Cabozantinib in hepatocellular carcinoma: results of a phase 2 placebo-controlled randomized discontinuation study.

BackgroundCabozantinib, an orally bioavailable inhibitor of tyrosine kinases including MET, AXL, and VEGF receptors, was assessed in patients with hepatocellular carcinoma (HCC) as part of a phase 2 randomized discontinuation trial with nine tumor-type cohorts.Patients and methodsEligible patients had Child-Pugh A liver function and ≤1 prior systemic anticancer regimen, completed ≥4 weeks before study entry. The cabozantinib starting dose was 100 mg daily. After an initial 12-week cabozantinib treatment period, patients with stable disease (SD) per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0 were randomized to cabozantinib or placebo. The primary endpoint of the lead-in stage was objective response rate (ORR) at week 12, and the primary endpoint of the randomized stage was progression-free survival (PFS).ResultsAmong the 41 HCC patients enrolled, the week 12 ORR was 5%, with 2 patients achieving a confirmed partial response (PR). The week 12 disease control rate (PR or SD) was 66% (Asian subgroup: 73%). Of patients with ≥1 post-baseline scan, 78% had tumor regression, with no apparent relationship to prior sorafenib therapy. Alpha-fetoprotein (AFP) response (>50% reduction from baseline) occurred in 9 of the 26 (35%) patients with elevated baseline AFP and ≥1 post-baseline measurement. Twenty-two patients with SD at week 12 were randomized. Median PFS after randomization was 2.5 months with cabozantinib and 1.4 months with placebo, although this difference was not statistically significant. Median PFS and overall survival from Day 1 in all patients were 5.2 and 11.5 months, respectively. The most common grade 3/4 adverse events, regardless of attribution, were diarrhea (20%), hand-foot syndrome (15%), and thrombocytopenia (15%). Dose reductions were utilized in 59% of patients.ConclusionsCabozantinib has clinical activity in HCC patients, including objective tumor responses, disease stabilization, and reductions in AFP. Adverse events were managed with dose reductions.Trial registration numberNCT00940225

484pretrospective ras analysis of the epic trial cetuximab plus irinotecan vs irinotecan in patients pts with second line metastatic colorectal cancer mcrc

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Incidence and time course of everolimus-related adverse events in postmenopausal women with hormone receptor-positive advanced breast cancer: insights from BOLERO-2.

BackgroundIn the BOLERO-2 trial, everolimus (EVE), an inhibitor of mammalian target of rapamycin, demonstrated significant clinical benefit with an acceptable safety profile when administered with exemestane (EXE) in postmenopausal women with hormone receptor-positive (HR(+)) advanced breast cancer. We report on the incidence, time course, severity, and resolution of treatment-emergent adverse events (AEs) as well as incidence of dose modifications during the extended follow-up of this study.Patients and methodsPatients were randomized (2:1) to receive EVE 10 mg/day or placebo (PBO), with open-label EXE 25 mg/day (n = 724). The primary end point was progression-free survival. Secondary end points included overall survival, objective response rate, and safety. Safety evaluations included recording of AEs, laboratory values, dose interruptions/adjustments, and study drug discontinuations.ResultsThe safety population comprised 720 patients (EVE + EXE, 482; PBO + EXE, 238). The median follow-up was 18 months. Class-effect toxicities, including stomatitis, pneumonitis, and hyperglycemia, were generally of mild or moderate severity and occurred relatively early after treatment initiation (except pneumonitis); incidence tapered off thereafter. EVE dose reduction and interruption (360 and 705 events, respectively) required for AE management were independent of patient age. The median duration of dose interruption was 7 days. Discontinuation of both study drugs because of AEs was higher with EVE + EXE (9%) versus PBO + EXE (3%).ConclusionsMost EVE-associated AEs occur soon after initiation of therapy, are typically of mild or moderate severity, and are generally manageable with dose reduction and interruption. Discontinuation due to toxicity was uncommon. Understanding the time course of class-effect AEs will help inform preventive and monitoring strategies as well as patient education.Trial registration numberNCT00863655

Comparison of high-latitude line-of-sight ozone column density with derived ozone fields and the effects of horizontal inhomogeneity

