Computational Insights into the Mechanism of Nitric Oxide Generation from S-Nitrosoglutathione Catalyzed by a Copper Metal-Organic Framework.

The controlled generation of nitric oxide (NO) from endogenous sources, such as S-nitrosoglutathione (GSNO), has significant implications for biomedical implants due to the vasodilatory and other beneficial properties of NO. The water-stable metal-organic framework (MOF) Cu-1,3,5-tris[1H-1,2,3-triazol-5-yl]benzene has been shown to catalyze the production of NO and glutathione disulfide (GSSG) from GSNO in aqueous solution as well as in blood. Previous experimental work provided kinetic data for the catalysis of the 2GSNO → 2NO + GSSG reaction, leading to various proposed mechanisms. Herein, this catalytic process is examined using density functional theory. Minimal functional models of the Cu-MOF cluster and glutathione moieties are established, and three distinct catalytic mechanisms are explored. The most thermodynamically favorable mechanism studied is consistent with prior experimental findings. This mechanism involves coordination of GSNO to copper via sulfur rather than nitrogen and requires a reductive elimination that produces a Cu(I) intermediate, implicating a redox-active copper site. The experimentally observed inhibition of reactivity at high pH values is explained in terms of deprotonation of a triazole linker, which decreases the structural stability of the Cu(I) intermediate. These fundamental mechanistic insights may be generally applicable to other MOF catalysts for NO generation.

Preoperative Evaluation of Thyroid Cancer: A Review of Current Best Practices.

OBJECTIVE: The incidence of thyroid cancer has significantly increased in recent decades. Although most thyroid cancers are small and carry an excellent prognosis, a subset of patients present with advanced thyroid cancer, which is associated with increased rates of morbidity and mortality. The management of thyroid cancer requires a thoughtful individualized approach to optimize oncologic outcomes and minimize morbidity associated with treatment. Because endocrinologists usually play a key role in the initial diagnosis and evaluation of thyroid cancers, a thorough understanding of the critical components of the preoperative evaluation facilitates the development of a timely and comprehensive management plan. The following review outlines considerations in the preoperative evaluation of patients with thyroid cancer. METHODS: A clinical review based on current literature was generated by a multidisciplinary author panel. RESULTS: A review of considerations in the preoperative evaluation of thyroid cancer is provided. The topic areas include initial clinical evaluation, imaging modalities, cytologic evaluation, and the evolving role of mutational testing. Special considerations in the management of advanced thyroid cancer are discussed. CONCLUSION: Thorough and thoughtful preoperative evaluation is critical for formulating an appropriate treatment strategy in the management of thyroid cancer.

Psychological adjustment to initial treatment for low-risk thyroid cancer: Preliminary study.

BACKGROUND: Low-risk papillary thyroid carcinoma (LR-PTC) can be managed by immediate surgery (IS) or active surveillance (AS). We compare the psychological impact of these treatments on patients with LR-PTC. METHODS: Psychological data were collected over 1 year, with assessments at the time of treatment decision (T1), at 6 months (T2) and 12 months (T3) follow-up. Assessments included 13 validated psychological tools. RESULTS: Of 27 enrolled patients, 20 chose AS and 7 chose IS. The average times to T2 and T3 were 5.7 and 11.3 months, respectively. For both groups, Impact of Events Scale scores significantly decreased (p = 0.001) at T2, and depressive/anxiety symptoms remained low. CONCLUSIONS: This study demonstrates the feasibility of assessing psychological outcomes among patients treated for LR-PTC. Further studies are needed to evaluate the impact of AS versus IS on quality of life and changes that patients experience over longer time periods following their treatment decision.

Active Surveillance of Papillary Thyroid Cancer: Frequency and Time Course of the Six Most Common Tumor Volume Kinetic Patterns.

