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M Baum

I must say how honoured I am to have been given this task. There are so many other people in this audience who could have spoken about the history, development and contemporary use of tamoxifen just as well, if not better, than myself. No talk about tamoxifen should begin without acknowledging the pioneering work of Arthur Walpole who synthesised the molecule in 1963 (Harper & Walpole 1966). Sadly he died long before its clinical importance could begin to be appreciated. As most of you know, it was developed originally as a contraceptive agent but was found paradoxically to act as a fertility drug acting, via its anti-oestrogenic properties, on the hypothalamus. Its agonistic as well as antagonistic properties continue to cause argument about how to classify its action. As far as the biochemists are concerned it is a tri-phenyl ethyline derivative with a potent hydroxylated metabolite (Fromson et al. 1973
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J S Davies, D A Rees, L M Evans, and M F Scanlon

Abstract

We report a case of apoplexy of an undiagnosed pituitary adenoma in a patient treated with intravenous combination chemotherapy for squamous cell carcinoma of the penis. Apoplexy occurred while he was receiving a second cycle of vinblastine, cisplatin and methotrexate and he presented with classic neuro-ophthalmological signs. He made a full recovery following conservative management with steroids alone.

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Takako Araki, Ning-Ai Liu, Yukiko Tone, Daniel Cuevas-Ramos, Roy Heltsley, Masahide Tone, and Shlomo Melmed

Cushing’s syndrome is caused by excessive adrenocorticotropic hormone (ACTH) secretion derived from pituitary corticotroph tumors (Cushing disease) or from non-pituitary tumors (ectopic Cushing’s syndrome). Hypercortisolemic features of ectopic Cushing’s syndrome are severe, and no definitive treatment for paraneoplastic ACTH excess is available. We aimed to identify subcellular therapeutic targets by elucidating transcriptional regulation of the human ACTH precursor POMC (proopiomelanocortin) and ACTH production in non-pituitary tumor cells and in cell lines derived from patients with ectopic Cushing’s syndrome. We show that ectopic hPOMC transcription proceeds independently of pituitary-specific Tpit/Pitx1 and demonstrate a novel E2F1-mediated transcriptional mechanism regulating hPOMC. We identify an E2F1 cluster binding to the proximal hPOMC promoter region (−42 to +68), with DNA-binding activity determined by the phosphorylation at Ser-337. hPOMC mRNA expression in cancer cells was upregulated (up to 40-fold) by the co-expression of E2F1 and its heterodimer partner DP1. Direct and indirect inhibitors of E2F1 activity suppressed hPOMC gene expression and ACTH by modifying E2F1 DNA-binding activity in ectopic Cushing’s cell lines and primary tumor cells, and also suppressed paraneoplastic ACTH and cortisol levels in xenografted mice. E2F1-mediated hPOMC transcription is a potential target for suppressing ACTH production in ectopic Cushing’s syndrome.

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Giampaolo Trivellin, Ricardo R Correa, Maria Batsis, Fabio R Faucz, Prashant Chittiboina, Ivana Bjelobaba, Darwin O Larco, Martha Quezado, Adrian F Daly, Stanko S Stojilkovic, T John Wu, Albert Beckers, Maya B Lodish, and Constantine A Stratakis

