Real-World Data and Clinical Implications of Next-Generation Sequencing (NGS)-Based Analysis in Metastatic Breast Cancer Patients

Over the last two decades, the use of Next-Generation Sequencing (NGS) in medical oncology has increased the likelihood of identifying druggable mutations that may be potentially susceptible to targeted treatments. The European Society for Medical Oncology (ESMO) currently does not recommend the use of the NGS test to determine the therapeutic course of patients with metastatic breast cancer (mBC) in daily clinical practice. However, the aim of this work is to evaluate the potential contribution of the NGS test in selecting targeted therapies for patients with mBC. Data were retrospectively collected from 101 patients diagnosed with metastatic breast cancer and treated at the Modena Cancer Center between January 2015 and April 2022. A NGS test was performed on the tumor tissue of each patient at the Laboratory of Molecular Pathology of the University Hospital of Modena. This study analyzed the clinical-pathological characteristics and mutational profile of the population using NGS tests, with a focus on actionable mutations that could be targeted in advanced stages of clinical development. The indicator of this study was to quantify the actionable mutations that resulted in a change of cancer treatment. In total, 101 patients with metastatic breast cancer were analyzed, including 86 with luminal phenotype, 10 who were HER2-positive and 5 who were triple-negative. Median age was 52 years. NGS analysis was conducted on 47 samples of primary breast cancer, 52 on metastatic sites of disease and 2 on liquid biopsies. A total of 85 gene mutations were found. The most common mutations were identified in the PIK3CA (47%), FGFR (19%) and ERBB2 genes (12%), and to a lesser extent in other genes. Of the 61 patients with pathogenic mutations, 46 (75%) had at least one actionable mutation. Of these, nine received treatment with a molecular target drug: eight patients with a mutation of the PIK3CA gene were treated with alpelisib and fulvestrant; one patient with FGFR1/2 amplifications received TAS120. Median PFS for these patients was 3.8 months. The study results show that using the NGS test on cancer tissue of metastatic breast cancer could influence the therapeutic choices, considering the small sample size and limited follow-up. About 9% of the study population had their therapy modified based on the results of NGS. The growing number of detectable mutations and increased accessibility of the test may lead to a greater number of potential therapeutic implications for the NGS assay. Perspectives suggest that NGS analysis can be implemented in daily clinical practice, particularly in contexts where a Molecular Tumor Board (MTB) is active.Over the last two decades, the use of Next-Generation Sequencing (NGS) in medical oncology has increased the likelihood of identifying druggable mutations that may be potentially susceptible to targeted treatments. The European Society for Medical Oncology (ESMO) currently does not recommend the use of the NGS test to determine the therapeutic course of patients with metastatic breast cancer (mBC) in daily clinical practice. However, the aim of this work is to evaluate the potential contribution of the NGS test in selecting targeted therapies for patients with mBC. Data were retrospectively collected from 101 patients diagnosed with metastatic breast cancer and treated at the Modena Cancer Center between January 2015 and April 2022. A NGS test was performed on the tumor tissue of each patient at the Laboratory of Molecular Pathology of the University Hospital of Modena. This study analyzed the clinical–pathological characteristics and mutational profile of the population using NGS tests, with a focus on actionable mutations that could be targeted in advanced stages of clinical development. The indicator of this study was to quantify the actionable mutations that resulted in a change of cancer treatment. In total, 101 patients with metastatic breast cancer were analyzed, including 86 with luminal phenotype, 10 who were HER2-positive and 5 who were triple-negative. Median age was 52 years. NGS analysis was conducted on 47 samples of primary breast cancer, 52 on metastatic sites of disease and 2 on liquid biopsies. A total of 85 gene mutations were found. The most common mutations were identified in the PIK3CA (47%), FGFR (19%) and ERBB2 genes (12%), and to a lesser extent in other genes. Of the 61 patients with pathogenic mutations, 46 (75%) had at least one actionable mutation. Of these, nine received treatment with a molecular target drug: eight patients with a mutation of the PIK3CA gene were treated with alpelisib and fulvestrant; one patient with FGFR1/2 amplifications received TAS120. Median PFS for these patients was 3.8 months. The study results show that using the NGS test on cancer tissue of metastatic breast cancer could influence the therapeutic choices, considering the small sample size and limited follow-up. About 9% of the study population had their therapy modified based on the results of NGS. The growing number of detectable mutations and increased accessibility of the test may lead to a greater number of potential therapeutic implications for the NGS assay. Perspectives suggest that NGS analysis can be implemented in daily clinical practice, particularly in contexts where a Molecular Tumor Board (MTB) is active