Background: The change in size of the papillary thyroid cancer (PTC) nodule during active surveillance has traditionally been characterized as either stable, increasing, or decreasing based on changes in maximal tumor diameter or tumor volume. More recently, it has been observed that the changes in tumor size observed during observation are more complex with tumor volume kinetic patterns that can be characterized either as stable (Pattern I), early increase in volume (Pattern II), later increase in volume (Pattern III), early increase in volume followed by stability (Pattern IV), stability followed by an increase in volume (Pattern V), or a decrease in tumor volume (Pattern VI). Methods: The frequency, time course, and clinical correlates of these six tumor volume kinetic patterns were analyzed in a cohort of 483 patients with low-risk PTC up to 1.5 cm in maximal diameter followed with active surveillance at our center for a median of 3.7 years. Results: The cumulative incidence of an increase in tumor volume for the entire cohort was 15.9% [confidence interval (CI) 11.8-20.0] at 5 years. At 5 years, most tumors demonstrated stability (78.8%, Pattern I) with 10.0% showing early growth (Pattern II), 4.1% late growth (Pattern III), 1.9% growth then stability (Pattern IV), 0.6% stability then growth (Pattern V), and 5.6% with a decrease in tumor volume (Pattern VI). Tumor volume doubling time during exponential growth significantly differed across the kinetic patterns, with median values of 2.4, 7.1, and 3.3 years for Patterns II, III, and IV, respectively (p < 0.01). Similarly, the time to a change in tumor volume was significantly different across the kinetic patterns, with median values of 1.5, 3, 1.6, 4.7, and 4.1 years for Patterns II, III, IV, V, and VI, respectively (analysis of variance, p < 0.01). Clinical correlates at baseline were not associated with tumor volume kinetic pattern. Conclusions: These six kinetic tumor volume patterns provide a comprehensive description of the changes in PTC tumor volume observed during the first 5 years of active surveillance.

Clinicopathologic and Prognostic Features of Pediatric Follicular Cell-derived Thyroid Carcinomas: A Retrospective Study of 222 Patients.

Pediatric thyroid carcinomas (TCs) are rare and mainly approached based on data extrapolated from adults. We retrospectively reviewed 222 pediatric TCs (patient age less than or equal to 21 y). Lymph node (LN) disease volume at presentation was considered high if the largest positive LN measured ≥1 cm and/or >5 LNs were positive. High-grade follicular cell-derived thyroid carcinoma (HGFCTC) were defined by the presence of marked mitotic count and/or tumor necrosis and considered as high-risk histology along with papillary thyroid carcinomas (PTC) diffuse sclerosing variant (DSV). Disease-free survival (DFS) was analyzed. LN involvement at presentation was significantly associated with male sex, larger tumor size, lymphatic invasion, positive surgical margins, and distant metastases at presentation. Five- and 10-year DFS was 84% and 77%, respectively. Only 1 patient with HGFCTC died of disease. Within PTC variants, PTC-DSV was associated with adverse histopathologic parameters and higher regional disease spread, unlike PTC tall cell variant which did not portend worse behavior. The presence of necrosis conferred worse DFS ( P =0.006), while increased mitotic activity did not. While the entire HGFCTC group did not correlate with outcome ( P =0.071), HGFCTC with necrosis imparted worse DFS ( P =0.006). When restricted to PTC-DSV and HGFCTC with necrosis, high-risk histologic classification emerged as an independent prognostic parameter of DFS ( P =0.020). The excellent prognosis of pediatric TCs differs from that of adult TCs showing similar histologic features. While neither increased mitotic activity nor PTC tall cell variant histology predict adverse outcome, PTC-DSV and tumors with necrosis constitute high-risk histologic variants with an increased risk of protracted disease.

