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Background Preserving health-related quality of life (HRQOL) is an important goal during renal cell carcinoma treatment. We report HRQOL outcomes from a phase II trial (NCT03173560). Patients and Methods HRQOL data were collected during a multicenter, randomized, open-label phase II study comparing the safety and efficacy of 2 different starting doses of lenvatinib (18 mg vs. 14 mg daily) in combination with everolimus (5 mg daily), following one prior vascular endothelial growth factor–targeted treatment. HRQOL was measured using 3 different instruments—FKSI-DRS, EORTC QLQ-C30, and EQ-5D-3L—which were all secondary endpoints. Change from baseline was assessed using linear mixed-effects models. Deterioration events for time to deterioration (TTD) analyses were defined using established thresholds for minimally important differences in the change from baseline for each scale. TTD for each treatment arm was estimated using the Kaplan–Meier method. Results Baseline characteristics of the 343 participants randomly assigned to 18 mg lenvatinib (n = 171) and 14 mg lenvatinib (n = 172) were well balanced. Least-squares mean estimates for change from baseline were favorable for the 18 mg group over the 14 mg group for the FKSI-DRS and most EORTC QLQ-C30 scales, but differences between treatments did not exceed the minimally important thresholds. Median TTD was longer among participants in the 18 mg group than those in the 14 mg group for most scales. Conclusions Participants who received an 18 mg lenvatinib starting dose had favorable HRQOL scores and longer TTD on most scales compared with those who received a 14 mg starting dose.

Background: Lenvatinib (18 mg) plus everolimus (5 mg) is approved for patients with advanced renal cell carcinoma (RCC) after one or more prior antiangiogenic therapies. Objective: To assess whether a lower starting dose of lenvatinib has comparable efficacy with improved tolerability for patients with advanced RCC treated with lenvatinib plus everolimus. Design, setting, and participants: A randomized, open-label, phase 2 global trial was conducted in patients with advanced clear cell RCC and disease progression after one prior vascular endothelial growth factor–targeted therapy (prior anti–programmed death-1/programmed death ligand-1 therapy permitted). Intervention: Patients were randomly assigned 1:1 to the 14- or 18-mg lenvatinib starting dose, both in combination with everolimus 5 mg/d. Patients in the 14-mg arm were to be uptitrated to lenvatinib 18 mg at cycle 2, day 1, barring intolerable grade 2 or any grade ≥3 treatment-emergent adverse events (TEAEs) requiring dose reduction occurring in the first 28-d cycle. Outcome measurements and statistical analysis: The primary efficacy endpoint was investigator-assessed objective response rate (ORR) as of week 24 (ORRwk24); the noninferiority threshold of the 14- versus 18-mg arm was p ≤ 0.045. The primary safety endpoint was the proportion of patients with intolerable grade 2 or any grade ≥3 TEAEs within 24 wk of randomization. Results and limitations: The ORRwk24 for the 14-mg arm (32% [95% confidence interval {CI} 25–39]) was not noninferior to the ORRwk24 in the 18-mg arm (35% [95% CI 27–42]; odds ratio: 0.88; 90% CI 0.59–1.32; p = 0.3). The proportion of intolerable grade 2 or any grade ≥3 TEAEs was similar between the two arms (14 mg, 83% vs 18 mg, 80%; p = 0.5). The secondary endpoints of overall ORR, progression-free survival, and overall survival numerically favored the 18-mg arm. A limitation of this study was that the study design did not allow for a full comparison of progression-free survival between treatment arms. Conclusions: The study findings support the approved dosing regimen of lenvatinib 18 mg plus everolimus 5 mg daily for patients with advanced RCC. Patient summary: In this report, we examined two doses of lenvatinib (the approved 18-mg dose and a lower dose of 14 mg) in people with advanced renal cell carcinoma to determine whether the lower dose (which was increased to the approved 18-mg dose after the first treatment cycle) could improve safety without affecting efficacy. The results showed that the efficacy of the lower lenvatinib dose (14 mg) was not the same as that of the approved (18 mg) dose, although safety results were similar, so the approved lenvatinib 18-mg dose should still be used. publishedVersion

[No Abstract Available], Merck Sharp Dohme Corp.; Eisai Inc., Woodcliff Lake, NJ, USA, Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA and Eisai Inc., Woodcliff Lake, NJ, USA.

