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Alexandra Chrisoulidou
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Gregory Kaltsas
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Ioannis Ilias
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Ashley B Grossman
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Malignant phaeochromocytomas are rare tumours accounting for ~10% of all phaeochromocytomas; the prevalence of malignancy among paragangliomas is higher, especially those associated with succinate dehydrogenase subunit B gene mutations. Although a subset of these tumours has metastatic disease at initial presentation, a significant number develops metastases during follow-up after excision of an apparently benign tumour. Clinical, biochemical and histological features cannot reliably distinguish malignant from benign tumours. Although a number of recently introduced molecular markers have been explored, their clinical significance remains to be elucidated from further studies. Several imaging modalities have been utilised for the diagnosis and staging of these tumours. Functional imaging using radiolabelled metaiodobenzylguanidine (MIBG) and more recently, 18F-fluorodopamine and 18F-fluorodopa positron emission tomography offer substantial sensitivity and specificity to correctly detect metastatic phaeochromocytoma and paraganglioma and helps identify patients suitable for treatment with radiopharmaceuticals. The 5-year mortality rate of patients with malignant phaeochromocytomas and paragangliomas greater than 50% indicates that there is considerable room for the improvement of currently available therapies. The main therapeutic target is tumour reduction and control of symptoms of excessive catecholamine secretion. Currently, the best adjunctive therapy to surgery is treatment with radiopharmaceuticals using 131I-MIBG; however, this is very rarely curative. Chemotherapy has been used for metastatic disease with only a partial and mainly palliative effect. The role of other forms of radionuclide treatment either alone or in combination with chemotherapy is currently evolving. Ongoing microarray studies may provide novel intracellular pathways of importance for proliferation/cell cycle control, and lead to the development of novel pharmacological agents.

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Krystallenia I Alexandraki Department of Surgery, Medical School, National and Kapodistrian University of Athens, Athens, Greece

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Gregory A Kaltsas Department of Propaedeutic Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

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Simona Grozinsky-Glasberg Department of Endocrinology and Metabolism, Neuroendocrine Tumor Unit, ENETS Center of Excellence, Hadassah Medical Organization and Faculty of Medicine, the Hebrew University, Jerusalem, Israel

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Pancreatic neuroendocrine neoplasms (panNENs) are rare relatively malignancies that, despite their frequently slow-growing pattern, have the ability to metastasize. Metastatic and/or advanced insulinomas and glucagonomas are functioning panNENs emerging from the pancreas displaying unique peculiarities, depending on their hormonal syndromes and increased malignant potential. Advanced insulinomas management follows usually the panNENs therapeutic algorithm, but some distinctions are well advised together with aiming to control hypoglycemias that occasionally can be severe and refractory to treatment. When first-generation somatostatin analogues (SSAs) fail to control hypoglycemia syndrome, second-generation SSAs and everolimus have to be considered for exploiting their hyperglycemic effect. There is evidence that everolimus is still effective after rechallenge retaining its hypoglycemic effect independently of its antitumor effect that seems to be mediated by different molecular pathways. Peptide receptor radionuclide therapy (PRRT) constitutes a promising therapeutic option for both its antisecretory and antitumoral action. Similarly, advanced and/or metastatic glucagonomas management also follows the panNENs therapeutic algorithm, but the clinical syndrome has to be addressed by aminoacid infusion and by first-generation SSAs to improve the patient performance status. PRRT seems to be an effective treatment when surgery and SSAs fail. The application of these therapeutic modalities has been shown to be efficacious in controlling the manifestations of the secretory syndrome and prolonging the overall survival of patients suffering from these malignancies.