Radioactive iodine therapy: multiple faces of the same polyhedron

ABSTRACT The incidence of differentiated thyroid carcinoma (DTC) has increased in recent decades with early stage, low risk papillary thyroid cancer (PTC) being detected and diagnosed. As a result, the psychological, financial, and clinical ramifications of overdiagnosis and excessively aggressive therapy are being increasingly recognized with many authorities calling for a re-evaluation of the traditional "one size fits all" management approaches. To address these critical issues, most thyroid cancer guidelines endorse a more risk adapted management strategy where the intensity of therapy and follow up is matched to the anticipated risk of recurrence and death from DTC for each patient. This "less is more" strategy provides for a minimalistic management approach for properly selected patients with low-risk DTC. This has re-kindled the long-standing debate regarding the routine use of radioactive iodine therapy (RIT) in DTC. Although recent guidelines have moved toward a more selective use of RIT, particular in patients with low-intermediate risk DTC, the proper selection of patients, the expected benefit, and the potential risks continue to be a source of ongoing controversy and debate. In this manuscript, we will review the wide range of clinical, imaging, medical team, and patient factors that must be considered when evaluating individual patients for RIT. Through a review of the current literature evaluating the potential benefits and risks of RIT, we will present a risk adapted approach to proper patient selection for RIT which emphasizes peri-operative risk stratification as the primary tool that clinicians should use to guide initial RIT management recommendations.

Radioactive iodine therapy: multiple faces of the same polyhedron.

The incidence of differentiated thyroid carcinoma (DTC) has increased in recent decades with early stage, low risk papillary thyroid cancer (PTC) being detected and diagnosed. As a result, the psychological, financial, and clinical ramifications of overdiagnosis and excessively aggressive therapy are being increasingly recognized with many authorities calling for a re-evaluation of the traditional "one size fits all" management approaches. To address these critical issues, most thyroid cancer guidelines endorse a more risk adapted management strategy where the intensity of therapy and follow up is matched to the anticipated risk of recurrence and death from DTC for each patient. This "less is more" strategy provides for a minimalistic management approach for properly selected patients with low-risk DTC. This has re-kindled the long-standing debate regarding the routine use of radioactive iodine therapy (RIT) in DTC. Although recent guidelines have moved toward a more selective use of RIT, particular in patients with low-intermediate risk DTC, the proper selection of patients, the expected benefit, and the potential risks continue to be a source of ongoing controversy and debate. In this manuscript, we will review the wide range of clinical, imaging, medical team, and patient factors that must be considered when evaluating individual patients for RIT. Through a review of the current literature evaluating the potential benefits and risks of RIT, we will present a risk adapted approach to proper patient selection for RIT which emphasizes peri-operative risk stratification as the primary tool that clinicians should use to guide initial RIT management recommendations.

Primary high-grade non-anaplastic thyroid carcinoma: a retrospective study of 364 cases.

AIMS: We aimed to study the clinicopathological and molecular features of high-grade non-anaplastic thyroid carcinomas (HGTCs), a carcinoma with a prognosis intermediate between those of well-differentiated carcinoma and anaplastic carcinoma. METHODS AND RESULTS: This study included 364 HGTC patients: 200 patients (54.9%) were diagnosed with poorly differentiated thyroid carcinoma (PDTC), based on the Turin consensus (HGTC-PDTC), and 164 were diagnosed with high-grade features that did not meet the Turin criteria (HGTC-nonPDTC). HGTCs are aggressive: the 3-year, 5-year, 10-year and 20-year disease-specific survival (DSS) rates were 89%, 76%, 60%, and 35%, respectively. Although DSS was similar between HGTC-PDTC and HGTC-nonPDTC patients, HGTC-PDTC was associated with higher rate of radioactive iodine avidity, a higher frequency of RAS mutations, a lower frequency of BRAF V600E mutations and a higher propensity for distant metastasis (DM) than HGTC-nonPDTC. Independent clinicopathological markers of worse outcome were: older age, male sex, extensive necrosis and lack of encapsulation for DSS; older age, male sex and vascular invasion for DM-free survival; and older age, necrosis, positive margins and lymph node metastasis for locoregional recurrence-free survival. The frequencies of BRAF, RAS, TERT, TP53 and PTEN alterations were 28%, 40%, 55%, 11%, and 10%, respectively. TP53, PTEN and TERT were independent molecular markers associated with an unfavourable outcome, independently of clinicopathological parameters. The coexistence of BRAF V600E and TERT promoter mutation increased the risk of DM. CONCLUSIONS: The above data support the classification of HGTC as a single group with two distinct subtypes based on tumour differentiation: HGTC-PDTC and HGTC-nonPDTC.

