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Mark S Stein Knox Private Hospital, Wantirna, Victoria, Australia

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Victor Kalff Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

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Scott G Williams Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

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Declan G Murphy Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

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Peter G Colman Department of Diabetes and Endocrinology, The Royal Melbourne Hospital and University of Melbourne Department of Medicine, Parkville, Victoria, Australia

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Michael S Hofman Molecular Imaging and Therapeutic Nuclear Medicine, Cancer Imaging, Prostate Cancer Theranostics and Imaging Centre of Excellence (ProsTIC), Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
Sir Peter MacCallum Department of Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia

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Objectives

The glucagon-like peptide-1 (GLP-1) receptor agonist, liraglutide, reduces human prostate cancer incidence, and similar GLP-1 receptor agonists reduce in vitro proliferation and in vivo growth of prostate cancer cell lines. Primary human prostate cancer expresses the GLP-1 receptor (GLP-1R) in vitro. Cancer evolves with stage, and whether advanced-stage human prostate cancer expresses GLP-1R is unknown. We hypothesised and aimed to prove that human metastatic castrate-resistant prostate cancer (mCRPC) expresses the GLP-1R in vivo. We hypothesised that mCRPC would thus be detectable by positron emission tomography/computed tomography (PET/CT) using a radiotracer bound to a GLP-1R ligand, as in exendin PET/CT.

Materials and methods

Men with mCRPC, with more than one prostate-specific membrane antigen (PSMA)-avid lesion on PET/CT scanning (pathognomic in that setting for prostate cancer lesions), were approached to undergo PET/CT with gallium68-Dota-exendin-4. We documented PET/CT PSMA-avid lesions, which were also PET/CT exendin avid, as evidence of in vivo GLP-1R expression.

Results

Out of the 24 men referred, three did not meet the inclusion criteria. Seventeen declined, largely because the study offered them no therapeutic benefit. Among the four men imaged, three had no exendin-avid lesions, while one had six osseous PSMA-avid lesions, three of which were also exendin avid.

Conclusions

We demonstrated in vivo GLP-1R expression by human mCPRC, detecting PET/CT lesions avid for both PSMA and exendin, in one of four participants. GLP-1R expression may thus occur even in advanced-stage prostate cancer. Our data contribute to growing evidence supporting the testing of GLP-1 receptor agonists for therapeutic benefit in prostate cancer.

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Prabesh Khatiwada Department of Biological Sciences, University of Toledo, Toledo, Ohio, USA
Center for Translational Immunology, Columbia University, New York, New York, USA

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Ujjwal Rimal Department of Biological Sciences, University of Toledo, Toledo, Ohio, USA

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Zhengyang Han Department of Biological Sciences, University of Toledo, Toledo, Ohio, USA
Dana-Farber Cancer Institute, Harvard University, Boston, Massachusetts, USA

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Lirim Shemshedini Department of Biological Sciences, University of Toledo, Toledo, Ohio, USA

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Androgen receptor (AR) and its constitutively active splice variant, AR Variant 7 (AR-V7), regulate genes essential for the development and progression of prostate cancer. Degradation of AR and AR-V7 by the ubiquitination proteasomal pathway is important for the regulation of both their protein stability. Our published results demonstrate that the interaction of TM4SF3 with either AR or AR-V7 leads to mutual stabilization due to a reduction in their ubiquitination and proteasomal degradation. These results led us to search for a common E3 ligase for AR, AR-V7, and TM4SF3. Depletion by siRNA of several E3 ligases identified MDM2 as the common E3 ligase. MDM2 inhibition by siRNA depletion or using a pharmacological inhibitor (MDM2i) of its E3 ligase activity led to elevated levels of endogenous AR, AR-V7, and TM4SF3 in prostate cancer cells. MDM2 knockdown in PC-3 cells, which do not express AR, also increased TM4SF3, demonstrating that MDM2 affects the TM4SF3 protein independent of AR. We further demonstrate that MDM2i treatment reduced the ubiquitination of AR and TM4SF3, suggesting that MDM2 can induce the ubiquitination of these proteins. Increased AR and AR-V7 protein levels induced by MDM2i treatment resulted in the expected increased expression of AR-regulated genes and enhanced proliferation and migration of both LNCaP and Enzalutamide-resistant CWR-22Rv1 prostate cancer cells. Thus, our study expands the known roles of MDM2 in prostate cancer to include its potential involvement in the important mutual stabilization that TM4SF3 exhibits when interacting with either AR or AR-V7.

