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Defining biomarkers for invasive pituitary neuroendocrine tumors (PitNETs) is highly desirable. The high mobility group A (HMGA) proteins are among the most widely expressed cancer-associated proteins. Indeed, their overexpression is a frequent feature of human malignancies, including PitNETs. We show that nonfunctioning PitNETs (NF-PitNETs) express significantly higher levels of HMGA1 than somatotropinomas (GHs) and corticotropinomas (ACTHs). Furthermore, HMGA2 expression was detected only in NF-PitNETs and was significantly higher in larger tumors than in smaller tumors. HMGA expression analysis generally focuses on nuclear staining. Here, cytoplasmic HMGA staining was also found. PitNETs displayed strong nuclear HMGA1 and strong cytoplasmic HMGA2 immunoreactivity. Interestingly, the HMGA1 and HMGA2 nuclear expression levels were significantly higher in invasive adenomas than in noninvasive adenomas. The highest levels of nuclear HMGA2 were found in GHs. In conclusion, we show that overexpression of nuclear HMGA proteins could be a potential biomarker of invasive PitNETs, particularly HMGA2 for GHs. HMGA2 might be a reliable biomarker for NF-PitNETs., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objectives: Dabigatran is a direct thrombin inhibitor shown to be an effective alternative to warfarin in patients with non-valvular atrial fibrillation (AF). We evaluated the use of dabigatran in patients with bioprosthetic mitral and/or aortic valve replacement and AF., Methods: We selected 34 and randomized 27 patients in a 1:1 ratio to receive dabigatran or warfarin. The primary endpoint was the presence of a new intracardiac thrombus at 90 days, by transesophageal echocardiogram (TEE). Secondary endpoints included the development of dense spontaneous echo contrast (SEC) and incidence of stroke (ischemic or hemorrhagic), myocardium infarction, valve thrombosis and peripheral embolic events., Results: The trial was terminated prematurely because of low enrollment. There were 27 patients in total: 15 patients placed in the dabigatran group and 12 in the warfarin group. After 90 days, one patient (8.3 %) in the warfarin group and none in the dabigatran group had developed a new intracardiac thrombus. In the dabigatran group, two patients (13.3 %) developed dense SEC versus one patient (8.3 %) in the warfarin group. In the warfarin group, one patient (8.3 %) presented ischemic stroke, and none did in the dabigatran group. We observed no cases of hemorrhagic stroke, valve thrombosis, embolic events or myocardial infarction in either group throughout the study. However, one patient (6.7 %) in the dabigatran group had a fully recovered transient ischemic attack and one patient in the warfarin group died of heart failure., Conclusions: The use of dabigatran appears to be similar to warfarin in preventing the formation of intracardiac thrombus., Trial Registration: Clinicaltrials.gov NCT01868243.

Background: Some pituitary adenomas exhibit fast growth and invade surrounding structures. To date, there is no robust marker to predict invasiveness., Aim: To evaluate Ki-67, p53 and aryl hydrocarbon receptor-interacting protein (AIP) expression and compare these between invasive and noninvasive somatotropinomas and nonfunctioning pituitary adenomas (NFPAs)., Methods: Protein expression was determined by immunohistochemistry. Tumors were classified according to percentage of immunolabeled nuclei for Ki-67 and p53. AIP immunopositivity was graded according to a score encompassing pattern and intensity. Invasiveness was defined according to radiological and surgical criteria., Results: Thirty-eight sporadic somatotropinomas were studied. Median Ki-67 labeling index in invasive and noninvasive tumors was 1.6 (range 0-20.6) and 0.26 (0-2.2), respectively (p = 0.01). With a 2.3% cut-off point obtained by ROC curve analysis, invasive adenomas were distinguished with 100% specificity, 39% sensitivity, and 63% accuracy. Low AIP expression was also correlated with tumor invasiveness (p = 0.001), with sensitivity, specificity and accuracy of 78, 80, and 79%, respectively. Expression of p53 was not different among tumors. Twenty-nine NFPAs were studied, with no significant difference between Ki-67, p53 and AIP expression in invasive and noninvasive tumors. High AIP expression was more frequent in NFPAs, with Ki-67 >3% (p = 0.051), especially when only gonadotrope cell adenomas (n = 25) were considered (p = 0.012)., Conclusions: These data suggest, for the first time, that AIP is a better marker of invasiveness in somatotropinomas than Ki-67 and p53. In addition, low AIP expression is observed in invasive somatotropinomas, in contrast with high AIP expression in NFPAs (mainly gonadotrope cell tumors) with high proliferative indices., (Copyright © 2010 S. Karger AG, Basel.)