Aim
This retrospective analysis focused on the effect of treatment with EVE/EXE in a real-world population outside of clinical trials. We examined the efficacy of this combination in terms of PFS and ...RR related to dose intensity (5 mg daily versus 10 mg daily) and tolerability.
Methods
163 HER2-negative ER+/PgR+ ABC patients, treated with EVE/EXE from May 2011 to March 2016, were included in the analysis. The primary endpoints were the correlation between the daily dose and RR and PFS, as well as an evaluation of the tolerability of the combination. Secondary endpoints were RR, PFS, and OS according to the line of treatment. Patients were classified into three different groups, each with a different dose intensity of everolimus (A, B, C).
Results
RR was 29.8% (A), 27.8% (B) (
p
= 0.953), and not evaluable (C). PFS was 9 months (95% CI 7–11) (A), 10 months (95% CI 9–11) (B), and 5 months (95% CI 2–8) (C),
p
= 0.956. OS was 38 months (95% CI 24–38) (A), median not reached (B), and 13 months (95% CI 10–25) (C),
p
= 0.002. Adverse events were stomatitis 57.7% (11.0% grade 3–4), asthenia 46.0% (6.1% grade 3–4), hypercholesterolemia 46.0% (0.6% grade 3–4), and hyperglycemia 35.6% (5.5% grade 3–4). The main reason for discontinuation/interruption was grade 2–3 stomatitis.
Conclusions
No correlation was found between dose intensity (5 vs. 10 mg labeled dose) and efficacy in terms of RR and PFS. The tolerability of the higher dose was poor in our experience, although this had no impact on efficacy.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
QVA149 is a dual bronchodilator, containing a fixed-dose combination of the long-acting β2-agonist indacaterol and long-acting muscarinic antagonist glycopyrronium, for the treatment of chronic ...obstructive pulmonary disease (COPD). Here we assess the potential of QVA149 (440/200 μg) at 4-fold the therapeutic dose for causing cardiac pharmacodynamic (PD) effects.
This double-blind, randomized study estimated the time-matched largest heart rate (HR) change and average HR change (over 24 hours) from baseline for QVA149 vs. placebo in healthy subjects. Similar analyses were done for QVA149 vs. indacaterol 600 μg, glycopyrronium 200 μg, and salmeterol 200 μg. The time-matched and average change from baseline in QT interval corrected for HR using Fridericia's formula (QTcF), effects on serum potassium and blood glucose, pharmacokinetic (PK) parameters, and safety were also assessed.
Of 50 subjects randomized, 43 completed the study. QVA149, when compared with placebo, showed the time-matched largest mean increase and decrease in HR of 5.69 bpm and -2.51 bpm, respectively, and average HR change from baseline of 0.62 bpm. QVA149 showed no tachycardic potential compared with indacaterol and no relevant tachycardic effect compared with glycopyrronium. No consistent differences were seen in the time-matched largest mean change and average change from baseline in QTcF for QVA149 vs. other treatments. There were no relevant effects of QVA149 on serum potassium and blood glucose. There was no apparent PK/PD relationship between the observed exposures to indacaterol and glycopyrronium in QVA149 on HR and QTcF. There were no deaths or serious adverse events.
Overall, short-term administration of QVA149 showed a good cardiovascular safety and tolerability profile in healthy subjects.