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Annabelle G Hayes Flinders Medical Centre, Adelaide, SA, Australia
University of Adelaide, Adelaide, SA, Australia

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Masoumeh G Shirazi University of Adelaide, Adelaide, SA, Australia
Department of Cardiology, Royal Adelaide Hospital, Adelaide, SA, Australia

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Anand Thiyagarajah University of Adelaide, Adelaide, SA, Australia
Department of Cardiology, Royal Adelaide Hospital, Adelaide, SA, Australia

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David J Torpy University of Adelaide, Adelaide, SA, Australia
Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia

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Sunita M C De Sousa University of Adelaide, Adelaide, SA, Australia
Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide, SA, Australia

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Summary

Cabergoline-associated valvulopathy (CAV) is defined by the echocardiographic triad of moderate or severe regurgitation, valvular thickening and restricted valvular motion. While it is a well-described complication of dopamine agonist therapy in Parkinson’s disease, only three convincing cases of CAV have previously been described in the treatment of prolactinoma, with none involving the tricuspid valve. We describe a case of CAV affecting the tricuspid valve, ultimately resulting in the patient’s death. The novel finding of CAV affecting the tricuspid valve suggests a possible link between confirmed cases of CAV and the echocardiographic surveillance studies of cabergoline-treated prolactinoma patients which have mostly demonstrated subclinical tricuspid valve changes. The risk of CAV, although small, prompts a mindful prescription of dopamine agonist therapy for prolactinomas and consideration of measures to minimise cabergoline exposure. The cumulative cabergoline doses and duration of therapy associated with CAV in published cases exceed what has been evaluated in case series and surveillance studies, underscoring the importance of case reports in understanding CAV.

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Sofia Maria Lider Burciulescu CI Parhon National Institute of Endocrinology, Bucharest, Romania

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Caren Randon Department of Thoracic and Vascular Surgery, Ghent University Hospital & Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, UGent, Ghent, Belgium

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Frederic Duprez Department of Radiotherapy-Oncology, Ghent University Hospital, Ghent Belgium & Department of Human Structure and Repair, Faculty of Medicine and Health Sciences, UGent, Ghent, Belgium

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Wouter Huvenne Department of Head and Neck Surgery, Ghent University Hospital & Department of Head & Skin, Faculty of Medicine and Health Sciences, UGent, Ghent, Belgium

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David Creytens Department of Pathology, Ghent University Hospital, Ghent University & Department of Diagnostic Sciences, Faculty of Medicine and Health Sciences, UGent, Ghent, Belgium

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Kathleen B M Claes Center for Medical Genetics, Ghent University Hospital & Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, UGent, Ghent, Belgium

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Robin de Putter Center for Medical Genetics, Ghent University Hospital & Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, UGent, Ghent, Belgium

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Guy T’Sjoen Department of Endocrinology, Ghent University Hospital & Department of Internal Medicine & Pediatrics, Faculty of Medicine and Health Sciences, UGent , Ghent, Belgium

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Corin Badiu CI Parhon National Institute of Endocrinology, Bucharest, Romania
Carol Davila University of Medicine and Pharmacy, Bucharest, Romania

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Bruno Lapauw Department of Endocrinology, Ghent University Hospital & Department of Internal Medicine & Pediatrics, Faculty of Medicine and Health Sciences, UGent , Ghent, Belgium

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Pheochromocytomas (PHEO) and paragangliomas (PGL) can occur sporadic or within genetic predisposition syndromes. Despite shared embryology, there are important differences between PHEO and PGL. The aim of this study was to describe the clinical presentation and disease characteristics of PHEO/PGL. A retrospective analysis of consecutively registered patients diagnosed with or treated for PHEO/PGL in a tertiary care centre was performed. Patients were compared according to anatomic location (PHEO vs PGL) and genetic status (sporadic vs hereditary). In total, we identified 38 women and 29 men, aged 50 ± 19 years. Of these, 42 (63%) had PHEO, and 25 (37%) had PGL. Patients with PHEO presented more frequently with sporadic than hereditary disease (45 years vs 27 (77%) vs 8 (23%)) than patients with PGL (9 (36%) vs 16 (64%), respectively) and were older at diagnosis (55 ± 17 vs 40 ± 18 years, P = 0.001), respectively). About half of the cases in both PHEO and PGL were diagnosed due to disease-related symptoms. In patients with PHEO, tumour diameter was larger (P = 0.001), metanephrine levels higher (P = 0.02), and there was more frequently a history of cardiovascular events than in patients with PGL. In conclusion, we found that patients with PGL more frequently have a hereditary predisposition than those with PHEO, contributing to the fact that diagnosis is generally made earlier in PGL. Although diagnosis in both PHEO and PGL was mostly due to related symptoms, patients with PHEO more often presented with cardiovascular comorbidities than those with PGL which might relate to a higher number of functionally active tumours in the former.

