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A latent variable modeling approach to evaluation of scale reliability in complex design studies is outlined. The procedure is readily applicable in empirical research for the purpose of point and interval estimation of reliability of multicomponent measuring instruments in the presence of probability sampling and possible nesting within higher order units. The method can be used to aid scale construction and development efforts in large-scale studies of substantially heterogeneous populations. The described approach is illustrated with data from an international educational survey. [ABSTRACT FROM PUBLISHER]

Background The objective of this study was to determine the maximum tolerated dose and safety of LR-103, a Vitamin D analogue, in patients with advanced cancer. Methods In Step A, patients received oral LR-103 once daily in 14-day cycles with intra-patient dose escalation per accelerated dose escalation design. Dose limiting toxicity for Step A was defined as ≥grade 2 hypercalcemia and/or >grade 2 other toxicities. Starting dose was 5 µg/day. Step B used a 3+3 design starting at Step A maximum tolerated dose with 28-day cycles. Dose limiting toxicity was defined as ≥grade 3 hypercalcemia or any grade 3 or 4 non-hematologic toxicity, except hypercalciuria. Results Twenty-one patients were enrolled; eight were treated in Step A. At dose level 3 (15 µg/day), two patients had dose limiting toxicity. One had grade 4 hyperuricemia. The other had grade 4 GGT plus grade 3 alkaline phosphatase, fatigue and urinary tract infection (UTI). Dose level 2 (10 µg/day) was the maximum tolerated dose for Step A and was starting dose for Step B. The dose was escalated to dose level 5 (30 µg/day) with a patient experiencing grade 3 dose limiting toxicity of hypercalcemia. The study was discontinued before reaching the maximum tolerated dose due to sponsor decision. Modest increases in serum osteocalcin and calcium and decrease in parathyroid hormone were noted. Best response was stable disease; four patients were on therapy for six months or longer. Conclusion Step A dose limiting toxicities limited accelerated dose escalation. The maximum tolerated dose of LR-103 was not reached prior to study termination and this agent is no longer being developed. [ABSTRACT FROM AUTHOR]

A readily applicable procedure for point and interval estimation of coefficient alpha is outlined for complex sample designs, in cases where this coefficient is close to composite reliability. As a by-product, point and interval estimation of the change in alpha due to measuring instrument revision is also possible. This approach can be used as an aid for scale construction and development in empirical investigations involving analyses of complex sample survey data, in particular for secondary data analyses from large-scale studies. The procedure is illustrated with data from an educational survey. [ABSTRACT FROM AUTHOR]

Background. A phase I, dose-escalation study of AT-101 with cisplatin and etoposide was conducted to determine the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D), safety and pharmacokinetics in patients with advanced solid tumors, with an expanded cohort in patients with extensive-stage small cell lung cancer (ES-SCLC) to assess preliminary activity. Methods. In the dose escalation portion, increasing doses of AT-101 were administered orally BID on days 1-3 along with cisplatin on day 1 and etoposide on days 1-3 of a 21 day cycle. At the RP2D, an additional 7 patients with untreated ES-SCLC were enrolled. Results. Twenty patients were enrolled in the dose-escalation cohort, and 7 patients with ES-SCLC were enrolled in the expanded cohort. The MTD/RP2D was established at AT-101 40 mg BID days 1-3 with cisplatin 60 mg/m2 and etoposide 120 mg/m2 on day 1 of a 21 day cycle with pegfilgrastim support. Two DLTs of neutropenic fever were seen at dose level 1. After the addition of pegfilgrastim, no additional DLTs were observed. Grade 3/4 treatment-related toxicities included: diarrhea, increased AST, neutropenia, hypophosphatemia, hyponatremia, myocardial infarction and pulmonary embolism. No apparent PK interactions were observed between the agents. Preliminary activity was observed with PRs in patients with ES-SCLC, high-grade neuroendocrine tumor, esophageal cancer and NSCLC. Conclusions. AT-101 with cisplatin and etoposide is well tolerated with growth factor support. Anti-tumor activity was observed in a variety of cancers including ES-SCLC, supporting further investigation with BH-3 mimetics in combination with standard chemotherapy for ES-SCLC. [ABSTRACT FROM AUTHOR]

Background/Context: The effects of class size on student achievement have gained considerable attention in education research and policy, especially over the last 30 years. Perhaps the best evidence about the effects of class size thus far has been produced from analyses of Project STAR data, a large-scale experiment where students and teachers were randomly assigned to smaller or larger classes within schools. Researchers have also analyzed observational data to examine the effects of class size, but the results have been mixed. Purpose/Objective/Research Question/Focus of Study: It is generally difficult to draw causal inferences about class size effects with observational data because of the omitted variables problem. This shortcoming can be overcome with instrumental variables (IV) methods that are designed to facilitate causal inferences. The present study uses IV methods to examine the effects of class size on reading achievement using data from the 2001 fourth-grade sample of the Progress in International Reading Literacy Study (PIRLS) in Greece. We took advantage of Greece's nationwide rule about maximum class size in elementary schools to construct IV estimates of class size. Population: PIRLS was designed to monitor children's achievement levels in fourth grade worldwide. We used reading achievement data from 2001 in Greece. The sample was a national probability sample of fourth graders. The use of appropriate weights helped us make projections to the fourth-grade student population in Greece in 2001. Research Design: The research design was secondary analysis. We examined whether class size predicts reading achievement for fourth graders in Greece net of student, teacher/classroom, and school characteristics. We used multilevel models to capture the dependency in the data (i.e., students nested within schools). We also used instrumental variables methods to facilitate causal inferences about class size effects. Conclusions: We investigated the effects of class size on reading achievement for fourth graders in Greece in 2001 using rich data from PIRLS. The results produced from the multilevel and the IV analyses were overall similar. Generally, the results indicated a positive association between class size and achievement. However, the association was typically statistically insignificant, especially when teacher/classroom and school variables were taken into account. [ABSTRACT FROM AUTHOR]

