Biomarker analyses of second-line ramucirumab in patients with advanced gastric cancer from RAINBOW, a global, randomized, double-blind, phase 3 study.

BACKGROUND: The RAINBOW trial showed that second-line ramucirumab with paclitaxel prolongs overall survival (OS) and progression-free survival (PFS) compared with placebo plus paclitaxel for treatment of advanced gastric/gastroesophageal junction cancer. Plasma samples were collected from patients during the trial and tested to identify predictive and prognostic biomarkers. PATIENTS AND METHODS: Circulating factors in plasma samples from mutually exclusive subsets of RAINBOW patients were assayed using: Intertek assays (24 markers, 380 samples, 57% of patients) and Lilly-developed assay (LDA) platform (5 markers, 257 samples, 39% of patients). Time-trend plots were generated for each marker from the Intertek assays. Baseline patient data were dichotomized into low- and high-marker subgroups. Markers were analyzed for predictive effects using interaction models and for prognostic effects using main-effects models. RESULTS: The Intertek and LDA populations were representative of the full trial population. Plasma levels of VEGF-D and PlGF increased from baseline levels during treatment, then declined after treatment discontinued. Angiopoietin-2 exhibited a decrease during treatment, then increased after treatment discontinuation. No clear time trend was evident with the other markers. Analyses of baseline biomarker expression and its relationship with efficacy variables found no biomarker was predictive for efficacy outcomes, including VEGF-D. However, CRP, HGF, ICAM-3, IL-8, SAA, and VCAM-1 were identified as potential prognostic markers with low baseline levels corresponding to longer OS and PFS. CONCLUSIONS: Pharmacodynamic and prognostic relationships were found from the exploratory biomarker analyses in RAINBOW; however, no predictive markers for ramucirumab in gastric cancer were identified in this trial. ispartof: Eur J Cancer vol:127 pages:150-157 ispartof: location:England status: publishe

ACTION:a randomized phase 3 study of ONC201 (dordaviprone) in patients with newly diagnosed H3 K27M-mutant diffuse glioma

BACKGROUND: H3 K27M-mutant diffuse glioma primarily affects children and young adults, is associated with a poor prognosis, and no effective systemic therapy is currently available. ONC201 (dordaviprone) has previously demonstrated efficacy in patients with recurrent disease. This phase 3 trial evaluates ONC201 in patients with newly diagnosed H3 K27M-mutant glioma.METHODS: ACTION (NCT05580562) is a randomized, double-blind, placebo-controlled, parallel-group, international phase 3 study of ONC201 in newly diagnosed H3 K27M-mutant diffuse glioma. Patients who have completed standard frontline radiotherapy are randomized 1:1:1 to receive placebo, once-weekly dordaviprone, or twice-weekly dordaviprone on 2 consecutive days. Primary efficacy endpoints are overall survival (OS) and progression-free survival (PFS); PFS is assessed by response assessment in neuro-oncology high-grade glioma criteria (RANO-HGG) by blind independent central review. Secondary objectives include safety, additional efficacy endpoints, clinical benefit, and quality of life. Eligible patients have histologically confirmed H3 K27M-mutant diffuse glioma, a Karnofsky/Lansky performance status ≥70, and completed first-line radiotherapy. Eligibility is not restricted by age; however, patients must be ≥10 kg at time of randomization. Patients with a primary spinal tumor, diffuse intrinsic pontine glioma, leptomeningeal disease, or cerebrospinal fluid dissemination are not eligible. ACTION is currently enrolling in multiple international sites.</p

Analysis of angiogenesis biomarkers for ramucirumab efficacy in patients with metastatic colorectal cancer from RAISE, a global, randomized, double-blind, phase III study

The phase III RAISE trial (NCT01183780) demonstrated that the vascular endothelial growth factor (VEGF) receptor (VEGFR)-2 binding monoclonal antibody ramucirumab plus 5-fluororuracil, leucovorin, and irinotecan (FOLFIRI) significantly improved overall survival (OS) and progression-free survival (PFS) compared with placebo + FOLFIRI as second-line metastatic colorectal cancer (mCRC) treatment. To identify patients who benefit the most from VEGFR-2 blockade, the RAISE trial design included a prospective and comprehensive biomarker program that assessed the association of biomarkers with ramucirumab efficacy outcomes. Plasma and tumor tissue collection was mandatory. Overall, 1072 patients were randomized 1 : 1 to the addition of ramucirumab or placebo to FOLFIRI chemotherapy. Patients were then randomized 1 : 2, for the biomarker program, to marker exploratory (ME) and marker confirmatory (MC) groups. Analyses were carried out using exploratory assays to assess the correlations of baseline marker levels [VEGF-C, VEGF-D, sVEGFR-1, sVEGFR-2, sVEGFR-3 (plasma), and VEGFR-2 (tumor tissue)] with clinical outcomes. Cox regression analyses were carried out for each candidate biomarker with stratification factor adjustment. Biomarker results were available from >80% (n = 894) of patients. Analysis of the ME subset determined a VEGF-D level of 115 pg/ml was appropriate for high/low subgroup analyses. Evaluation of the combined ME + MC populations found that the median OS in the ramucirumab + FOLFIRI arm compared with placebo + FOLFIRI showed an improvement of 2.4 months in the high VEGF-D subgroup [13.9 months (95% CI 12.5–15.6) versus 11.5 months (95% CI 10.1–12.4), respectively], and a decrease of 0.5 month in the low VEGF-D subgroup [12.6 months (95% CI 10.7–14.0) versus 13.1 months (95% CI 11.8–17.0), respectively]. PFS results were consistent with OS. No trends were evident with the other antiangiogenic candidate biomarkers. The RAISE biomarker program identified VEGF-D as a potential predictive biomarker for ramucirumab efficacy in second-line mCRC. Development of an assay appropriate for testing in clinical practice is currently ongoing. NCT01183780