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Maria P Yavropoulou Endocrinοlogy Unit, 1st Department of Propaedeutic Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

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Marina Tsoli Endocrinοlogy Unit, 1st Department of Propaedeutic Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

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Konstantinos Barkas Department of Neurosurgery, General Hospital of Nikaia-Peiraia, Agios Panteleimon, Athens, Greece

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Gregory Kaltsas Endocrinοlogy Unit, 1st Department of Propaedeutic Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

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Ashley Grossman Centre for Endocrinology, Barts and the London School of Medicine, Queen Mary University of London, London, UK
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK

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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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Gregory A Kaltsas
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Jane Evanson Endocrine Unit, Department of Academic Radiology, Department of Endocrinology, Department of Endocrinology, Department of Pathophysiology, National University of Athens, Athens, Greece

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Alexandra Chrisoulidou Endocrine Unit, Department of Academic Radiology, Department of Endocrinology, Department of Endocrinology, Department of Pathophysiology, National University of Athens, Athens, Greece

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Ashley B Grossman Endocrine Unit, Department of Academic Radiology, Department of Endocrinology, Department of Endocrinology, Department of Pathophysiology, National University of Athens, Athens, Greece

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The sellar and parasellar region is an anatomically complex area where a number of neoplastic, inflammatory, infectious, developmental and vascular diseases can develop. Although most sellar lesions are due to pituitary adenomas, a number of other pathologies involving the parasellar region can present in a similar manner. The diagnosis of such lesions involves a multidisciplinary approach, and detailed endocrinological, ophthalmological, neuroimaging, neurological and finally histological studies are required. Correct diagnosis prior to any intervention is essential as the treatment of choice will be different for each disorder, particularly in the case of primary malignant parasellar tumours. The complexity of structures that define the parasellar region can produce a variety of neoplastic processes, the malignant potential of which relies on histological grading. In the majority of parasellar tumours, a multimodal therapeutic approach is frequently necessary including surgery, radiotherapy, primary or adjuvant medical treatment and replacement of apparent endocrine deficits. Disease-specific medical therapies are mandatory in order to prevent recurrence or further tumour growth. This is particularly important as neoplastic lesions of the parasellar region tend to recur after prolonged follow-up, even when optimally treated. Apart from the type of treatment, identification of clinical and radiological features that could predict patients with different prognosis seems necessary in order to identify high-risk patients. Due to their rarity, central registration of parasellar tumours is required in order to be able to provide evidence-based diagnostic and mainly therapeutic approaches.

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Anna Angelousi Endocrine Unit, 1st Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece

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Eva Kassi Endocrine Unit, 1st Department of Internal Medicine, Laiko Hospital, National and Kapodistrian University of Athens, Athens, Greece
Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece

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Narjes Ansari-Nasiri Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece

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Harpal Randeva Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK

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Gregory Kaltsas Endocrine Unit, 1st Department of Propaedeutic Medicine, Laiko University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece

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George Chrousos First Department of Pediatrics, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece

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Circadian rhythms at a central and peripheral level are operated by transcriptional/translational feedback loops involving a set of genes called ‘clock genes’ that have been implicated in the development of several diseases, including malignancies. Dysregulation of the Clock system can influence cancer susceptibility by regulating DNA damage and repair mechanisms, as well as apoptosis. A number of oncogenic pathways can be dysregulated via clock genes’ epigenetic alterations, including hypermethylation of clock genes’ promoters or variants of clock genes. Clock gene disruption has been studied in breast, lung and prostate cancer, and haematological malignancies. However, it is still not entirely clear whether clock gene disruption is the cause or the consequence of tumourigenesis and data in endocrine neoplasms are scarce. Recent findings suggest that clock genes are implicated in benign and malignant adrenocortical neoplasias. They have been also associated with follicular and papillary thyroid carcinomas and parathyroid adenomas, as well as pituitary adenomas and craniopharyngiomas. Dysregulation of clock genes is also encountered in ovarian and testicular tumours and may also be related with their susceptibility to chemotherapeutic agents. The most common clock genes that are implicated in endocrine neoplasms are PER1, CRY1; in most cases their expression is downregulated in tumoural compared to normal tissues. Although there is still a lot to be done for the better understanding of the role of clock genes in endocrine tumourigenenesis, existing evidence could guide research and help identify novel therapeutic targets aiming mainly at the peripheral components of the clock gene system.