Introduction The primary objective of this phase II trial was to evaluate the efficacy and tolerability of vorinostat and bortezomib as third-line therapy in advanced non-small cell lung cancer (NSCLC) patients. Methods Eligibility criteria included recurrent/metastatic NSCLC, having received 2 prior systemic regimens, and performance status 0-2. Patients took vorinostat 400 mg PO daily days 1-14 and bortezomib 1.3 mg/m2 IV day 1, 4, 8 and 11 in a 21-day cycle. Primary endpoint was 3-month progression free survival (3m-PFS), with a goal of at least 40 % of patients being free of progression at that time point. This study followed a two-stage minimax design. Results Eighteen patients were enrolled in the first stage. All patients had two prior lines of treatment. Patients received a median of two treatment cycles (range: 1-6) on study. There were no anti-tumor responses; stable disease was observed in 5 patients (27.8 %). Median PFS was 1.5 months, 3m-PFS rate 11.1 %, and median overall survival 4.7 months. The most common grade 3/4 toxicities were thrombocytopenia and fatigue. Two patients who had baseline taxane-related grade 1 peripheral neuropathy developed grade 3 neuropathy. The study was closed at its first interim analysis for lack of efficacy. Conclusions Bortezomib and vorinostat displayed minimal anti-tumor activity as third-line therapy in NSCLC. We do not recommend this regimen for further investigation in unselected patients. [ABSTRACT FROM AUTHOR]

Background A phase I study to assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics (PK) and antitumor activity of vorinostat in combination with bortezomib in patients with advanced solid tumors. Methods Patients received vorinostat orally once daily on days 1-14 and bortezomib intravenously on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (level 1) was vorinostat (400 mg) and bortezomib (0.7 mg/m). Bortezomib dosing was increased using a standard phase I dose-escalation schema. PKs were evaluated during cycle 1. Results Twenty-three patients received 57 cycles of treatment on four dose levels ranging from bortezomib 0.7 mg/m to 1.5 mg/m. The MTD was established at vorinostat 400 mg daily and bortezomib 1.3 mg/m. DLTs consisted of grade 3 fatigue in three patients (1 mg/m,1.3 mg/m and 1.5 mg/m) and grade 3 hyponatremia in one patient (1.5 mg/m). The most common grade 1/2 toxicities included nausea (60.9 %), fatigue (34.8 %), diaphoresis (34.8 %), anorexia (30.4 %) and constipation (26.1 %). Objective partial responses were observed in one patient with NSCLC and in one patient with treatment-refractory soft tissue sarcoma. Bortezomib did not affect the PKs of vorinostat; however, the Cmax and AUC of the acid metabolite were significantly increased on day 2 compared with day 1. Conclusions This combination was generally well-tolerated at doses that achieved clinical benefit. The MTD was established at vorinostat 400 mg daily × 14 days and bortezomib 1.3 mg/m on days 1, 4, 8 and 11 of a 21-day cycle. [ABSTRACT FROM AUTHOR]

In international achievement studies, questionnaires typically ask about the presence of particular household assets in students' homes. Responses to the assets questions are used to compute a total score, which is intended to represent household wealth in models of test performance. This study uses item analysis and confirmatory factor analysis to assess the validity of assets indices as wealth measures in three educational surveys of primary or secondary school students. We find that scores generated from binary household asset items can reasonably be interpreted as predominantly measuring a single wealth factor, but some scores are imprecise, with between one-third and onehalf of their variability attributable to measurement error. Our study illustrates the potential of psychometric analyses to contribute to improvement of the household wealth items administered in similar international achievement assessments. [ABSTRACT FROM AUTHOR]

