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Chemotherapy has historically proven ineffective in advanced differentiated thyroid cancers, but the realisation that various tyrosine kinases are activated in the disease suggested a potential therapeutic role for tyrosine-kinase inhibitors. We investigated the safety and efficacy of pazopanib. This phase 2 trial was done from Feb 22, 2008, to Jan 31, 2009, in patients with metastatic, rapidly progressive, radioiodine-refractory differentiated thyroid cancers. Each patient received 800 mg continuous pazopanib daily in 4-week cycles until disease progression, drug intolerance, or both occurred. Up to two previous therapies were allowed, and measurable disease with radiographic progression in the 6-month period before enrolment was a requirement for inclusion. The primary endpoint was any tumour response, according to the Response Evaluation Criteria in Solid Tumors 1.0. This study is registered with ClinicalTrials.gov, number NCT00625846. 39 patients were enrolled. One patient had received no previous radioiodine therapy and another withdrew consent before treatment. Clinical outcomes could, therefore, be assessed in 37 patients (19 [51%] men, median age 63 years). The study is closed to accrual of new patients, but several enrolled patients are still being treated. Patients received a median of 12 cycles (range 1 to >23, total >383). Confirmed partial responses were recorded in 18 patients (response rate 49%, 95% CI 35–68), with likelihood of response lasting longer than 1 year calculated to be 66%. Maximum concentration of pazopanib in plasma during cycle one was significantly correlated with radiographic response ( r=−0·40, p=0·021). 16 (43%) patients required dose reductions owing to adverse events, the most frequent of which (any grade) were fatigue (29 patients), skin and hair hypopigmentation (28), diarrhoea (27), and nausea (27). Two patients who died during treatment had pre-existing contributory disorders. Pazopanib seems to represent a promising therapeutic option for patients with advanced differentiated thyroid cancers. The correlation of the patient's response and pazopanib concentration during the first cycle might indicate that treatment can be individualised to achieve optimum outcomes. Assessment of pazopanib in an expanded cohort of patients with differentiated thyroid cancer, as well as in cohorts of patients with medullary and anaplastic thyroid cancers, is presently being done. National Cancer Institute, supported in part by NCI CA15083 and CM62205.

Abstract Context Clinical applications of genomic assessment of thyroid cancers are rapidly evolving. Objectives, Design, and Setting We studied tumor samples from patients with imminently threatening and rare thyroid cancers to identify genomic alterations that might correlate with outcomes and/or be productively therapeutically targetable. Patient Context Progressive and metastatic, and/or rare, thyroid cancers were studied, 2012 to 2016, at Mayo Clinic sites. Intervention The intervention was Foundation One tumor interrogation. Main Outcome Measures Main outcome measures included genomic alterations, patient characteristics, and overall survival. Results Samples from 55 patients were evaluated: 20 anaplastic thyroid cancers (ATCs) (36%), 25 radioactive iodine–refractory differentiated thyroid cancers (DTCs)/poorly differentiated thyroid cancers (PDTCs) (45%; 14 papillary thyroid cancer [PTCs], 6 PDTCs, 5 Hürthle cell cancers), 8 medullary thyroid cancers (MTCs) (15%), and 2 others (a spindle epithelial tumor with thymus-like differentiation, and a primary thyroid sarcoma). Overall, 72% of DTCs, 79% of ATCs, and 75% of MTCs were deemed to have potentially productively targetable alterations. The most commonly encountered mutation was of TERT promoter (56% of DTCs, 68% of ATCs)—but this is not presently targetable. Targetable BRAFV600E mutations were found in 40% of DTCs/PDTCs (83% of PTCs) and 32% of ATCs; of MTCs, 75% had targetable RET mutations, and 25% HRAS mutations. Of patient tumors with nonmutated BRAFV600E, 53% of DTC/PDTCs and 69% of ATCs had other potentially productively targetable mutations. Genomic alterations in our series of poor prognosis metastatic DTC/PDTCs also closely resembled those seen in ATC. Conclusions Whereas genomic interrogation of favorable prognosis thyroid cancer seems ill advised, potentially productively targetable mutations were demonstrated in the majority of tumors from patients with metastatic thyroid cancers requiring systemic therapy, suggesting a rationale for the selective application of this technology.

