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      Peptide Receptor Radionuclide Therapy as a Novel Treatment for Metastatic and Invasive Phaeochromocytoma and Paraganglioma

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          At present there is no clinical guideline or standardised protocol for the treatment of metastatic or invasive phaeochromocytoma and paraganglioma (collectively known as PPGL) due to the rarity of the disease and the lack of prospective studies or extended national databases. Prognosis is mainly determined by genetic predisposition, tumour burden, rate of disease progression, and location of metastases. For patients with progressive or symptomatic disease that is not amenable to surgery, there are various palliative treatment options available. These include localised therapies including radiotherapy, radiofrequency, or cryoablation, as well as liver-directed therapies for those patients with hepatic metastases (e.g., transarterial chemoembolisation) and systemic therapies including chemotherapy or molecular targeted therapies. There is currently intense research interest in the value of radionuclide therapy for neuroendocrine tumours, including phaeochromocytoma and paraganglioma, with either iodine-131 (<sup>131</sup>I)-radiolabelled metaiodobenzylguanidine or very recently peptide receptor radionuclide therapy (PRRT), and the most important contemporary clinical studies will be highlighted in this review. The studies to date suggest that PRRT may induce major clinical, biochemical, and radiological changes, with <sup>177</sup>Lu-DOTATATE being most efficacious and presenting less toxicity than <sup>90</sup>Y-DOTATATE. Newer combination therapies with combined radioisotopes, or combinations with chemotherapeutic agents, also look promising. Given the favourable efficacy, logistic, and safety profiles, we believe that PRRT will probably become the standard treatment for inoperable metastatic PPGL in the near future, but we await data from definitive randomised controlled trials to understand its role.

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          Update on Adrenal Tumours in 2017 World Health Organization (WHO) of Endocrine Tumours.

           Alfred Lam (2017)
          The fourth edition of the World Health Organization (WHO) classification of endocrine tumours contains substantial new findings for the adrenal tumours. The tumours are presented in two chapters labelled as "Tumours of the adrenal cortex" and "Tumours of the adrenal medulla and extra-adrenal paraganglia." Tumours of the adrenal cortex are classified as cortical carcinoma, cortical adenoma, sex cord stromal tumours, adenomatoid tumour, mesenchymal and stromal tumours (myelolipoma and schwannoma), haematological tumours, and secondary tumours. Amongst them, schwannoma and haematological tumours are newly documented. The major updates in adrenal cortical lesions are noted in the genetics of the cortical carcinoma and cortical adenoma based on the data from The Cancer Genome Atlas (TCGA). Also, a system for differentiation of oncocytoma from oncocytic cortical carcinoma is adopted. Tumours of the adrenal medulla and extra-adrenal paraganglia comprise pheochromocytoma, paraganglioma (head and neck paraganglioma and sympathetic paraganglioma), neuroblastic tumours (neuroblastoma, nodular ganglioneuroblastoma, intermixed ganglioneuroblastoma, and ganglioneuroma), composite pheochromocytoma, and composite paraganglioma. In this group, neuroblastic tumours are newly included in the classification. The clinical features, histology, associated pathologies, genetics, and predictive factors of pheochromocytoma and paraganglioma are the main changes introduced in this chapter of WHO classification of endocrine tumours. The term "metastatic pheochromocytoma/paraganglioma" is used to replace "malignant pheochromocytoma/paraganglioma." Also, composite pheochromocytoma and composite paraganglioma are now documented in separate sections instead of one. Overall, the new classification incorporated new data on pathology, clinical behaviour, and genetics of the adrenal tumours that are important for current management of patients with these tumours.
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            Pheochromocytoma: recommendations for clinical practice from the First International Symposium. October 2005.

            The First International Symposium on Pheochromocytoma, held in October 2005, included discussions about developments concerning these rare catecholamine-producing tumors. Recommendations were made during the symposium for biochemical diagnosis, localization, genetics, and treatment. Measurement of plasma or urinary fractionated metanephrines, the most accurate screening approach, was recommended as the first-line test for diagnosis; reference intervals should favor sensitivity over specificity. Localization studies should only follow reasonable clinical evidence of a tumor. Preoperative pharmacologic blockade of circulatory responses to catecholamines is mandatory. Because approximately a quarter of tumors develop secondary to germ-line mutations in any one of five genes, mutation testing should be considered; however, it is not currently cost effective to test every gene in every patient. Consideration of tumor location, presence of multiple tumors, presence of metastases, and type of catecholamine produced is useful in deciding which genes to test. Inadequate methods to distinguish malignant from benign tumors and a lack of effective treatments for malignancy are important problems requiring further resolution.
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              213Bi-DOTATOC receptor-targeted alpha-radionuclide therapy induces remission in neuroendocrine tumours refractory to beta radiation: a first-in-human experience

              Purpose Radiopeptide therapy using a somatostatin analogue labelled with a beta emitter such as 90Y/177Lu-DOTATOC is a new therapeutic option in neuroendocrine cancer. Alternative treatments for patients with refractory disease are rare. Here we report the first-in-human experience with 213Bi-DOTATOC targeted alpha therapy (TAT) in patients pretreated with beta emitters. Methods Seven patients with progressive advanced neuroendocrine liver metastases refractory to treatment with 90Y/177Lu-DOTATOC were treated with an intraarterial infusion of 213Bi-DOTATOC, and one patient with bone marrow carcinosis was treated with a systemic infusion of 213Bi-DOTATOC. Haematological, kidney and endocrine toxicities were assessed according to CTCAE criteria. Radiological response was assessed with contrast-enhanced MRI and 68Ga-DOTATOC-PET/CT. More than 2 years of follow-up were available in seven patients. Results The biodistribution of 213Bi-DOTATOC was evaluable with 440 keV gamma emission scans, and demonstrated specific tumour binding. Enduring responses were observed in all treated patients. Chronic kidney toxicity was moderate. Acute haematotoxicity was even less pronounced than with the preceding beta therapies. Conclusion TAT can induce remission of tumours refractory to beta radiation with favourable acute and mid-term toxicity at therapeutic effective doses. Electronic supplementary material The online version of this article (doi:10.1007/s00259-014-2857-9) contains supplementary material, which is available to authorized users.

                Author and article information

                S. Karger AG
                November 2019
                12 March 2019
                : 109
                : 4
                : 287-298
                Neuroendocrine Tumour Unit, ENETS Centre of Excellence, Royal Free Hospital, London, United Kingdom
                Author notes
                *Ingrid Yin Fung Mak, Department of Medicine, Queen Elizabeth Hospital, 30 Gascoigne Road, Kowloon, Hong Kong, SAR (China), E-Mail myf729@ha.org.hk
                499497 Neuroendocrinology 2019;109:287–298
                © 2019 S. Karger AG, Basel

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                Page count
                Figures: 3, Tables: 1, Pages: 12
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