Shaping of a laser-accelerated proton beam for radiobiology applications via genetic algorithm.

Laser-accelerated protons have a great potential for innovative experiments in radiation biology due to the sub-picosecond pulse duration and high dose rate achievable. However, the broad angular divergence makes them not optimal for applications with stringent requirements on dose homogeneity and total flux at the irradiated target. The strategy otherwise adopted to increase the homogeneity is to increase the distance between the source and the irradiation plane or to spread the beam with flat scattering systems or through the transport system itself. Such methods considerably reduce the proton flux and are not optimal for laser-accelerated protons. In this paper we demonstrate the use of a Genetic Algorithm (GA) to design an optimal non-flat scattering system to shape the beam and efficiently flatten the transversal dose distribution at the irradiated target. The system is placed in the magnetic transport system to take advantage of the presence of chromatic focusing elements to further mix the proton trajectories. The effect of a flat scattering system placed after the transport system is also presented for comparison. The general structure of the GA and its application to the shaping of a laser-accelerated proton beam are presented, as well as its application to the optimisation of dose distribution in a water target in air.

Fast dose fractionation using ultra-short laser accelerated proton pulses can increase cancer cell mortality, which relies on functional PARP1 protein.

Radiotherapy is a cornerstone of cancer management. The improvement of spatial dose distribution in the tumor volume by minimizing the dose deposited in the healthy tissues have been a major concern during the last decades. Temporal aspects of dose deposition are yet to be investigated. Laser-plasma-based particle accelerators are able to emit pulsed-proton beams at extremely high peak dose rates (~109 Gy/s) during several nanoseconds. The impact of such dose rates on resistant glioblastoma cell lines, SF763 and U87-MG, was compared to conventionally accelerated protons and X-rays. No difference was observed in DNA double-strand breaks generation and cells killing. The variation of the repetition rate of the proton bunches produced an oscillation of the radio-induced cell susceptibility in human colon carcinoma HCT116 cells, which appeared to be related to the presence of the PARP1 protein and an efficient parylation process. Interestingly, when laser-driven proton bunches were applied at 0.5 Hz, survival of the radioresistant HCT116 p53-/- cells equaled that of its radiosensitive counterpart, HCT116 WT, which was also similar to cells treated with the PARP1 inhibitor Olaparib. Altogether, these results suggest that the application modality of ultrashort bunches of particles could provide a great therapeutic potential in radiotherapy.

Detailed Experimental Study of Ion Acceleration by Interaction of an Ultra-Short Intense Laser with an Underdense Plasma.

Ion acceleration from intense (Iλ(2) > 10(18) Wcm(-2) µm(2)) laser-plasma interaction is experimentally studied within a wide range of He gas densities. Focusing an ultrashort pulse (duration ion plasma period) on a newly designed submillimetric gas jet system, enabled us to inhibit total evacuation of electrons from the central propagation channel reducing the radial ion acceleration associated with ponderomotive Coulomb explosion, a mechanism predominant in the long pulse scenario. New ion acceleration mechanism have been unveiled in this regime leading to non-Maxwellian quasi monoenergetic features in the ion energy spectra. The emitted nonthermal ion bunches show a new scaling of the ion peak energy with plasma density. The scaling identified in this new regime differs from previously reported studies.

Demonstration of relativistic electron beam focusing by a laser-plasma lens.

Laser-plasma technology promises a drastic reduction of the size of high-energy electron accelerators. It could make free-electron lasers available to a broad scientific community and push further the limits of electron accelerators for high-energy physics. Furthermore, the unique femtosecond nature of the source makes it a promising tool for the study of ultrafast phenomena. However, applications are hindered by the lack of suitable lens to transport this kind of high-current electron beams mainly due to their divergence. Here we show that this issue can be solved by using a laser-plasma lens in which the field gradients are five order of magnitude larger than in conventional optics. We demonstrate a reduction of the divergence by nearly a factor of three, which should allow for an efficient coupling of the beam with a conventional beam transport line.

