Proneuropeptide Y and neuropeptide Y metabolites in healthy volunteers and patients with a pheochromocytoma or paraganglioma.

Neuropeptide Y (NPY1-36) is a vasoconstrictor peptide co-secreted with catecholamines by sympathetic nerves, the adrenal medulla, and neoplasms such as pheochromocytomas and paragangliomas (PPGLs). It is produced by the intracellular cleavage of proNPY and metabolized into multiple fragments with distinct biological activities. NPY immunoassays for PPGL have a diagnostic sensitivity ranging from 33 to 100%, depending on the antibody used. We have validated a multiplex micro-UHPLC-MS/MS assay for the specific and sensitive quantification of proNPY, NPY1-39, NPY1-37, NPY1-36, NPY2-36, NPY3-36, NPY1-35, NPY3-35, and the C-flanking peptide of NPY (CPON) (collectively termed NPYs), and determined the NPYs reference intervals and concentrations in 32 PPGL patients before, during, and after surgery. Depending on the peptide measured, NPYs were above the upper reference limit (URL) in 20% to 67% of patients, whereas plasma free metanephrine and normetanephrine, the gold standard for PPGL, were above the URL in 40% and 87% of patients, respectively. Age, sex, tachycardia, and tumor localization were not correlated with NPYs. Plasma free metanephrines performed better than NPYs in the detection of PPGL, but NPYs may be a substitute for an early diagnosis of PPGL for patients that suffer from severe kidney impairment or receiving treatments that interfere with catecholamine reuptake.

Personalized drug testing in human pheochromocytoma/paraganglioma primary cultures.

Aggressive pheochromocytomas and paragangliomas (PPGLs) are difficult to treat, and molecular targeting is being increasingly considered, but with variable results. This study investigates established and novel molecular-targeted drugs and chemotherapeutic agents for the treatment of PPGLs in human primary cultures and murine cell line spheroids. In PPGLs from 33 patients, including 7 metastatic PPGLs, we identified germline or somatic driver mutations in 79% of cases, allowing us to assess potential differences in drug responsivity between pseudohypoxia-associated cluster 1-related (n = 10) and kinase signaling-associated cluster 2-related (n = 14) PPGL primary cultures. Single anti-cancer drugs were either more effective in cluster 1 (cabozantinib, selpercatinib, and 5-FU) or similarly effective in both clusters (everolimus, sunitinib, alpelisib, trametinib, niraparib, entinostat, gemcitabine, AR-A014418, and high-dose zoledronic acid). High-dose estrogen and low-dose zoledronic acid were the only single substances more effective in cluster 2. Neither cluster 1- nor cluster 2-related patient primary cultures responded to HIF-2a inhibitors, temozolomide, dabrafenib, or octreotide. We showed particular efficacy of targeted combination treatments (cabozantinib/everolimus, alpelisib/everolimus, alpelisib/trametinib) in both clusters, with higher efficacy of some targeted combinations in cluster 2 and overall synergistic effects (cabozantinib/everolimus, alpelisib/trametinib) or synergistic effects in cluster 2 (alpelisib/everolimus). Cabozantinib/everolimus combination therapy, gemcitabine, and high-dose zoledronic acid appear to be promising treatment options with particularly high efficacy in SDHB-mutant and metastatic tumors. In conclusion, only minor differences regarding drug responsivity were found between cluster 1 and cluster 2: some single anti-cancer drugs were more effective in cluster 1 and some targeted combination treatments were more effective in cluster 2.

The association between adverse childhood experiences and quality of partnership in adult women.

BACKGROUND: Adverse childhood experiences (ACE) have a significant effect on psychological and physical child development and represent a risk factor for interpersonal difficulties. OBJECTIVE: This study aims to investigate the association between ACE, in particular physical, sexual, emotional abuse and neglect, and partnership quality during adulthood in women. PARTICIPANTS AND SETTING: This study is a secondary analysis of a retrospective multi-center study evaluating risk factors and quality of life in women with and without endometriosis, a chronic, disabling gynecological disease. The investigation includes 533 consenting adult women (159 with ACE and 374 women without) recruited from various hospitals in Switzerland, Austria and Germany. METHODS: To evaluate the association between ACE and partnership, a questionnaire including the Childhood Trauma Questionnaire and a validated partnership questionnaire were used. RESULTS: Altogether, 29.8 % (N = 159) women experienced maltreatment in childhood, 9.7 % (N = 52) of them more than one type. Women who went through ACE showed a lower level of happiness (P = 0.013) and of quality of partnership (P = 0.001) as well as a higher number of conflict areas (P < 0.001). Emotional (P = 0.03; 95 % CI=-1.27,-0.070) and sexual abuse (P = 0.01; 95 % CI=-1.765,-0.197) had the strongest association with reduced partnership quality. CONCLUSION: Our study showed a significant association between ACE, in particular sexual and emotional abuse, and reduced partnership quality. As the quality of partnership is a key factor in the quality of life, improvement in social support with a special focus on intimate relationships should be part of the strategy to address the consequences of ACE already during childhood/adolescence.