NATIONAL SURVEY OF ENDOCRINOLOGISTS AND SURGEONS REGARDING ACTIVE SURVEILLANCE FOR LOW-RISK PAPILLARY THYROID CANCER.

OBJECTIVE: Active surveillance for low-risk papillary thyroid cancer (PTC) was endorsed by the American Thyroid Association guidelines in 2015. The attitudes and beliefs of physicians treating thyroid cancer regarding the active surveillance approach are not known. METHODS: A national survey of endocrinologists and surgeons treating thyroid cancer was conducted from August to September 2017 via professional society emails. This mixed-methods analysis reported attitudes toward potential factors impacting decision-making regarding active surveillance, beliefs about barriers and facilitators of its use, and reasons why physicians would pick a given management strategy for themselves if they were diagnosed with a low-risk PTC. Survey items about attitudes and beliefs were derived from the Cabana model of barriers to guideline adherence and theoretical domains framework of behavior change. RESULTS: Among 345 respondents, 324 (94%) agreed that active surveillance was appropriate for at least some patients, 81% agreed that active surveillance was at least somewhat underused, and 76% said that they would choose surgery for themselves if diagnosed with a PTC of ≤1 cm. Majority of the respondents believed that the guidelines supporting active surveillance were too vague and that the current supporting evidence was too weak. Malpractice and financial concerns were identified as additional barriers to offering active surveillance. The respondents endorsed improved information resources and evidence as possible facilitators to offering active surveillance. CONCLUSION: Although there is general support among physicians who treat low-risk PTC for the active surveillance approach, there is reluctance to offer it because of the lack of robust evidence, guidelines, and protocols.

Thermogravimetric Analysis and Mass Spectrometry Allow for Determination of Chemisorbed Reaction Products on Metal Organic Frameworks.

Thermogravimetric analysis (TGA) is a technique which can probe chemisorption of substrates onto metal organic frameworks. A TGA method was developed to examine the catalytic oxidation of S-nitrosoglutathione (GSNO) by the MOF H3[(Cu4Cl)3(BTTri)8] (abbr. Cu-BTTri; H3BTTri = 1,3,5-tris(1H-1,2,3-triazol-5-yl)benzene), yielding glutathione disulfide (GSSG) and nitric oxide (NO). Thermal analysis of reduced glutathione (GSH), GSSG, GSNO, and Cu-BTTri revealed thermal resolution of all four analytes through different thermal onset temperatures and weight percent changes. Two reaction systems were probed: an aerobic column flow reaction and an anaerobic solution batch reaction with gas agitation. In both systems, Cu-BTTri was reacted with a 1 mM GSH, GSSG, or GSNO solution, copiously rinsed with distilled-deionized water (dd-H2O), dried (25 °C, < 1 Torr), and assessed by TGA. Additionally, stock, effluent or supernatant, and rinse solutions for each glutathione derivative within each reaction system were assessed by mass spectrometry (MS) to inform on chemical transformations promoted by Cu-BTTri as well as relative analyte concentrations. Both reaction systems exhibited chemisorption of glutathione derivatives to the MOF by TGA. Mass spectrometry analyses revealed that in both systems, GSH was oxidized to GSSG, which chemisorbed to the MOF whereas GSSG remained unchanged during chemisorption. For GSNO, chemisorption to the MOF without reaction was observed in the aerobic column setup, whereas conversion to GSSG and subsequent chemisorption was observed in the anaerobic batch setup. These findings suggest that within this reaction system, GSSG is the primary adsorbent of concern with regards to strong binding to Cu-BTTri. Development of similar thermal methods could allow for the probing of MOF reactivity for a wide range of systems, informing on important considerations such as reduced catalytic efficiency from poisoning, recyclability, and loading capacities of contaminants or toxins with MOFs.

Phase 2 study of vascular endothelial growth factor trap for the treatment of metastatic thyroid cancer.

