Adult and paediatric patients with pathogenic variants in the gene encoding succinate dehydrogenase (SDH) subunit B (SDHB) often have locally aggressive, recurrent or metastatic phaeochromocytomas and paragangliomas (PPGLs). Furthermore, SDHB PPGLs have the highest rates of disease-specific morbidity and mortality compared with other hereditary PPGLs. PPGLs with SDHB pathogenic variants are often less differentiated and do not produce substantial amounts of catecholamines (in some patients, they produce only dopamine) compared with other hereditary subtypes, which enables these tumours to grow subclinically for a long time. In addition, SDHB pathogenic variants support tumour growth through high levels of the oncometabolite succinate and other mechanisms related to cancer initiation and progression. As a result, pseudohypoxia and upregulation of genes related to the hypoxia signalling pathway occur, promoting the growth, migration, invasiveness and metastasis of cancer cells. These factors, along with a high rate of metastasis, support early surgical intervention and total resection of PPGLs, regardless of the tumour size. The treatment of metastases is challenging and relies on either local or systemic therapies, or sometimes both. This Consensus statement should help guide clinicians in the diagnosis and management of patients with SDHB PPGLs.

Targeted radionuclide therapies (TRT) using 131I-metaiodobenzylguanidine (131I-MIBG) and peptide receptor radionuclide therapy (177Lu or 90Y) represent several of the therapeutic options in the management of metastatic/inoperable pheochromocytoma/paraganglioma. Recently, high-specific-activity-131I-MIBG therapy was approved by the FDA and both 177Lu-DOTATATE and 131I-MIBG therapy were recommended by the National Comprehensive Cancer Network guidelines for the treatment of metastatic pheochromocytoma/paraganglioma. However, a clinical dilemma often arises in the selection of TRT, especially when a patient can be treated with either type of therapy based on eligibility by MIBG and somatostatin receptor imaging. To address this problem, we assembled a group of international experts, including oncologists, endocrinologists, and nuclear medicine physicians, with substantial experience in treating neuroendocrine tumors with TRTs to develop consensus and provide expert recommendations and perspectives on how to select between these two therapeutic options for metastatic/inoperable pheochromocytoma/paraganglioma. This article aims to summarize the survival outcomes of the available TRTs; discuss personalized treatment strategies based on functional imaging scans; address practical issues, including regulatory approvals; and compare toxicities and risk factors across treatments. Furthermore, it discusses the emerging TRTs.

BACKGROUND AND PURPOSE: Differentiating glioma recurrence from treatment-induced necrosis can be a challenge on conventional imaging. This study aimed to assess the diagnostic performance of each functional MR imaging and PET parameter derived by using simultaneous FDG-PET/MR imaging individually and in combination in the evaluation of suspected glioma recurrence. MATERIALS AND METHODS: Thirty-five treated glioma patients with 41 enhancing lesions (World Health Organization grade II = 9, III = 13, IV = 19) on MR imaging after an operation followed by radiation therapy and/or chemotherapy formed part of this study. Using PET/MR imaging, we calculated the normalized mean relative CBV, mean ADC, Cho/Cr, and maximum and mean target-to-background ratios. Statistical analysis was performed to determine the diagnostic performance of each parameter by receiver operating characteristic analysis individually and in combination with multivariate receiver operating characteristic analysis for the detection of glioma recurrence. Histopathology or clinicoradiologic follow-up was considered the criterion standard. RESULTS: Of 35 patients, 25 (30 lesions) were classified as having a recurrence and 10 (11 lesions) patients as having treatment-induced necrosis. Parameters like rCBV_mean (mean relative CBV), ADC_mean, Cho/Cr, and maximum and mean target-to-background ratios were statistically significant in the detection of recurrent lesions with an accuracy of 77.5%, 78.0%, 90.9%, 87.8%, and 87.8%, respectively. On multivariate receiver operating characteristic analysis, the combination of all 3 MR imaging parameters resulted in an area under the curve of 0.913 ± 0.053. Furthermore, an area under the curve of 0.935 ± 0.046 was obtained when MR imaging parameters (ADC_mean and Cho/Cr) were combined with the PET parameter (mean target-to-background ratio), demonstrating an increase in diagnostic accuracy. CONCLUSIONS: Simultaneous PET/MR imaging with FDG offers correlative and synergistic multiparametric assessment of glioma recurrence with increased accuracy and clinical utility.

Therapeutic options for metastatic pheochromocytoma/paraganglioma (PHEO/PGL) are limited. Here, we tested an immunotherapeutic approach based on intratumoral injections of mannan-BAM with toll-like receptor ligands into subcutaneous PHEO in a mouse model. This therapy elicited a strong innate immunity-mediated antitumor response and resulted in a significantly lower PHEO volume compared to the phosphate buffered saline (PBS)-treated group and in a significant improvement in mice survival. The cytotoxic effect of neutrophils, as innate immune cells predominantly infiltrating treated tumors, was verified in vitro. Moreover, the combination of mannan-BAM and toll-like receptor ligands with agonistic anti-CD40 was associated with increased mice survival. Subsequent tumor re-challenge also supported adaptive immunity activation, reflected primarily by long-term tumor-specific memory. These results were further verified in metastatic PHEO, where the intratumoral injections of mannan-BAM, toll-like receptor ligands, and anti-CD40 into subcutaneous tumors resulted in significantly less intense bioluminescence signals of liver metastatic lesions induced by tail vein injection compared to the PBS-treated group. Subsequent experiments focusing on the depletion of T cell subpopulations confirmed the crucial role of CD8⁺ T cells in inhibition of bioluminescence signal intensity of liver metastatic lesions. These data call for a new therapeutic approach in patients with metastatic PHEO/PGL using immunotherapy that initially activates innate immunity followed by an adaptive immune response.