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Maria P Yavropoulou, Marina Tsoli, Konstantinos Barkas, Gregory Kaltsas, and Ashley Grossman

Non-functioning pituitary adenomas, recently alternatively termed pituitary neuroendocrine tumours (NFpitNETs), are mostly benign neoplasms that are not associated with a hormonal hypersecretory syndrome. The clinical spectrum of NFpitNETs varies from completely asymptomatic to the development of panhypopituitarism and manifestations attributed to mass effects on nearby structures. NFpitNETs follow generally an indolent course, but in 5–10% of cases they exhibit more aggressive behaviour, characterised by rapid growth, invasiveness and early recurrence. The initial size of the adenoma, the presence of symptoms and the histological subtype are related to the natural course of NFpitNETs. Active surveillance is usually the strategy of choice in the case of an asymptomatic NFpitNET, while surgical resection is recommended in case of visual and/or neurological abnormalities or rapid tumour growth. Based on previous and emerging data, approximately 50% of patients show tumour growth, while 20% of patients with NF-macroadenomas on active surveillance may require further intervention during a follow-up period of 7 years. Adjuvant radiotherapy is usually considered for large residual tumours or recurrent and/or aggressive adenomas, but there is evidence that medical therapy, especially with cabergoline, can occasionally be beneficial, whereas newer molecular agents are under investigation. Thus, while highly effective medical therapy is awaited, a move towards a more conservative approach seems appropriate, at least until we have better molecular markers of progressiveness.

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Dorota Dworakowska and Ashley B Grossman

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterised by the development of multiple hamartomas in numerous organs. It is caused by mutations of two tumour suppressor genes, TSC1 on chromosome 9q34 and TSC2 on chromosome 16p13.3, which encode for hamartin and tuberin respectively. The interaction between these two proteins, the tuberin–hamartin complex, has been shown to be critical to multiple intracellular signalling pathways, especially those controlling cell growth and proliferation. TSC may affect skin, central nervous system, kidneys, heart, eyes, blood vessels, lung, bone and gastrointestinal tract. Small series and case reports have documented that in tuberous sclerosis patients many endocrine system alterations might occur, affecting the function of the pituitary, parathyroid and other neuroendocrine tissue. There have been scattered reports of the involvement of such tissue in the pathological process of TSC, but no systematic review as to whether this is a true association. We have therefore systematically assessed all available published literature in this area. We conclude that there may be an association with pituitary and parathyroid tumours, and two recent descriptions of Cushing's disease are especially intriguing. However, the evidence seems more firm in the case of islet cell tumours, particularly insulinomas. As these latter may cause changes in mental state that may be confused with the cerebral manifestations of TSC per se, it is particularly important for physicians working with these patients to be aware of the putative and indeed likely association.

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Ben C Whitelaw

Temozolomide is an oral chemotherapy used to treat aggressive pituitary tumours since 2006. It is inexpensive and well tolerated, the main side effects are fatigue, nausea and cytopenia. Overall the studies demonstrate approximately 70% response rate for temozolomide, if response is defined radiologically as complete, partial response or stable disease. Using the more stringent criteria of complete or partial response, the success rate is near 40%. Functioning tumours respond more frequently than non-functioning tumours. Tumours which are depleted of methyl guanine methyltransferase (MGMT), as assessed by immunohistochemistry, also are more likely to respond. Temozolomide has an established role in treating pituitary tumours which have demonstrated metastases or which are refractory and progressing, despite all conventional treatment (so-called salvage treatment). The challenge is to offer temozolomide earlier in the pathway if appropriate. Tumours which demonstrate aggressive clinical behaviour (defined as clinically relevant growth despite optimal treatment) should be considered for temozolomide. One common situation when this might occur is tumour progression after surgery and radiotherapy. It is unnecessary to wait until salvage treatment is required. Anticipated (but not yet demonstrated) aggressive behaviour can be regarded as a potential indication for temozolomide, but there is currently insufficient evidence to recommend this. Ideally a trial should assess this potential indication. Early treatment could be considered in selected cases when high levels of proliferation and invasion were demonstrated, causing significant clinical concern.