Abstract PURPOSE and INTRODUCTION: In vivo a dermal filler hyaluronic gel-based loaded with CXCL12 (CLG) was able to divert B16-hCXCR4 cells from lung metastases. Herein, CLG was assessed for the ...capability to isolate human circulating cancer cells (CTCs). Moreover, in vivo CLGs and lungs were characterized to dissect natural (lung) and artificial (gel) microenvironment composition. EXPERIMENTAL DESIGN: “TRAP4MET” clinical trial was conducted in 48 advanced cancer patients characterized at diagnosis for CLG-dependent CTCs-isolation as compared to ScreenCell™ filters. C57/B6 mice were s.c. injected with Empty Gel (EG) or CLG and five days later i.v. injected with GFP-LLC (Lewis lung) cells. Lungs and gels were collected at time 0 (before tumour cells injection), after 4 hours and 10 days post tumour cells inoculation. Lungs and gels were analysed through flow-cytometry for GFP-LLC cells, innate and adaptive immunity. RESULTS: In TRAP4MET clinical trial CLG-CTCs were isolated in 8/8 patients with ovarian (OC), 6/8 with lung (LC), 6/8 with colorectal (CRC), 8/8 with endometrial (EC), 8/8 with renal (RCC) cancer and 5/8 with glioblastoma (GBM). In OC, LC and GBM, CLG isolated more CTCs than the conventional ScreenCell™ (CLG/SC ratio=1.88 for OC, 2.47 for LC and 11.89 for GBM). To dissect the in vivo efficacy of CLG, GFP-LLC were i.v. injected in C57/B6 mice five days later the s.c CLG or EG injection. Five days after CLG/EG gels and lungs were recovered. In CLG a lower % of total Macrophages (MΦ), inactive/precursor Tregs and higher % of M2-MΦ was observed compared to EG while no major differences were revealed in lungs from CLG/EG/CTRL groups. 4 hours post injection revealed in CLG a lower % of MΦ, lower inactive/precursor Tregs and a higher % of M2- MΦ and CXCR4+ MΦ versus EG. In correspondent CLG-lungs, lower % of mature neutrophils and inactive/progenitor Tregs as compared to EG-lung and CTRL-lung, respectively. 10 days post cells inoculation, CLG gels revealed again low total MΦ, low inactive/precursor Tregs and high M2-MΦ, CXCR4+ MΦ as to EG. The corresponding CLG-lungs displayed higher non-aged neutrophils and and NK cells, lower CXCR4+ MΦ, lower total neutrophils, lower aged (CXCR4+) neutrophils and lower inactive Tregs as compared to EG and CTRL, respectively. Consistently, GFP-LLC cells were higher in CLG compared to EG at either 4 hours and 10 days post cell injection while reduced in lungs of CLG-mice compared to EG- and CTRL-lungs mice at 4 hours and 10 days post cell inoculation, respectively. CONCLUSION: CLG may support OC, LC and GBM- CTC counting in cancers at today orphan of CTCs reliable methods. In vivo, CLG attracted GFL-LLC cells while reducing lung GFP-LLC cells as early as after 4 hours post cell inoculation. CLG/EG and correspondent lung analysis revealed an immunosuppressive microenvironment within CLG compared to EG reduced in the corresponding lungs. Citation Format: Giuseppe Guardascione, Luigi Portella, Dario Guido Di Febbraro, Giulia Bertolini, Giuseppina Rea, Caterina Ieranò, Crescenzo D'Alterio, Maria Napolitano, Sara Santagata, Anna Maria Trotta, Emilia Scarpa, Sabrina Chiara Cecere, Alessandro Ottaiano, Giuliano Palumbo, Alessandro Morabito, Teresa Somma, Roberto Pacelli, Sandro Pignata, Stefania Scala. CXCL12-loaded-hydrogel (CLG) in vivo modifies lung metastatic niche toward an immunoactive microenvironment reducing lung metastasis development abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6815.
Background:
Chemotherapy plus targeted therapy is the established treatment for human epidermal growth factor receptor 2 (HER2)–overexpressing breast cancer (BC). Limited data regarding the safety ...and activity of the combination of eribulin and trastuzumab (E/T) in pretreated HER2-positive advanced BC (ABC) are available. The aim of this observational, retrospective, multicenter study was to examine the tolerability and the clinical activity of E/T in this setting.
Methods:
Patients treated with eribulin mesylate plus standard dose of trastuzumab were included. Data on overall response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety were reported.