Introduction: Vorinostat is a small molecule inhibitor of class I and II histone deacetylase enzymes which alters the expression of target genes including the cell cycle gene p21, leading to cell cycle arrest and apoptosis. Methods: Patients enrolled in a phase I trial were treated with vorinostat alone on day 1 and vorinostat and bortezomib in combination on day 9. Paired biopsies were obtained in eleven subjects. Blood samples were obtained on days 1 and 9 of cycle 1 prior to dosing and 2 and 6 h post-dosing in all 60 subjects. Gene expression of p21, HSP70, AKT, Nur77, ERB1, and ERB2 was evaluated in peripheral blood mononuclear cells and tissue samples. Chromatin immunoprecipitation of p21, HSP70, and Nur77 was also performed in biopsy samples. Results: In peripheral blood mononuclear cells, Nur77 was significantly and consistently decreased 2 h after vorinostat administration on both days 1 and 9, median ratio of gene expression relative to baseline of 0.69 with interquartile range 0.49-1.04 ( p < 0.001); 0.28 (0.15-0.7) ( p < 0.001), respectively, with more pronounced decrease on day 9, when patients received both vorinostat and bortezomib. p21, a downstream target of Nur77, was significantly decreased on day 9, 2 and 6 h after administration of vorinostat and bortezomib, 0.67 (0.41-1.03) ( p < 0.01); 0.44 (0.25-1.3) ( p < 0.01), respectively. The ChIP assay demonstrated a protein-DNA interaction, in this case interaction of Nur77, HSP70 and p21 with acetylated histone H3, at baseline and at day 9 after treatment with vorinostat in tissue biopsies in most patients. Conclusion: Vorinostat inhibits Nur77 expression, which in turn may decrease p21 and AKT expression in PBMCs. The influence of vorinostat on target gene expression in tumor tissue was variable; however, most patients demonstrated interaction of acetylated H3 with Nur77, HSP70, and p21 which provides evidence of interaction with the transcriptionally active acetylated H3. [ABSTRACT FROM AUTHOR]

Chemotherapy has yielded minimal clinical benefit in pancreatic and biliary tract cancer. A high-dose, short course capecitabine schedule with oxaliplatin, has shown some efficacy with a lower incidence of palmar-plantar erythrodysesthesia. Achieving high exposures of the targeted agent sorafenib may be possible with this shorter schedule of capecitabine by avoiding dermatologic toxicity. All patients had pancreatic or biliary tract cancer. Patients in both cohorts received oxaliplatin 85 mg/m2 followed by capecitabine 2,250 mg/m2 PO every 8 h x 6 doses starting on days 1 and 15 of a 28 day cycle, or 2DOC (2 Day Oxaliplatin/Capecitabine). Cohort 1 used sorafenib 200 mg BID, and cohort 2 used sorafenib 400 mg BID. Sixteen patients were enrolled. Across all cycles the most common grade 1 or 2 adverse events were fatigue (10 pts), diarrhea (10 pts), nausea (9 pts), vomiting (8 pts), sensory neuropathy (8 pts), thrombocytopenia (7 pts), neutropenia (5 pts), and hand-foot syndrome (5 pts). Grade 3 toxicites included neutropenia, mucositis, fatigue, vomiting and diarrhea. Cohort 1 represented the MTD. Two partial responses were seen, one each in pancreatic and biliary tract cancers. The recommended phase II dose of sorafenib in combination with 2DOC is 200 mg BID. There were infrequent grade 3 toxicities, most evident with sorafenib at 400 mg BID. [ABSTRACT FROM AUTHOR]

This study proposed a path model of relationships among understanding and acceptance of evolution, views on nature of science, and self-efficacy beliefs regarding teaching evolution. A total of 415 pre-service science teachers completed a series of self-report instruments for the specified purpose. After the estimation of scale scores using unidimensional IRT models, path analysis suggested that sophisticated views on NOS were associated with higher levels of both understanding and acceptance of evolution, and the higher level of understanding of evolution was related to the higher level of acceptance of evolution. Besides, higher levels of both understanding and acceptance of the theory and naïve views on NOS were found to be associated with stronger self-efficacy beliefs for teaching evolution effectively. [ABSTRACT FROM AUTHOR]

Objectives: A patient specific nomogram based biological dose selection (NBDS) model may allow for selection of a safe and effective dose schedule to treat early peripheral stage non-small cell lung cancer (NSCLC) with stereotactic body radiotherapy (SBRT). We report the initial clinical outcomes testing these concepts. Methods: 23 patients with stage IA/B NSCLC were treated with SBRT. All patients had a prescription isodose volume/residual lung volume ratio of 2-3%, permitting a wide range of dose fractionation schemes under the NBDS-model that should yield a sufficiently low grade 2 or higher pneumonitis rate that the resultant long-term grade 3 or higher complication rate would be <20%. Based on the predications of the patient specific NBDS-model all patients could be safely treated using a modal prescription of 60 Gy in 5 fractions over 10 calendar days, with a median normalized tissue dose (NTD) of 122.4 Gy10. Kaplan-Meier analysis was performed to assess local control, overall, cause-speciic and disease free survival. Toxicities and response rates were analyzed. Results: Median follow-up was 43.2 months for all living patients. Analysis of 20 evaluable lesions demonstrated a major response rate of 80%. 3 year actuarial overall, cause-specific, and disease free survival, were 60, 79, and 55%, respectively. 3 year actuarial local control was 89%. Grade 2 or higher acute pulmonary toxicity was observed in 5 patients. The 1, 2 and 3-year actuarial incidence of grade 2 or higher pulmonary toxicity was 15, 27 and 27% (95% CI = 5 - 48%), with corresponding grade 3 incidence of 4, 10, and 10%. No grade 3 or higher non-pulmonary side-effects were observed. Conclusions: SBRT using a biological model-based fractionation scheme yields local control and survival rates comparable to other series that treat to higher NTDs; the pulmonary toxicity rate and grades are within the model-predicted parameters, but further follow-up is necessary for long-term validity of the model. [ABSTRACT FROM AUTHOR]

