Inconsistent flanker congruency effects across stimulus types and age groups: A cautionary tale.

The flanker task is a common measure of selective attention and response competition across populations, age groups, and experiential contexts. Adapting it for different uses often involves changing methodological features that are rarely empirically compared with the previous design. This paper presents an example of how typical methodological changes can differentially elicit congruency effects across age groups. We compared two flanker tasks, using direction stimuli on a laptop versus color stimuli on a tablet, in young children (2-7 years; Experiment 1), older children (6-10 years; Experiment 2a), and adults (19-23 years; Experiment 2b). Young children showed the expected congruency effects in the direction task, and one year later a subset of the sample completed the color task, also showing congruency effects. Longitudinal comparisons showed no difference in the congruency effect across tasks, but nearly half of the sample was excluded due to high error rates. To avoid excluding children with few correct trials, we modified a new measure, signed residual time, to incorporate correctness and reaction time per trial. With the larger sample, this measure showed no difference in congruency effects across tasks. To compare these tasks when completed within the same session, we tested older children and young adults in both tasks and found congruency effects in the direction task but not the color task. These results raise concern that tasks adapted for young children may not perform comparably in other samples, and we caution researchers to anticipate this possibility when modifying cognitive tasks.

A Phase 1 Dose-Escalation Trial of Radiation Therapy and Concurrent Cisplatin for Stage II and III Triple-Negative Breast Cancer.

PURPOSE: Patients with triple-negative breast cancer (TNBC) experience higher local-regional recurrence rates than those with luminal or HER2-positive tumors. This prospective, phase 1B trial was designed to assess the safety and to establish the maximum tolerated dose (MTD) of cisplatin with radiation therapy for women with early-stage TNBC. METHODS AND MATERIALS: Eligible patients had stage II or III TNBC. Cisplatin was initiated at 10 mg/m2 intravenously once weekly during radiation and then escalated in a 3 + 3 design by 10 mg/m2 at each dose level until 40 mg/m2, or the MTD, was reached. Patients undergoing breast-conserving therapy (BCT) or mastectomy were accrued in separate parallel cohorts during dose escalation, followed by a 10-patient expansion at the MTD. RESULTS: During 2013 to 2018, 55 patients were accrued. Four patients developed dose-limiting toxicity. In the BCT cohort, 1 patient receiving 40 mg/m2 developed tinnitus resulting in a cisplatin delay; therefore, this was the BCT cohort MTD. In the mastectomy cohort, 1 patient receiving 20 mg/m2 developed a grade 3 urinary infection, and 2 additional patients had dose-limiting toxicities at 40 mg/m2 (grade 3 neutropenia and grade 2 tinnitus), both resulting in cisplatin delay. Thus, 30 mg/m2 was the mastectomy cohort MTD. Median follow-up was 48.5 months. Three-year disease-free survival was 74.7% for the BCT cohort and 64.4% for the mastectomy cohort. CONCLUSIONS: Adjuvant radiation therapy with concurrent cisplatin is feasible with a recommended phase 2 dose of 30 mg/m2 and 40 mg/m2 intravenously weekly in mastectomy and BCT cohorts, respectively.

Effect of Eribulin With or Without Pembrolizumab on Progression-Free Survival for Patients With Hormone Receptor-Positive, ERBB2-Negative Metastatic Breast Cancer: A Randomized Clinical Trial.