Results:
Between October 2012 and November 2015, 24 consecutive patients with HER2-positive ABC were included. All patients were heavily pretreated: the median number of prior chemotherapy regimens for ABC was 3 (range 2–9). The median number of cycles with E/T was 11.5 (range 2–26). The ORR was 41.7%. Median PFS was 5.4 months, median postprogression survival was 5.4 months, and median OS was 8 months. Neutropenia was the most common grade 3/4 clinical adverse event (16.7%).
Conclusions:
Tolerability and clinical activity of the E/T combination schedule are encouraging. The results of this study indicate that this combination might be considered for treatment of pretreated HER2 ABC.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Introduction: Breast cancer (BC) is the most common cancer in women. Although therapeutic armamentarium like chemotherapy, endocrine and target agents have increased survival, cardiovascular side ...effects have been observed. A comprehensive risk assessment, early detection and management of cardiac adverse events is therefore needed.
Areas covered: In this review we focus on cardiotoxicity data deriving from Phase III randomized trials, systematic reviews and meta-analysis in BC patients. We provide insight into advances that have been made in the molecular mechanisms, clinical presentation and management of such adverse event.
Expert opinion: Despite the large number of data from Phase III trials about cardiac events incidence, there are poor evidences for detection, monitoring and management of cardiotoxicity during BC treatment. Future cardiotoxicity-oriented clinical cancer research can help to predict the risk of cardiac adverse events and improve patients' outcome. Multidisciplinary approach as well as integration of blood biomarkers with imaging will be desirable.
In conjunction with Eljen Technology, Inc. (Sweetwater,TX) we have designed, constructed, and evaluated a 3 in. x 3 in. deuterated-xylene organic liquid scintillator (C8D10; EJ301D) as a fast neutron ...detector. Similar to deuterated benzene (C6D6; NE230, BC537, and EJ315) this scintillator can provide good pulse-shape discrimination between neutrons and gamma rays, has good timing characteristics, and can provide a light spectrum with peaks corresponding to discrete neutron energy groups up to ca. 20 MeV. Unlike benzene-based detectors, deuterated xylene is less volatile, less toxic, is not known to be carci-nogenic, has a higher flashpoint, and hence is much safer for many applications. In addition EJ301D can provide slightly more light output and better PSD than deuterated-benzene scintillators. We show that, as with deuterated-benzene scintillators, the light-response spectra can be unfolded to provide useable neutron energy spectra without need for time-of-flight (ToF). An array of these detectors arranged at many angles close to a reaction target can be much more effective ( x 10 to x 100 or more) than an array of long-path ToF detectors which must utilize a narrowly-bunched and pulse-selected beam. As we demonstrate using a small Van de Graaff accelerator, measurements can thus be performed when a bunched and pulse-selected beam (as needed for time-of-flight) is not available.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Gene editing in human embryonic stem cells (hESCs) has been significantly enhanced by the discovery and development of CRISPR Cas9, a programmable nuclease system that can introduce targeted ...double-stranded breaks. The system relies on the optimal selection of a sgRNA sequence with low off-targets and high efficiency. We designed an improved monomeric red fluorescent protein reporter, GEmCherry2, for assessing CRISPR Cas9 activity and for optimizing sgRNA. By incorporating an out-of-frame sequence to the N-terminal of the red fluorescent protein mCherry, we created a visual tool for assessing the indel frequency after cutting with CRISPR Cas9. When a sgRNA-Cas9 construct is co-transfected with a corresponding GEmCherry2 construct, single nucleotide indels can move the GEmCherry2 sequence back in-frame and allow quantification and comparison of the efficiency of different sgRNA target sites by measuring red fluorescence. With this GEmCherry2 assay, we compared four target sites in the safe harbor
locus and found significant differences in target site activity. We verified the activity using TIDE, which ranked our target sites in a similar order as the GEmCherry2 system. We also identified an AAV short inverted terminal repeat sequence within the Cas9 construct that, upon removal significantly improved transient transfection and expression in hESCs. Moreover, using GEmCherry2, we designed a sgRNA to target
in hESCs and successfully introduced indels into the coding sequence of
.
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