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Leo Baxendale-Smith Department of Medical Oncology, Edinburgh Cancer Centre, Western General Hospital, Crewe Road, South, Edinburgh, United Kingdom

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Karim El-Shakankery Department of Medical Oncology, Edinburgh Cancer Centre, Western General Hospital, Crewe Road, South, Edinburgh, United Kingdom

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James Gordon-Smith Department of Interventional Radiology, Royal Infirmary of Edinburgh, Edinburgh, United Kingdom

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Lucy Wall Department of Medical Oncology, Edinburgh Cancer Centre, Western General Hospital, Crewe Road, South, Edinburgh, United Kingdom

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Selective internal radiation therapy (SIRT) is a novel intervention for both primary and metastatic malignant liver lesions. Adrenocortical carcinoma (ACC) is rare with limited treatment options; evidence for SIRT in ACC liver metastases consists of case reports only. Selective internal radiation therapy (SIRT) was employed to treat recurrent liver metastases in a 49-year-old gentleman with ACC, who previously underwent a left-sided hepatectomy. The patient opted for SIRT after reviewing the literature regarding mitotane chemotherapy and its toxicities. Selective internal radiation therapy (SIRT) provided several months of progression-free survival (PFS), with no toxicity and an excellent radiological response. The patient re-presented 12 years after the initial diagnosis with skeletal metastases and sadly died in September 2022. Substantial unmet need exists for effective treatments in ACC, with 75% of patients presenting with incurable disease. Developing widespread disease, SIRT offered 2 years’ PFS in our patient; this was well tolerated with minimal residual liver impairment. Its use in ACC liver-limited disease warrants investigation.

Significance statement

Adrenocortical carcinoma (ACC) is a rare and aggressive tumour with limited treatments. Once metastatic disease develops, existing standard-of-care treatments offer a dismal overall survival, alongside marked toxicities. Selective internal radiation therapy (SIRT) may represent a new intervention in the treatment paradigm for liver-limited, metastatic ACC. Here, we present the case of a patient treated with multiple rounds of SIRT for relapsed, liver-limited ACC, prolonging survival by several years. Recurrent SIRT led to maintained liver function and no toxicities. Little evidence outlines its use in ACC but further study is certainly warranted to ascertain the value of SIRT, considering the limited treatment landscape that currently exists.

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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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Dheeratama Siripongsatian National Cyclotron and PET Centre, Chulabhorn Hospital, Bangkok, Thailand

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Quido G de Lussanet de la Sablonière Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, Netherlands

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Frederik Anton Verburg Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, Netherlands

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Tessa Brabander Department of Radiology & Nuclear Medicine, Erasmus MC, Rotterdam, Netherlands

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The field of nuclear theranostic clinical trials is continuously expanding as an increasing number of novel agents and treatment combinations are explored for treating advanced and metastatic cancers. Moving from ‘bench-to-bedside’ is oftentimes a complex and lengthy process. The objective of this overview is to explore the basic elements involved in designing clinical trials with a special focus on theranostics in nuclear medicine. The 'bench-to-bedside' journey involves translating basic scientific research into patient-effective treatments. Preclinical studies, a crucial initial step, are a complex process encompassing in vitro experiments, in vivo studies, and animal models to explore hypotheses in humans. Clinical trials follow, with predefined phases assessing safety, effectiveness, and comparisons to existing treatments. This process demands investments in data management, statistics, good clinical practice (GCP) accreditations, and collaborative efforts for funding and sustainable pricing. Theranostics, merging diagnostics and personalized treatment, is at the forefront. Continuous efforts to enhance existing agents involve reducing adverse effects, exploring new indications, and incorporating advanced imaging modalities. Radionuclide therapy, unique with non-uniform distribution and complex radiobiology, plays a distinct role. This article explores trends and challenges in each clinical trial phase in light of the emerging field of theranostics in nuclear medicine, emphasizing meticulous trial design, dosimetry optimization, and the necessity of collaborative stakeholder efforts for successful implementation.

