Resident experience increases diagnostic rate of thyroid fine-needle aspiration biopsies.

RATIONALE AND OBJECTIVES: The aim of this study was to determine whether the diagnostic yield of thyroid fine-needle aspirations (FNAs) changes over the course of residency training. MATERIALS AND METHODS: We identified 5418 ultrasound-guided thyroid nodule FNAs performed in our radiology department from 2004 through 2012. For each FNA, we recorded if the FNA was performed by a resident and if so the name of the resident and supervising attending radiologist. For each resident, we determined the level of training based on their graduation year from our residency program and the date of the FNA as well as prior surgical training and if they completed subsequent interventional radiology fellowship. Pathology reports were reviewed, and FNAs were classified as diagnostic or nondiagnostic (ND). Generalized mixed models were used to assess ND rate with postgraduate years, including residents with and without prior surgical training or if they subsequently completed an interventional radiology fellowship. RESULTS: Of the 5418 thyroid FNAs, 3164 (58.4%) were performed by a radiology resident under the direct supervision of an attending physician. There was a significant decrease in ND rate as postgraduate years increased (P < .05). A significant decrease in ND rate was found as postgraduate years increased for residents without prior surgical training (P = .0007) or subsequent training in interventional radiology (P = .0014); however, no significant decrease was found for residents with surgical training (P = .37) or completing an interventional radiology fellowship (P = .08). In addition, no significant difference was found for ND rate between postgraduate year 4 (PGY4) and PGY5 (P > .05). CONCLUSIONS: ND thyroid FNA rates progressively decrease with training level, suggesting that early and continued participation in procedures throughout residency improves outcomes. This is particularly true for residents without prior surgical training or subsequent interventional radiology fellowship.

Management of nodules with initially nondiagnostic results of thyroid fine-needle aspiration: can we avoid repeat biopsy?

PURPOSE: To identify demographic and ultrasonographic (US) features associated with malignancy after initially nondiagnostic results of fine-needle aspiration (FNA) to help clarify the role of repeat FNA, surgical excision, or serial US in these nodules. MATERIALS AND METHODS: This study was HIPAA compliant and institutional review board approved; informed consent was waived. Thyroid nodules (n = 5349) that underwent US-guided FNA in 2004-2012 were identified; 393 were single nodules with nondiagnostic FNA results but adequate cytologic, surgical, or US follow-up. Demographic information and diameters and volume at US at first biopsy were modeled with malignancy as outcome through medical record review. Exact logistic regression was used to model malignancy outcomes, demographic comparisons with age were made (Student t test, Satterthwaite test), and proportion confidence intervals (CIs) were estimated (Clopper-Pearson method). RESULTS: Of 393 nodules with initially nondiagnostic results, nine malignancies (2.3%) were subsequently diagnosed with repeat FNA (n = 2, 0.5%) or surgical pathologic examination (n = 7, 1.8%), 330 (84.0%) were benign, and 54 (13.7%) were stable or decreased in size at serial US (mean follow-up, 3.0 years; median, 2.5 years; range, 1.0-7.8 years). Patients with malignancies were significantly older (mean age, 62.7 years; median, 64 years; range, 47-77 years) than those without (mean age, 55.4 years; median, 57 years; range, 12-94 years; P = .0392). Odds of malignancy were 4.2 times higher for men versus women (P = .045) and increased significantly for each 1-cm increase in anteroposterior, minimum, and mean nodule diameter (1.78, 2.10, and 1.96, respectively). In 393 nodules, no malignancies were detected in cystic or spongiform nodules (both, n = 11, 2.8%; 95% CI: 1.4%, 5.0%), nodules with eggshell calcifications (n = 9, 2.3%; 95% CI: 1.1%, 4.3%), or indeterminate echogenic foci (n = 39, 9.9%; 95% CI: 7.2%, 13.3%). CONCLUSION: Very few malignancies were diagnosed with repeat FNA following nondiagnostic FNA results (two of 336, 0.6%); therefore, clinical and US follow-up may be more appropriate than repeat FNA following nondiagnostic biopsy results.

Aortic aneurysm generation in mice with targeted deletion of integrin-linked kinase in vascular smooth muscle cells.

