Circulating Plasma MicroRNA in Patients With Active Acromegaly.

CONTEXT: Excessive production of growth hormone causes marked multiorgan changes in patients with acromegaly, which may involve epigenetic mechanisms. OBJECTIVE: To evaluate differences in circulating microRNAs (miRNAs) associated with chronic growth hormone overproduction in adults. DESIGN AND SETTING: A cross-sectional case-control study was conducted at a tertiary medical center. PARTICIPANTS: We enrolled 12 consecutive patients with acromegaly along with 12 age- and sex-matched controls in the discovery phase of the study and then extended this cohort to 47 patients with acromegaly and 28 healthy controls for the validation study. MAIN OUTCOME MEASURES: Plasma miRNAs were quantified by next-generation sequencing (NGS) in the discovery phase. Levels of selected miRNAs were validated on extended cohorts using reverse transcription quantitative polymerase chain reaction (RT-qPCR), compared between groups, and correlated with clinical parameters. RESULTS: Based on NGS data, we selected 3 plasma miRNAs downregulated in patients with acromegaly compared to healthy controls: miR-4446-3p -1.317 (P = 0.001), miR-215-5p -3.040 (P = 0.005), and miR-342-5p -1.875 (P = 0.013) without multiplicity correction for all 3 miRNAs. These results were confirmed by RT-qPCR in the validation phase for 2 miRNAs out of 3: miR-4446-3p (P < 0.001, Padjusted < 0.001), area under the receiver-operator curve (AUC) 0.862 (95% CI 0.723-0.936; P < 0.001) and miR-215-5p (P < 0.001, Padjusted < 0.001), AUC 0.829 (95% CI 0.698-0.907; P < 0.001) to differentiate patients with acromegaly from healthy controls. CONCLUSIONS: In a 2-phase experiment using 2 different techniques we found and validated the downregulation of plasma miR-4446-3p and miR-215-5p in patients with acromegaly compared to healthy subjects, which makes them promising biomarkers for further research.

Clinical Outcomes and Complications of Pituitary Blastoma.

CONTEXT: Pituitary blastoma is a rare, dysontogenetic hypophyseal tumor of infancy first described in 2008, strongly suggestive of DICER1 syndrome. OBJECTIVE: This work aims to describe genetic alterations, clinical courses, outcomes, and complications in all known pituitary blastoma cases. DESIGN AND SETTING: A multi-institutional case series is presented from tertiary pediatric oncology centers. PATIENTS: Patients included children with pituitary blastoma. INTERVENTIONS: Genetic testing, surgery, oncologic therapy, endocrine support are reported. OUTCOME MEASURES: Outcome measures included survival, long-term morbidities, and germline and tumor DICER1 genotypes. RESULTS: Seventeen pituitary blastoma cases were studied (10 girls and 7 boys); median age at diagnosis was 11 months (range, 2-24 months). Cushing syndrome was the most frequent presentation (n = 10). Cushingoid stigmata were absent in 7 children (2 with increased adrenocorticotropin [ACTH]; 5 with normal/unmeasured ACTH). Ophthalmoplegia and increased intracranial pressure were also observed. Surgical procedures included gross/near-total resection (n = 7), subtotal resection (n = 9), and biopsy (n = 1). Six children received adjuvant therapy. At a median follow-up of 6.7 years, 9 patients were alive; 8 patients died of the following causes: early medical/surgical complications (n = 3), sepsis (n = 1), catheter-related complication (n = 1), aneurysmal bleeding (n = 1), second brain tumor (n = 1), and progression (n = 1). Surgery was the only intervention for 5 of 9 survivors. Extent of resection, but neither Ki67 labeling index nor adjuvant therapy, was significantly associated with survival. Chronic complications included neuroendocrine (n = 8), visual (n = 4), and neurodevelopmental (n = 3) deficits. Sixteen pituitary blastomas were attributed to DICER1 abnormalities. CONCLUSIONS: Pituitary blastoma is a locally destructive tumor associated with high mortality. Surgical resection alone provides long-term disease control for some patients. Quality survival is possible with long-term neuroendocrine management.

Circulating Plasma microRNA to Differentiate Cushing's Disease From Ectopic ACTH Syndrome.

Corticotropinomas and adrenocorticotropic hormone (ACTH)-secreting neuroendocrine tumors exhibit differential levels of some microRNAs (miRs) compared to normal tissue. Because miRs can be released from tissues into circulation, they offer promise as novel disease biomarkers. Objective: To evaluate whether miRs are differentially detected in plasma samples of patients with ACTH-dependent Cushing's syndrome (CS). Design: Case-control study. Methods: Morning fasting plasma samples were collected from 41 consecutive patients with confirmed ACTH-dependent CS and 11 healthy subjects and stored at -80°C. Twenty-one miRs previously reported to be differentially expressed in ACTH-secreting tumors vs. healthy tissue samples were quantified in plasma by qPCR. Results: Among enrolled subjects, 28 were confirmed to have Cushing's disease (CD), 13 had ectopic ACTH secretion (EAS) and 11 were healthy controls. We found statistically significant differences in the circulating levels of miR-16-5p [45.04 (95% CI 28.77-61.31) in CD vs. 5.26 (2.65-7.87) in EAS, P < 0.001; q = 0.001], miR-145-5p [0.097 (0.027-0.167) in CD vs. undetectable levels in EAS, P = 0.008; q = 0.087] and differences in miR-7g-5p [1.842 (1.283-2.400) in CD vs. 0.847 (0.187-1.507) in EAS, P = 0.02; q = 0.14]. The area under the receiver-operator (ROC) curve was 0.879 (95% CI 0.770-0.987), p < 0.001, when using miR-16-5p to distinguish between CD and EAS. Circulating levels of miR-16-5p in the healthy control group differed from that of both the CD and EAS groups. Conclusions: Plasma miR levels differ in patients with CD and EAS. In particular, miR-16-5p, miR-145-5p and miR-7g-5p are promising biomarkers for further research to differentiate ACTH-dependent CS.