This study examined the impact of restricting Calculus 1 and Business Calculus classes based upon whether students had prior calculus experience. We compared the performance and experience of students in sections comprised entirely of those who had previously taken calculus, those who had not previously taken calculus, and those in traditional mixed population sections. No dramatic differences in performance emerged between the mixed and restricted populations; students with prior calculus experience outperformed students without previous experience by similar margins in both settings. However, working with the restricted populations indicated that the two groups have very different needs, which are not always evident in mixed settings. This study did not offer differentiated instruction or assignments to the two populations. Although our study showed no statistical differences between the settings, our experience suggests both student populations could be better served by a course targeting stude...

Rationale and objectives Alpha-1 antitrypsin deficiency (AATD) is a genetic condition that leads to an increased risk of emphysema and liver disease. Despite extensive investigation, there remain unanswered questions concerning the natural history, pathophysiology, genetics and the prognosis of the lung disease in association with AATD. The European Alpha-1 Clinical Research Collaboration (EARCO) is designed to bring together researchers from European countries and to create a standardised database for the follow-up of patients with AATD. Study design and population The EARCO Registry is a non-interventional, multicentre, pan-European, longitudinal observational cohort study enrolling patients with AATD. Data will be collected prospectively without interference/modification of patient's management by the study team. The major inclusion criterion is diagnosed severe AATD, defined by an AAT serum level, The EARCO Registry is a non-interventional, multicentre, pan-European, longitudinal observational cohort study enrolling patients with AATD to elucidate the natural history, pathophysiology, genetics and prognosis of this condition http://bit.ly/369ScCc

Alpha-1 antitrypsin deficiency (AATD) is one of the most frequent rare diseases in Europe and may result in serious lung disease and/or liver disease in adults. People with this condition have a much lower level than normal of the protective protein alpha-1 antitrypsin (AAT) in their blood. AAT protects the body from a powerful enzyme called neutrophil elastase. AATD is an inherited condition that is caused by mutations in the SERPINA1 gene, which can lead to a shortage of AAT or an abnormal form of the protein that cannot control neutrophil elastase. The SERPINA1 gene has more than 100 variants, coded for by two alleles (different versions of the same gene). PiMM is the normal allele, while PiMZ has one normal and one defective allele and PiZZ is the most common allele that causes AATD. The signs and symptoms of the condition and the age at which they appear vary significantly among individuals. The heterogeneity of the clinical picture of AATD depends on a variety of genetic and external aspects. Environmental factors, such as exposure to tobacco smoke, chemicals and dust, probably impact the severity of AATD-associated lung disease., Three people with alpha-1 antitrypsin deficiency (AATD) share their experiences of living with this rare, genetic condition. They reflect on living with AATD and its impact on their lives including inequality of access to treatment across Europe. https://bit.ly/3rrYS9s

307 Background: LEN 18 mg + EVE 5 mg is approved for advanced RCC following anti-angiogenic therapy. Study 218 was a phase II study evaluating LEN 14 mg vs LEN 18 mg, both in combination with EVE 5 mg, for the treatment of clear cell RCC following treatment with a VEGF-targeted therapy. We have previously reported that the LEN 14 mg arm did not demonstrate noninferiority vs the LEN 18 mg arm for objective response rate (ORR) as of wk 24 by investigator assessment, the primary endpoint of the study. In this exploratory analysis of Study 218 data, we evaluated the efficacy of LEN 14 mg vs LEN 18 mg, both in combination with EVE 5 mg, per IIR assessment and by prior ICI status per investigator assessment. Methods: Pts with measurable clear cell RCC (1 prior VEGF-targeted therapy; prior PD-1/PD-L1 therapy permitted) were randomly assigned 1:1 to LEN 14 mg or 18 mg (starting dose) + EVE 5 mg daily. 115 pts in the LEN 14 mg arm were titrated to LEN 18 mg at cycle 2 as they did not experience intolerable grade 2 or any grade ≥3 TEAEs requiring dose reduction within cycle 1. We analyzed ORR and PFS by IIR per RECIST v1.1; additionally, efficacy endpoints (ORR, PFS, and OS) were analyzed by investigator assessment per RECIST v1.1 by prior ICI status. Results: 311 pts (LEN 14 mg arm, n=156; LEN 18 mg arm, n=155) were included in the efficacy analysis and 341 pts (LEN 14 mg arm, n=173; LEN 18 mg arm, n=168) were included in the summary safety analysis. ORR by IIR (LEN 14 mg arm: 39.7%, 95% CI 32.1–47.4; LEN 18 mg arm: 38.7%, 95% CI 31.0–46.4) was similar between treatment arms. PFS by IIR was numerically longer in the LEN 18 mg arm (median 12.9 mos, 95% CI 9.2–17.1) vs the LEN 14 mg arm (median 11.0 mos, 95% CI 9.3–12.9). OS was numerically longer in the LEN 18 mg arm (median not evaluable [NE], 95% CI 23.8–NE) vs the LEN 14 mg arm (median 27.0 mos, 95% CI 18.3-NE) (previously reported). In 82 pts with prior ICI, for the LEN 14 mg (n=43) vs 18 mg (n=39) arms (95% CI): ORR was 30.2% (17.2–46.1) vs 51.3% (34.8–67.6) by investigator assessment, respectively; median PFS was 12.0 mos (8.9–16.7) vs 12.9 mos (8.4–NE) by investigator assessment, respectively; and median OS was 17.1 mos (10.6–NE) vs 18.0 mos (13.1–NE), respectively. Endpoints were generally numerically improved in the LEN 18 mg arm in pts without prior ICI (data will be presented). As previously reported, the safety profile was similar in both treatment arms: 71.7% of pts in the LEN 14 mg arm and 76.8% of pts in the LEN 18 mg arm had grade 3/4 TEAEs. Conclusions: ORR was similar between treatment arms and PFS was numerically longer in the LEN 18 mg arm per IIR. Efficacy outcomes were generally numerically improved for the LEN 18 mg arm compared with the LEN 14 mg arm, regardless of prior ICI. As previously reported, safety was similar in both treatment arms. These results further support starting pts with RCC at the higher 18 mg dose of LEN + EVE 5 mg. Clinical trial information: NCT03173560 .