Importance: Prior studies have shown that only a small proportion of patients with hormone receptor (HR)-positive metastatic breast cancer (MBC) experience benefit from programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) inhibitors given as monotherapy. There are data suggesting that activity may be greater with combination strategies. Objective: To compare the efficacy of eribulin plus pembrolizumab vs eribulin alone in patients with HR-positive, ERBB2 (formerly HER2)-negative MBC. Design, Setting, and Participants: Multicenter phase 2 randomized clinical trial of patients with HR-positive, ERBB2-negative MBC who had received 2 or more lines of hormonal therapy and 0 to 2 lines of chemotherapy. Interventions: Patients were randomized 1:1 to eribulin, 1.4 mg/m2 intravenously, on days 1 and 8 plus pembrolizumab, 200 mg/m2 intravenously, on day 1 of a 21-day cycle or eribulin alone. At time of progression, patients in the eribulin monotherapy arm could cross over and receive pembrolizumab monotherapy. Main Outcomes and Measures: The primary end point was progression-free survival (PFS). Secondary end points were objective response rate (ORR) and overall survival (OS). Exploratory analyses assessed the association between PFS and PD-L1 status, tumor-infiltrating lymphocytes (TILs), tumor mutational burden (TMB), and genomic alterations. Results: Eighty-eight patients started protocol therapy; the median (range) age was 57 (30-76) years, median (range) number of prior lines of chemotherapy was 1 (0-2), and median (range) number of prior lines of hormonal therapy was 2 (0-5). Median follow-up was 10.5 (95% CI, 0.4-22.8) months. Median PFS and ORR were not different between the 2 groups (PFS, 4.1 vs 4.2 months; hazard ratio, 0.80; 95% CI, 0.50-1.26; P = .33; ORR, 27% vs 34%, respectively; P = .49). Fourteen patients started crossover treatment with pembrolizumab; 1 patient experienced stable disease. All-cause adverse events occurred in all patients (grade ≥3, 65%) including 2 treatment-related deaths in the combination group, both from immune-related colitis in the setting of sepsis, attributed to both drugs. The PD-L1 22C3 assay was performed on archival tumor samples in 65 patients: 24 (37%) had PD-L1-positive tumors. Analysis indicated that PD-L1 status, TILs, TMB, and genomic alterations were not associated with PFS. Conclusions and Relevance: In this randomized clinical trial of patients with HR-positive, ERBB2-negative MBC, the addition of pembrolizumab to eribulin did not improve PFS, ORR, or OS compared with eribulin alone in either the intention-to-treat or PD-L1-positive populations. Further efforts to explore the benefits of adding checkpoint inhibition to chemotherapy among less heavily pretreated patients are needed. Trial Registration: ClinicalTrials.gov Identifier: NCT03051659.

Speech and Gesture Production Provide Unique Insights Into Young Children's Spatial Reasoning.

This study took a novel approach to understanding the role of language in spatial development by combining approaches from spatial language and gesture research. It analyzed forty-three 4.5- to 6-year-old's speech and gesture production during explanations of reasoning behind performance on Spatial Analogies and Children's Mental Transformation Tasks. Results showed that speech and gesture relevant for solving the trials (disambiguating correct choices) predicted spatial performance when controlling for age, gender, and spatial words and gestures produced. Children performed the spatial tasks well if they produced relevant information either verbally through speech or nonverbally through gesture. These results highlight the importance of not only focusing on concepts children can reference but also on how such concepts are used in spatial tasks.

A Phase II Study of Pembrolizumab in Combination With Palliative Radiotherapy for Hormone Receptor-positive Metastatic Breast Cancer.

BACKGROUND: The purpose of this study was to investigate whether combining pembrolizumab with palliative radiation therapy (RT) improves outcomes in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). PATIENTS AND METHODS: Eligible patients had HR+/human epidermal growth factor receptor 2-negative MBC; were candidates for RT to ≥ 1 bone, soft tissue, or lymph node lesion; and had ≥ 1 lesion outside the RT field. Patients received 200 mg pembrolizumab intravenously 2 to 7 days prior to RT and on day 1 of repeating 21-day cycles. RT was delivered to a previously unirradiated area in 5 treatments each of 4 Gy. The primary endpoint was objective response rate. The study used a 2-stage design: 8 women were enrolled into the first stage, and if at least 1 of 8 patients experienced an objective response, 19 more would be enrolled. Secondary endpoints included progression-free survival, overall survival, and safety. Exploratory endpoints included association of overall response rate with programmed death-ligand 1 status and tumor-infiltrating lymphocytes. RESULTS: Eight patients were enrolled in stage 1. The median age was 59 years, and the median prior lines of chemotherapy for metastatic disease was 2. There were no objective responses, and the study was closed to further accrual. The median progression-free survival was 1.4 months (95% confidence interval, 0.4-2.1 months), and the median overall survival was 2.9 months (95% confidence interval, 0.9-3.6 months). All-cause adverse events occurred in 87.5% of patients, including just 1 grade 3 event (elevation of aspartate aminotransferase). CONCLUSIONS: RT combined with pembrolizumab did not produce an objective response in patients with heavily pre-treated HR+ MBC. Future studies should consider alternative radiation dosing and fractionation in patients with less heavily pre-treated HR+ MBC.

