Treatment of inoperable or metastatic paragangliomas and pheochromocytomas with peptide receptor radionuclide therapy using 177Lu-DOTATATE.

OBJECTIVES: Inoperable or metastatic paragangliomas (PGLs) and malignant pheochromocytomas (PCCs) are rare tumours with limited options for systemic treatment. Aim of this study was to assess the safety and efficacy of the radiolabelled somatostatin analogue (177LutetiumDOTA0-Tyr3)octreotate (177Lu-DOTATATE) for the treatment of PGLs and PCCs. METHODS: Patients with histologically proven inoperable or malignant PGLs and PCCs treated with 177Lu-DOTATATE at our centre were retrospectively analysed. Patients were treated with up to four cycles of 177Lu-DOTATATE with an intended dose of 7.4 Gb per cycle. Response was assessed with use of RECIST 1.1. RESULTS: Thirty patients were included: 17 with parasympathetic, 10 with sympathetic PGLs and 3 with PCCs. Grade 3/4 subacute haematotoxicity occurred in 6 (20%) of patients. A reversible subacute adverse event due to cardiac failure following possible catecholamine release occurred in two patients. Best tumour response was partial response in 7 (23%) and stable disease in 20 (67%), whereas 3 (10%) patients had progressive disease. In 20 patients with baseline disease progression, tumour control was observed in 17 (85%); the median progression-free survival was 91 months in patients with parasympathetic PGLs, 13 months in patients with sympathetic PGLs and 10 months in patients with metastatic PCCs. CONCLUSION: This study suggests that PRRT with 177Lu-DOTATATE is a safe and effective treatment option for patients with inoperable or malignant PGL and PCC.

Somatostatin Receptor 2-Targeting Compounds.

The molecular imaging and treatment of neuroendocrine tumors (NETs) with radiolabeled somatostatin analogs represent a milestone in the development of theranostic compounds. Whole-body scintigraphy with 111In-pentetreotide has revolutionized the diagnosis and staging of NETs and the evaluation of treatment outcomes. At present, diagnostic accuracy with positron-emitting radionuclides is greater than 90%. Peptide receptor radionuclide therapy (PRRT) has become a well-accepted treatment for patients with well-differentiated inoperable or metastatic NETs and disease progression after first-line treatment. Disease control rates (complete or partial remission or stable disease in patients with formerly progressive disease) of up to 95%, with a low incidence of long-term hematologic and renal toxicity, have been reported. In a recently published randomized trial, compared with intensified treatment of midgut NETs with long-acting and repeatable octreotide, PRRT reduced the hazard of disease progression and death by 79%. Upcoming developments in PRRT include the use of somatostatin receptor antagonists and α-emitting radionuclides, which may further enhance treatment outcomes.

Reduced connexin40 protein expression in the right atrial appendage of patients bearing the minor connexin40 allele (-44 G --> A).

AIMS: The occurrence of connexin40 (Cx40) minor polymorphism (-44 G → A) was increased in patients with idiopathic atrial fibrillation (AF), although its effect on atrial Cx40 protein expression is unknown. We aimed to evaluate whether alterations in Cx40 are directly linked to the development of AF, we studied the effect of this polymorphism on Cx40 expression and distribution in patients without any history of AF and in patients who developed post-operative AF. METHODS AND RESULTS: Hundred and eight patients (mean age 67 ± 9 years), without a history of AF or conditions that predispose to AF, were included. During heart surgery, 10 cc blood was collected for DNA genotyping and the right atrial appendage was partly excised. Ten patients (9%) were homozygous for the minor allele (AA, Group 1), 30 (28%) were heterozygous (AG, Group 2), and 68 (63%) were non-carriers (GG, Group 3). Ten age- and sex-matched tissue samples per group were analysed for Cx40 expression by: (i) real-time quantitative polymerase chain reaction (Q-PCR), (ii) western blotting, and (iii) immunohistochemistry on cryosections. Real-time quantitative polymerase chain reaction showed no significant differences of Cx40 mRNA among the groups. Western blot analysis, however, revealed a reduction in Cx40 protein in Groups 1 (-36.4%) and 2 (-39.5%) as compared with Group 3. Immunohistochemistry confirmed this reduction but indicated an unaltered subcellular distribution of the remaining Cx40. Incidence of post-operative AF (28%) was age-dependent but unrelated to the presence of the polymorphism or fibrosis. CONCLUSION: Presence of the Cx40 minor allele (-44 G → A) results in a uniform down-regulation of right atrial appendage Cx40 protein which was not significantly related to development of post-operative AF.