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Anaplastic thyroid cancer is a rare and aggressive cancer with no standard radiotherapy-based local treatment. Based on data suggesting synergy between pazopanib and paclitaxel in anaplastic thyroid cancer, NRG Oncology did a double-blind, placebo-controlled, randomised phase 2 clinical trial comparing concurrent paclitaxel and intensity-modulated radiotherapy (IMRT) with the addition of pazopanib or placebo with the aim of improving overall survival in this patient population. Eligible patients were aged 18 years or older with a pathological diagnosis of anaplastic thyroid cancer, any TNM stage, Zubrod performance status of 0–2, no recent haemoptysis or bleeding, and no brain metastases. Patients were enrolled from 34 centres in the USA. Initially, a run-in was done to establish safety. In the randomised phase 2 trial, patients in the experimental group (pazopanib) received 2–3 weeks of weekly paclitaxel (80 mg/m2) intravenously and daily pazopanib suspension 400 mg orally followed by concurrent weekly paclitaxel (50 mg/m2), daily pazopanib (300 mg), and IMRT 66 Gy given in 33 daily fractions (2 Gy fractions). In the control group (placebo), pazopanib was replaced by matching placebo. Patients were randomly assigned (1:1) to the two treatment groups by permuted block randomisation by NRG Oncology with stratification by metastatic disease. All investigators, patients, and funders of the study were masked to group allocation. The primary endpoint was overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered with Clinicaltrials.gov, NCT01236547, and is complete. The safety run-showed the final dosing regimen to be safe based on two out of nine participants having adverse events of predefined concern. Between June 23, 2014, and Dec 30, 2016, 89 patients were enrolled to the phase 2 trial, of whom 71 were eligible (36 in the pazopanib group and 35 in the placebo group; 34 [48%] males and 37 [52%] females). At the final analysis (data cutoff March 9, 2020), with a median follow-up of 2·9 years (IQR 0·002–4·0), 61 patients had died. Overall survival was not significantly improved with pazopanib versus placebo, with a median overall survival of 5·7 months (95% CI 4·0–12·8) in the pazopanib group versus 7·3 months (4·3–10·6) in the placebo group (hazard ratio 0·86, 95% CI 0·52–1·43; one-sided log-rank p=0·28). 1-year overall survival was 37·1% (95% CI 21·1–53·2) in the pazopanib group and 29·0% (13·2–44·8) in the placebo group. The incidence of grade 3–5 adverse events did not differ significantly between the treatment groups (pazopanib 88·9% [32 of 36 patients] and placebo 85·3% [29 of 34 patients]; p=0·73). The most common clinically significant grade 3–4 adverse events in the 70 eligible treated patients (36 in the pazopanib group and 34 in the placebo group) were dysphagia (13 [36%] vs 10 [29%]), radiation dermatitis (8 [22%] vs 13 [38%]), increased alanine aminotransferase (12 [33%] vs none), increased aspartate aminotransferase (eight [22%] vs none), and oral mucositis (five [14%] vs eight [24%]). Treatment-related serious adverse events were reported for 16 (44%) patients on pazopanib and 12 (35%) patients on placebo. The most common serious adverse events were dehydration and thromboembolic event (three [8%] each) in patients on pazopanib and oral mucositis (three [8%]) in those on placebo. There was one treatment-related death in each group (sepsis in the pazopanib group and pneumonitis in the placebo group). To our knowledge, this study is the largest randomised anaplastic thyroid cancer study that has completed accrual showing feasibility in a multicenter NCI National Clinical Trials Network setting. Although no significant improvement in overall survival was recorded in the pazopanib group, the treatment combination was shown to be feasible and safe, and hypothesis-generating data that might warrant further investigation were generated. National Cancer Institute and Novartis.

NRG Oncology's Developmental Therapeutics and Radiation Therapy Subcommittee assembled an interdisciplinary group of investigators to address barriers to successful early phase clinical trials of novel combination therapies involving radiation. This Policy Review elucidates some of the many challenges associated with study design for early phase trials combining radiotherapy with novel systemic agents, which are distinct from drug–drug combination development and are often overlooked. We also advocate for potential solutions that could mitigate or eliminate some of these barriers, providing examples of specific clinical trial designs that could help facilitate efficient and effective evaluation of novel drug–radiotherapy combinations.

