, while a higher proportion are associated with the ectopic ACTH syndrome, and occasionally both. We discuss the classification of these tumours, their biology as far as is known, and their clinical, biochemical and imaging features. We also review possible management options and suggest stratagems to optimise their treatment, which even today is far from optimal.

Health-related quality of life in patients treated for nonfunctioning pituitary adenomas during the years 2000-2010.

OBJECTIVE: The published data on health-related quality of life (HRQoL) after treatment of nonfunctioning pituitary adenomas (NFPAs) are conflicting. We evaluated HRQoL in a recent series of patients who had surgery for an NFPA. DESIGN: Cross-sectional study including a large control population. PATIENTS AND MEASUREMENTS: A HRQoL questionnaire (15D) was sent to all patients (n = 161) having undergone transsphenoidal surgery for NFPA in the years 2000-2010 at the Helsinki University Hospital. The 15D score and dimension scores of the study population (n = 137) were compared with those of a large (n = 4967) gender- and age-standardized control population. Possible independent predictors of HRQoL in the patients were estimated with multivariate regression analysis. RESULTS: Postoperatively, 57% of the patients had normal visual function. After a mean follow-up of 7·4 ± 3·2 years (mean ± SD), 62% suffered from hypopituitarism. Overall, HRQoL was near-normal in patients compared to controls (15D scores 0·885 ± 0·114 vs 0·903 ± 0·093, respectively, P = 0·07). On single dimensions, patients had impaired vision and sexual activity (both P < 0·0005), more depression and distress (both P < 0·005) and less discomfort and symptoms (P < 0·05). Age, body mass index, diabetes, depression and reoperation were independent predictors of impaired HRQoL (all P < 0·05). Thyroxine substitution was associated with impaired and hydrocortisone and testosterone substitution (males only) with better HRQoL (all P < 0·05). CONCLUSIONS: This recent series of NFPA patients demonstrates that overall HRQoL is near-normal after medium term follow-up; the most impaired dimensions were in vision and sexual activity. Comorbidities are strong predictors of impaired HRQoL.

Long-term outcomes of children treated for Cushing's disease: a single center experience.

PURPOSE: Pediatric Cushing's disease (CD) is rare and there are limited data on the long-term outcomes. We assessed CD recurrence, body composition, pituitary function and psychiatric comorbidity in a cohort of pediatric CD patients. METHODS: Retrospective review of 21 CD patients, mean age at diagnosis 12.1 years (5.7-17.8), managed in our center between 1986 and 2010. Mean follow-up from definitive treatment was 10.6 years (2.9-27.2). RESULTS: Fifteen patients were in remission following transsphenoidal surgery (TSS) and 5 were in remission following TSS + external pituitary radiotherapy (RT). One patient underwent bilateral adrenalectomy (BA). CD recurrence occurred in 3 (14.3 %) patients: 2 at 2 and 6 years after TSS and 1 7.6 years post-RT. The BA patient developed Nelson's syndrome requiring pituitary RT 0.6 years post-surgery. Short-term growth hormone deficiency (GHD) was present in 14 patients (81 % patients tested) (11 following TSS and 3 after RT) and 4 (44 % of tested) had long-term GHD. Gonadotropin deficiency caused impaired pubertal development in 9 patients (43 %), 4 requiring sex steroid replacement post-puberty. Four patients (19 %) had more than one pituitary hormone deficiency, 3 after TSS and 1 post-RT. Five patients (24 %) had long-term psychiatric co-morbidities (cognitive dysfunction or mood disturbance). There were significant long-term improvements in growth, weight and bone density but not complete reversal to normal in all patients. CONCLUSIONS: The long-term consequences of the diagnosis and treatment of CD in children is broadly similar to that seen in adults, with recurrence of CD after successful treatment uncommon but still seen. Pituitary hormone deficiencies occurred in the majority of patients after remission, and assessment and appropriate treatment of GHD is essential. However, while many parameters improve, some children may still have mild but persistent defects.

Carcinoid Heart Disease: From Pathophysiology to Treatment--'Something in the Way It Moves'.

Carcinoid heart disease (CHD) is a rare cardiac manifestation occurring in patients with advanced neuroendocrine tumours and the carcinoid syndrome, usually involving the right-sided heart valves and eventually leading to right heart failure. The pathophysiology of CHD is still obscure and believed to be multifactorial, as a variety of vasoactive substances secreted by the tumour appear to be involved. The management of patients with CHD is complex, as both the systemic malignant disease and the heart involvement have to be addressed. Timely diagnosis and early surgical treatment in appropriately selected patients are of outmost importance, as CHD is associated with increased morbidity and mortality. Valve replacement surgery alleviates right heart failure and may also contribute to improved survival. In the present study we have comprehensively reviewed the existing literature to date, mainly focusing on the pathophysiology of CHD. Other aspects of CHD (such as the clinical presentation, diagnostic tools and therapeutic approach) are addressed in brief.

Emerging drugs for Cushing's disease.

INTRODUCTION: Considering the effects of uncontrolled hypercortisolism on morbidity and mortality, there is a clear need for effective medical therapy for patients with Cushing's disease (CD). Therefore, the search for new medical effective tools remains active, and already promising results have been obtained. AREAS COVERED: The importance of the design and conduct of trials to validate old drugs or to test new compounds is discussed. The results of the ongoing clinical trials, targeting the specific properties of drugs, such as ketoconazole, LCI699, mifepristone, etomidate and pasireotide, are also reported. The authors also emphasise the advantages and drawbacks of each particular drug, and the potential combined use of agents with complementary mechanisms of action. EXPERT OPINION: CD is an excellent example of a situation where effective therapy is essential, but where the balance of risk and benefit must be carefully judged. Metyrapone is the drug of choice when rapid control of the hypercortisolaemia is required, ketoconazole represents a good second-line drug, although in the future LCI699 may be a better alternative. Mifepristone can also be used in the rare situation when previous drugs are inappropriate. Etomidate is useful where immediate parenteral action is required. For drugs working directly on the pituitary, cabergoline is occasionally effective and pasireotide can be attempted in patients with mild CD.