Identifying interface-dominated behavior and cell configuration effects on the electrochemistry of calcium foil anodes

Thesis: S.M., Massachusetts Institute of Technology, Department of Mechanical Engineering, February, 2021Cataloged from the official PDF version of thesis.Includes bibliographical references (pages 46-49).Fundamental research and practical assembly of rechargeable calcium (Ca)-based batteries will benefit from the ability to use Ca metal anodes to provide a sufficient Ca²⁺ reservoir for full cell electrochemistry. When Ca metal comes in contact with an organic electrolyte, a native solid electrolyte interphase (SEI) forms which dramatically alters the electrode, and in some instances fully passivates it. Considering that Ca deposition and dissolution is widely believed to be a surface-film-controlled process, understanding the role of the interface on Ca electrochemistry is paramount. This study examines the electrochemical signatures of several Ca interfaces in a current benchmark electrolyte, Ca(BH₄)₂ in tetrahydrofuran (THF). Preparation methodologies of Ca foils are presented, along with Ca plating/stripping through either pre-existing, native calcium hydride (CaH₂), or pre-formed calcium fluoride (CaF₂) interfaces.In contrast to earlier work examining Ca foil in other electrolytes, Ca foils are accessible for reversible electrochemistry in Ca(BH₄)₂/THF. However, the first cyclic voltammetry (CV) cycle reflects a persistent and history-dependent layer from its prior handling, which manifests as reduction/oxidation overpotentials and characteristic interface-derived CV features. The initial surface-dependent behavior diminishes as Ca is continuously cycled, but formation of the native CaH₂ interface can return the CV to interface-dominated behavior. Imparting a synthetic, nanoscale-thickness CaF₂ layer prior to cell assembly can successfully decouple the Ca anode from the electrolyte; however, access points for more-active Ca plating/stripping form throughout cycling, progressively breaking through the film, and the interface is not chemically stable after several days.CVs are compared in both three-electrode glass cell and two-electrode coin cell configurations, where the cell configuration is also shown to have significant effects on the resulting electrochemistry. The electrochemical signature of the native passivation layer is still present during the first cycle in coin cells, but high current density and cycle life are achievable with moderate cycling parameters.by Aaron M. Melemed.S.M.S.M. Massachusetts Institute of Technology, Department of Mechanical Engineerin

Electrochemical Signatures of Interface-Dominated Behavior in the Testing of Calcium Foil Anodes

© 2020 The Author(s). Published on behalf of The Electrochemical Society by IOP Publishing Limited. Fundamental research and practical assembly of rechargeable calcium (Ca) batteries will benefit from an ability to use Ca foil anodes. Given that Ca electrochemistry is considered a surface-film-controlled process, understanding the interface’s role is paramount. This study examines electrochemical signatures of several Ca interfaces in a benchmark electrolyte, Ca(BH4)2/tetrahydrofuran (THF). Preparation methodologies of Ca foils are presented, along with Ca plating/stripping through either pre-existing, native calcium hydride (CaH2), or pre-formed calcium fluoride (CaF2) interfaces. In contrast to earlier work examining Ca foil in other electrolytes, Ca foils are accessible for reversible electrochemistry in Ca(BH4)2/THF. However, the first cyclic voltammetry (CV) cycle reflects persistent, history-dependent behavior from prior handling, which manifests as characteristic interface-derived features. This behavior diminishes as Ca is cycled, though formation of a native interface can return the CV to interface-dominated behavior. CaF2 modification enhances such interface-dominance; however, continued cycling suppresses such features, collectively indicating the dynamic nature of certain Ca interfaces. Cell configuration is also found to significantly influence electrochemistry. With appropriate preparation of Ca foils, the signature of interface-dominated behavior is still present during the first cycle in coin cells, but higher current density compared to three-electrode cells along with moderate cycle life are readily achievable.NSF (DMR-14-19807

Assessing parking patrons' perceptions of safety and security.

Our report involved our work with the Montgomery County, Maryland Department of Public Works and Transportation. We created a way to annually survey parking patrons and assess their perceptions of security in parking facilities. To do this, we first created a questionnaire based on the topics of demographics, parking behavior, and safety and security issues. We then determined our sample, pre-tested the questionnaire, and distributed it. We then analyzed the responses to draw conclusions about the patrons' perceptions

2023-2024 Master Class - Mackenzie Melemed (Piano)

https://spiral.lynn.edu/conservatory_masterclasses/1245/thumbnail.jp

Current Understanding of Nonaqueous Electrolytes for Calcium‐Based Batteries

Calcium metal batteries are receiving growing research attention due to significant breakthroughs in recentyears that have indicatedreversible Ca plating/stripping with attractive Coulombic efficiencies (90-95%), once thought to be out of reach. While the Ca anode is often described as being surface film-controlled,the ability to access reversible Ca electrochemistry is highly electrolyte-dependentin general,which affects both interfacial chemistryon plated Caalong with more fundamental Ca2+/Ca redox properties. This mini-review describes recent progress towards a reversible Ca anode from the point of view of the most successful electrolyte chemistries identified to date. Thisincludes, centrally, what is currently knownabout the Ca2+solvation environment in these systems. Experimental (physico-chemical and spectroscopy) and computationalresultsare summarized forthe two major solvent classes—carbonates and ethers—that have yieldedpromising results so far. Current knowledge gaps and opportunities toimprove fundamental understandingofCa2+/Ca redox are also identified