Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways. In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison with cluster II PCPGs that are related to kinase signaling and often present as benign tumors. We found that cluster I PCPGs develop a dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B ()-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with knockdown PCPG allograft. In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with mutations..

To the authors' knowledge, this is the third largest study of its kind worldwide. The incidence of chronic hypopituitarism after TBI was higher than the authors expected. After TBI, patients are usually observed on the neurological and rehabilitative wards, and endocrine dysfunction can be overlooked. This dysfunction can be life threatening and other clinical symptoms can worsen the neurological deficit, extend the duration of physiotherapy, and lead to mental illness. The authors recommend routine pituitary hormone testing after moderate or severe TBI within 6 months and 1 year of injury.

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Phaeochromocytomas and paragangliomas are rare tumors. Nowadays, about 30% or more of them are thought to be of inherited origin due to germ-line mutations in at least ten genes. There is data linking specific genotypes of these tumors to specific locations, typical biochemical phenotypes or future clinical behaviors. Conversely, clinical features, catecholamine production and histological evaluation can help with the proper order of genetic testing for phaeochromocytoma and paraganglioma. The identification of a germ-line mutation can lead to an early diagnosis, appropriate treatment, regular surveillance and better prognosis not only for the patient, but also for their family members. Moreover, the latest discoveries in molecular pathogenesis will probably provide a basis for future personalized therapy.

Pheochromocytomas and paragangliomas (PHEOs/PGLs) are rare, usually sporadic, catecholamine-producing tumors. However, about 30% of these tumors have been identified of inherited origin. Up to date, nine genes have been confirmed to participate in PHEOs/PGLs tumorigenesis. Germline mutations used to be found in 100% of syndromic cases and in about 90% of patients with positive familial history. In non-syndromic patients with apparently sporadic tumors the frequency of genetic mutations has been recorded up to 27%. Nowadays, genetic testing is recommended for all patients with PHEOs/PGLs. Patients with syndromic lesions and/or positive family history should be tested for appertaining gene. Latest discoveries have shown that the proper order of tested genes in non-syndromic, non-familial cases could be based on histological evaluation, localization and biochemical phenotype of PHEOs/PGLs -the "rule of three". Identification of gene mutation may lead to early diagnosis, treatment, regular surveillance and better prognosis for patients and their relatives.

BackgroundSuccinate dehydrogenase subunit B (SDHB) mutations are associated with aggressive pheochromocytoma (PHEO)/paraganglioma (PGL) behavior, often resulting in metastatic disease and fatal outcomes. These tumors are often larger, extra-adrenal, and contain lower catecholamine concentrations than other hereditary PHEOs/PGLs. This study evaluated the size and age at diagnosis of primary SDHB-related PHEOs/PGLs as independent predictors of their metastatic behavior and outcome (survival).MethodsOne hundred six patients with SDHB mutation-related PHEO/PGL were included in this retrospective study. The recorded largest diameters, locations, and patient ages at initial diagnosis of SDHB-related primary tumors were analyzed in the context of time to metastasis and patient survival.ResultsFirst, the development of metastatic disease in patients with primary tumors ≥4.5 cm was significantly earlier than in patients with smaller tumors (P = 0.003). Second, patients with primary tumors larger than 5.5 cm also had worse overall survival than patients with smaller tumors (P = 0.008). Third, age at initial diagnosis was found to be an independent predictor of patient survival (PHEOs: P = 0.041; PGLs: P < 0.001). Fourth, we did not observe a significant difference in survival based on the specific SDHB mutations or patient sex.ConclusionReceiver operating characteristic curves established 4.5 cm as the best value to dichotomize the primary SDHB-related PHEO/PGL in order to evaluate the development of metastatic disease and 5.5 cm as the best value for survival prediction. Subsequently, the size of the primary tumor was found as an age-independent predictor of patient survival and metastases development in PGL. In both PHEO and PGL, age at diagnosis was found to be a size-independent predictor of patient survival. No significant difference was found in metastases development or patient survival between males and females or among specific SDHB mutations. This data further extends and supports previous recommendations that carriers with SDHB mutations must undergo early and regular evaluations to detect PHEO/PGL in order to achieve the best clinical outcome.

Introduction: Glucocorticoids represent the therapy of choice for active and moderate-to-severe Graves' orbitopathy (GO). In some patients, rituximab, a monoclonal antibody against the cluster of differentiation (CD) 20 receptor of B-lymphocytes, can serve as a second-line or an alternative treatment. The effect of very low-dose of rituximab on the clinical activity of GO and corresponding clinical or laboratory changes is reported. Material and methods: Changes of Clinical Activity Score (CAS) for GO, proptosis, levels of thyroid-stimulating hormone receptor antibodies, and depletion of CD19+ and CD20+ B-lymphocytes were determined in ten patients (two men and eight women) with active moderate-to-severe GO treated with a single 100-mg dose of rituximab. Correlations between differences of clinical and laboratory parameters were performed. Results: A significant decrease of CAS was found during subsequent examinations compared to the baseline values. A significant depletion of CD19+ and CD20+ B-lymphocytes was detected after rituximab administration. Differences between follow-up and baseline levels of CD20+ positively correlated with differences in CAS after six (p < 0.05) and 12 months (p < 0.01). Differences in CD19+ levels correlated with differences in CAS after 12 months (p < 0.05) of the treatment. Two patients developed dysthyroid optic neuropathy (DON) requiring orbital decompression. No other rituximab side effects were reported during the whole study duration. Conclusions: A single very low-dose of rituximab appears to be very well tolerated and effective enough to reduce clinical activity in active moderate-to-severe GO patients without impending DON. (Endokrynol Pol 2017; 68 (5): 498-504)

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