Ribociclib Plus Trastuzumab in Advanced HER2-Positive Breast Cancer: Results of a Phase 1b/2 Trial.

BACKGROUND: Signaling through the cyclin-dependent kinase 4 and 6 (CDK4/6) pathway can mediate therapeutic resistance in HER2-positive breast cancer. Preclinical studies have demonstrated that CDK4/6 inhibitors can resensitize resistant HER2-positive breast cancer to anti-HER2 therapies. PATIENTS AND METHODS: We conducted a phase 1b/2 study of ribociclib (400 mg per day on a continuous schedule) plus trastuzumab (6 mg/kg every 3 weeks) in patients with advanced HER2-positive breast cancer previously treated with trastuzumab, pertuzumab, and trastuzumab emtansine. There were no restrictions on the number of prior therapy lines. Primary objective was clinical benefit rate at 24 weeks, and secondary objectives included safety, objective response, rate and progression-free survival. The study was enrolled at ClinicalTrials.gov as NCT02657343. RESULTS: From March 2016 to March 2017, 13 patients were enrolled. One patient was found to have HER2-negative disease and did not receive treatment. Median number of prior lines in the metastatic setting was 5 (range, 0-14); 67% had hormone receptor-positive disease. No dose-limiting toxicities were observed during the safety run-in phase, and ribociclib was thus dosed at 400 mg per day continuously for the expansion cohort. Grade 3 adverse events were observed in 4 patients (33.3%) and included neutropenia (n = 2) as well as fatigue and pain in 1 patient each. No grade 4/5 adverse events or QTc prolongation were observed. One patient (8.3%) experienced stable disease > 24 weeks; no objective responses were observed, and median progression-free survival was 1.33 months (95% confidence interval, 0.92-2.57). CONCLUSION: Continuous low-dose ribociclib (400 mg) plus trastuzumab is safe, with no new safety concerns. The limited activity observed in this study suggests that further study of CDK4/6 inhibitor/anti-HER2 combinations should focus on a less pretreated population.

The Impact of High-Dose Glucocorticoids on the Outcome of Immune-Checkpoint Inhibitor-Related Thyroid Disorders.

Thyroid disorders have emerged as one of the most common immune-related adverse events (irAE), yet optimum management and biomarkers to predict vulnerable individuals remain to be explored. High-dose glucocorticoid (HDG) therapy is routinely recommended for irAEs. However, systematic analysis of the impact of glucocorticoid therapy on the outcome of immune-checkpoint inhibitor (ICI)-induced thyroid disorders is lacking. We analyzed 151 patients with or without ICI-related thyroid disorders. We divided the patients with ICI-related thyroid disorders into two subgroups: those with and without HDG treatment. Our results showed no significant differences between HDG and no HDG groups in terms of the median duration of thyrotoxicosis: 28 (range, 7-85) and 42 (range, 14-273) days, the median time to conversion from thyrotoxicosis to hypothyroidism: 39 days (range, 14-169) and 42 days (range, 14-315) days, the median time to onset of hypothyroidism: 63 (range, 21-190) and 63 (range, 14-489) days, and the median maintenance dose of levothyroxine: 1.5 (range, 0.4-2.3) µg/kg/day, and 1.3 (range, 0.3-2.5) µg/kg/day. The median pretreatment TSH was 2.3 (range, 0.3-5.2) mIU/L and 1.7 (range, 0.5-4.5) mIU/L in patients with and without ICI-related thyroid disorders, respectively. Baseline TSH was significantly higher in patients who developed ICI-related thyroid disorders (P = 0.05). Subgroup analysis revealed significantly higher baseline TSH in male but not in female patients with ICI-induced thyroid dysfunction. Our results show that HDG treatment did not improve the outcome of ICI-related thyroid disorders.