Purpose: To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and tolerability of the 24-h continuous intravenous (CIV) infusion of MK-0457, a novel pan-Aurora kinase inhibitor, in patients with advanced solid tumors and to determine the bioavailability of an oral dose of 100 mg MK-0457. Study design: MK-0457 was administered as a 24-h CIV infusion every 21 days. Dose escalation proceeded per toxicity criteria. A 100-mg oral dose was administered to seven patients 48 h prior to the CIV infusion dose of 64 mg/m/h. Results: Twenty-seven patients received a total of 86 infusions of MK-0457. Dose-limiting toxicity at 96 mg/m/h included grade 4 neutropenia and grade 3 herpes zoster. The MTD was identified as 64 mg/m/h. The most common adverse events were nausea, vomiting, diarrhea, and fatigue. Pharmacokinetic analyses revealed that CIV infusion MK-0457 had an estimated mean terminal half-life of approximately 6.6-10.2 h and that end-of-infusion concentrations and mean AUCs were approximately dose proportional. The estimated mean oral bioavailability of MK-0457 was 7.9%. One patient with advanced ovarian cancer attained prolonged stable disease for 11 months. Conclusions: MK-0457 was well tolerated in this schedule. Almost half the patients attained stable disease. Further development of this class of agents will likely occur in combination with other anti-cancer treatments. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to develop a population pharmacokinetic (PK) model for 3-AP, to evaluate the effect of ABCB1 polymorphisms on the pharmacokinetic profile of 3-AP, and to assess the relationship between 3AP disposition and patient covariates.Methods: A total of 40 patients with advanced cancer from two phase 1 studies were included in the population PK model building. Patients received 3-AP 25-105 mg/m(2) IV on day 1. 3-AP plasma and erythrocyte levels were sampled at 10 timepoints over a 24-h period and measured by a validated HPLC method. Data were analyzed by a nonlinear mixed-effects modeling approach using the NONMEM system.Results: 3-AP pharmacokinetics were described as a 3-compartment model with first-order elimination, with one compartment representing the plasma and another representing erythrocyte concentrations. Gender was associated with volume of distribution, in which women had a lower V2. The number of cycles administered was associated with clearance; those with decreased clearance were more likely to receive less than 2 cycles before going off study.Conclusion: This study suggests that monitoring 3-AP plasma concentrations in the first cycle and dose adjustment in those with decreased clearance may be helpful in decreasing toxicity associated with the 3-AP. [ABSTRACT FROM AUTHOR]

To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics and antitumor activity of Triapine® administered in combination with doxorubicin. Patients were treated with doxorubicin intravenously (IV) on day 1 and Triapine® IV on days 1–4 of a 21-day cycle. The starting dose (level 1) was doxorubicin 60 mg/m2 and Triapine® 25 mg/m2. PK analysis was performed at various time-points before and after treatment. Twenty patients received a total of 49 courses of treatment on study. At dose level 2 (doxorubicin 60 mg/m2, Triapine® 45 mg/m2), two patients experienced DLTs (febrile neutropenia, grade 4 thrombocytopenia). An additional three patients were enrolled at dose level 1 without initial toxicity. Enrollment then resumed at dose level 2a with a decreased dose of doxorubicin (45 mg/m2) with Triapine® 45 mg/m2. The two patients enrolled on this level had two DLTs (diarrhea, CVA). Enrollment was planned to resume at dose level 1; however, the sixth patient enrolled to this cohort developed grade 5 heart failure (ejection fraction 20%, pretreatment EF 62%) after the second course. Thus, doxorubicin and Triapine® were reduced to 45 and 25 mg/m2, respectively (level 1a), prior to resuming enrollment at dose level 1, the MTD. The main drug-related toxicity was myelosuppression. Non-hematologic toxicities included mild-to-moderate fatigue, grade 3 diarrhea and grade 4 CVA. There was one treatment-related death due to heart failure. While no objective responses were observed, subjective evidence of clinical activity was observed in patients with refractory melanoma and prostate cancer. Pretreated patients with advanced malignancies can tolerate the combination of Triapine® and doxorubicin at doses that achieve subjective clinical benefit with the main treatment-related toxicities being myelosuppression and fatigue. The MTD was determined to be doxorubicin 60 mg/m2 on day 1 and Triapine® 25 mg/m2 on days 1–4 of a 21-day cycle. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Estrogen receptor beta (ERβ) has been detected in non-small cell lung cancer (NSCLC) cell lines and tumor specimens. The ER down-regulator, fulvestrant, blocked estradiol-stimulation of tumor growth and gene transcription in NSCLC preclinical models and showed additive effects with the epidermal growth factor receptor (EGFR) inhibitor gefitinib. The safety and tolerability of combination therapy with the EGFR inhibitor, gefitinib, and fulvestrant was explored. Methods: Post-menopausal women with advanced NSCLC received gefitinib 250mgpo daily and fulvestrant 250mgIM monthly. Results: Twenty-two patients were enrolled. Eight patients had adenocarcinoma, six NSCLC-NOS, four squamous cell, and four BAC. Seven patients were never-smokers. Eight patients received ≥2 lines of prior chemotherapy, six received one prior chemotherapy, and eight were treatment-naïve. One patient experienced grade 4 dyspnea possibly related to treatment; all other grade 3/4 toxicities were unrelated to treatment. Twenty patients were evaluable for response: three partial responses (PRs) were confirmed (response rate of 15%, 95% CI: 5–36%). The median progression-free survival (PFS), overall survival (OS), and estimated 1-year OS were 12 weeks (3–112 weeks), 38.5 weeks (7–135 weeks), and 41% (95% CI: 20–62%), respectively. Survival outcomes did not differ by prior lines of therapy. A subset analysis revealed that OS in the eight patients whose tumors exhibited at least 60% ERβ nuclear IHC staining measured 65.5 weeks, while that of the five patients with ERβ staining of less than 60% was 21 weeks. One patient with bronchioalveolar carcinoma (BAC) and a PR had an EGFR L858R mutation in exon 21. There was no correlation between ERβ IHC expression and histology or smoking history. Conclusions: Combination therapy with gefitinib and fulvestrant in this population was well tolerated and demonstrated disease activity. [Copyright &y& Elsevier]