RATIONALE: Integrin-linked kinase (ILK) is located at focal adhesions and links the extracellular matrix (ECM) to the actin cytoskeleton via ß1- and ß3-integrins. ILK plays a role in the activation of kinases including protein kinase B/Akt and glycogen synthase kinase 3ß and regulates cell proliferation, motility, and survival. OBJECTIVE: To determine the function of ILK in vascular smooth muscle cells (SMCs) in vivo. METHODS AND RESULTS: SM22Cre(+)Ilk(Fl/Fl) conditional mutant mice were generated in which the Ilk gene was selectively ablated in SMCs. SM22Cre(+)Ilk(Fl/Fl) conditional mutant mice survive to birth but die in the perinatal period exhibiting multiple vascular pathologies including aneurysmal dilatation of the aorta and patent ductus arteriosus (PDA). Defects in morphogenetic development of the aorta were observed as early as E12.5 in SM22Cre(+)Ilk(Fl/Fl) mutant embryos. By late gestation (E16.5 to 18.5), striking expansion of the thoracic aorta was observed in ILK mutant embryos. Histological analyses revealed that the structural organization of the arterial tunica media is severely disrupted with profound derangements in SMC morphology, cell-cell, and cell-matrix relationships, including disruption of the elastic lamellae. ILK deletion in primary aortic SMCs results in alterations of RhoA/cytoskeletal signaling transduced through aberrant localization of myocardin-related transcription factor (MRTF)-A repressing the transcription and expression of SMC genes, which are required for the maintenance of the contractile SMC phenotype. CONCLUSIONS: These data identify a molecular pathway linking ILK signaling to the contractile SMC gene program. Activation of this pathway is required for morphogenetic development of the aorta and ductus arteriosus during embryonic and postnatal survival.

Pharmacological inhibition of BLT1 diminishes early abdominal aneurysm formation.

Leukotriene B(4) (LTB(4)) is a pro-inflammatory lipid mediator generated by the enzymes 5-lipoxygenase (5-LO) and LTA(4)-hydrolase. LTB(4) signals primarily through its G protein-coupled receptor BLT1, which is highly expressed on specific leukocyte subsets. Recent genetic studies in humans as well as knockout studies in mice have implicated the leukotriene synthesis pathway in several vascular pathologies. Here we tested the hypothesis that pharmacological inhibition of BLT1 diminishes abdominal aortic aneurysm (AAA) formation, a major complication associated with atherosclerotic vascular disease. Chow-fed Apoe(-/-) mice were treated with a 4-week infusion of Angiotensin II (AngII, 1000 ng/(kg min)) beginning at 10 weeks of age, in a well-established murine AAA model. Administration of the selective BLT1 antagonist CP-105,696 beginning simultaneously with AngII infusion reduced the incidence of AAA formation from 82% to 40% (p<0.05). There was a concordant reduction in maximal aortic diameter from 2.35 mm to 1.56 mm (p<0.05). While administration of the antagonist on day 14 after the onset of AngII infusion diminished lesional macrophage accumulation, it did not significantly alter the size of AAA by day 42. Thus, pharmacological inhibition of BLT1 may ultimately hold clinical promise, but early intervention may be critical.

Kynurenic acid triggers firm arrest of leukocytes to vascular endothelium under flow conditions.

Recent studies have demonstrated that kynurenic acid (KYNA), a compound produced endogenously by the interferon-gamma-induced degradation of tryptophan by indoleamine 2,3-dioxygenase, activates the previously orphaned G protein-coupled receptor, GPR35. This receptor is expressed in immune tissues, although its potential function in immunomodulation remains to be explored. We determined that GPR35 was most highly expressed on human peripheral monocytes. In an in vitro vascular flow model, KYNA triggered the firm arrest of monocytes to both fibronectin and ICAM-1, via beta(1) integrin- and beta(2) integrin-mediated mechanisms, respectively. Incubation of monocytes with pertussis toxin prior to use in flow experiments significantly reduced the KYNA-induced monocyte adhesion, suggesting that adhesion is triggered by a G(i)-mediated process. Furthermore, KYNA-triggered adhesion of monocytic cells was reduced by short hairpin RNA-mediated silencing of GPR35. Although GPR35 is expressed at slightly lower levels on neutrophils, KYNA induced firm adhesion of these cells to an ICAM-1-expressing monolayer as well. KYNA also elicited neutrophil shedding of surface L-selectin, another indicator of leukocyte activation. Taken together, these data suggest that KYNA could be an important early mediator of leukocyte recruitment.