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Gregory Kaltsas
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Ioannis I Androulakis
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Wouter W de Herder Endocrine Unit, Department of Pathophysiology, National University of Athens, Department of Internal Medicine, Sector of Endocrinology, Department of Endocrinology, St Bartholomew's Hospital, Mikras Asias 75, 11527 Athens, Greece

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Ashley B Grossman Endocrine Unit, Department of Pathophysiology, National University of Athens, Department of Internal Medicine, Sector of Endocrinology, Department of Endocrinology, St Bartholomew's Hospital, Mikras Asias 75, 11527 Athens, Greece

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Neuroendocrine tumours may be either benign or malignant tumours, and have the ability to synthesise and secrete biologically active substances characteristic of the cell of origin that can cause distinct clinical syndromes. The term ‘paraneoplastic syndromes’ (PNSs) is used to denote syndromes secondary to substances secreted from tumours not related to their specific organ or tissue of origin and/or production of autoantibodies against tumour cells; such syndromes are mainly associated with hormonal and neurological symptoms. Appreciation of the presence of such syndromes is important as clinical presentation, if not identified, may delay the diagnosis of the underlying neoplasia. Conversely, early recognition can allow for more rapid diagnosis, particularly as the coexistence of a neoplasm with a clinical or biochemical marker offers an additional determinant of tumour status/progression. PNSs can complicate the patient's clinical course, response to treatment, impact prognosis and even be confused as metastatic spread. Their diagnosis involves a multidisciplinary approach, and detailed endocrinological, neurological, radiological and histological studies are required. Correct diagnosis is essential as the treatment of choice will be different for each disorder, particularly in the case of malignant tumours; it is therefore important to develop appropriate means to correctly identify and localise these tumours. Clinical awareness and the incorporation into clinical practise of 111In-octreotide scintigraphy, chromogranin A and other evolving biochemical marker measurement techniques have substantially contributed to the identification of patients harbouring such syndromes. Disease-specific medical therapies are mandatory in order to prevent recurrence and/or further tumour growth. Owing to their rarity, central registration of these syndromes is very helpful in order to be able to provide evidence-based diagnostic and therapeutic approaches.

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Anna Angelousi Department of Pathophysiology, Sector of Endocrinology, National & Kapodistrian University of Athens, Athens, Greece

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Georgios K Dimitriadis Division of Translational and Experimental Medicine, University of Warwick Medical School, Clinical Sciences Research Laboratories, Coventry, UK

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Georgios Zografos Third Department of Surgery, Athens General Hospital “Georgios Gennimatas”, Athens, Greece

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Svenja Nölting Department of Internal Medicine II, Campus Grosshadern, University-Hospital, Ludwig-Maximilians-University of Munich, Munich, Germany

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Gregory Kaltsas Department of Pathophysiology, Sector of Endocrinology, National & Kapodistrian University of Athens, Athens, Greece
Division of Translational and Experimental Medicine, University of Warwick Medical School, Clinical Sciences Research Laboratories, Coventry, UK
Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK

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Ashley Grossman Department of Endocrinology, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, University of Oxford, Oxford, UK