Cognitive abilities are related to job performance. However, there is less agreement about the relative contribution of general versus specific cognitive abilities to job performance. Similarly, it is not clear how cognitive abilities operate in the context of complex occupations. This study assessed the role of cognitive abilities on the performance of three aviation-related jobs: flying, navigation, and air battle management (ABM). Correlated-factor and bifactor models were used to draw a conclusion about the predictive relations between cognitive abilities and job performance. Overall, the importance of particular cognitive abilities tends to vary across the three occupations, and each occupation has different sets of essential abilities. Importantly, the interplay of general versus specific abilities is different across occupations, and some specific abilities also show substantial predictive power. [ABSTRACT FROM AUTHOR]

This meta-analysis explores the effect of using scoring rubrics on self-efficacy and self-regulation in K-16 formal learning settings and its potential moderators. From the literature, we identified 14 relevant experimental or quasi-experimental primary studies conducted with a total of 2793 students. We retrieved 17 effect sizes for self-efficacy and 18 effect sizes for self-regulation outcomes from the primary studies. Rubric use has a statistically significant moderate to large positive effect on students’ self-efficacy (Hedges’ g = 0.39) and self-regulation (Hedges’ g = 1.00). Large within- and -between study variability of effect sizes is common: self-efficacy (Hedges’ g: −.06; 2.47) and self-regulation (Hedges’ g: −1.17; 3.30). We found no significant moderation of the effect of rubric use by students’ level of education, providing feedback, or instruction using the rubric, whereas there is evidence of an effect of rubrics on self-efficacy and self-regulation, variability of theoretical approaches, measures, and implementation quality raise questions about best practices for rubric development and use. [ABSTRACT FROM AUTHOR]

Ablative local treatment of all radiographically detected metastatic sites in patients with oligometastatic non-small cell lung cancer (NSCLC) increases progression-free survival (PFS) and overall survival (OS). Prior studies demonstrated the safety of combining stereotactic body radiation therapy (SBRT) with single-agent immunotherapy. We investigated the safety of combining SBRT to all metastatic tumor sites with dual checkpoint, anticytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4), and anti–programmed cell death ligand 1 (anti-PD-L1) immunotherapy for patients with oligometastatic NSCLC. We conducted a phase 1b clinical trial in patients with oligometastatic NSCLC with up to 6 sites of extracranial metastatic disease. All sites of disease were treated with SBRT to a dose of 30 to 50 Gy in 5 fractions. Dual checkpoint immunotherapy was started 7 days after completion of radiation using anti-CTLA-4 (tremelimumab) and anti-PD-L1 (durvalumab) immunotherapy for a total of 4 cycles followed by durvalumab alone until progression or toxicity. Of the 17 patients enrolled in this study, 15 patients received at least 1 dose of combination immunotherapy per protocol. The study was closed early (17 of planned 21 patients) due to slow accrual during the COVID-19 pandemic. Grade 3+ treatment-related adverse events were observed in 6 patients (40%), of which only one was possibly related to the addition of SBRT to immunotherapy. Median PFS was 42 months and median OS has not yet been reached. Delivering ablative SBRT to all sites of metastatic disease in combination with dual checkpoint immunotherapy did not result in excessive rates of toxicity compared with historical studies of dual checkpoint immunotherapy alone. Although the study was not powered for treatment efficacy results, durable PFS and OS results suggest potential therapeutic benefit compared with immunotherapy or radiation alone in this patient population. [ABSTRACT FROM AUTHOR]