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Trinidad Raices Laboratory of Molecular Endocrinology and Signal Transduction, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina
Centro de Investigaciones Endocrinológicas ’Dr. César Bergadá’ (CEDIE-CONICET-FEI), División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina

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María Luisa Varela Departments of Neurosurgery, and Cell and Developmental Biology, University of Michigan, School of Medicine, Ann Arbor, Michigan, USA

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Adriana María Belén Abiuso Laboratory of Molecular Endocrinology and Signal Transduction, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina

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Elba N Pereyra Laboratory of Molecular Endocrinology and Signal Transduction, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina

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Carolina Mondillo Laboratory of Molecular Endocrinology and Signal Transduction, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina

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Omar P Pignataro Laboratory of Molecular Endocrinology and Signal Transduction, Instituto de Biología y Medicina Experimental (IBYME-CONICET), Buenos Aires, Argentina

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María Fernanda Riera Centro de Investigaciones Endocrinológicas ’Dr. César Bergadá’ (CEDIE-CONICET-FEI), División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina

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Curcumin has been ascribed with countless therapeutic effects, but its impact on testicular function has been scarcely researched. Leydig cells comprise the androgen-secreting population of the testis and may give rise to Leydig cell tumours (LCTs). Due to their steroid-secreting nature, LCTs entail endocrine, reproductive, and psychological disorders. Approximately 10% are malignant and do not respond to chemotherapy and radiotherapy. The aim of this study was to assess curcumin’s impact on Leydig cells’ functions and its potential effect on LCT growth. In vitro assays on MA-10 Leydig cells showed that curcumin (20–80 µmol/L) stimulates acute steroidogenesis, both in the presence and absence of db-cAMP. This effect is accompanied by an increase in StAR expression. Regarding curcumin’s in vitro cytostatic capacity, we show that 40–80 µmol/L curcumin reduces MA-10 Leydig cells’ proliferative capacity, which could be explained by the arrest in G2/M and the reduced viability due to the activation of the apoptotic pathway. Finally, CB6F1 mice were inoculated with MA-10 cells to generate ectopic LCT in both flanks. They received i.p. injections of 20 mg/kg curcumin or vehicle every other day for 15 days. We unveiled curcumin’s capacity to inhibit LCT growth as evidenced by reduced tumour volume, weight, and area under the growth curves. No detrimental effects on general health parameters or testicular integrity were observed. These results provide novel evidence of curcumin’s effects on the endocrine cell population of the testis and propose this natural compound as a therapeutic agent for LCT.

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Stéphanie Larose Division of Endocrinology, Department of Medicine, Centre hospitalier de l’Université de Montréal (CHUM), Université de Montréal, Montréal, QC, Canada

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Dany Rioux Division of Endocrinology, Department of Medicine, Centre hospitalier universitaire régional, Trois-Rivières, QC, Canada

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Roula Albadine Department of Pathology, Centre hospitalier de l’Université de Montréal, Université de Montréal (CHUM), Université de Montréal, Montréal, QC, Canada, Montréal, QC, Canada

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André Lacroix Division of Endocrinology, Department of Medicine, Centre hospitalier de l’Université de Montréal (CHUM), Université de Montréal, Montréal, QC, Canada