Cushing’s disease (CD) in children is caused by adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas. Germline or somatic mutations in genes such as MEN1, CDKIs, AIP, and USP8 have been identified in pediatric CD, but the genetic defects in a significant percentage of cases are still unknown. In this study, we investigated the orphan G-protein-coupled receptor GPR101, a gene known to be involved in somatotropinomas, for its possible involvement in corticotropinomas. We performed GPR101 sequencing, expression analyses by RT-qPCR and immunostaining, and functional studies (cell proliferation, pituitary hormone secretion, and cAMP measurement) in a series of patients with sporadic CD secondary to ACTH-secreting adenomas in whom we extracted DNA from peripheral blood and pituitary tumor samples (n=36). No increased GPR101 expression was observed in tumors compared with normal pituitary (NP) tissues, nor did we find a correlation between GPR101 and ACTH expression levels. Sequence analysis revealed a very rare germline heterozygous GPR101 variant (p.G31S) in one patient with CD. Overexpression of the p.G31S variant did not lead to increased growth and proliferation, although modest effects on cAMP signaling were observed. GPR101 is not overexpressed in ACTH-secreting tumors compared with NPs. In conclusion, rare germline GPR101 variant was found in one patient with CD, but in vitro studies did not support a consistent pathogenic effect. GPR101 is unlikely to be involved in the pathogenesis of CD.

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Anna Angelousi, Krystallenia I Alexandraki, George Kyriakopoulos, Marina Tsoli, Dimitrios Thomas, Gregory Kaltsas, and Ashley Grossman

Endocrine organs are metastatic targets for several primary cancers, either through direct extension from nearby tumour cells or dissemination via the venous, arterial and lymphatic routes. Although any endocrine tissue can be affected, most clinically relevant metastases involve the pituitary and adrenal glands with the commonest manifestations being diabetes insipidus and adrenal insufficiency respectively. The most common primary tumours metastasing to the adrenals include melanomas, breast and lung carcinomas, which may lead to adrenal insufficiency in the presence of bilateral adrenal involvement. Breast and lung cancers are the most common primaries metastasing to the pituitary, leading to pituitary dysfunction in approximately 30% of cases. The thyroid gland can be affected by renal, colorectal, lung and breast carcinomas, and melanomas, but has rarely been associated with thyroid dysfunction. Pancreatic metastasis can lead to exo-/endocrine insufficiency with renal carcinoma being the most common primary. Most parathyroid metastases originate from breast and lung carcinomas and melanoma. Breast and colorectal cancers are the most frequent ovarian metastases; prostate cancer commonly affects the testes. In the presence of endocrine deficiencies, glucocorticoid replacement for adrenal and pituitary involvement can be life saving. As most metastases to endocrine organs develop in the context of disseminated disease, surgical resection or other local therapies should only be considered to ameliorate symptoms and reduce tumour volume. Although few consensus statements can be made regarding the management of metastases to endocrine tissues because of the heterogeneity of the variable therapies, it is important that clinicians are aware of their presence in diagnosis.

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Paraskevi Xekouki and Constantine A Stratakis

Succinate dehydrogenase (SDH) or mitochondrial complex II is a multimeric enzyme that is bound to the inner membrane of mitochondria and has a dual role as it serves both as a critical step of the tricarboxylic acid or Krebs cycle and as a member of the respiratory chain that transfers electrons directly to the ubiquinone pool. Mutations in SDH subunits have been implicated in the formation of familial paragangliomas (PGLs) and/or pheochromocytomas (PHEOs) and in Carney–Stratakis syndrome. More recently, SDH defects were associated with predisposition to a Cowden disease phenotype, renal, and thyroid cancer. We recently described a kindred with the coexistence of familial PGLs and an aggressive GH-secreting pituitary adenoma, harboring an SDHD mutation. The pituitary tumor showed loss of heterozygosity at the SDHD locus, indicating the possibility that SDHD's loss was causatively linked to the development of the neoplasm. In total, 29 cases of pituitary adenomas presenting in association with PHEOs and/or extra-adrenal PGLs have been reported in the literature since 1952. Although a number of other genetic defects are possible in these cases, we speculate that the association of PHEOs and/or PGLs with pituitary tumors is a new syndromic association and a novel phenotype for SDH defects.