A Statistical Inference Method for Interpreting the CLASP Observations

On 3rd September 2015, the Chromospheric Lyman-Alpha SpectroPolarimeter (CLASP) successfully measured the linear polarization produced by scattering processes in the hydrogen Lyman-$\alpha$ line of the solar disk radiation, revealing conspicuous spatial variations in the $Q/I$ and $U/I$ signals. Via the Hanle effect the line-center $Q/I$ and $U/I$ amplitudes encode information on the magnetic field of the chromosphere-corona transition region (TR), but they are also sensitive to the three-dimensional structure of this corrugated interface region. With the help of a simple line formation model, here we propose a statistical inference method for interpreting the Lyman-$\alpha$ line-center polarization observed by CLASP.Comment: Accepted for publication in The Astrophysical Journa

CLASP Constraints on the Magnetization and Geometrical Complexity of the Chromosphere-Corona Transition Region

The Chromospheric Lyman-Alpha Spectro-Polarimeter (CLASP) is a suborbital rocket experiment that on 3rd September 2015 measured the linear polarization produced by scattering processes in the hydrogen Ly-$\alpha$ line of the solar disk radiation, whose line-center photons stem from the chromosphere-corona transition region (TR). These unprecedented spectropolarimetric observations revealed an interesting surprise, namely that there is practically no center-to-limb variation (CLV) in the $Q/I$ line-center signals. Using an analytical model, we first show that the geometrical complexity of the corrugated surface that delineates the TR has a crucial impact on the CLV of the $Q/I$ and $U/I$ line-center signals. Secondly, we introduce a statistical description of the solar atmosphere based on a three-dimensional (3D) model derived from a state-of-the-art radiation magneto-hydrodynamic simulation. Each realization of the statistical ensemble is a 3D model characterized by a given degree of magnetization and corrugation of the TR, and for each such realization we solve the full 3D radiative transfer problem taking into account the impact of the CLASP instrument degradation on the calculated polarization signals. Finally, we apply the statistical inference method presented in a previous paper to show that the TR of the 3D model that produces the best agreement with the CLASP observations has a relatively weak magnetic field and a relatively high degree of corrugation. We emphasize that a suitable way to validate or refute numerical models of the upper solar chromosphere is by confronting calculations and observations of the scattering polarization in ultraviolet lines sensitive to the Hanle effect.Comment: Accepted for publication in The Astrophysical Journal Letter

The use of antimicrobials in italian heavy pig fattening farms

Data on antimicrobial use (AMU) in heavy pig production (>150 kg) are limited. The aim of this study was to investigate the AMU in this production. Data from 2015 were collected for 143 fattening farms. The AMU was estimated through a treatment index per 100 days (TI100) using the defined daily dose animal for Italy (DDDAit). When possible, a comparison with the European Medicines Agency’s defined daily doses for animals (DDDvet) was performed. The median TI100 was 10.7 (range, 0.2–49.5). Group treatments represented 94.6% of overall consumption. The AMU calculated using DDDAit and DDDvet were strongly correlated (ρ = 0.976; p < 0.001). The AMU was negatively correlated with injectables use (ρ = −0.46, p < 0.001) and positively correlated with oral products (ρ = 0.21, p = 0.014), premixes (ρ = 0.26, p = 0.002), and mortality (ρ = 0.18; p = 0.027). Farm size was negatively correlated with AMU (ρ = −0.29, p < 0.001). Smaller farms were more frequently above the median TI100 (odds ratio = 2.3, 95% confidence interval = 1.2–4.7), suggesting that they may have lower biosecurity and management standards. The results of this study should provide useful insights for the development of an Italian monitoring system

Recent Advances in Chromospheric and Coronal Polarization Diagnostics

I review some recent advances in methods to diagnose polarized radiation with which we may hope to explore the magnetism of the solar chromosphere and corona. These methods are based on the remarkable signatures that the radiatively induced quantum coherences produce in the emergent spectral line polarization and on the joint action of the Hanle and Zeeman effects. Some applications to spicules, prominences, active region filaments, emerging flux regions and the quiet chromosphere are discussed.Comment: Review paper to appear in "Magnetic Coupling between the Interior and the Atmosphere of the Sun", eds. S. S. Hasan and R. J. Rutten, Astrophysics and Space Science Proceedings, Springer-Verlag, 200

Magnetic Imaging of the Outer Solar Atmosphere (MImOSA): Unlocking the driver of the dynamics in the upper solar atmosphere