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K A S Al-Shoumer, S A Beshyah, and D G Johnston

INTRODUCTION The use of growth hormone replacement therapy in children with growth hormone deficiency is widely accepted (Milner et al. 1979, Shalet et al. 1981, Romshe et al. 1984, Hindmarsh & Brook 1992). It is prescribed through childhood until growth is complete. Its use in adults deficient of growth hormone is still under trial and in selected patients it has been shown to have some beneficial actions (Jorgensen et al. 1989, Salomon et al. 1989, Whitehead et al. 1992, Bengtsson et al. 1993). Questions exist about the oncogenic potential of this mitogenic hormone and whether it might cause recurrence of pituitary tumours, the development of other solid tumours or leukaemia. This has special relevance in adult life where growth hormone therapy may be continued for many years. Growth hormone (GH) is the major hormone stimulating longitudinal growth, after the early post-natal period. It rapidly induces c-myc protooncogene expression in
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R C F Leonard, A Ray, L Lee, T Leonard, and P Hopwood

Introduction Hormonal and antihormonal manipulations have been used in the palliative treatment of advanced breast cancer with increasing frequency since the first experiments of Beatson in 1895. Androgen therapy commenced in the 1930s, followed by oestrogen therapy, and in the 1950s surgical ablation of the adrenals and of the pituitary became widely adopted as effective if drastic interventions. All produced similar anticancer effects but with different attendant costs to the patient. Tamoxifen, synthesised in 1963, was reported to produce anticancer effects in the early 1970s and soon rose to the front-line status it still enjoys because of its perceived ease of administration, low frequency of side-effects and satisfactory anticancer effect. Stabilisation of the cancer or induction of remission is seen in 50-70% of selected patients, with an overall regression rate across all patients of about one-third. Remission from any first-line endocrine manoeuvre is likely to last 1-2 years
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Thomas J Giordano

The classification of human cancers represents one of the cornerstones of modern pathology. Over the last century, surgical pathologists established the current taxonomy of neoplasia using traditional histopathological parameters, which include tumor architecture, cytological features and cellular proliferation. This morphological classification is efficient and robust with high reproducibility and has served patients and health care providers well. The most recent decade has witnessed an explosion of genome-wide molecular genetic and epigenetic data for most cancers, including tumors of endocrine organs. The availability of this expansive multi-dimensional genomic data, collectively termed the cancer genome, has catalyzed a re-examination of the classification of endocrine tumors. Here, recent cancer genome studies of various endocrine tumors, including those of the thyroid, pituitary and adrenal glands, pancreas, small bowel, lung and skin, are presented with special emphasis on how genomic insights are impacting endocrine tumor classification.

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Simona Grozinsky-Glasberg, Ilan Shimon, Márta Korbonits, and Ashley B Grossman

Neuroendocrine tumours (NETs) represent a heterogeneous family of neoplasms, which may develop from different endocrine glands (such as the pituitary, the parathyroid or the neuroendocrine adrenal glands), endocrine islets (within the thyroid or pancreas) as well as from endocrine cells dispersed between exocrine cells throughout the digestive and respiratory tracts. The development of somatostatin analogues (SSA) as important diagnostic and treatment tools has revolutionised the clinical management of patients with NETs. However, although symptomatic relief and stabilisation of tumour growth for various periods of time are observed in many patients treated with SSA, tumour regression is rare. Possible mechanisms when this does occur include antagonism of local growth factor release and effects, probably including activation of tyrosine and serine–threonine phosphatases, and indirect effects via anti-angiogenesis. The development of new SSA, new drug combination therapies and chimaeric molecules should further improve the clinical management of these patients, as should a more complete understanding of their mode of action.

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S K Khoo, R Pendek, R Nickolov, D C Luccio-Camelo, T L Newton, A Massie, D Petillo, J Menon, D Cameron, B T Teh, and S-P Chan

