Context Pituitary corticotroph adenomas are rare tumors that can be associated with excess adrenocorticotropic hormone (ACTH) and adrenal cortisol production, resulting in the clinically debilitating endocrine condition Cushing disease. A subset of corticotroph tumors behave aggressively, and genomic drivers behind the development of these tumors are largely unknown. Objective To investigate genomic drivers of corticotroph tumors at risk for aggressive behavior. Design Whole-exome sequencing of patient-matched corticotroph tumor and normal DNA from a patient cohort enriched for tumors at risk for aggressive behavior. Setting Tertiary care center Patients 27 corticotroph tumors from 22 patients analyzed. 12 tumors were macroadenomas, of which 6 were silent ACTH tumors, 2 were Crooke’s cell tumors, and 1 was a corticotroph carcinoma. Intervention Whole-exome sequencing Main outcome measure Somatic mutation genomic biomarkers Results We found recurrent somatic mutations in USP8 and TP53 genes, both with higher allelic fractions than other somatic mutations. These mutations were mutually exclusive, with TP53 mutations occurring only in USP8-wildtype (WT) tumors, indicating they may be independent driver genes. USP8-WT tumors were characterized by extensive somatic copy number variation compared to USP8-mutated tumors. Independent of molecular driver status, we found an association between invasiveness, macroadenomas, and aneuploidy. Conclusions Our data suggest that corticotroph tumors may be categorized into a USP8-mutated, genome-stable subtype versus a USP8-WT, genome-disrupted subtype, the latter of which has a TP53-mutated subtype with high level of chromosome instability. These findings could help identify high risk corticotroph tumors, namely those with widespread CNV, that may need closer monitoring and more aggressive treatment.

BACKGROUND Epidemiologic data on anesthesia-related complications occurring during labor and delivery are essential for measuring and evaluating the safety and quality of obstetric anesthesia care but are lacking. We aimed to fill this research gap by exploring the epidemiologic patterns and risk factors of anesthesia-related complications in a large sample of women giving birth in New York hospitals. METHODS Using the Healthcare Cost and Utilization Project State Inpatient Databases files, we identified all discharge records for labor and delivery from New York hospitals between 2002 and 2005. We then identified women who experienced any recorded anesthesia-related complication during labor and delivery as determined by International Classification of Diseases, Ninth Revision, Clinical Modification codes. The incidence of anesthesia-related complications was calculated by demographic and clinical characteristics. Multivariate logistic regression was performed to assess risk factors of anesthesia-related complications. RESULTS Of the 957,471 deliveries studied, 4438 (0.46%) had at least one anesthesia-related complication. The majority (55%) of anesthesia-related events occurring during labor and delivery were spinal complications, followed by systemic complications (43%) and overdose or adverse effects (2%). Multivariate logistic regression revealed five risk factors of anesthesia-related complications: cesarean delivery (odds ratio [OR] 2.51, 95% confidence interval [CI] 2.36–2.68), rural area (OR 1.33, 95% CI 1.21–1.46), Charlson-Deyo Comorbidity Index ≥1 (OR 1.47, 95% CI 1.28–1.69), Caucasian race (OR 1.37, 95% CI 1.24–1.52), and scheduled admission (OR 1.10, 95% CI 1.03–1.18). Anesthesia-related complications were associated with about a one-day increase in the average length of stay (3.89 ± 3.69 [mean ± sd] days vs 2.92 ± 2.38 days for deliveries without anesthesia-related complications, P < 0.0001) and a 22-fold increased risk of maternal mortality (OR 22.26, 95% CI 11.20–44.24). CONCLUSION The incidence of anesthesia-related complications during labor and delivery seems to be low but remains a cause of concern, particularly in women undergoing cesarean delivery, living in rural areas, or having preexisting medical conditions.

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