International audienceExtensive ozone measurements were made during the second SAGE III Ozone Loss and Validation Experiment (SOLVE II). We compare high-latitude line-of-sight (LOS) slant column ozone measurements from the NASA DC-8 to ozone simulated by forward integration of measurement-derived ozone fields constructed both with and without the assumption of horizontal homogeneity. The average bias and rms error of the simulations assuming homogeneity are relatively small (?6 and 10%, respectively) in comparison to the LOS measurements. The comparison improves significantly (?2% bias; 8% rms error) using forward integrations of three-dimensional proxy ozone fields reconstructed from potential vorticity-O3 correlations. The comparisons provide additional verification of the proxy fields and quantify the influence of large-scale ozone inhomogeneity. The spatial inhomogeneity of the atmosphere is a source of error in the retrieval of trace gas vertical profiles and column abundance from LOS measurements, as well as a complicating factor in intercomparisons that include LOS measurements at large solar zenith angles

A Formalization of the Theorem of Existence of First-Order Most General Unifiers

This work presents a formalization of the theorem of existence of most general unifiers in first-order signatures in the higher-order proof assistant PVS. The distinguishing feature of this formalization is that it remains close to the textbook proofs that are based on proving the correctness of the well-known Robinson's first-order unification algorithm. The formalization was applied inside a PVS development for term rewriting systems that provides a complete formalization of the Knuth-Bendix Critical Pair theorem, among other relevant theorems of the theory of rewriting. In addition, the formalization methodology has been proved of practical use in order to verify the correctness of unification algorithms in the style of the original Robinson's unification algorithm.Comment: In Proceedings LSFA 2011, arXiv:1203.542

Prenatal Vitamin Use and Vitamin D Status during Pregnancy, Differences by Race and Overweight Status

Objective: We aimed to study whether prenatal vitamin (PNV) use protects against low 25(OH)D levels in all women and particularly in obese and black women who are both at risk of vitamin D deficiency and poor pregnancy outcomes. Study design We studied 1019 women enrolled in a prospective study at Brigham and Women’s Hospital in Boston, 2007–2009. We used multivariable logistic regression to analyze associations of PNV use and odds of vitamin D deficiency defined as 25(OH)D levels < 50 nmol/L. Results: 56% of black and 86% of white women reported pre- and/or post-conceptional PNV use. 75% of black and 19% of white women were vitamin D deficient in the first trimester. PNV use among black women was not associated with vitamin D deficiency (adjusted OR 1.0, 95%CI 0.4, 2.3) but was among white women (3.5, 95%CI 2.1, 5.8)(Interaction P<0.01). Conclusions: Ongoing trials of vitamin D supplementation during pregnancy should consider potential effect modification by race/ethnicity

Emerging Strategies for Healthy Urban Governance

Urban health promotion is not simply a matter of the right interventions, or even the necessary resources. Urban (and indeed global) health depends to an important extent on governance, the institutions and processes through which societies manage the course of events. This paper describes the concept of governance, distinguishing between reforms aimed at improving how government works and innovations that more fundamentally reinvent governance by developing new institutions and processes of local stakeholder control. The paper highlights strategies urban governors can use to maximize their influence on the national and international decisions that structure urban life. It concludes with some observations on the limitations of local governance strategies and the importance of establishing a “virtuous circuit” of governance through which urban dwellers play a greater role in the formation and implementation of policy at the national and global levels

Discovery of Dust Emission Activity Emanating from Main-belt Asteroid 2015 FW412

We present the discovery of activity emanating from main-belt asteroid 2015 FW412, a finding stemming from the Citizen Science project Active Asteroids, a NASA Partner program. We identified a pronounced tail originating from 2015 FW412 and oriented in the anti-motion direction in archival Blanco 4-m (Cerro Tololo Inter-American Observatory, Chile) Dark Energy Camera (DECam) images from UT 2015 April 13, 18, 19, 21 and 22. Activity occurred near perihelion, consistent with the main-belt comets (MBCs), an active asteroid subset known for sublimation-driven activity in the main asteroid belt; thus 2015 FW412 is a candidate MBC. We did not detect activity on UT 2021 December 12 using the Inamori-Magellan Areal Camera and Spectrograph (IMACS) on the 6.5 m Baade telescope, when 2015 FW412 was near aphelion.Comment: 4 pages, 1 figur