Xavier M. Keutgen

A Panel of Four miRNAs Accurately Differentiates Malignant from Benign Indeterminate Thyroid Lesions on Fine Needle Aspiration

Purpose: Indeterminate thyroid lesions on fine needle aspiration (FNA) harbor malignancy in about 25% of cases. Hemi- or total thyroidectomy has, therefore, been routinely advocated for definitive diagnosis. In this study, we analyzed miRNA expression in indeterminate FNA samples and determined its prognostic effects on final pathologic diagnosis. Experimental Design: A predictive model was derived using 29 ex vivo indeterminate thyroid lesions on FNA to differentiate malignant from benign tumors at a tertiary referral center and validated on an independent set of 72 prospectively collected in vivo FNA samples. Expression levels of miR-222, miR-328, miR-197, miR-21, miR-181a, and miR-146b were determined using reverse transcriptase PCR. A statistical model was developed using the support vector machine (SVM) approach. Results: A SVM model with four miRNAs (miR-222, miR-328, miR-197, and miR-21) was initially estimated to have 86% predictive accuracy using cross-validation. When applied to the 72 independent in vivo validation samples, performance was actually better than predicted with a sensitivity of 100% and specificity of 86%, for a predictive accuracy of 90% in differentiating malignant from benign indeterminate lesions. When Hurthle cell lesions were excluded, overall accuracy improved to 97% with 100% sensitivity and 95% specificity. Conclusions: This study shows that that the expression of miR-222, miR-328, miR-197, and miR-21 combined in a predictive model is accurate at differentiating malignant from benign indeterminate thyroid lesions on FNA. These findings suggest that FNA miRNA analysis could be a useful adjunct in the management algorithm of patients with thyroid nodules. Clin Cancer Res; 18(7); 2032–8. ©2012 AACR.

The role of chelators in preventing biofilm formation and catheter-related bloodstream infections

Purpose of review As metallic cations are essential to microbial adherence, biofilm formation, and bacterial growth, efforts have been directed toward utilizing metal-binding chelators that have the capability of inhibiting bacterial growth by disrupting surface adherence and preventing biofilm production. This review focuses on recent advances in the role of chelators in biofilm disruption and prevention of catheter-related bloodstream infections. Recent findings The most important factor in the pathogenesis of catheter-related bloodstream infections is the intraluminal colonization of the central venous catheters through the formation of bacterial biofilm matrix in which microbial organisms embed themselves and eventually become a source of catheter-related bloodstream infections. It has been demonstrated that high-affinity metal-binding chelators including ethylenediamine-tetraacetic acid and citrate have the capacity of inhibiting microbial growth by disrupting surface adherence and preventing biofilm production. Furthermore, ethylenediamine-tetraacetic acid and citrate have been clinically shown to be highly effective and outperform heparin in the prevention and treatment of catheter-related bloodstream infections when used as a component of antimicrobial catheter lock solutions. Summary It is suggested that the addition of chelators such as ethylenediamine-tetraacetic acid and citrate to antimicrobial lock solutions provides an innovative and superior alternative to heparin lock solution in the prevention and treatment of catheter-related bloodstream infections.

Resection of primary tumor site is associated with prolonged survival in metastatic nonfunctioning pancreatic neuroendocrine tumors

BACKGROUND Nonfunctioning pancreatic neuroendocrine tumors (NFpNET) present with distant metastases in up to 50% of patients. It is unknown whether removal of the primary tumor in patients with NFpNET and metastases is beneficial. METHODS We used the Surveillance, Epidemiology, and End Results database to identify patients with NFpNET and distant metastases. The primary outcome measure in this study was overall survival. RESULTS We identified 882 patients with metastatic NFpNET who had survival data; 303 (34%) patients had operative removal of their primary tumor of which 243 (80%) were grade I or II. Median survival of patients undergoing resection of the primary site was 65 (95% confidence interval 60-86) versus 10 (8-12) months for those without resection (P < .0001). Patients diagnosed after 2003 (n = 625, 71%) were more likely to undergo an operation than those diagnosed earlier (P = .001). Multivariable analysis showed that a lesser tumor grade (P < .0001), younger age (P < .0001), diagnosis during or after 2003 (P = .0003), tumor site in the body/tail (P = .009), and operative resection of the primary tumor site (P < .0001) were associated with prolonged survival of patients with NFpNET and distant metastases. CONCLUSION This study suggests that resection of the site of the primary NFpNET is associated with greater survival in patients with distant metastases and could therefore be considered as a additional treatment option in this patient population.