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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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Vasiliki Venetsanaki Department of Endocrinology, Theagenio Hospital, Thessaloniki, Greece

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Eleana Zisimopoulou Department of Endocrinology, Theagenio Hospital, Thessaloniki, Greece

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Chrysanthi Zouli Department of Endocrinology, Theagenio Hospital, Thessaloniki, Greece

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Maria Boudina Department of Endocrinology, Theagenio Hospital, Thessaloniki, Greece

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Konstantinos Gkiouras Department of Endocrinology, Theagenio Hospital, Thessaloniki, Greece

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Persefoni Xirou Department of Pathology, Theagenio Hospital, Thessaloniki, Greece

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Aimilia Fotiadou Department of Endocrinology, Theagenio Hospital, Thessaloniki, Greece

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Mariana Stamati Department of Endocrinology, Theagenio Hospital, Thessaloniki, Greece

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Elpiniki Argyropoulou Department of Endocrinology, Theagenio Hospital, Thessaloniki, Greece

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Alexandra Chrisoulidou Department of Endocrinology, Theagenio Hospital, Thessaloniki, Greece

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Background

Mönckeberg sclerosis is a form of calcification of the tunica media of small and medium size arteries. It occurs more often in the peripheral arteries of the lower limbs and it has been associated with diabetes and renal disease. Although there are a few reports of Mönckeberg sclerosis in thyroid vessels, there are no data regarding its significance in thyroid disease.

Objective

The aim was to investigate the possible prognostic value of Mönckeberg sclerosis in thyroid vessels of patients with diagnosed thyroid cancer.

Methods

We retrospectively studied patients with papillary thyroid cancer treated at the Theagenio Hospital of Thessaloniki from 2005 to 2021. The patients were divided into two groups based on the presence, or absence, of histopathological findings of Mönckeberg sclerosis in the thyroid vessels along with papillary thyroid cancer. Patient characteristics, histopathological details, personal history of thyroid disease, and metabolic parameters were compared between the two groups.

Results

Thirty-three patients with papillary thyroid carcinoma and Mönckeberg sclerosis were identified and matched to 33 controls with papillary thyroid cancer, without evidence of Mönckeberg sclerosis. The metabolic profile of patients with Mönckeberg sclerosis was not significantly different from those who did not have Mönckeberg sclerosis. Moreover, the comparison between the two groups did not reveal any remarkable differences in terms of the aggressiveness of the disease.

Conclusion

The presence of Mönckeberg sclerosis does not seem to impact on histological characteristics of patients with papillary thyroid cancer.

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Catherine M Skefos The University of Texas MD Anderson Cancer Center, Clinical Cancer Genetics Program, Houston, Texas, USA

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Pamela L Brock The Ohio State University College of Medicine, Division of Human Genetics, Comprehensive Cancer Center, Columbus, Ohio, USA

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Erica Blouch Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA

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Samantha E Greenberg Department of Health Care Sciences, UT Southwestern Medical Center, Dallas, Texas, USA

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This commentary explores the complexities faced by clinicians when encountering a secondary SDHA pathogenic variant (PV) in patients without a personal or family history of SDHA-related tumors. The increasing use of germline multi-gene panel testing has led to a rise in such secondary findings, necessitating a nuanced approach to counseling, surveillance, and decision-making. We aim to discuss the current data surrounding the penetrance of SDHA PVs, the spectrum of screening guidelines, recommendations for educating individuals and families about their secondary findings, and the need for future research to optimize care for these individuals. Practical recommendations for clinicians dealing with patients with secondary SDHA findings include acknowledging the limitations of existing guidelines, fostering shared decision-making, and considering specialist referrals. Overall, the evolving landscape of SDHA penetrance data warrants ongoing reassessment of surveillance approaches.

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Jose E Nunez Division of Medical Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada

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Sylvia Ng Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada

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Hanbo Chen Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada

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Simron Singh Division of Medical Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada

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Julie Hallet Department of Surgery, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada

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Calvin Law Department of Surgery, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada

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Sten Myrehaug Department of Radiation Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada

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There is interest in optimizing peptide receptor radionuclide therapy (PRRT) for the management of metastatic neuroendocrine neoplasms (NEN). The addition of stereotactic body radiation therapy (SBRT) may provide synergistic benefits by targeting specific sites of disease that may represent areas of tumor heterogeneity. Little is known about the efficacy or potential toxicity of this approach; understanding the outcomes of patients treated with these two modalities in a sequential fashion will provide insights into the appropriateness of embarking on a combined therapy strategy. An institutional retrospective review of 21 patients with NEN treated with sequential PRRT and SBRT (64 targets) was performed. Median overall survival and progression-free survival were 19.6 months and 12.8 months, respectively. Median time to local recurrence at the SBRT site was not reached, with rates at 12 and 24 months of 1.8% and 5.9%, respectively. The toxicity profile remains favorable. Given the safety and efficacy of sequential SBRT and PRRT, further trials evaluating a concurrent treatment approach may be warranted.

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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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