Interferon-gamma and the interferon-inducible chemokine CXCL10 protect against aneurysm formation and rupture.

BACKGROUND: Vascular disease can manifest as stenotic plaques or ectatic aneurysms, although the mechanisms culminating in these divergent disease manifestations remain poorly understood. T-helper type 1 cytokines, including interferon-gamma and CXCL10, have been strongly implicated in atherosclerotic plaque development. METHODS AND RESULTS: Here, we specifically examined their role in the formation of abdominal aortic aneurysms in the angiotensin II-induced murine model. Unexpectedly, we found increased suprarenal aortic diameters, abdominal aortic aneurysm incidence, and aneurysmal death in apolipoprotein E- and interferon-gamma-deficient (Apoe(-/-)/Ifng(-/-)) mice compared with Apoe(-/-) controls, although atherosclerotic luminal plaque formation was attenuated. The interferon-gamma-inducible T-cell chemoattractant CXCL10 was highly induced by angiotensin II infusion in Apoe(-/-) mice, but this induction was markedly attenuated in Apoe(-/-)/Ifng(-/-) mice. Apoe(-/-)/Cxcl10(-/-) mice had decreased luminal plaque but also increased aortic size, worse morphological grades of aneurysms, and a higher incidence of death due to aortic rupture than Apoe(-/-) controls. Furthermore, abdominal aortic aneurysms in Apoe(-/-)/Cxcl10(-/-) mice were enriched for non-T-helper type 1-related signals, including transforming growth factor-beta1. Treatment of Apoe(-/-)/Cxcl10(-/-) mice with anti-transforming growth factor-beta neutralizing antibody diminished angiotensin II-induced aortic dilation. CONCLUSIONS: The present study defines a novel pathway in which interferon-gamma and its effector, CXCL10, contribute to divergent pathways in abdominal aortic aneurysm versus plaque formation, inhibiting the former pathology but promoting the latter. Thus, efforts to develop antiinflammatory strategies for atherosclerosis must carefully consider potential effects on all manifestations of vascular disease.

Inhibited aortic aneurysm formation in BLT1-deficient mice.

Leukotriene B(4) is a proinflammatory lipid mediator generated by the enzymes 5-lipoxygenase and leukotriene A(4) hydrolase. Leukotriene B(4) signals primarily through its high-affinity G protein-coupled receptor, BLT1, which is highly expressed on specific leukocyte subsets. Recent genetic studies in humans as well as knockout studies in mice have implicated the leukotriene synthesis pathway in several vascular pathologies. In this study, we tested the hypothesis that BLT1 is necessary for abdominal aortic aneurysm (AAA) formation, a major complication of atherosclerotic vascular disease. Chow-fed Apoe(-/-) and Apoe(-/-)/Blt1(-/-) mice were treated with a 4-wk infusion of angiotensin II (1000 ng/min/kg) beginning at 20 wk of age, in a well-established murine AAA model. We found a reduced incidence of AAA formation as well as concordant reductions in the maximum suprarenal/infrarenal diameter and total suprarenal/infrarenal area in the angiotensin II-treated Apoe(-/-)/Blt1(-/-) mice as compared with the Apoe(-/-) controls. Diminished AAA formation in BLT1-deficient mice was associated with significant reductions in mononuclear cell chemoattractants and leukocyte accumulation in the vessel wall, as well as striking reductions in the production of matrix metalloproteinases-2 and -9. Thus, we have shown that BLT1 contributes to the frequency and size of abdominal aortic aneurysms in mice and that BLT1 deletion in turn inhibits proinflammatory circuits and enzymes that modulate vessel wall integrity. These findings extend the role of BLT1 to a critical complication of vascular disease and underscore its potential as a target for intervention in modulating multiple pathologies related to atherosclerosis.