Isolated familial somatotropinoma (IFS) accounts for 18% of familial isolated pituitary adenoma (FIPA) cases. Recently, germline mutations of the aryl hydrocarbon receptor-interacting protein gene (AIP) have been found in families with pituitary adenoma predisposition, FIPA, and IFS. In this study, we investigate the AIP mutation status and perform a genome-wide scan to search for the modifier regions of acromegalic phenotypes in an IFS family of 31 aborigines from Borneo. Complete endocrine diagnosis and data could not be collected due to logistical and cultural reasons. AIP mutation screening was carried out by direct sequencing and the genome-wide scan was performed using 400 microsatellites. Non-parametric linkage analysis was performed to obtain the logarithm of odds (LOD) scores. A novel AIP frameshift mutation in exon 4 (c.500delC) (p.P167HfsX3) was identified in all members with acromegalic features, as well as in 15 members without acromegalic features, revealing incomplete penetrance of AIP. The data showed that patients with the same mutation may express acromegalic features of differing severity, suggesting the existence of modifier genes. The highest LOD score of 2.2 was obtained near D19S571 (19q13.41). We also found weak linkages on chromosomes 3q28, 8q12.1, and 21q22.13, with LOD scores of 1.1, 1.8, and 1.4 respectively. Our results show the first genome-wide scan that identifies novel modifier loci for acromegalic phenotypes in an IFS family. Identification of modifier loci may provide further insight into the disease mechanism and explain the clinical variability observed in its patients.

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Maria Chiara Zatelli, Daniela Piccin, Cristina Vignali, Federico Tagliati, Maria Rosaria Ambrosio, Marta Bondanelli, Vincenzo Cimino, Antonio Bianchi, Herbert A Schmid, Massimo Scanarini, Alfredo Pontecorvi, Laura De Marinis, Giulio Maira, and Ettore C degli Uberti

Somatostatin (SRIF) analogs have been employed in medical therapy of non-functioning pituitary adenomas (NFA), with contrasting results. Previous evidence showed that SRIF can exert its antiproliferative effects by reducing vascular endothelial growth factor (VEGF) secretion and action, and that VEGF expression may be related to pituitary tumor growth. The aim of our study was to clarify the possible effects of a multireceptor SRIF ligand on VEGF secretion and cell proliferation in human NFA primary cultures. We assessed the expression of SRIF receptors (SSTR1–5), the in vitro effects on VEGF secretion, and on cell viability of SRIF and of the stable SRIF analog pasireotide (SOM230), which activates SSTR1, 2, 3, and 5. Twenty-five NFA were examined by RT-PCR for expression of α-subunit, SSTR, VEGF, and VEGF receptors 1 (VEGF-R1) and 2 (VEGF-R2). Primary cultures were tested with SRIF and with pasireotide. All NFA samples expressed α-sub, VEGF and VEGFR-1 and 2, while SSTR expression pattern was highly variable. Two different groups were identified according to VEGF secretion inhibition by SRIF. VEGF secretion and cell viability were reduced by SRIF and pasireotide in the ‘responder’ group, but not in the ‘non-responder’ group, including NFA expressing SSTR5. SRIF and pasireotide completely blocked forskolin-induced VEGF secretion. In addition, SRIF and pasireotide completely abrogated the promoting effects of VEGF on NFA cell viability. Our data demonstrate that pasireotide can inhibit NFA cell viability by inhibiting VEGF secretion, and suggest that the multireceptor-SSTR agonist pasireotide might be useful in medical therapy of selected NFA.

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Federico Gatto and Leo J Hofland

Somatostatin (SS) and dopamine (DA) receptors have been highlighted as two critical regulators in the negative control of hormonal secretion in a wide group of human endocrine tumors. Both families of receptors belong to the superfamily of G protein-coupled receptors and share a number of structural and functional characteristics. Because of the generally reported high expression of somatostatin receptors (SSTRs) in neuroendocrine tumors (NET), somatostatin analogs (SSA) have a pronounced role in the medical therapy for this class of tumors, especially pituitary adenomas and well-differentiated gastroenteropancreatic NET (GEP NET). Moreover, NET express not only SSTR but also frequently dopamine receptors (DRs), and DA agonists targeting the D2 receptor (D2) have been demonstrated to be effective in controlling hormone secretion and cell proliferation in in vivo and in vitro studies. The treatment with SSAs combined with DA agonists has already been demonstrated efficacious in a subgroup of patients with GH-secreting pituitary adenomas and few reported cases of carcinoids. The recent availability of new selective and universal SSA and DA agonists, as well as the chimeric SS/DA compounds, may shed new light on the potential role of SSTR and D2 as combined targets for biotherapy in NET. This review provides an overview of the latest studies evaluating the expression of SSTR and DR in NET, focusing on their co-expression and the possible clinical implications of such co-expression. Moreover, the most recent insights in SSTR and D2 pathophysiology and the future perspectives for treatment with SSA, DA agonists, and SS/DA chimeric compounds are discussed.