Oncology and mechanics: landmark studies and promising clinical applications

Clinical management of cancer has continuously evolved for several decades. Biochemical, molecular and genomics approaches have brought and still bring numerous insights into cancerous diseases. It is now accepted that some phenomena, allowed by favorable biological conditions, emerge via mechanical signaling at the cellular scale and via mechanical forces at the macroscale. Mechanical phenomena in cancer have been studied in-depth over the last decades, and their clinical applications are starting to be understood. If numerous models and experimental setups have been proposed, only a few have led to clinical applications. The objective of this contribution is to propose to review a large scope of mechanical findings which have consequences on the clinical management of cancer. This review is mainly addressed to doctoral candidates in mechanics and applied mathematics who are faced with the challenge of the mechanics-based modeling of cancer with the aim of clinical applications. We show that the collaboration of the biological and mechanical approaches has led to promising advances in terms of modeling, experimental design and therapeutic targets. Additionally, a specific focus is brought on imaging-informed mechanics-based models, which we believe can further the development of new therapeutic targets and the advent of personalized medicine. We study in detail several successful workflows on patient-specific targeted therapies based on mechanistic modeling

Non-operable glioblastoma: Proposition of patient-specific forecasting by image-informed poromechanical model

Work funding with a grant fromLuxembourg National Research Fund (FNR) grant number INTER/ANR/21/16399490 and from Réseau Santé des Arts et Métiers.We propose a novel image-informed glioblastoma mathematical model within a reactive multiphase poromechanical framework. Poromechanics offers to model in a coupled manner the interplay between tissue deformation and pressure-driven fluid flows, these phenomena existing simultaneously in cancer disease. The model also relies on two mechano-biological hypotheses responsible for the heterogeneity of the GBM: hypoxia signaling cascade and interaction between extra-cellular matrix and tumor cells. The model belongs to the category of patient-specific image-informed models as it is initialized, calibrated and evaluated by the means of patient imaging data. The model is calibrated with patient data after 6 cycles of concomitant radiotherapy chemotherapy and shows good agreement with treatment response 3 months after chemotherapy maintenance. Sensitivity of the solution to parameters and to boundary conditions is provided. As this work is only a first step of the inclusion of poromechanical framework in image-informed glioblastoma mathematical models, leads of improvement are provided in the conclusion. Statement of significance: In this study, we employ mechanics of reactive porous media to effectively model the dynamic progression of a glioblastoma. Traditionally, glioblastoma tumors are surgically removed a few weeks post-diagnosis. To address this, we focus on a non-operable clinical scenario which allows us to have sufficient time points for the calibration and subsequent validation of our mathematical model. It is paramount to underscore that the tumor’s evolution is significantly influenced by chemotherapy and radiotherapy. These therapeutic effects find incorporation within our mathematical framework. Notably, the approach we present is distinctive for two key reasons: Firstly, the mathematical model inherently captures the complex multiphase and hierarchical nature of brain tissue. Secondly, our constitutive laws factor in the ever-changing properties of cells and tissues, mirroring the local phenotypic alterations observed within the tumor. This work constitutes an initial stride towards systematically integrating multiphase poromechanics into patient-specific glioblastoma growth modeling. As we look ahead, we acknowledge areas for potential enhancement in pursuit of advancing this promising direction

Deep Broadband Observations of the Distant Gamma-ray Blazar PKS 1424+240

We present deep VERITAS observations of the blazar PKS 1424+240, along with contemporaneous Fermi Large Area Telescope, Swift X-ray Telescope and Swift UV Optical Telescope data between 2009 February 19 and 2013 June 8. This blazar resides at a redshift of $z\ge0.6035$, displaying a significantly attenuated gamma-ray flux above 100 GeV due to photon absorption via pair-production with the extragalactic background light. We present more than 100 hours of VERITAS observations from three years, a multiwavelength light curve and the contemporaneous spectral energy distributions. The source shows a higher flux of (2.1$\pm0.3$)$\times10^{-7}$ ph m$^{-2}$s$^{-1}$ above 120 GeV in 2009 and 2011 as compared to the flux measured in 2013, corresponding to (1.02$\pm0.08$)$\times10^{-7}$ ph m$^{-2}$s$^{-1}$ above 120 GeV. The measured differential very high energy (VHE; $E\ge100$ GeV) spectral indices are $\Gamma=$3.8$\pm$0.3, 4.3$\pm$0.6 and 4.5$\pm$0.2 in 2009, 2011 and 2013, respectively. No significant spectral change across the observation epochs is detected. We find no evidence for variability at gamma-ray opacities of greater than $\tau=2$, where it is postulated that any variability would be small and occur on longer than year timescales if hadronic cosmic-ray interactions with extragalactic photon fields provide a secondary VHE photon flux. The data cannot rule out such variability due to low statistics.Comment: ApJL accepted March 17, 201

