Abstract Objective Aggressive pituitary neuroendocrine tumors (PitNETs) that progress despite surgery, radiotherapy (RT), and medical therapy are heterogenous; only a subset exhibits overtly malignant behavior. We examined genetic determinants of metastatic behavior and poor prognosis. Design Retrospective genomic cohort study of 39 patients (62 tumor samples) with aggressive PitNETs. Methods Next-generation sequencing was performed using the MSK-IMPACT platform on a sequencing protocol. Genetic alterations were correlated with metastatic status, and progression-free and overall survival (PFS and OS) from first progression following RT. Results Cell-cycle alterations were found in 23.1% of patients and were more frequently identified in metastatic compared to non-metastatic tumors (42.1% vs 5.0%; OR=12.9; p=0.008). TP53, ATRX, DAXX, and/or SF3B1 alterations were associated with adverse clinical outcomes but did not differ by metastatic status (53% of metastatic vs 60% of non-metastatic tumors). Within the corticotroph lineage, gene-level alterations in TP53, ATRX, and/or DAXX captured corticotrophs with recurrent chromosomal loss-of-heterozygosity (rcLOH), and were associated with shorter PFS (10.1 vs 149.9 months; p=0.009) and OS (116.6 months vs not reached [NR]; p=0.022). A subset of corticotrophs lacking rcLOH harbored gain-of-function USP8 mutations and were associated with longer PFS (149.9 vs 11.5 months; p=0.022). In lactotroph PitNETs, TP53, ATRX, and/or SF3B1 mutations were associated with shorter PFS (4.6 vs 21.5 months; p=0.049). Conclusions Cell-cycle alterations were enriched in metastatic PitNETs and may contribute to metastatic dissemination. Next-generation sequencing segregates aggressive PitNETs into prognostic subgroups.
Abstract Objective Primary aldosteronism (PA) is a common cause of hypertension and is associated with increased cardiovascular morbidity. However, its impact on work capacity remains unknown. We investigated sickness absence and disability pension among patients with PA and in matched reference groups with and without hypertension. Methods A nationwide eight-year longitudinal cohort study based on linked register data, including 838 individuals with PA aged 18–67 in 2019 and two matched reference cohorts with and without hypertension. Outcomes included annual proportions of individuals with sickness absence (in spells >14 days) or disability pension, mean annual net days, and trajectories of absence days. Results Patients with PA had a higher mean annual proportion with sickness absence than individuals with hypertension (21% (range: 18-23%) vs 17% (range: 17-19%) and those without hypertension (10% (range: 9-12%)). Mean annual sickness absence days were 27, 20, and 9, respectively. The combined mean annual number of sickness absence and disability pension days was similar in PA and hypertension (54 (range: 40-66) vs 53 (range: 50-57), and higher than in those without hypertension (25 (range: 22-29)). Trajectory analysis identified four patterns of absence days; 12% of patients with PA had persistently high absence, significantly associated with female sex, higher age, lower education, unmarried status, rural residence, cardiovascular disease, and treatment with mineralocorticoid receptor antagonists. Conclusion PA is associated with substantial and sustained sickness absence and disability pension, comparable to that observed in hypertension and higher than in individuals without hypertension. These findings extend the clinical impact of PA beyond cardiovascular morbidity and highlight the importance of considering work capacity in clinical management. Objective Primary aldosteronism (PA) is a common cause of hypertension and is associated with increased cardiovascular morbidity. However, its impact on work capacity remains unknown. We investigated sickness absence and disability pension among patients with PA and in matched reference groups with and without hypertension. Methods A nationwide eight-year longitudinal cohort study based on linked register data, including 838 individuals with PA aged 18–67 in 2019 and two matched reference cohorts with and without hypertension. Outcomes included annual proportions of individuals with sickness absence (in spells >14 days) or disability pension, mean annual net days, and trajectories of absence days. Results Patients with PA had a higher mean annual proportion with sickness absence than individuals with hypertension (21% (range: 18-23%) vs 17% (range: 17-19%) and those without hypertension (10% (range: 9-12%)). Mean annual sickness absence days were 27, 20, and 9, respectively. The combined mean annual number of sickness absence and disability pension days was similar in PA and hypertension (54 (range: 40-66) vs 53 (range: 50-57), and higher than in those without hypertension (25 (range: 22-29)). Trajectory analysis identified four patterns of absence days; 12% of patients with PA had persistently high absence, significantly associated with female sex, higher age, lower education, unmarried status, rural residence, cardiovascular disease, and treatment with mineralocorticoid receptor antagonists. Conclusion PA is associated with substantial and sustained sickness absence and disability pension, comparable to that observed in hypertension and higher than in individuals without hypertension. These findings extend the clinical impact of PA beyond cardiovascular morbidity and highlight the importance of considering work capacity in clinical management.
