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.