Imaging practice in low-grade gliomas among European specialized centers and proposal for a minimum core of imaging

Objective: Imaging studies in diffuse low-grade gliomas (DLGG) vary across centers. In order to establish a minimal core of imaging necessary for further investigations and clinical trials in the field of DLGG, we aimed to establish the status quo within specialized European centers. Methods: An online survey composed of 46 items was sent out to members of the European Low-Grade Glioma Network, the European Association of Neurosurgical Societies, the German Society of Neurosurgery and the Austrian Society of Neurosurgery. Results: A total of 128 fully completed surveys were received and analyzed. Most centers (n=96, 75%) were academic and half of the centers (n=64, 50%) adhered to a dedicated treatment program for DLGG. There were national differences regarding the sequences enclosed in MRI imaging and use of PET, however most included T1 (without and with contrast, 100%), T2 (100%) and TIRM or FLAIR (20, 98%). DWI is performed by 80% of centers and 61% of centers regularly performed PWI.ConclusionA minimal core of imaging composed of T1 (w/wo contrast), T2, TIRM/FLAIR, PWI and DWI could be identified. All morphologic images should be obtained in a slice thickness of 3mm. No common standard could be obtained regarding advanced MRI protocols and PET. Importance of the study: We believe that our study makes a significant contribution to the literature because we were able to determine similarities in numerous aspects of LGG imaging. Using the proposed minimal core of imaging in clinical routine will facilitate future cooperative studies

Discovery of very high energy gamma rays from PKS 1424+240 and multiwavelength constraints on its redshift

We report the first detection of very-high-energy (VHE) gamma-ray emission above 140 GeV from PKS 1424+240, a BL Lac object with an unknown redshift. The photon spectrum above 140 GeV measured by VERITAS is well described by a power law with a photon index of 3.8 +- 0.5_stat +- 0.3_syst and a flux normalization at 200 GeV of (5.1 +- 0.9_stat +- 0.5_syst) x 10^{-11} TeV^-1 cm^-2 s^-1, where stat and syst denote the statistical and systematical uncertainty, respectively. The VHE flux is steady over the observation period between MJD 54881 and 55003 (2009 February 19 to June 21). Flux variability is also not observed in contemporaneous high energy observations with the Fermi Large Area Telescope (LAT). Contemporaneous X-ray and optical data were also obtained from the Swift XRT and MDM observatory, respectively. The broadband spectral energy distribution (SED) is well described by a one-zone synchrotron self-Compton (SSC) model favoring a redshift of less than 0.1. Using the photon index measured with Fermi in combination with recent extragalactic background light (EBL) absorption models it can be concluded from the VERITAS data that the redshift of PKS 1424+240 is less than 0.66.Comment: accepted for publication, Ap

Imaging practice in low-grade gliomas among European specialized centers and proposal for a minimum core of imaging.

OBJECTIVE: Imaging studies in diffuse low-grade gliomas (DLGG) vary across centers. In order to establish a minimal core of imaging necessary for further investigations and clinical trials in the field of DLGG, we aimed to establish the status quo within specialized European centers. METHODS: An online survey composed of 46 items was sent out to members of the European Low-Grade Glioma Network, the European Association of Neurosurgical Societies, the German Society of Neurosurgery and the Austrian Society of Neurosurgery. RESULTS: A total of 128 fully completed surveys were received and analyzed. Most centers (n = 96, 75%) were academic and half of the centers (n = 64, 50%) adhered to a dedicated treatment program for DLGG. There were national differences regarding the sequences enclosed in MRI imaging and use of PET, however most included T1 (without and with contrast, 100%), T2 (100%) and TIRM or FLAIR (20, 98%). DWI is performed by 80% of centers and 61% of centers regularly performed PWI. CONCLUSION: A minimal core of imaging composed of T1 (w/wo contrast), T2, TIRM/FLAIR, PWI and DWI could be identified. All morphologic images should be obtained in a slice thickness of ≤ 3 mm. No common standard could be obtained regarding advanced MRI protocols and PET. IMPORTANCE OF THE STUDY: We believe that our study makes a significant contribution to the literature because we were able to determine similarities in numerous aspects of LGG imaging. Using the proposed "minimal core of imaging" in clinical routine will facilitate future cooperative studies