The magnetic activity of the Sun directly impacts the Earth and human life. Likewise, other stars will have an impact on the habitability of planets orbiting these host stars. The lack of information on the magnetic field in the higher atmospheric layers hampers our progress in understanding solar magnetic activity. Overcoming this limitation would allow us to address four paramount long-standing questions: (1) How does the magnetic field couple the different layers of the atmosphere, and how does it transport energy? (2) How does the magnetic field structure, drive and interact with the plasma in the chromosphere and upper atmosphere? (3) How does the magnetic field destabilise the outer solar atmosphere and thus affect the interplanetary environment? (4) How do magnetic processes accelerate particles to high energies? New ground-breaking observations are needed to address these science questions. We suggest a suite of three instruments that far exceed current capabilities in terms of spatial resolution, light-gathering power, and polarimetric performance: (a) A large-aperture UV-to-IR telescope of the 1-3 m class aimed mainly to measure the magnetic field in the chromosphere by combining high spatial resolution and high sensitivity. (b) An extreme-UV-to-IR coronagraph that is designed to measure the large-scale magnetic field in the corona with an aperture of about 40 cm. (c) An extreme-UV imaging polarimeter based on a 30 cm telescope that combines high throughput in the extreme UV with polarimetry to connect the magnetic measurements of the other two instruments. This mission to measure the magnetic field will unlock the driver of the dynamics in the outer solar atmosphere and thereby greatly advance our understanding of the Sun and the heliosphere.Comment: Submitted to Experimental Astronomy (on 28. Jul. 2020). Based on a proposal submitted in response to a call for white papers in the Voyage 2050 long-term plan in the ESA science programme. 36 pages, 10 figure

CLASP2: The Chromospheric LAyer Spectro-Polarimeter

A major remaining challenge for heliophysicsis to decipher the magnetic structure of the chromosphere, due to its "large role in defining how energy is transported into the corona and solar wind" (NASA's Heliophysics Roadmap). Recent observational advances enabled by the Interface Region Imaging Spectrometer (IRIS) have revolutionized our view of the critical role this highly dynamic interface between the photosphere and corona plays in energizing and structuring the outer solar atmosphere. Despite these advances, a major impediment to better understanding the solar atmosphere is our lack of empirical knowledge regarding the direction and strength of the magnetic field in the upper chromosphere. Such measurements are crucial to address several major unresolved issues in solar physics: for example, to constrain the energy flux carried by the Alfven waves propagating through the chromosphere (De Pontieuet al., 2014), and to determine the height at which the plasma Beta = 1 transition occurs, which has important consequences for the braiding of magnetic fields (Cirtainet al., 2013; Guerreiroet al., 2014), for propagation and mode conversion of waves (Tian et al., 2014a; Straus et al., 2008) and for non-linear force-free extrapolation methods that are key to determining what drives instabilities such as flares or coronal mass ejections (e.g.,De Rosa et al., 2009). The most reliable method used to determine the solar magnetic field vector is the observation and interpretation of polarization signals in spectral lines, associated with the Zeeman and Hanle effects. Magnetically sensitive ultraviolet spectral lines formed in the upper chromosphere and transition region provide a powerful tool with which to probe this key boundary region (e.g., Trujillo Bueno, 2014). Probing the magnetic nature of the chromosphere requires measurement of the Stokes I, Q, U and V profiles of the relevant spectral lines (of which Q, U and V encode the magnetic field information)

Arachidonic Acid but not Eicosapentaenoic Acid (EPA) and Oleic Acid Activates NF-κB and Elevates ICAM-1 Expression in Caco-2 Cells

In patients with inflammatory bowel disease (IBD), intestinal activation of the transcription factor NF-κB as well as intercellular adhesion molecule (ICAM)-1 expression, which is involved in recruiting leukocytes to the side of inflammation is increased. Moreover, colonic arachidonic acid (ARA) proportions are increased and oleic acid (OA) proportions are decreased. Fish oils are protective in IBD patients however, a side-by-side comparison between effects of fish oils, ARA and OA has not been made. We therefore, compared effects of eicosapentaenoic acid (EPA) versus ARA and OA on ICAM-1 expression in Caco-2 enterocytes. To validate our model we showed that dexamethasone, sulfasalazine and PPARα (GW7647) or PPARγ (troglitazone) agonists significantly lowered ICAM-1 expression. ICAM-1 expression of non-stimulated and cytokine stimulated Caco-2 cells cultured for 22 days with ARA was significant higher as compared to EPA and OA. Furthermore, ARA increased NF-κB activation in a reporter cell-line as compared to EPA. Antibody array analysis of multiple inflammatory proteins particularly showed an increased monocyte chemotactic protein (MCP)-1 and angiogenin production and a decreased interleukin (IL)-6 and IL-10 production by ARA as compared to EPA. Our results showed that ARA but not EPA and OA activates NF-κB and elevates ICAM-1 expression in Caco-2 enterocytes. It suggests that replacement of ARA by EPA or OA in the colon mucosa might have beneficial effects for IBD patients. Finally, we suggest that the pro-inflammatory effects of ARA versus EPA and OA are not related to PPARγ activation and/or eicosanoid formation