The queen conch Lobatus gigas continues to support a commercial fishery in Puerto Rico despite a history of overfishing and low population densities. The goals of this study were to generate density estimates for the queen conch, to assess temporal trends, and to evaluate hypotheses of management interest using generalized linear models. Density data were supplemented by size- and age-class data. Total mean density was 14.1/ha (adults = 7.3/ha; juveniles = 6.6/ha). Year plus habitat and depth (associated effects) were significant factors influencing adult and juvenile density. Lower densities of both juvenile and adult queen conchs were observed in 1997 and 2001 than in 2013, but there have been no differences since 2006. This indicates an improvement in the population, though not recently. A location effect compared sites within the U.S. Exclusive Economic Zone (EEZ), which is closed to fishing, with those in local waters, which are open to fishing. The location term was significant for adults, with lower densities inshore regardless of year. For juveniles, both the location and year × location terms were significant; the EEZ had a higher juvenile density and a proportionally greater density increase (from 2.3/h to 10.0/ha) from 1997 to 2013. Lengthfrequency diagrams showed an increase in the proportion of adult conchs of 16–20-cm shell length in 2013 relative to 1997. This suggests an effect of the 22.86-cm minimum size limit implemented in 2004. Juveniles comprised 50% of the population in 2013, compared with 70% in 1997, and adults were found in the oldest age-class during the 2013 survey. This suggests an overall decrease in fishing mortality since 1997. Changes in survey methodology are recommended, including but not limited to shortening transects to increase the number of sites, utilizing a twostage design, not utilizing scooters, standardizing the areas surveyed, and stratifying by depth and habitat.

Management of patients with locoregionally advanced head and neck squamous cell carcinoma (HNSCC) when cisplatin is contraindicated is controversial. We aimed to assess whether radiotherapy with concurrent and adjuvant durvalumab would improve outcomes compared with radiotherapy with cetuximab. NRG-HN004 was designed as an open-label, multicentre, parallel-group, randomised, phase 2/3 trial with safety lead-in conducted at 89 academic and community medical centres in North America. Eligible patients were aged 18 years or older with American Joint Committee on Cancer 8th edition stage III–IVB p16-negative HNSCC or unfavourable stage I–III p16-positive oropharyngeal or unknown primary carcinoma, who had a contraindication to cisplatin (Eastern Cooperative Oncology Group [ECOG] performance status 2, renal or hearing impairment, peripheral neuropathy, aged at least 70 years with moderate or severe comorbidity, or aged younger than 70 years with severe comorbidity). Patients were randomly assigned (2:1) by permuted block randomisation (multiples of 6) to intravenous durvalumab 1500 mg starting 2 weeks before radiotherapy then every 4 weeks starting week 2 of radiotherapy (seven cycles) or intravenous cetuximab 400 mg/m2 1 week before radiotherapy then 250 mg/m2 weekly beginning week 1 of radiotherapy (eight cycles), with intensity-modulated radiotherapy (70 Gy in 35 fractions over 7 weeks). Stratification factors were tumour and nodal stage, ECOG performance status and comorbidity, and primary site and p16 status. The phase 2 primary endpoint was progression-free survival in the intention-to-treat population. There was one prespecified interim futility analysis at 50% of progression-free survival information. If the observed hazard ratio was 1·0 or more, favouring cetuximab, early stopping would be considered. Extended follow-up analysis was post hoc. This trial is registered with ClinicalTrials.gov, NCT03258554, and is closed to enrolment. Following a ten-patient safety lead-in, the phase 2 trial enrolled 190 patients from March 12, 2019, to July 30, 2021, 186 of whom were randomly assigned (123 to durvalumab and 63 to cetuximab). Median age was 72 years (IQR 64–77), 30 (16%) patients were women and 156 (84%) were men. Phase 2 accrual was suspended in July 30, 2021, following an interim futility analysis, and permanently closed in Sept 1, 2022. The phase 3 part of the trial was not conducted. At a median follow-up of 2·3 years (IQR 1·9–3·1) for the extended follow-up (data cutoff July 31, 2023; post-hoc analysis), 2-year progression-free survival was 50·6% (95% CI 41·5–59·8) in the durvalumab group versus 63·7% (51·3–76·1) in the cetuximab group (hazard ratio 1·33 [95% CI 0·84–2·12]; p=0·89). Adverse events were similar in both groups. The most common grade 3–4 adverse events were dysphagia (26 [22%] of 119 patients in the durvalumab group vs 18 [30%] of 61 patients in the cetuximab group), lymphopenia (33 [28%] vs 20 [33%]), and oral mucositis (13 [11%] vs 11 [18%]). Four (3%) patients in the durvalumab group and one (2%) in the cetuximab group died from treatment-related adverse events (death not otherwise specified, laryngeal oedema, lung infection, and respiratory failure in the durvalumab group and sudden death not otherwise specified in the cetuximab group). Our findings suggest that durvalumab did not improve outcomes compared with cetuximab in patients with HNSCC with contraindications to cisplatin. Further trials are needed to define the standard of care for this population. US National Cancer Institute and AstraZeneca.