BACKGROUND: Several multitargeted tyrosine kinase inhibitors (TKIs) have demonstrated activity in patients with thyroid cancer that is refractory to radioactive iodine (RAI). The antitumor effect is attributed at least in part to the ability of these TKIs to inhibit angiogenesis in these vascular tumors. Vascular endothelial growth factor (VEGF) Trap (VT) is a recombinantly produced fusion protein consisting solely of human sequences for VEGF receptors 1 and 2 extracellular domains and human immunoglobulin 1. Evaluating VT in patients with thyroid cancer is reasonable considering the activity observed with TKIs targeting VEGF. METHODS: The current study was a single-institution, phase 2, Simon 2-stage design (21 to >41 patients) study based on the objective response rate and/or 6-month progression-free survival as the primary endpoints. Eligible patients were required to have progressive, RAI-refractory and/or [18 F]fludeoxyglucose-avid, recurrent and/or metastatic, nonmedullary, nonanaplastic thyroid cancer; disease that was measurable using Response Evaluation Criteria In Solid Tumors (RECIST) criteria; and adequate organ and bone marrow function. VT at a dose of 4 mg/kg intravenously was administered every 14 days. RESULTS: A total of 40 patients were included in the analysis. Of these patients, 24 had papillary thyroid cancer, 2 had follicular thyroid cancer, and 11 had Hurthle cell thyroid cancer. The final 3 tumors were classified as poorly differentiated. There were no complete and/or partial responses noted; 34 patients achieved stable disease and 6 patients experienced disease progression as their best response. Of the 34 patients with stable disease, 16 remained on the study for >6 months and 6 patients remained on the study for >12 months. The median duration on treatment was 4.1 months (range, 0.6-30.8 months). CONCLUSIONS: Unlike TKIs, which have shown responses in this setting, to the authors' knowledge there have been no responses observed with the use of single-agent VT to date. It does not appear to be a promising drug for the treatment of patients with thyroid cancer.

Prolongation of tumour volume doubling time (midDT) is associated with improvement in disease-specific survival in patients with rapidly progressive radioactive iodine refractory differentiated thyroid cancer selected for molecular targeted therapy.

PURPOSE: To assess molecular targeted therapy (MTT)'s ability to affect tumour volume doubling time (TVDT) and disease-specific survival (DSS) in patients presenting with lung metastasis from radioactive iodine refractory progressive thyroid cancer. METHODS: In this retrospective study, we examined the clinical characteristics, average tumour volume doubling times of lung metastasis and disease-specific survival of patients with lung metastasis from differentiated thyroid cancer who were treated with MTT. RESULTS: The 5-year DSS from the distant metastasis (DM) diagnosis was 72% with median survival of 8 years (95% CI: 6.6-9.5). The median survival was 2.9 years after MTT start (95% CI: 2.1-3.6). On MTT, lung average tumour volume doubling time (midDT) was prolonged to midDT ≥3 years in 75% of patients with baseline midDT ≤1 year and 100% of patients with midDT 1-3 years. In patients with rapidly progressive thyroid cancer (midDT ≤1 year at baseline), the median survival was 4.5 years in those with MTT-achieved midDT ≥3 years (95% CI: 2.9-6.2), as opposed to 2.3 years (95% CI: 0.3-4.3) and 0.7 years (95% CI: 0.2-1.3) in those with MTT-achieved midDT of 1-3 years and MTT-achieved midDT ≤1 year, respectively (log rank P < 0.001). CONCLUSION: Lung midDT is a useful and important clinical marker of disease-specific survival for patients with progressive radioactive iodine refractory (RAIR) metastatic thyroid cancer. In patients with rapidly progressive metastatic RAIR thyroid cancer, molecular targeted therapy prolongs lung tumour volume doubling time and is associated with improved disease-specific survival.

Surgical considerations for papillary thyroid microcarcinomas.

We reevaluate current treatment recommendations of papillary thyroid microcarcinomas taking into account the indolent behavior of these tumors, and the potential morbidity that may result from an unnecessary surgery. The goals of this communication are to: 1) provide surgeons and endocrinologists with the most up-to-date evidence on management of microcarcinomas, 2) outline appropriate instances for active surveillance, and 3) describe the role of surgical interventions for microcarcinomas including lobectomy, total thyroidectomy, and central neck dissection.

Metastatic thyroid carcinoma without identifiable primary tumor within the thyroid gland: a retrospective study of a rare phenomenon.