Open access

Laura C Hernández-Ramírez, Ryhem Gam, Nuria Valdés, Maya B Lodish, Nathan Pankratz, Aurelio Balsalobre, Yves Gauthier, Fabio R Faucz, Giampaolo Trivellin, Prashant Chittiboina, John Lane, Denise M Kay, Aggeliki Dimopoulos, Stephan Gaillard, Mario Neou, Jérôme Bertherat, Guillaume Assié, Chiara Villa, James L Mills, Jacques Drouin, and Constantine A Stratakis

The CABLES1 cell cycle regulator participates in the adrenal–pituitary negative feedback, and its expression is reduced in corticotropinomas, pituitary tumors with a largely unexplained genetic basis. We investigated the presence of CABLES1 mutations/copy number variations (CNVs) and their associated clinical, histopathological and molecular features in patients with Cushing’s disease (CD). Samples from 146 pediatric (118 germline DNA only/28 germline and tumor DNA) and 35 adult (tumor DNA) CD patients were screened for CABLES1 mutations. CNVs were assessed in 116 pediatric CD patients (87 germline DNA only/29 germline and tumor DNA). Four potentially pathogenic missense variants in CABLES1 were identified, two in young adults (c.532G > A, p.E178K and c.718C > T, p.L240F) and two in children (c.935G > A, p.G312D and c.1388A > G, and p.D463G) with CD; no CNVs were found. The four variants affected residues within or close to the predicted cyclin-dependent kinase-3 (CDK3)-binding region of the CABLES1 protein and impaired its ability to block cell growth in a mouse corticotropinoma cell line (AtT20/D16v-F2). The four patients had macroadenomas. We provide evidence for a role of CABLES1 as a novel pituitary tumor-predisposing gene. Its function might link two of the main molecular mechanisms altered in corticotropinomas: the cyclin-dependent kinase/cyclin group of cell cycle regulators and the epidermal growth factor receptor signaling pathway. Further studies are needed to assess the prevalence of CABLES1 mutations among patients with other types of pituitary adenomas and to elucidate the pituitary-specific functions of this gene.

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F W F Hanna, C F Johnston, J E S Ardill, and K D Buchanan

Abstract

Background: Salmon calcitonin (sCT) injection into rats has been reported to induce pituitary tumours. We have demonstrated the co-existence, in the rat-derived α-TSH cell line, of an sCT-like peptide, as well as a receptor for sCT.

Aim: This was to investigate the possible existence of sCT-like immunoreactivity (sCT-LI) in human neuroendocrine tumours.

Methods: A collection of human neuroendocrine tumours was tested, using a highly specific antibody for sCT. Immunostaining was abolished by preabsorption with sCT at concentrations higher than 1 μg/ml. However, as immunofluorescence was still obvious at the highest concentration (100 pg/ml) of hCT employed, any significant cross-reactivity was excluded.

Results: Of the human pituitary null cell tumours studied, positive staining was obtained in 2 out of 12, suggesting a similarity between the rat and human pituitary glands. None of the other pituitary tumours tested showed sCT-LI (these included 8 corticotroph tumours, 6 prolactinomas and 2 somatotroph tumours).

This work was extended to medullary thyroid carcinomas (MTCs) and a further group of neuroendocrine tumours, looking for the specificity of this sCT-LI among the various APUDomas.

All the tested MTCs (n=14) expressed sCT-LI, while none of the examined phaeochromocytomas (n=23), intestinal carcinoids (n=14), lung carcinoids (n=16), stomach carcinoids (n=2), rectal carcinoids (n=2), gastrinomas (n=4), insulinomas (n=12), oat cell carcinomas (n=7), carotid body tumours (n=9), VIPomas (n=3), or a glucagonoma (n=1) expressed sCT-LI. This indicates that this sCT-LI might be unique to MTC (and possibly the pituitary).

Conclusion: The possible existence of the most potent form of CT may provide an explanation for the vasomotor disturbances in MTC and may be a potential new tumour marker for MTC. Phylogenetically, the presence of a lower form of CT in mammalian tissues would give an insight into the conservation of the CT peptide family in evolution.