The 2016 Guidelines for Assessment and Instruction in Statistics Education (GAISE) College Report emphasized six recommendations to teach introductory courses in statistics. Among them: use of real data with context and purpose. Many educators have created databases consisting of multiple datasets for use in class; sometimes making hundreds of datasets available. Yet “the context and purpose” component of the data may remain elusive if just a generic database is made available. We describe the use of open data in introductory courses. Countries and cities continue to share data through open data portals. Hence, educators can find regional data that engage their students more effectively. We present excerpts from case studies that show the application of statistical methods to data on: crime, housing, rainfall, tourist travel, and others. Data wrangling and discussion of results are recognized as important case study components. Thus, the open data based case studies attend most GAISE College Report recommendations. Reproducible R code is made available for each case study. Example uses of open data in more advanced courses in statistics are also described. Supplementary materials for this article are available online.

Many problems in biostatistics involve response variables that are difficult to measure accurately. Muscular strength in animals and humans quantified through the grip strength, and usual nutrient intake of an individual, are two examples of such variables. These studies often collect, on the same subject, multiple measurements of the response variable containing measurement error. One research interest in these studies is estimating the conditional quantile function of the latent response variable given a set of subject-specific covariates and the contaminated replicates. Conventional quantile regression (QR) is an established technique to estimate the conditional quantile function of a response variable. However, it cannot be directly employed for estimation in the current problem because the response variable is observed with measurement error. Naively replacing the latent response variable by the subject-specific average of the contaminated replicates in a QR model could lead to serious bias in the quantile estimates. Other methods based on transformations have been proposed to estimate the conditional quantiles of a latent variable. However, these methods: i) rely on the existence of a transformation to achieve both constant variance and normality, which could be unrealistic in many problems; and ii) do not provide a method to compute quantile curves when a continuous covariate is present. Therefore, we propose a new seminonparametric estimation approach to estimate the conditional quantile function of a latent variable given subject-specific covariates and contaminated replicates. The proposed method, described in Chapter 2, involves a location-scale shift model that allows the subject-specific random effects to follow a flexible seminonparametric distribution and accounts for measurement errors. A virtue of the proposed method is that it does not rely on the normality and constant variance assumptions on the subject-specific random effects. Moreover, the variance of the subject-specific random effects distribution is allowed to be a function of continuous covariates. We derive the asymptotic results for the proposed estimator and, through simulation studies, demonstrate that the proposed method leads to consistent estimates of the conditional quantiles of the latent response variable. To assess the practical usage of the proposed method, a grip strength data set from laboratory mice is analyzed. In Chapter 3, we extend the location-scale shift model proposed in Chapter 2 by allowing the location and scale functions to be modeled nonparametrically. This current model handles the possible misspecification of the location and scale functions in the model proposed in Chapter 2. We illustrate the value of the proposed method by estimating the conditional quantile curves of usual sodium intake as a function of age. This application entails careful work to deal with the estimation and selection of tuning parameters in our method under a complex survey design. We handle these challenges by incorporating sampling weights into the estimation procedure and a replication method for variance estimation with the proposed method. In Chapter 4 we investigate the performance of some adaptations of the existing estimation methods based on QR and bias-correction approaches. An advantage of these methods is that some of the model assumptions required in Chapters 2-3 can be avoided. First, we propose the simulation-extrapolation (SIMEX) and empirical SIMEX methods to mitigate the bias of the naive QR. Second, we propose two estimators based on corrected-loss functions in a QR model. SIMEX-based methods slightly reduce the bias of quantile coefficients, particularly for the intercept. The performance of the SIMEX-based estimators is highly dependent on the extrapolant being considered. The corrected-loss estimators give approximately unbiased estimates of the conditional quantiles. However, practical implementation of these estimators is challenging due to the computational issues that characterize corrected-score methods.

This work presents different alternatives for modeling binary longitudinal data for continuous and categorical outcomes. Using a logistic model with random intercept, we propose the Percentile Curves concept, which are conditional probability curves across time representing percentiles of distribution of curves generated by the random intercept. We also analyze the density and cumulative distribution of subject-specific probabilities across time induced by the logistic model with random intercept. We apply this concept to two binary longitudinal data sets (Toenail and Garlic). Also, we expand the percentile curves concept to a logistic model with a random intercept and slope, and we propose a methodology to compute them.