SummaryBackground Adrenal cortical carcinoma (ACC) is a rare cancer with treatment options of limited efficacy, and poor prognosis if metastatic. AT-101 is a more potent inhibitor of B cell lymphoma 2 family apoptosis-related proteins than its racemic form, gossypol, which showed preliminary clinical activity in ACC. We thus evaluated the efficacy of AT-101 in patients with advanced ACC. Methods Patients with histologically confirmed metastatic, recurrent, or primarily unresectable ACC were treated with AT-101 (20 mg/day orally, 21 days out of 28-day cycles) until disease progression and/or prohibitive toxicity. The primary endpoint was objective response rate, wherein a Response Evaluation Criteria In Solid Tumors (RECIST) partial response rate of 25% would be considered promising and 10% not, with a Type I error of 10% and 90% power. In a 2-stage design, 2 responses were required of the first 21 assessable subjects to warrant complete accrual of 44 patients. Secondary endpoints included safety, progression-free survival and overall survival. Results This study accrued 29 patients between 2009 and 2011; median number of cycles was 2. Seven percent experienced grade 4 toxicity including cardiac troponin elevations and hypokalemia. None of the first 21 patients attained RECIST partial response; accordingly, study therapy was deemed ineffective and the trial was permanently closed. Conclusions AT-101 had no meaningful clinical activity in this study in patients with advanced ACC, but demonstrated feasibility of prospective therapeutic clinical trials in this rare cancer.

An abundance of previous theories and empirical studies have verified that leadership styles indeed can influence members' creativity and effectiveness in both traditional team settings and in a virtual context. Moreover, past research has also indicated that leaders can build relationships among team members and increase mutual trust due to the face to face interaction made possible in a traditional office environment. However, there is little empirical work that articulates how leaders behave and motivate their members in a virtual context. This study employed an experimental design with 50 undergraduate juniors who acted as the team members and 23 Executive MBA students who acted as the team leaders. The main goal was to study the impact of leaders' motivating language (i.e., empathetic, direction-giving, and mixed usage) on team members' creative performance. Key findings indicate that there are slightly significant differences between three kinds of motivating language approaches. The study shows that leaders who give virtual team members feedback via written communication that is both directional and empathetic are perceived as more effective and lead to better performance.

Aim To identify potential landscapes for the conservation of the black‐tailed prairie dog (Cynomys ludovicianus; BTPD) ecosystem, across their historical geographical range within the United States. Location Central Grasslands of the United States. Methods We used a structured decision analysis approach to identify landscapes with high conservation potential (HCP) for the BTPD ecosystem. Our analysis incorporated ecological, political and social factors, along with changing climate and land use to maximise long‐term conservation potential. Results The landscapes we identified with HCP (top 30% rangewide) represented 22% of the historical distribution of BTPDs and remained strongholds under projected climate change. We provide a suite of HCP area scenarios to help inform different conservation and management interests, including those that consider projected climate change and jurisdictional (state‐level) boundaries. Main Conclusions Our findings highlight the large conservation potential for BTPDs and associated species, and the maps we generated can be incorporated into other large‐scale, multispecies conservation planning efforts being developed for the Central Grasslands of North America.

Purpose - This exploratory study seeks to bridge a gap in the literature by exploring the life cycle-strategy relationship to discover the preferred strategy for high and low performing firms in four of the five stages of the organizational life cycle. Design/methodology/approach - In total, 600 managers randomly chosen from chamber of commerce membership lists in the southern USA were mailed an extensive scale that included items to measure life cycle stage, generic strategy, industry attractiveness and stability, size, and satisfaction with performance. The instrument included 20 life-cycle items, four items for each of the five stages. Findings - Partial support was found for the expected relationship between strategy and performance as firms move through the organizational life cycle. New, high-performing organizations that were satisfied with their performance preferred first mover strategies, while renewing organizations categorized as high performers also emphasized the first mover strategic approach. Mature high performers preferred a uniqueness strategy over one based on efficiency. Research limitations/implications - The fifth proposition, concerning declining firms, could not be adequately tested. Other limitations of this study include the limited sample size, the limited size variance of participating firms, and the cross-industry nature of the sample. Combining the research stream of organizational life cycle with generic strategies and satisfaction with performance complicated the project. Practical implications - Life cycle and performance research provides managers with a snapshot of high and low performing firms and an understanding of how their situation, decision-making style, strategy and structure fit. High performers focus on proactive, first mover strategies. Originality/value - The organizational life cycle is operationalized, demonstrating characteristics for high and low performing firms in each stage except decline.