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Tumourigenesis is a relatively common event in endocrine tissues. Currently, specific guidelines have been developed for common malignant endocrine tumours, which also incorporate advances in molecular targeted therapies (MTT), as in thyroid cancer and in gastrointestinal neuroendocrine malignancies. However, there is little information regarding the role and efficacy of MTT in the relatively rare malignant endocrine tumours mainly involving the adrenal medulla, adrenal cortex, pituitary, and parathyroid glands. Due to the rarity of these tumours and the lack of prospective studies, current guidelines are mostly based on retrospective data derived from surgical, locoregional and ablative therapies, and studies with systemic chemotherapy. In addition, in many of these malignancies the prognosis remains poor with individual patients responding differently to currently available treatments, necessitating the development of new personalised therapeutic strategies. Recently, major advances in the molecular understanding of endocrine tumours based on genomic, epigenomic, and transcriptome analysis have emerged, resulting in new insights into their pathogenesis and molecular pathology. This in turn has led to the use of novel MTTs in increasing numbers of patients. In this review, we aim to present currently existing and evolving data using MTT in the treatment of adrenal, pituitary and malignant parathyroid tumours, and explore the current utility and effectiveness of such therapies and their future evolution.

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Georgios K Dimitriadis The Arden NET CoE, Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals of Coventry and Warwickshire NHS Trust, Coventry, UK
Division of Translational and Experimental Medicine, Warwick Medical School, University of Warwick, Coventry, UK
Division of Endocrinology and Investigative Medicine, Imperial College London, Hammersmith Campus, London, UK

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Martin O Weickert The Arden NET CoE, Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals of Coventry and Warwickshire NHS Trust, Coventry, UK
Division of Translational and Experimental Medicine, Warwick Medical School, University of Warwick, Coventry, UK
Centre for Applied Biological and Exercise Sciences, Coventry University, Coventry, UK

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Harpal S Randeva The Arden NET CoE, Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals of Coventry and Warwickshire NHS Trust, Coventry, UK
Division of Translational and Experimental Medicine, Warwick Medical School, University of Warwick, Coventry, UK
Centre for Applied Biological and Exercise Sciences, Coventry University, Coventry, UK

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Gregory Kaltsas The Arden NET CoE, Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism, University Hospitals of Coventry and Warwickshire NHS Trust, Coventry, UK
Division of Pathophysiology, National and Kapodistrian University of Athens Medical School, Athens, Greece
Oxford Center for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK

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Ashley Grossman Oxford Center for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK

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Although recent epidemiological evidence indicates that the prevalence of non-functioning gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) is rising, a significant number of GEP-NETs still present with symptoms related to the secretion of biologically active substances leading to the development of distinct clinical syndromes. In the past, these syndromes were associated with substantial morbidity and mortality due to the lack of specific therapies; however, since the introduction of long-acting somatostatin analogues and medications such as proton pump inhibitors, their control has been greatly improved. As a result, nowadays, the main cause of morbidity and mortality in GEP-NETs is mostly directly related to tumour growth and the extent of metastatic disease. However, in some patients with functioning tumours and extensive disease, control of the secretory syndrome still remains problematic, necessitating the employment of several cytoreductive techniques, which may not always be sufficient. Recently, new agents directed against tumour growth, or exerting increased binding activity to receptors expressed in these tumours, or interfering with the synthetic pathway of some of the compounds secreted by these tumours, have been developed. Since there are no specific guidelines addressing the totality of the management of the secretory syndromes related to GEP-NETs, this review aims at critically analysing the medical management of previously recognised secretory syndromes; it also addresses areas of uncertainty, assesses the newer therapeutic developments and also addresses recently described but poorly characterised secretory syndromes related to GEP-NETs.

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Georgios K Dimitriadis The Arden NET CoE, Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals of Coventry and Warwickshire NHS Trust, Coventry, UK

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Anna Angelousi Division of Pathophysiology, National and Kapodistrian University of Athens Medical School, Athens, Greece

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Martin O Weickert The Arden NET CoE, Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals of Coventry and Warwickshire NHS Trust, Coventry, UK

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Harpal S Randeva The Arden NET CoE, Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals of Coventry and Warwickshire NHS Trust, Coventry, UK

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Gregory Kaltsas The Arden NET CoE, Warwickshire Institute for the Study of Diabetes, Endocrinology and Metabolism (WISDEM), University Hospitals of Coventry and Warwickshire NHS Trust, Coventry, UK
Division of Pathophysiology, National and Kapodistrian University of Athens Medical School, Athens, Greece
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK

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Ashley Grossman Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK

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The majority of neoplasms are responsible for symptoms caused by mass effects to surrounding tissues and/or through the development of metastases. However, occasionally neoplasms, with or without endocrine differentiation, acquire the ability to secrete a variety of bioactive substances or induce immune cross-reactivity with the normal tissues that can lead to the development of characteristic clinical syndromes. These syndromes are named endocrine paraneoplastic syndromes when the specific secretory components (hormones, peptides or cytokines) are unrelated to the anticipated tissue or organ of origin. Endocrine paraneoplastic syndromes can complicate the patient’s clinical course, response to treatment, impact prognosis and even be confused as metastatic spread. These syndromes can precede, occur concomitantly or present at a later stage of tumour development, and along with the secreted substances constitute the biological ‘fingerprint’ of the tumour. Their detection can facilitate early diagnosis of the underlying neoplasia, monitor response to treatment and/or detect early recurrences following successful initial management. Although when associated with tumours of low malignant potential they usually do not affect long-term outcome, in cases of highly malignant tumours, endocrine paraneoplastic syndromes are usually associated with poorer survival outcomes. Recent medical advances have not only improved our understanding of paraneoplastic syndrome pathogenesis in general but also enhanced their diagnosis and treatment. Yet, given the rarity of endocrine paraneoplastic syndromes, there is a paucity of prospective clinical trials to guide management. The development of well-designed prospective multicentre trials remains a priority in the field in order to fully characterise these syndromes and provide evidence-based diagnostic and therapeutic protocols.

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Gregory A Kaltsas
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Janet L Cunningham Department of Pathophysiology, Section of Endocrine Oncology, Department of Clinical Pathology and Cytology, Department of Genetics and Pathology, National University of Athens, Athens 11527, Greece

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Sture E Falkmer Department of Pathophysiology, Section of Endocrine Oncology, Department of Clinical Pathology and Cytology, Department of Genetics and Pathology, National University of Athens, Athens 11527, Greece

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Lars Grimelius Department of Pathophysiology, Section of Endocrine Oncology, Department of Clinical Pathology and Cytology, Department of Genetics and Pathology, National University of Athens, Athens 11527, Greece

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Apostolos V Tsolakis Department of Pathophysiology, Section of Endocrine Oncology, Department of Clinical Pathology and Cytology, Department of Genetics and Pathology, National University of Athens, Athens 11527, Greece

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Connective tissue growth factor (CTGF) and IGF1 are both expressed in a variety of tumours and are involved in tumourigenesis. However, information about their expression in the gastrointestinal (GI) neuroendocrine (NE) cells and tumours is mainly limited, with the exception of midgut carcinoids where abundant CTGF expression has been demonstrated. Normal mucosa specimens from stomach and ileum, as well as tumour tissue specimens from gastric NE tumours (GNETs; n=58) and midgut NETs (n=38) were included. Immunohistochemical techniques were used to investigate the possible expression of CTGF and IGF1 in GI NE cells and tumours. The latter results were correlated with various clinico-biochemical and histopathological variables. CTGF was expressed in a proportion of NE cells of the normal GI mucosa but not in enterochromaffin-like (ECL) cells, whereas IGF1 was undetectable. CTGF was absent in the foci of ECL cell hyperplasia, and in most of the poorly differentiated carcinomas, but present in some GNETs (mainly in type III ECL cell carcinoids (ECL-CCs)) and in all but one midgut NETs. CTGF correlated with tumour stage in well-differentiated GNETs and with size larger than 1 cm but only in the subgroup of type I ECL-CCs. IGF1 was detected in the foci of ECL cell hyperplasia and in all GI NETs. These findings suggest that both CTGF and IGF1 may be involved in the neoplastic transformation of GI NE cells, whereas IGF1 may play an important role even at early stage.

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