Metastatic papillary thyroid carcinoma (PTC) without an identifiable primary tumor despite extensive microscopic examination of the thyroid gland is a rare but true phenomenon.We retrieved 7 of such cases and described in detail the clinical and pathologic features of these tumors. BRAF V600E immunohistochemistry and Sequenom molecular profile were conducted in selected cases. All patients harbored metastatic disease in the central (n=3), lateral (n=3), or both neck compartments (n=1). The histotype of the metastatic disease was PTC (n=5), poorly differentiated thyroid carcinoma in association with a PTC columnar variant (n=1), and anaplastic thyroid carcinoma in association with a PTC tall cell variant (n=1). Fibrosis was present in the thyroid of 5 patients. All patients with PTC were alive without evidence of recurrence. The 76-year-old patient with poorly differentiated thyroid carcinoma did not recur and died of unknown causes. Finally, the patient with anaplastic thyroid carcinoma was alive with distant metastasis at last follow-up. The median follow-up for this cohort was 2.2years (range, 0.8-17). BRAF V600E was detected in 4 of 6 cases by immunohistochemistry. In conclusion, metastatic nodal disease without identifiable thyroid primary is a rare but real phenomenon of unknown mechanisms. Although most tumors are low grade and well differentiated, aggressive behavior due to poorly differentiated or anaplastic carcinoma can happen. Most cases are BRAFV600E-positive thyroid tumors. A papillary carcinoma phenotype is found in all reported cases.

The Delphian Node Revisited: An Uncommon Site of Recurrence.

The Delphian nodes (DNs) are frequently involved in cancers of the head and neck, including laryngeal and thyroid malignancies. Positivity in the DN has been considered a predictor of recurrence as well as an overall aggressive tumor biology. However, little has been written regarding the consequences of recurrence at the site of the DN. We present two case reports regarding recurrence in the DN and the unique challenges associated with DN metastases. In addition, we discuss our surgical approach to disease at the prelaryngeal space, including workup, imaging, and resection.

Role of RAI in the management of incidental N1a disease in papillary thyroid cancer.

BACKGROUND: Following total thyroidectomy (TT) for papillary thyroid cancer (PTC), pathological assessment can occasionally reveal incidental perithyroidal lymph nodes (LNs) with occult metastases. These cN0pN1a patients often receive radioactive iodine (RAI) therapy for this indication alone. The aim of this study was to determine the central compartment nodal recurrence-free survival in patients treated without RAI compared to those who received RAI treatment. METHODS: An institutional database of 3664 previously untreated patients with differentiated thyroid cancer operated between 1986 and 2010 was reviewed. A total of 232 pT1-3 patients managed with TT and no neck dissection were subsequently found to have incidental level 6 LNs on pathology. Patients with other indications for RAI, such as extrathyroidal extension and close or positive margins, were excluded. One hundred and four patients remained for analysis. Kaplan-Meier method was used to determine central neck LN recurrence-free survival (RFS). RESULTS: The median age of the cohort was 40 years (range 17-83). The median follow-up was 53 months (range 1-211). The median number of positive LNs removed and maximum LN diameter were 1 (range 1-8) and 5 mm (range 1-16 mm), respectively. A total of 67 (64%) patients had adjuvant RAI and 37 (36%) did not. Patients with vascular invasion (P = 0·01), LNs >2 mm (P = 0·07) and >2 positive nodes (P = 0·06) were more likely to be selected for adjuvant RAI therapy. Patients without RAI therapy had similar 5-year central neck LN RFS compared to those treated with RAI: 96·2% vs 94·6%, respectively (P = 0·92). CONCLUSION: There is no difference in the 5-year central compartment nodal recurrence-free survival in patients treated without RAI compared to those who received RAI treatment.

Undetectable Thyroglobulin Levels in Poorly Differentiated Thyroid Carcinoma Patients Free of Macroscopic Disease After Initial Treatment: Are They Useful?