The Discovery of gamma-Ray Emission From The Blazar RGB J0710+591

The high-frequency-peaked BL Lacertae object RGB J0710+591 was observed in the very high-energy (VHE; E > 100 GeV) wave band by the VERITAS array of atmospheric Cherenkov telescopes. The observations, taken between 2008 December and 2009 March and totaling 22.1 hr, yield the discovery of VHE gamma rays from the source. RGB J0710+591 is detected at a statistical significance of 5.5 standard deviations (5.5{\sigma}) above the background, corresponding to an integral flux of (3.9 +/- 0.8) x 10-12 cm-2 s-1 (3% of the Crab Nebula's flux) above 300 GeV. The observed spectrum can be fit by a power law from 0.31 to 4.6 TeV with a photon spectral index of 2.69 +/- 0.26stat +/- 0.20sys. These data are complemented by contemporaneous multiwavelength data from the Fermi Large Area Telescope, the Swift X-ray Telescope, the Swift Ultra-Violet and Optical Telescope, and the Michigan-Dartmouth-MIT observatory. Modeling the broadband spectral energy distribution (SED) with an equilibrium synchrotron self-Compton model yields a good statistical fit to the data. The addition of an external-Compton component to the model does not improve the fit nor brings the system closer to equipartition. The combined Fermi and VERITAS data constrain the properties of the high-energy emission component of the source over 4 orders of magnitude and give measurements of the rising and falling sections of the SED

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta

Insights into the high-energy γ-ray emission of Markarian 501 from extensive multifrequency observations in the Fermi era

We report on the γ-ray activity of the blazar Mrk 501 during the first 480 days of Fermi operation. We find that the average Large Area Telescope (LAT) γ-ray spectrum of Mrk 501 can be well described by a single power-law function with a photon index of 1.78 ± 0.03. While we observe relatively mild flux variations with the Fermi-LAT (within less than a factor of two), we detect remarkable spectral variability where the hardest observed spectral index within the LAT energy range is 1.52 ± 0.14, and the softest one is 2.51 ± 0.20. These unexpected spectral changes do not correlate with the measured flux variations above 0.3 GeV. In this paper, we also present the first results from the 4.5 month long multifrequency campaign (2009 March 15-August 1) on Mrk 501, which included the Very Long Baseline Array (VLBA), Swift, RXTE, MAGIC, and VERITAS, the F-GAMMA, GASP-WEBT, and other collaborations and instruments which provided excellent temporal and energy coverage of the source throughout the entire campaign. The extensive radio to TeV data set from this campaign provides us with the most detailed spectral energy distribution yet collected for this source during its relatively low activity. The average spectral energy distribution of Mrk 501 is well described by the standard one-zone synchrotron self-Compton (SSC) model. In the framework of this model, we find that the dominant emission region is characterized by a size ≲0.1 pc (comparable within a factor of few to the size of the partially resolved VLBA core at 15-43 GHz), and that the total jet power (≃1044 erg s-1) constitutes only a small fraction (∼10-3) of the Eddington luminosity. The energy distribution of the freshly accelerated radiating electrons required to fit the time-averaged data has a broken power-law form in the energy range 0.3 GeV-10 TeV, with spectral indices 2.2 and 2.7 below and above the break energy of 20 GeV. We argue that such a form is consistent with a scenario in which the bulk of the energy dissipation within the dominant emission zone of Mrk 501 is due to relativistic, proton-mediated shocks. We find that the ultrarelativistic electrons and mildly relativistic protons within the blazar zone, if comparable in number, are in approximate energy equipartition, with their energy dominating the jet magnetic field energy by about two orders of magnitude. © 2011. The American Astronomical Society