Background/Context: In this article we explore equity issues related to school district decisionmaking about students' opportunities to learn algebra. We chose algebra because of the important role it plays in the U.S. as a gatekeeper to future academic success. Current research has not yet explored issues of equity in district-level decision-making. Purpose/Objective/Research Question/Focus of Study: We examine the extent to which district decision-makers for mathematics attend to aspects of equity when they make decisions about resources related to the teaching and learning of algebra. The research questions guiding this study were: How do district decision-makers for mathematics report considering issues of equity when making decisions about students' opportunities to learn Algebra I? How do district characteristics, particularly students' racial and ethnic diversity, affect the extent of equity considerations by mathematics decision-makers? Research Design: We surveyed a national probability sample of 993 district decision-makers for mathematics about criteria that they consider when they select and distribute resources and structure learning opportunities in algebra for students and teachers in their districts. These survey items were our attempt to identify district-level practices in relationship to an equity framework. In this study, we examine national patterns in criteria for decision-making about algebra resources and examine the relation of these criteria to district features using a structural equation model. Findings: Our findings suggest that fewer decision-makers considered equity-related criteria in their decision-making about algebra, while many tended to endorse equality-related items addressing considerations for all students, such as giving all students the same resources or attending to preparation for standardized testing. The vast majority of decision-makers reported considering real life contexts for algebra when making decisions about professional development (PD) and curriculum, while fewer considered the students' culture or culturally relevant teaching. Decision-makers in only about half of the districts reported considering structural aspects, such as tracking. Modeling of the survey responses indicates that decisionmakers in the most racially or ethnically and linguistically diverse districts have the greatest tendency to consider equity criteria in structuring students' opportunities to learn algebra. Conclusions/Recommendations: The extent to which district decision-makers for mathematics attend to aspects of equity is noteworthy because their decisions inform the selection and distribution of educational resources for learning algebra across districts. These findings raise important concerns with respect to how district decision-making mobilizes and shapes the resources available to teachers and students. Recommendations include supporting district decision-makers in a) expanding their conceptions of real life contexts to include students' culture, b) considering different framings of the problem of participation gaps, c) reconsidering ability grouping and understanding the negative consequences of tracking, and d) carefully examining the kinds of stated and unarticulated rules, rewards, and sanctions that get put into place to uncover how inequitable practices get perpetuated. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy using a checkpoint inhibitor (CPI) alone or in combination with chemotherapy is the standard of care for treatment‐naive patients with advanced non–small cell lung cancer (NSCLC) without driver mutations for which targeted therapies have been approved. It is unknown whether continuing CPI treatment beyond disease progression results in improved outcomes. Methods: Patients who experienced progressive disease (PD) after a clinical benefit from chemotherapy plus a CPI were enrolled. Patients received pembrolizumab (200 mg every 3 weeks) plus next‐line chemotherapy. The primary end point was progression‐free survival (PFS) according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Key secondary end points included the overall survival (OS), clinical benefit rate, and toxicity. The authors' hypothesis was that continuing pembrolizumab beyond progression would improve the median PFS to 6 months in comparison with a historical control of 3 months with single‐agent chemotherapy alone. Results: Between May 2017 and February 2020, 35 patients were enrolled. The patient and disease characteristics were as follows: 51.4% were male; 82.9% were current or former smokers; and 74.3%, 20%, and 5.7% had adenocarcinoma, squamous cell carcinoma, and NSCLC not otherwise specified, respectively. The null hypothesis that the median PFS would be 3 months was rejected (p <.05). The median PFS was 5.1 months (95% confidence interval [CI], 3.6–8.0 months). The median OS was 24.5 months (95% CI, 15.6–30.9 months). The most common treatment‐related adverse events were fatigue (60%), anemia (54.3%), and nausea (42.9%). There were no treatment‐related deaths. Conclusions: Pembrolizumab plus next‐line chemotherapy in patients with advanced NSCLC who experienced PD after a clinical benefit from a CPI was associated with statistically significant higher PFS in comparison with historical controls of single‐agent chemotherapy alone. Pembrolizumab plus next‐line chemotherapy in patients with advanced non–small cell lung cancer who experienced progressive disease after a clinical benefit from a checkpoint inhibitor was associated with statistically significant higher progression‐free survival in comparison with a historical control of single‐agent chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: PF-00337210 is an oral, highly selective vascular endothelial growth factor receptor (VEGFR) inhibitor. We evaluated a composite of biomarkers in real time to identify the recommended phase 2 dose (RP2D) and preliminary anticancer activity of PF-00337210.Patients and Methods: Patients (Pts) with advanced cancers were treated once (QD) or twice daily (BID) with escalating doses. Acute effects on tumor perfusion and vascularity were assessed using DCE-MRI, weekly BP readings, soluble VEGFR-2, and hemoglobin levels.Results: Forty-six pts were treated with 0.67-9 mg QD and 4-6 mg BID of PF-00337210. Nineteen pts (41%) previously received VEGF/VEGFR inhibitors. Two pts had dose-limiting toxicity (DLT) at 9 mg QD (troponin I increase and hypertension). The MTD at QD dose was 8 mg. Common drug-related adverse events were hypertension, fatigue, proteinuria, and nausea. Hypertension incidence and intensity corresponded with dose, but was well controlled with medication. Two confirmed partial responses and minor regressions (>10 to <30% reduction in target lesions) were noted. Complete DCE-MRI was acquired in 21 pts (20 evaluable for vascular response). Ten pts were vascular responders, including 5/6 pts at BID doses. Greatest modulation of soluble VEGFR-2 was at 6 mg BID. The maximum change from baseline in diastolic BP was higher at BID doses. There were no significant differences for systolic BP and hemoglobin levels.Conclusions: PF-00337210 has profound VEGFR inhibition effects at well-tolerated doses. Antitumor activity and VEGF inhibition effects were observed across BID doses. The RP2D was 6 mg BID. [ABSTRACT FROM AUTHOR]