Much of the literature suggests that strategies are formulated in light of perceived environmental conditions and internal capabilities. This study supports the notion that strategy is formulated in part as a response to management uncertainties about competitors, customers, and the environment. Responses from 137 wholesale grocers demonstrate that uncertainty varies by generic strategy, suggesting that businesses consider both the type and degree of uncertainty when crafting a competitive strategy. Specifically, the data suggest that viable strategic options may be limited more by the cognitive and perceptual abilities of an organization's managers than by objective measures of factors such as organizational resources and industry competitiveness. The premise that strategy must \"fit\" with organizational or environmental factors to be effective may be incomplete. Rather, a strategy - to be successful - should also fit with the psychological characteristics and constraints of the managers responsible for its formulation and implementation.

Childhood trauma constitutes a major public health crisis in the United States, with an estimated two thirds of children experiencing at least one traumatic event by the age of 16. Despite the prevalence of childhood trauma, there has been very little sociological research on this subject. Using rich data from the National Longitudinal Study of Adolescent Health, the current dissertation project offers important new insights on the contours and consequences of childhood trauma. The first analytic chapter shows how neighborhood racial segregation is an important determinant for exposure to multiple types of violence. The findings suggest that adolescents living in more racially segregated communities are more likely to report exposure to violence. The second analytic chapter examines whether exposure to multiple traumas or “complex trauma” mediates the association between family structure and various “markers” of life chances in adulthood. The analysis shows that children born to single mother families, relative to children who are born to two biological or adoptive parent families, are more likely to experience complex trauma in childhood, which accounts for a significant portion of the association between family structure, adult incarceration, and college completion. Finally, the third analytic chapter examines the relationship between witnessing community violence and criminal legal system involvement in young adulthood. This analysis shows that adolescents who witness community violence are significantly more likely to become incarcerated in young adulthood. The analysis also finds significant racial disparities in witnessing violence, suggesting that exposure to community violence is a potentially important mechanism in the production of racial inequalities in criminal legal system involvement.

SummaryPurpose. Targeting the vascular endothelial growth factor (VEGF) pathway improves progression free survival in multiple advanced malignancies but durable responses are uncommon. Inhibition of the VEGF pathway at multiple levels of signal transduction may improve clinical outcomes. Preclinical data with cediranib, an inhibitor of all 3 VEGF receptors, in combination with selumetinib, an inhibitor of MEK 1/2, demonstrated improved tumor control experimentally. This phase I trial was designed to test the two agents in combination to evaluate the tolerability, safety and assess disease response. Methods. Patients with advanced solid malignancies were enrolled into this phase I trial. Cediranib and selumetinib were dosed using a toxicity-adaptive isotonic design for the dose escalation/de-escalation of each agent. Both cediranib and selumetinib were administered daily and continuously. Cycles were 28 days in length. Results. Eighteen patients were enrolled. At all dose levels, dose limiting toxicities (DLT) were observed, which limited dose escalation and further evaluation. The maximum tolerated dose of cediranib and selumetinib in combination could not be determined. The best response of stable disease was observed in eight patients. Conclusions. Cediranib and selumetinib in combination on a continuous schedule was not tolerable, with patients experiencing cardiovascular and other DLTs. Intermittent schedules may be needed to establish a safe and tolerable combination of cediranib and selumetinib.

Formulating a winning strategy for an organization is a complex process, and managers at different levels bring different viewpoints and priorities to the process. In particular, their perspectives may reflect whether they view management as an art or science, whether they emphasize consistency or flexibility, or whether they believe the process should be top down or bottom up. Ideally, all levels of management should share some common ground on strategy formulation, but a survey highlights where differences arise, especially from attitudes on these three philosophical areas. Understanding how differences arise can help top managers construct a more harmonious process. [PUBLICATION ABSTRACT]