314 Background: Renal cell carcinoma (RCC) is the most common type of kidney cancer, constituting 80% to 85% of primary renal neoplasms. Preserving health-related quality of life (HRQOL) is an important goal during RCC treatment, but HRQOL analyses in prospective clinical trials in RCC are limited. We report changes in HRQOL, a secondary endpoint of this phase II trial. Methods: HRQOL data were collected during a multicenter, randomized, open-label phase II study comparing the safety and efficacy of two different starting doses of lenvatinib (18 mg vs. 14 mg daily [QD]) in combination with everolimus (5 mg QD), following one prior vascular endothelial growth factor–targeted treatment (NCT03173560). HRQOL was measured using three different instruments, including the FKSI-DRS, EORTC QLQ-C30, and EQ-5D-3L. Change from baseline HRQOL was assessed using linear mixed-effects models. Deterioration events for time to deterioration (TTD) analyses were defined using established thresholds for minimally important differences in the change from baseline for each scale (i.e., 10 points for EORTC, 3 points for FKSI-DRS, 0.08 points for EQ-5D index, and 10 points for EQ-VAS). The distribution of TTD and median TTD for each treatment arm were estimated using the Kaplan-Meier method. Results: Baseline characteristics, including baseline scores of the 343 participants randomly assigned to 14 mg QD lenvatinib (n = 172) and 18 mg QD lenvatinib (n = 171), were well balanced. The average scores for the 18 mg QD group were generally higher, with lower symptom severity than the 14 mg QD group. The least squares mean estimates for change from baseline were favorable for the 18 mg QD group over the 14 mg QD group for the FKSI-DRS and most EORTC QLQ-C30 scales; however, the differences between treatments did not exceed the minimally important difference for clinical significance. Both study arms showed an increase diarrhea severity. Median TTD was longer among participants in the 18 mg QD group than those in the 14 mg QD group for most scales. Conclusions: In most scales, participants who received an 18 mg QD lenvatinib starting dose had better HRQOL and longer time to deterioration than those who received a 14 mg QD starting dose. These findings suggest that the approved treatment regimen of an 18 mg starting dose of lenvatinib in combination with everolimus remains favorable for RCC treatment, following one prior vascular endothelial growth factor–targeted treatment. Clinical trial information: NCT03173560 .

Our study compared a flipped class with a standard lecture class in four introductory courses: finite mathematics, precalculus, business calculus, and calculus 1. The flipped sections watched video lectures outside of class and spent time in class actively working on problems. The traditional sections had lectures in class and did homework outside of class. No statistical difference was found in test scores of the students, though qualitative data indicated potential problems with implementing the flipped pedagogy. Specifically, many students had negative opinions of the flipped model, and attitudes toward math in general tended to decline, comparatively, for students in the flipped class.