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Ectopic adrenocorticotrophic hormone (ACTH) secretion (EAS) is a rare cause of ACTH-dependent Cushing’s syndrome (CS), most often caused by a thoracic neuroendocrine tumor (NET). Large-cell neuroendocrine carcinomas (LCNEC) with EAS are rare and usually present a more severe ACTH secretion and hypercortisolism. We report a 44-year-old non-smoker man, who presented clinical and biochemical evidence of ACTH-dependent CS. Desmopressin 10 μg i.v. produced a 157% increase in ACTH and a 25% increase in cortisol from baseline; there was no stimulation of ACTH or cortisol during the corticotropin-releasing hormone (CRH) test and no suppression with high dose dexamethasone. Pituitary MRI identified a 5 mm lesion, but inferior petrosal venous sinus sampling under desmopressin did not identify a central ACTH source. Thorax and abdominal imaging identified a left lung micronodule. Surgery confirmed a lung LCNEC with strongly positive ACTH immunohistochemistry (IHC) in the primary and lymph node metastasis. The patient was in CS remission after surgery and adjuvant chemotherapy but developed a recurrence 9.5 years later, with LCNEC pulmonary left hilar metastases, ectopic CS, and positive ACTH IHC. This is the first report of LCNEC, with morphologic feature of carcinoid tumor of the lung with ectopic ACTH stimulated by desmopressin. Long delay prior to metastatic recurrence indicates relatively indolent NET. This case report indicates that response to desmopressin, which usually occurs in Cushing’s disease or benign NETs, can occur in malignant LCNEC.

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Justo P Castaño Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain
Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Cordoba, Spain
Reina Sofía University Hospital, Cordoba, Spain
Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y Nutrición, (CIBERobn), Cordoba, Spain

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Nele F Lenders Department of Endocrinology, St Vincent’s Hospital, Sydney, NSW, Australia
Garvan Institute of Medical Research, Sydney, NSW, Australia
St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia

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Peter E Earls Department of Anatomical Pathology and Cytopathology, St Vincent’s Pathology, Sydney, NSW, Australia

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Warrick J Inder Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane, QLD, Australia
Faculty of Medicine, the University of Queensland, Brisbane, QLD, Australia

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Ann I McCormack Department of Endocrinology, St Vincent’s Hospital, Sydney, NSW, Australia
Garvan Institute of Medical Research, Sydney, NSW, Australia
St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, Australia

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Objective

Pituitary tumours comprise a pathologically and clinically diverse group of neoplasms. Classification frameworks have changed dramatically in the past two decades, reflecting improving understanding of tumour biology. This narrative review examines the evolution of pituitary tumour classification, from a clinical perspective.

Results

In 2004, pituitary tumours were classified as ‘typical’ or ‘atypical’, based on the presence of markers of proliferation, Ki67, mitotic count and p53. In 2017, the new WHO marked a major paradigm shift, with a new focus on lineage-based classification, determined by transcription factor and hormonal immunohistochemistry. The terms ‘typical’ and ‘atypical’ were omitted, though the importance of proliferative markers Ki67 and mitotic count was acknowledged. The recent WHO 2022 classification incorporates further refinements, specifically recognising some less common types that may represent less well-differentiated tumours. Whilst ‘high risk’ tumour types have been identified, further work is still required to improve prognostication.

Conclusions

Recent WHO classifications have marked significant progress in the diagnostic evaluation of pituitary tumours, though shortcomings and challenges remain for both clinicians and pathologists in managing these tumours.

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Molly Endicott University of Exeter Medical School, RILD Building, RD&E Hospital Wonford, Exeter, UK

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Chrissie Thirlwell University of Exeter Medical School, RILD Building, RD&E Hospital Wonford, Exeter, UK

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Amy P Webster University of Exeter Medical School, RILD Building, RD&E Hospital Wonford, Exeter, UK

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Diabetes and cancer are two heterogenous diseases which are rapidly increasing in prevalence globally. A link between these two non-communicable diseases was first identified over 100 years ago; however, recent epidemiological studies and advances in genomic research have provided greater insight into the association between diabetes and cancer. Epidemiological studies have suggested that individuals with diabetes have an increased risk of several types of cancer (including liver, pancreas, colorectal, breast, and endometrial) and an increased risk of cancer mortality. However, this increased risk is not observed in all cancers, for example, there is a reduced risk of prostate cancer in individuals with diabetes. It has also been observed that cancer patients have an increased risk of developing diabetes, highlighting that the relationship between these diseases is not straightforward. Evidence of a shared genetic aetiology along with numerous lifestyle and clinical factors have made it challenging to establish if the relationship between the two diseases is causal or a result of confounding factors. This review takes a pan-cancer approach to highlight the complexities of the interactions between type 2 diabetes and cancer development, indicating where advances in genomic research have enabled a greater insight into these two diseases.

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