This study examined relations among parents' involvement in students' mathematics homework, mathematics teachers' homework involvement in students' homework, students' mathematics homework disaffection and mathematics achievement outcomes in east-central China using multilevel structural equation modeling where students were treated as the within level and class was treated as the between level. A total of 6100 7th and 8th grader, their parents and 220 mathematics teachers from the Investigation of Curriculum and Instruction in China participated in the study. The results showed that parent homework involvement had a negative relation with student's homework disaffection (γ = −0.120, p <.001), and student's homework disaffection had a negative relation with student mathematics achievement outcomes (γ = −0.060, p =.002), while parent homework involvement had a small positive indirect relation with student mathematics achievement outcomes through student's homework disaffection (γ = 0.007, p =.006). Types of homework that the teacher assigned, the grading method, and the consistency between homework and class content also were associated with student's homework disaffection. The implications of the study were discussed. • Parent homework involvement has a negative relation with student's homework disaffection. • Student's homework disaffection has a negative relation with student mathematics achievement. • Parent homework involvement has a small positive indirect relation with student mathematics achievement. • Homework consistency, homework types, and grading method are associated with student's homework disaffection. [ABSTRACT FROM AUTHOR]

Background: Adjuvant chemotherapy for resected early-stage non-small-cell lung cancer (NSCLC) provides a modest survival benefit. Bevacizumab, a monoclonal antibody directed against VEGF, improves outcomes when added to platinum-based chemotherapy in advanced-stage non-squamous NSCLC. We aimed to evaluate the addition of bevacizumab to adjuvant chemotherapy in early-stage resected NSCLC.Methods: We did an open-label, randomised, phase 3 trial of adult patients (aged ≥18 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and who had completely resected stage IB (≥4 cm) to IIIA (defined by the American Joint Committee on Cancer 6th edition) NSCLC. We enrolled patients from across the US National Clinical Trials Network, including patients from the Eastern Cooperative Oncology Group-American College of Radiology Imaging Network (ECOG-ACRIN) affiliates in Europe and from the Canadian Cancer Trials Group, within 6-12 weeks of surgery. The chemotherapy regimen for each patient was selected before randomisation and administered intravenously; it consisted of four 21-day cycles of cisplatin (75 mg/m2 on day 1 in all regimens) in combination with investigator's choice of vinorelbine (30 mg/m2 on days 1 and 8), docetaxel (75 mg/m2 on day 1), gemcitabine (1200 mg/m2 on days 1 and 8), or pemetrexed (500 mg/m2 on day 1). Patients in the bevacizumab group received bevacizumab 15 mg/kg intravenously every 21 days starting with cycle 1 of chemotherapy and continuing for 1 year. We randomly allocated patients (1:1) to group A (chemotherapy alone) or group B (chemotherapy plus bevacizumab), centrally, using permuted blocks sizes and stratified by chemotherapy regimen, stage of disease, histology, and sex. No one was masked to treatment assignment, except the Data Safety and Monitoring Committee. The primary endpoint was overall survival, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00324805.Findings: Between June 1, 2007, and Sept 20, 2013, 1501 patients were enrolled and randomly assigned to the two treatment groups: 749 to group A (chemotherapy alone) and 752 to group B (chemotherapy plus bevacizumab). 383 (26%) of 1458 patients (with complete staging information) had stage IB, 636 (44%) had stage II, and 439 (30%) had stage IIIA disease (stage of disease data were missing for 43 patients). Squamous cell histology was reported for 422 (28%) of 1501 patients. All four cisplatin-based chemotherapy regimens were used: 377 (25%) patients received vinorelbine, 343 (23%) received docetaxel, 283 (19%) received gemcitabine, and 497 (33%) received pemetrexed. At a median follow-up of 50·3 months (IQR 32·9-68·0), the estimated median overall survival in group A has not been reached, and in group B was 85·8 months (95% CI 74·9 to not reached); hazard ratio (group B vs group A) 0·99 (95% CI 0·82-1·19; p=0·90). Grade 3-5 toxicities of note (all attributions) that were reported more frequently in group B (the bevacizumab group) than in group A (chemotherapy alone) were overall worst grade (ie, all grade 3-5 toxicities; 496 [67%] of 738 in group A vs 610 [83%] of 735 in group B), hypertension (60 [8%] vs 219 [30%]), and neutropenia (241 [33%] vs 275 [37%]). The number of deaths on treatment did not differ between the groups (15 deaths in group A vs 19 in group B). Of these deaths, three in group A and ten in group B were considered at least possibly related to treatment.Interpretation: Addition of bevacizumab to adjuvant chemotherapy did not improve overall survival for patients with surgically resected early-stage NSCLC. Bevacizumab does not have a role in this setting and should not be considered as an adjuvant therapy for patients with resected early-stage NSCLC.Funding: National Cancer Institute of the National Institutes of Health. [ABSTRACT FROM AUTHOR]