Endocrine-Related Cancer (1997) 4 191-195

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Liliya Rostomyan, Adrian F Daly, Patrick Petrossians, Emil Nachev, Anurag R Lila, Anne-Lise Lecoq, Beatriz Lecumberri, Giampaolo Trivellin, Roberto Salvatori, Andreas G Moraitis, Ian Holdaway, Dianne J Kranenburg - van Klaveren, Maria Chiara Zatelli, Nuria Palacios, Cecile Nozieres, Margaret Zacharin, Tapani Ebeling, Marja Ojaniemi, Liudmila Rozhinskaya, Elisa Verrua, Marie-Lise Jaffrain-Rea, Silvia Filipponi, Daria Gusakova, Vyacheslav Pronin, Jerome Bertherat, Zhanna Belaya, Irena Ilovayskaya, Mona Sahnoun-Fathallah, Caroline Sievers, Gunter K Stalla, Emilie Castermans, Jean-Hubert Caberg, Ekaterina Sorkina, Renata Simona Auriemma, Sachin Mittal, Maria Kareva, Philippe A Lysy, Philippe Emy, Ernesto De Menis, Catherine S Choong, Giovanna Mantovani, Vincent Bours, Wouter De Herder, Thierry Brue, Anne Barlier, Sebastian J C M M Neggers, Sabina Zacharieva, Philippe Chanson, Nalini Samir Shah, Constantine A Stratakis, Luciana A Naves, and Albert Beckers

Despite being a classical growth disorder, pituitary gigantism has not been studied previously in a standardized way. We performed a retrospective, multicenter, international study to characterize a large series of pituitary gigantism patients. We included 208 patients (163 males; 78.4%) with growth hormone excess and a current/previous abnormal growth velocity for age or final height >2 s.d. above country normal means. The median onset of rapid growth was 13 years and occurred significantly earlier in females than in males; pituitary adenomas were diagnosed earlier in females than males (15.8 vs 21.5 years respectively). Adenomas were ≥10 mm (i.e., macroadenomas) in 84%, of which extrasellar extension occurred in 77% and invasion in 54%. GH/IGF1 control was achieved in 39% during long-term follow-up. Final height was greater in younger onset patients, with larger tumors and higher GH levels. Later disease control was associated with a greater difference from mid-parental height (r=0.23, P=0.02). AIP mutations occurred in 29%; microduplication at Xq26.3 – X-linked acrogigantism (X-LAG) – occurred in two familial isolated pituitary adenoma kindreds and in ten sporadic patients. Tumor size was not different in X-LAG, AIP mutated and genetically negative patient groups. AIP-mutated and X-LAG patients were significantly younger at onset and diagnosis, but disease control was worse in genetically negative cases. Pituitary gigantism patients are characterized by male predominance and large tumors that are difficult to control. Treatment delay increases final height and symptom burden. AIP mutations and X-LAG explain many cases, but no genetic etiology is seen in >50% of cases.

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J S Jenkins

INTRODUCTION Primary tumours of the pituitary gland are, with rare exceptions, adenomas arising from the adenohypophysial cells and they account for about 10% of clinically treated intracranial tumours. They can be characterized histologically by immunocytochemical staining and they often result in the excessive secretion of one or more hormones, giving rise to particular clinical disorders. It also appears that small, clinically unrecognized pituitary tumours are very common, since the incidence of solitary adenomas in unselected postmortem examinations is as great as 27%, of which 41% stain for prolactin (Costello 1936, Burrow et al. 1981). The largest group of clinically hypersecretory adenomas are prolactin-secreting tumours, many of which are microadenomas (i.e. <10 mm when they are detected), followed by somatotrophic and then corticotrophic tumours. Gonadotrophic tumours with hypersecretion which is clinically apparent are uncommon, and thyrotrophic adenomas are rare (Smallridge 1987), amounting to 0.2% in one large surgical series (Wilson 1984).