Pheochromocytomas/paragangliomas are characterized by a unique molecular landscape that allows their assignment to clusters depending on underlying genetic alterations. With around 30-35% of Caucasian patients (a lower percentage in the Chinese population) showing germline mutations in susceptibility genes, pheochromocytomas/paragangliomas have the highest rate of heritability among all tumors. A further 35-40% of Caucasian patients (a higher percentage in the Chinese population) are affected by somatic driver-mutations. Thus, around 70% of all patients with pheochromocytoma/paraganglioma can be assigned to one of three main molecular clusters with different phenotypes and clinical behavior. Krebs cycle/VHL/EPAS1-related cluster 1 tumors tend to a noradrenergic biochemical phenotype, and require very close follow-up due to the risk of metastasis and recurrence. In contrast, kinase signaling-related cluster 2 tumors are characterized by an adrenergic phenotype and episodic symptoms, with generally a less aggressive course. The clinical correlates of patients with Wnt signaling-related cluster 3 tumors are currently poorly described, but aggressive behavior seems likely. In this review, we explore and explain why cluster-specific (personalized) management of pheochromocytoma/paraganglioma is essential to ascertain clinical behavior and prognosis, guide individual diagnostic procedures (biochemical interpretation, choice of the most sensitive imaging modalities), and personalized management and follow-up. Although cluster-specific therapy of inoperable/metastatic disease has not yet entered routine clinical practice, we suggest that informed personalized genetic-driven treatment should be implemented as a logical next step. This review amalgamates published guidelines and expert views within each cluster for a coherent individualized patient management plan.

Pheochromocytomas and paragangliomas (PCC/PGLs) are rare, mostly catecholamine-producing neuroendocrine tumors of the adrenal gland (PCCs) or the extra-adrenal paraganglia (PGL). They can be separated into three different molecular clusters depending on their underlying gene mutations in any of the at least 20 known susceptibility genes: The pseudohypoxia-associated cluster 1, the kinase signaling-associated cluster 2, and the Wnt signaling-associated cluster 3. In addition to tumor size, location (adrenal vs. extra-adrenal), multiplicity, age of first diagnosis, and presence of metastatic disease (including tumor burden), other decisive factors for best clinical management of PCC/PGL include the underlying germline mutation. The above factors can impact the choice of different biomarkers and imaging modalities for PCC/PGL diagnosis, as well as screening for other neoplasms, staging, follow-up, and therapy options. This review provides a guide for practicing clinicians summarizing current management of PCC/PGL according to tumor size, location, age of first diagnosis, presence of metastases, and especially underlying mutations in the era of precision medicine.

Structural alterations of the cellular prion protein (PrP C ) seem to be the core of the pathogenesis of prion diseases. However, the physiological function of PrP C remains an enigma. Cell culture experiments have indicated that PrP C and in particular its Nterminal octarepeat region together with the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathways have a fundamental involvement in neuroprotection and oxidative stress reactions. We used wild-type mice, PrP knockout (Prnp -/-) animals and transgenic mice that lack the octarepeat region (C4/-) and subjected them to controlled ischemia. We identified an increased cleavage and synthesis of PrP C in ischemic brain areas of wild-type mice compared with sham controls. The infarct size in Prnp -/-animals was increased threefold when compared with wild-type mice. The infarct size in C4/-animals was identical to Prnp -/-mice, that is, around three times larger than in wild-type mice. We showed that the PrP in C4/-mice does not functionally rescue the Prnp -/-phenotype; furthermore it is unable to undergo b cleavage, although an increased amount of C1 fragments was found in ischemic brain areas compared with sham controls. We demonstrated that the N-terminal octarepeat region has a lead function in PrP C physiology and neuroprotection against oxidative stress in vivo. Pathol 2007;17:174-183. Brain INTRODUCTIONThe cellular prion protein (PrP C ) is a copper-binding protein (3, 17) located at the synapse (13) and has a primary role in the pathogenesis of prion diseases. A templated conformational transition of PrP C seems to be the cause of transmissibility and pathogenesis (25). PrP C has been shown to play a role in cellular antioxidative defense mechanisms (15,27) and to protect human neurons in primary culture against Bax-mediated cell death (2). Experiments in cerebellar granule cells (5) have shown a loss of neuroprotective activity of PrP C by a deletion of all five N-terminal octarepeats (PrP∆51-90). We have recently identified a functional link between PrP C expression and phosphatidylinositol 3-kinase (PI3K) activation, a regulator of Akt phosphorylation and a protein kinase that plays a pivotal role in cell survival (33). Our findings are in agreement with published results that showed reduced Phospho-Akt expression levels in Prnp −/− mouse brains following ischemia (38). We could also demonstrate that hippocampal cells that lack the octarepeat region showed reduced PI3K levels and decreased survival under stress conditions similar to PrP C knockout cells. In neuroblastoma cells it could be demonstrated that the octapeptide repeats are required for the β cleavage and their absence (PrP∆oct) correlates with increased sensitivity of cells to oxidative stress (36). The cleavage of the molecule seems to play a major role in the biological properties of PrP C but succession of these proteolysis procedures as well as relations between the two cleavages is controversial and still remains to be elucidated and in particular, the relevance of the octapeptide re...