Bendamustine + rituximab ( BR) has demonstrated high response rates in relapsed/refractory (R/R) chronic lymphocytic leukaemia ( CLL) and small lymphocytic lymphoma ( SLL). However, progression-free survival ( PFS) after BR is <18 months. This study was designed to determine if maintenance lenalidomide after BR induction could improve PFS in R/R CLL/ SLL. Thirty-four patients with R/R CLL/ SLL who had received 1-5 prior chemotherapy regimens were treated with 6 cycles of BR induction. Patients achieving at least a minor response received twelve 28-d cycles of lenalidomide 5-10 mg/d. The primary endpoint was PFS. The median age was 67 years, with a median of 2 prior therapies. Eleven patients had confirmed presence of 17p and/or 11q deletions. Twenty-five (74%) completed 6 cycles of induction BR (response rate 56%). Nineteen (56%) patients received maintenance lenalidomide; only 6 patients completed the intended 12 cycles, highlighting the limited feasibility of lenalidomide in this setting, primarily due to haematological and infectious toxicities. The observed median PFS of 18·3 months is not significantly different from that of BR induction in R/R CLL/ SLL without maintenance therapy (15·2 months). It is possible that lenalidomide maintenance may be more feasible and effective in the front-line setting, which is being tested in an ongoing trial ( NCT01754857). [ABSTRACT FROM AUTHOR]

Background: Proteasome inhibitors and mammalian target of rapamycin inhibitors each have activity in various B-cell malignancies and affect distinct cellular pathways. Their combination has demonstrated synergy in vitro and in mouse models.Methods: The authors conducted a single-arm, phase 2 trial of combined temsirolimus and bortezomib in patients with relapsed and refractory B-cell non-Hodgkin lymphoma (NHL) using a dosing scheme that was previously tested in multiple myeloma. The patients received bortezomib and temsirolimus weekly on days 1, 8, 15, and 22 of a 35-day cycle.Results: Of 39 patients who received treatment, 3 achieved a complete response (7.7%; 95% confidence interval [CI], 1.6%-21%), and 9 had a partial response (PR) (23%; 95% CI, 11%-39%). Thus, the overall response rate (12 of 39 patients) was 31% (95% CI, 17%-48%), and the median progression-free survival was 4.7 months (95% CI, 2.1-7.8 months; 2 months for patients with diffuse large B-cell lymphoma [n = 18], 7.5 months for those with mantle cell lymphoma [n = 7], and 16.5 months for those with follicular lymphoma [n = 9]). Two extensively treated patients with diffuse large B-cell lymphoma achieved a complete response. There were no unexpected toxicities from the combination.Conclusions: The current results demonstrate that the combination of a mammalian target of rapamycin inhibitor and a proteasome inhibitor is safe and has activity in patients with heavily pretreated B-cell NHL. Further studies with this combination are warranted in specific subtypes of NHL. [ABSTRACT FROM AUTHOR]

Purpose: Fluoropyrimidines and oxaliplatin have demonstrated some efficacy against pancreatic adenocarcinoma, but survival remains brief. Sorafenib is an oral multikinase inhibitor which we sought to combine with a unique capecitabine and oxaliplatin regimen for pancreatic adenocarcinoma. Methods: We performed a multicenter phase II study of sorafenib 200 mg orally twice daily along with oxaliplatin 85 mg/m IV on days 1 and 15, followed by capecitabine 2250 mg/m orally every 8 h for six doses starting on days 1 and 15 of a 28-day cycle in patients who had no more than one previous chemotherapy regimen for their pancreatic adenocarcinoma. The primary objective was response rate; secondary objectives were progression-free survival (PFS), overall survival (OS), and safety. Results: Twenty-four patients were enrolled; median age was 63 years (range 48-83). The most common related toxicities were fatigue, neuropathy, anemia, thrombocytopenia, diarrhea, nausea, leukopenia, and hand-foot syndrome. Grade 3 hand-foot syndrome was rare (4 %). Other grade 4 toxicities included abdominal pain (8 %), pulmonary embolism (4 %), and anemia (4 %). Three partial responses were seen (13 %), and 11 patients had stable disease (46 %) as their best response. Median PFS was 6.0 months (range 1.5-13 months). Median OS was 8.1 months (range 1.5-13.6 months). Conclusions: Sorafenib, oxaliplatin, and capecitabine produced partial responses in patients with advanced pancreatic cancer including previously treated patients and demonstrated a PFS of 6 months with few grade 3/4 toxicities. [ABSTRACT FROM AUTHOR]

Abstract: Background: The purpose of this systematic review was to summarize previously published case reports of primary lung carcinoma metastasis to the breast to assess common clinical and pathologic features and management strategies. Materials and methods: Case reports describing breast metastasis of primary lung carcinoma were systematically evaluated in MEDLINE and EMBASE. Results: Thirty-one reported cases of non-small-cell lung carcinoma (NSCLC) metastasized to the breast were identified, along with eight cases of small-cell lung carcinoma. Sixty-seven percent of reported NSCLC metastases to the breast were detected metachronously with the primary lung abnormality, whereas 80% of small-cell lung carcinoma breast metastases appeared synchronously. Thyroid transcription factor 1 was found to be expressed in 58% of total NSCLC breast metastases, including 83% of those of adenocarcinoma origin. Therapeutic strategies among NSCLC cases varied widely, and only 36% of NSCLC breast metastasis patients were administered chemotherapy. Additional sites of metastasis in these cases are summarized as well. Conclusions: It is recommended to include metastatic lung cancer in the differential diagnosis of patients presenting with a breast abnormality in the context of a suspected lung cancer. Thyroid transcription factor 1 expression should be examined in these cases. The metachronous versus synchronous nature of lung carcinoma metastasis to the breast has consequences for both detection of the primary and secondary lesions and patient outlook. Clinical correlation is vital to effective management of the care of patients harboring these atypical secondary lesions. [Copyright &y& Elsevier]