Noninvasive Prenatal Diagnosis of Fetal Trisomy 18 and Trisomy 13 by Maternal Plasma DNA Sequencing

Massively parallel sequencing of DNA molecules in the plasma of pregnant women has been shown to allow accurate and noninvasive prenatal detection of fetal trisomy 21. However, whether the sequencing approach is as accurate for the noninvasive prenatal diagnosis of trisomy 13 and 18 is unclear due to the lack of data from a large sample set. We studied 392 pregnancies, among which 25 involved a trisomy 13 fetus and 37 involved a trisomy 18 fetus, by massively parallel sequencing. By using our previously reported standard z-score approach, we demonstrated that this approach could identify 36.0% and 73.0% of trisomy 13 and 18 at specificities of 92.4% and 97.2%, respectively. We aimed to improve the detection of trisomy 13 and 18 by using a non-repeat-masked reference human genome instead of a repeat-masked one to increase the number of aligned sequence reads for each sample. We then applied a bioinformatics approach to correct GC content bias in the sequencing data. With these measures, we detected all (25 out of 25) trisomy 13 fetuses at a specificity of 98.9% (261 out of 264 non-trisomy 13 cases), and 91.9% (34 out of 37) of the trisomy 18 fetuses at 98.0% specificity (247 out of 252 non-trisomy 18 cases). These data indicate that with appropriate bioinformatics analysis, noninvasive prenatal diagnosis of trisomy 13 and trisomy 18 by maternal plasma DNA sequencing is achievable

Going “Straight to the Source”: Directly Measuring Ambivalent Sexism in Women’s Social Networks and Examining Its Health Implications

This study, which takes place on a university campus, seeks to examine how the presence of hostile sexism (a component of ambivalent sexism) among the men in women’s social networks relates to women’s health outcomes as well as how this relationship might be moderated by emotional support. It was expected that the more hostile sexism present among the men in women’s social networks, the more negative women’s reported mental and physical health outcomes. Additionally, emotional support was hypothesized to moderate these expected associations such that women who reported low levels of emotional support would be particularly vulnerable to the effects associated with high levels of social network hostile sexism. While no support was ultimately found for these hypotheses, alternative explanations relating to the study’s methodology as well as directions for future research are discussed

Lorlatinib Tolerability and Association With Clinical Outcomes in Patients With Advanced ALK- or ROS1-Rearranged NSCLC: A Brief Report

Introduction: Treatment with lorlatinib for patients with advanced ALK- and ROS1-rearranged NSCLC (ALK+ and ROS1+ NSCLC) is associated with a unique set of adverse events (AEs) often requiring dose reduction. However, the impact of dose reductions on outcomes remains unclear and is mainly limited to analyses from prospective studies of lorlatinib in the first-line setting. Methods: We reviewed the course of 144 patients with advanced ALK- or ROS1-rearranged NSCLC treated with lorlatinib in the second-line or later setting to assess the frequency of dose reductions resulting from treatment-related AEs (TRAEs) and the association between dose reductions and progression-free survival (PFS) and overall survival (OS). Results: A total of 58 patients (40%) had TRAE-related dose reductions, most (59%) owing to neurocognitive AEs or neuropathy. Among all patients, the median PFS was 8.1 months (95% confidence interval [CI]: 6.4–11.8); the median OS was 20.7 months (95% CI: 16.3–30.5). Among patients who were started on lorlatinib 100 mg/d (n = 122), a Cox regression model with the occurrence of a dose reduction as a time-dependent covariate indicated no association between dose reduction and PFS (hazard ratio = 0.86, 95% CI: 0.54–1.39) or OS (hazard ratio = 0.78, 95% CI: 0.47–1.30). Conclusions: Lorlatinib dose reductions were not associated with inferior clinical outcomes in this multicenter analysis. Prompt identification of lorlatinib TRAEs and implementation of dose reductions may help maximize tolerability without compromising outcomes

Early on-treatment assessment of T-cells, cytokines and tumor DNA with adaptively-dosed nivolumab + ipilimumab: final results from the phase 2 ADAPT-IT study.

PURPOSE: ADAPT-IT (NCT03122522) investigated adaptive ipilimumab discontinuation in melanoma based on early radiographic assessment. Initial findings indicated similar effectiveness compared to conventional nivolumab-ipilimumab (nivo-ipi). Exploratory biomarker analyses and final clinical results are now reported. PATIENTS AND METHODS: Patients with unresectable melanoma received two doses of nivo-ipi. Radiographic assessment at Week 6 informed continuation of ipilimumab before nivolumab maintenance. The primary endpoint was overall response rate (ORR) at Week 12. Plasma was assayed for circulating tumor DNA (ctDNA) and ten cytokines using a multiplex immunoassay. Flow cytometry of peripheral blood mononuclear cells was performed with an 11-color panel. RESULTS: Among treated patients, expansion of proliferating T-cell populations was observed in both responders and non-responders. Baseline IL-6 levels were lower in patients achieving an objective radiographic response (median 1.30 vs 2.86 pg/mL; p=0.025). Higher baseline IL-6 levels were associated with shorter progression-freesurvival (PFS; hazard ratio (HR)=1.24, 95% CI:1.01-1.52; p=0.041). At Week 6, patients with response had lower average tumor variant allele fractions (VAF) compared to non-responders (median 0.000 v 0.019; p=0.014). Greater increases in average VAF from baseline to Week 6 correlated with shorter PFS (HR=1.11, 95% CI:1.01-1.21; p=0.023). Week 12 ORR was 47% (95% CI:35-59%) with a median follow-up of 34 months among survivors. Median PFS was 21 months (95% CI:10-not reached); 76% of responses (95% CI:64%-91%) persisted at 36 months. CONCLUSIONS: Adaptively dosed nivo-ipi responses are durable and resemble historical data for conventional nivo-ipi. Baseline IL-6 and ctDNA changes during treatment warrant further study as biomarkers of nivo-ipi response