Management of anaplastic thyroid cancer.

Anaplastic thyroid cancer (ATC) is a deadly disease with a dismal prognosis. Molecular analyses of ATC tumors have yielded interesting results, which could help in understanding the underlying mechanisms of this aggressive disease process. Managing ATC can be challenging and includes rapid diagnosis, adequate staging, and interdisciplinary, multimodal treatments to optimize patient outcome. Treatments include surgical resection to gross negative margins when possible, as well as neo- or adjuvant treatment with chemotherapy or external beam radiation (XRT) for locoregional disease. New treatment strategies include evaluating the benefits of vascular disrupting agents and tyrosine kinase inhibitors for advanced ATC with driver mutations, which can be targeted. This review summarizes key concepts in managing ATC.

Molecular diagnosis for indeterminate thyroid nodules on fine needle aspiration: advances and limitations

Indeterminate thyroid lesions are diagnosed in up to 30% of fine needle aspirations. These nodules harbor malignancy in more than 25% of cases, and hemithyroidectomy or total thyroidectomy has therefore been advocated in order to achieve definitive diagnosis. Recently, many molecular markers have been investigated in an attempt to increase diagnostic accuracy of indeterminate fine needle aspiration cytology and thereby avoid unnecessary complications and costs associated with thyroid surgery. Somatic mutation testing, mRNA gene expression platforms, protein immunocytochemistry and miRNA panels have improved the diagnostic accuracy of indeterminate thyroid nodules, and although no test is perfectly accurate, in the authors’ opinion, these methods will most certainly become an important part of the diagnostic tools for clinicians and cytopathologists in the future.

Treatment of Scaphoid Non-Unions of the Proximal third with Conventional Bone Grafting and Mini-Herbert Screws: an Analysis of Clinical and Radiological Results:

This study assessed the clinical and radiological outcomes after treatment of scaphoid non-union of the proximal third by non-vascularised bone grafts and stabilisation by Mini-Herbert Screws from a dorsal approach. Thirty-one patients, one woman and 30 men, were reviewed retrospectively at a mean of 42 (12–77) months. All patients received pre- and postoperative CT scans to assess bone union. In addition to demographic data, the range of motion, grip strength, DASH score, Krimmer score, Mayo wrist score and radiological parameters (carpal height, scapholunate and radiolunate angles) were recorded. Bone union was achieved in 21 patients. The average DASH score in patients with bone union was 12 and that in patients with persistent non-union it was 30. No progression into carpal collapse or increase of scapholunate angles was detected. Our study demonstrates that acceptable union rates can be achieved with non-vascularised bone grafts, and this technique compares favourably with other reports in the literature.

A general method to derive robust organ-specific gene expression-based differentiation indices: application to thyroid cancer diagnostic

Differentiation is central to development, while dedifferentiation is central to cancer progression. Hence, a quantitative assessment of differentiation would be most useful. We propose an unbiased method to derive organ-specific differentiation indices from gene expression data and demonstrate its usefulness in thyroid cancer diagnosis. We derived a list of thyroid-specific genes by selecting automatically those genes that are expressed at higher level in the thyroid than in any other organ in a normal tissues genome-wide gene expression compendium. The thyroid index of a tissue was defined as the median expression of these thyroid-specific genes in that tissue. As expected, the thyroid index was inversely correlated with meta-PCNA, a proliferation metagene, across a wide range of thyroid tumors. By contrast, the two indices were positively correlated in a time course of thyroid-stimulating hormone (TSH) activation of primary thyrocytes. Thus, the thyroid index captures biological information not integrated by proliferation rates. The differential diagnostic of follicular thyroid adenomas and follicular thyroid carcinoma is a notorious challenge for pathologists. The thyroid index discriminated them as accurately as did machine-learning classifiers trained on the genome-wide cancer data. Hence, although it was established exclusively from normal tissue data, the thyroid index integrates the relevant diagnostic information contained in tumoral transcriptomes. Similar results were obtained for the classification of the follicular vs classical variants of papillary thyroid cancers, that is, tumors dedifferentiating along a different route. The automated procedures demonstrated in the thyroid are applicable to other organs.

Calcimimetics versus parathyroidectomy for treatment of primary hyperparathyroidism: retrospective chart analysis of a prospective database.