BACKGROUND: Predictive role of undetectable thyroglobulin (Tg) in patients with poorly differentiated thyroid carcinoma (PDTC) is unclear. Our goal was to report on Tg levels following total thyroidectomy and adjuvant RAI in PDTC patients and to correlate Tg levels with recurrence. METHODS: Forty patients with PDTC with no distant metastases at presentation (M0) and managed by total thyroidectomy and adjuvant RAI were identified from a database of 91 PDTC patients. Of these, 31 patients had Tg values recorded and formed the basis of our analysis. A nonstimulated Tg level <1 ng/ml was used as a cutoff point for undetectable Tg levels. Association of patient and tumor characteristics with Tg levels was examined by χ (2) test. Recurrence-free survival (RFS) stratified by postop Tg level was calculated by Kaplan-Meier method and compared by log-rank test. RESULTS: Twenty patients had undetectable Tg (<1 ng/ml) and 11 had detectable Tg (≥1 ng/ml; range 2-129 ng/ml) following surgery. After adjuvant RAI, 24 patients had undetectable Tg (<1 ng/ml) and 7 had detectable Tg (≥1 ng/ml; range 1-57 ng/ml). Patients with undetectable Tg were less likely to have pathologically positive margins compared to those with detectable Tg (33 vs. 72 % respectively; p = 0.03). Patients with undetectable Tg levels had better 5-year regional control and distant control than patients with detectable Tg level (5-year regional recurrence-free survival 96 vs. 69 %; p = 0.03; 5-year distant recurrence-free survival 96 vs. 46 %, p = 0.11). CONCLUSION: Postoperative thyroglobulin levels in subset of patients with PDTC appear to have predictive value for recurrence. Patients with undetectable Tg have a low rate of recurrence.

Reducing duplicate testing: a comparison of two clinical decision support tools.

OBJECTIVES: Unnecessary duplicate laboratory testing is common and costly. Systems-based means to avert unnecessary testing should be investigated and employed. METHODS: We compared the effectiveness and cost savings associated with two clinical decision support tools to stop duplicate testing. The Hard Stop required telephone contact with the laboratory and justification to have the duplicate test performed, whereas the Smart Alert allowed the provider to bypass the alert at the point of order entry without justification. RESULTS: The Hard Stop alert was significantly more effective than the Smart Alert (92.3% vs 42.6%, respectively; P < .0001). The cost savings realized per alert activation was $16.08/alert for the Hard Stop alert vs $3.52/alert for the Smart Alert. CONCLUSIONS: Structural and process changes that require laboratory contact and justification for duplicate testing are more effective than interventions that allow providers to bypass alerts without justification at point of computerized physician order entry.

Patterns, causes and consequences of defensive microbiome dynamics across multiple scales.

The microbiome can significantly impact host phenotypes and serve as an additional source of heritable genetic variation. While patterns across eukaryotes are consistent with a role for symbiotic microbes in host macroevolution, few studies have examined symbiont-driven host evolution or the ecological implications of a dynamic microbiome across temporal, spatial or ecological scales. The pea aphid, Acyrthosiphon pisum, and its eight heritable bacterial endosymbionts have served as a model for studies on symbiosis and its potential contributions to host ecology and evolution. But we know little about the natural dynamics or ecological impacts of the heritable microbiome of this cosmopolitan insect pest. Here we report seasonal shifts in the frequencies of heritable defensive bacteria from natural pea aphid populations across two host races and geographic regions. Microbiome dynamics were consistent with symbiont responses to host-level selection and findings from one population suggested symbiont-driven adaptation to seasonally changing parasitoid pressures. Conversely, symbiont levels were negatively correlated with enemy-driven mortality when measured across host races, suggesting important ecological impacts of host race microbiome divergence. Rapid drops in symbiont frequencies following seasonal peaks suggest microbiome instability in several populations, with potentially large costs of 'superinfection' under certain environmental conditions. In summary, the realization of several laboratory-derived, a priori expectations suggests important natural impacts of defensive symbionts in host-enemy eco-evolutionary feedbacks. Yet negative findings and unanticipated correlations suggest complexities within this system may limit or obscure symbiont-driven contemporary evolution, a finding of broad significance given the widespread nature of defensive microbes across plants and animals.