The long-term outcomes associated with adding bevacizumab, a vascular endothelial growth factor inhibitor, to standard chemoradiation have continued to be favorable for a group of patients with locoregionally advanced nasopharyngeal carcinoma (NPC). To assess long-term toxic effects and clinical outcomes associated with chemotherapy, radiation therapy (RT), and bevacizumab for NPC. This single-arm phase II nonrandomized controlled trial was conducted by the National Cancer Trials Network group and NRG Oncology (formerly Radiation Therapy Oncology Group), with accrual from December 13, 2006, to February 5, 2009, and data analysis from June 26 to July 1, 2019. The study was conducted at 19 cancer centers with a median (IQR) follow-up of 9.0 (7.7-9.3) years. Included patients were adults (aged ≥18 years) with NPC that was World Health Organization (WHO) histologic grade I to IIb or III, American Joint Committee on Cancer stage IIB or greater, and with or without lymph node involvement. Patients received 3 cycles of bevacizumab (15 mg/kg) concurrently with standard cisplatin (100 mg/m2) and RT (69.96 Gy) followed by 3 cycles of adjuvant bevacizumab (15 mg/kg) given concurrently with cisplatin (80 mg/m2) and fluorouracil (1000 mg/m2/d). The primary end point was grade 4 hemorrhage or grade 5 adverse events in the first year. Secondary end points were locoregional progression-free (LRPF) interval, distant metastasis-free (DMF) interval, progression-free survival (PFS), overall survival (OS), and other adverse events. Long-term toxic effects and clinical outcomes were reported due to the limited follow-up in the initial report for this trial and the importance of long-term outcomes when combining bevacizumab with chemoradiation. Among 46 patients with NPC who were enrolled, 44 patients were analyzed (29 males [65.9%]; 23 Asian [52.3%], 2 Black [4.5%], and 16 White [36.4%]; 38 not Hispanic [86.4%]; median [IQR] age, 48.5 [39.0-56.0] years). There were 33 patients with a Zubrod performance status of 0, indicating that they were fully functional and asymptomatic (75.0%); 32 patients with a WHO histologic grade of IIb or III (72.7%); and 39 patients with stage III or IVB disease (88.6%). Among analyzed patients, 42 individuals received radiation therapy of 69.96 Gy or greater (95.5%; dose range, 65.72-70.00 Gy); 30 patients received 3 cycles of cisplatin (68.2%) with RT, and 31 patients received 3 cycles of bevacizumab with RT (70.5%); this was followed by 3 cycles of adjuvant cisplatin in 21 patients (47.7%), fluorouracil in 24 patients (54.5%), and bevacizumab in 23 patients (52.3%). No grade 4 hemorrhage or grade 5 AEs were reported in the first year or thereafter. Late grade 3 AEs occurred in 16 patients (36.4%), including 7 patients with dysphagia (15.9%), 6 patients with hearing impairment (13.6%), and 2 patients with dry mouth (4.5%). The 1- and 5-year rates of feeding tube use were 5 of 41 patients (12.2%) and 0 of 27 patients, respectively. There were 19 patients (43.2%) who progressed or died without disease progression (6 patients with locoregional progression [13.6%], 8 patients with distant progression [18.2%], and 5 patients who died without progression [11.4%]). The 5- and 7-year rates were 79.5% (95% CI, 67.6%-91.5%) and 69.7% (95% CI, 55.9%-83.5%) for OS, 61.2% (95% CI, 46.8%-75.6%) and 56.3% (95% CI, 41.5%-71.1%) for PFS, 74.9% (95% CI, 61.4%-86.6%) and 72.3% (95% CI, 58.4%-84.7%) for LRPF interval, and 79.5% (95% CI,66.4%-90.0%) for both times for DMF interval. Among 13 patients who died, death was due to disease in 8 patients (61.5%). In this nonrandomized controlled trial, no grade 4 hemorrhage or grade 5 AEs were reported in the first year or thereafter among patients with NPC receiving bevacizumab combined with chemoradiation. The rate of distant metastasis was low although 89% of patients had stage III to IVB disease, suggesting that further investigation may be warranted. ClinicalTrials.gov Identifier: NCT00408694.

Background In recent years, the adoption of artificial intelligence (AI) has become increasingly relevant in various sectors, including higher education. This study investigates the psychosocial factors influencing AI adoption among Peruvian university students and uses an extended UTAUT2 model to examine various constructs that may impact AI acceptance and use. Method This study employed a quantitative approach with a survey-based design. A total of 482 students from public and private universities in Peru participated in the research. The study utilized partial least squares structural equation modeling (PLS-SEM) to analyze the data and test the hypothesized relationships between the constructs. Results The findings revealed that three out of the six hypothesized factors significantly influenced AI adoption among Peruvian university students. Performance expectancy (β = 0.274), social influence (β = 0.355), and AI learning self-efficacy (β = 0.431) were found to have significant positive effects on AI adoption. In contrast to expectations, ethical awareness, perceived playfulness, AI readiness and AI anxiety did not have significant impacts on AI appropriation in this context. Conclusion This study highlights the importance of practical benefits, the social context, and self-confidence in the adoption of AI within Peruvian higher education. These findings contribute to the understanding of AI adoption in diverse educational settings and provide a framework for developing effective AI implementation strategies in higher education institutions. The results can guide universities and policymakers in creating targeted approaches to enhance AI adoption and integration in academic environments, focusing on demonstrating the practical value of AI, leveraging social networks, and building students’ confidence in their ability to learn and use AI technologies.