Objective:This study aims to determine the efficacy of calcimimetics in improving bone mineral density (BMD) in patients with primary hyperparathyroidism (pHPT) and compare those results to patients undergoing parathyroidectomy. Background:Parathyroidectomy has been shown to improve BMD in pHPT, but calcimimetics have recently been advocated as a medical alternative to parathyroidectomy for pHPT. Materials and Methods:We identified 17 patients that were treated with calcimimetics for pHPT. Seventeen patients with pHPT who underwent parathyroidectomy served as surgical controls. Serum calcium level, parathyroid hormone (PTH) level, and femur and spine BMD T scores were compared before and 1 year after therapy. Results:Both groups were demographically matched. Calcium levels normalized in 70.6% of medically versus 100% of surgically treated patients (P = 0.026). PTH levels normalized in 35% of patients treated with calcimimetics versus 76% of surgical patients (P = 0.036). Femur BMD improved in 18.8% of medically treated patients versus 58.8% of surgical patients (P = 0.032). Spine BMD improved in 70.6% of medically treated patients versus 82.4% of surgical patients (P = 0.69). Further analysis demonstrated that regardless of treatment, normalization of PTH was associated with significant improvement in femur (P = 0.03) and spine BMD (P < 0.001). Normalization of calcium without normalization of PTH did not impact BMD. Conclusions:Parathyroidectomy results in greater normalization of serum calcium and PTH levels and significantly improves cortical BMD compared to calcimimetics. Regardless of treatment, normalization of PTH is associated with significant improvement in spine and femur BMD, suggesting that the superior effects of surgery may be mediated by better control of PTH.

Predictive factors of morbidity and mortality in grade IV and V liver trauma undergoing perihepatic packing: Single institution 14 years experience at European trauma centre

PURPOSE Major liver trauma in polytraumatic patients accounts for significant morbidity and mortality. We aimed to assess prognostic factors for morbidity and mortality in patients with severe liver trauma undergoing perihepatic packing. METHODS Prospectively collected records of 293 consecutive polytrauma patients with liver injury admitted at a level I trauma centre between 1996 and 2008 were reviewed. 39 patients with grade IV-V AAST liver injury and treated with peri-hepatic packing were identified and included for analysis. Univariate and multivariate analyses were performed to assess prognostic factors for morbidity and mortality. RESULTS Mean age of patients was 41 years. 34 patients were haemodynamically unstable at initial presentation. Ten of 39 patients were treated with angiographic embolization in addition to perihepatic packing. The overall mortality rate was 51.3%. Liver-related death occurred in 23.1%. Overall and liver-related morbidity rates were 90% and 28%, respectively. Glasgow Coma Scale (GCS), respiratory rate, packed red blood cells (PRBC) transfusion, pH and Base Excess (BE), Revised Trauma Score (RTS) and Trauma Injury Severity Score (TRISS), need for angiographic embolization as well as early OR and ICU admission were associated with significant decrease of early mortality. CONCLUSIONS Revised Trauma Score, haemodynamic instability, blood pH and BE are important prognostic factors influencing morbidity and mortality in polytrauma patients with grade IV/V liver injury. Furthermore, fast and effective surgical damage control procedure with perihepatic packing, followed by early ICU admission is associated with lower complication rate and shorter ICU stays in this patient population.

Risk stratification of indeterminate thyroid fine-needle aspiration biopsy specimens based on mutation analysis

BACKGROUND Mutation analysis is potentially a powerful tool to enhance the diagnostic accuracy of thyroid fine-needle aspiration (FNA) biopsy specimens. However, some clinicians may rely on a negative mutation panel to exclude malignancy. We aimed to determine the malignancy rate in indeterminate lesions with negative mutation analysis. METHODS A literature review established a mutation analysis model using the prevalence of BRAF, RET, RAS, and PAX8/peroxisome proliferator-activated receptor-γ mutations in indeterminate lesions. This model was applied retrospectively to a study cohort of 466 consecutive indeterminate lesions that underwent hemi- or total thyroidectomy for definitive diagnosis, to evaluate its accuracy for identifying malignancy. RESULTS Of 466 indeterminate lesions in the study, 30% (139) were malignant. These included 66 cases of papillary thyroid cancer, 45 cases of follicular variant of papillary thyroid cancer, 18 cases of follicular thyroid cancer, and 10 others. The risk of malignancy was 42% when cytologic atypia was present vs 17% without. The mutation analysis model would correctly identify only 48 of 139 (34%) of malignant indeterminate lesions. Therefore, when mutation analysis is negative, the overall risk of malignancy would be 23%. When atypia is present, the risk of malignancy would be 31% vs 13% in lesions without. CONCLUSION Indeterminate lesions with a negative mutation analysis still carry a significant risk of malignancy, especially in the presence of atypia, requiring surgery for definitive diagnosis.