Instrumentation for diagnostics and control of laser-accelerated proton (ion) beams.

Suitable instrumentation for laser-accelerated proton (ion) beams is critical for development of integrated, laser-driven ion accelerator systems. Instrumentation aimed at beam diagnostics and control must be applied to the driving laser pulse, the laser-plasma that forms at the target and the emergent proton (ion) bunch in a correlated way to develop these novel accelerators. This report is a brief overview of established diagnostic techniques and new developments based on material presented at the first workshop on 'Instrumentation for Diagnostics and Control of Laser-accelerated Proton (Ion) Beams' in Abingdon, UK. It includes radiochromic film (RCF), image plates (IP), micro-channel plates (MCP), Thomson spectrometers, prompt inline scintillators, time and space-resolved interferometry (TASRI) and nuclear activation schemes. Repetition-rated instrumentation requirements for target metrology are also addressed.

Short intense laser pulse collapse in near-critical plasma.

It is observed that the interaction of an intense ultrashort laser pulse with a near-critical gas jet results in the pulse collapse and the deposition of a significant fraction of the energy. This deposition happens in a small and well-localized volume in the rising part of the gas jet, where the electrons are efficiently accelerated and heated. A collisionless plasma expansion over ~ 150 µm at a subrelativistic velocity (~ c/3) has been optically monitored in time and space, and attributed to the quasistatic field ionization of the gas associated with the hot electron current. Numerical simulations in good agreement with the observations suggest the acceleration in the collapse region of relativistic electrons, along with the excitation of a sizable magnetic dipole that sustains the electron current over several picoseconds.

Concomitant high gene copy number and protein overexpression of IGF1R and EGFR negatively affect disease-free survival of surgically resected non-small-cell-lung cancer patients.

BACKGROUND: Insulin-like growth factor 1 receptor (IGF1R) represents a novel molecular target in non-small-cell-lung cancer (NSCLC). IGF1R and epidermal growth factor receptor (EGFR) activation are essential to mediate tumor cell survival, proliferation, and invasion. This study investigates the prognostic role of IGF1R and EGFR in surgically resected NSCLC. MATERIALS AND METHODS: IGF1R and EGFR copy number gain (CNG) were tested by fluorescence in situ hybridization (FISH) and protein expression by immunohistochemistry (IHC) in 125 stage I-II-IIIA NSCLC patients. RESULTS: Fourty-six tumors (40.3%) were IGF1R FISH-positive (FISH+), and 76 (67.2%) were EGFR FISH+. Tumors with concomitant IGF1R/EGFR FISH+ were observed in 34 cases (30.1%). IGF1R and EGFR FISH+ were associated with SCC histology (p = 0.01 and p = 0.04, respectively). IGF1R and EGFR protein over-expression (IHC+) were detected in 45 (36.0%) and 69 (55.2%) cases, respectively. Tumors with concomitant IGF1R/EGFR IHC+ were detected in 31 (24.8%) patients. IGF1R/EGFR FISH+ and IGF1R/EGFR IHC+ were significantly associated (χ(2) = 4.02, p = 0.04). Patients with IGF1R/EGFR FISH+ and IGF1R/EGFR IHC+ were associated with shorter disease-free survival (DFS) (p = 0.05 and p = 0.05, respectively). Patients with concomitant IGF1R/EGFR FISH+/IHC+ had a worse DFS and overall survival (p = 0.005 and p = 0.01, respectively). The multivariate model confirmed that IGF1R/EGFR FISH+/IHC+ (hazard ratio (HR), 4.08; p = 0.01) and tumor stage (II-III vs I) (HR, 4.77; p = 0.003) were significantly associated with worse DFS. CONCLUSIONS: IGF1R/EGFR FISH+ correlates with IGF1R/EGFR IHC+. IGF1R/EGFR FISH+/IHC+ is an independent negative prognostic factor for DFS in early NSCLC. These features may have important implications for future anti-IGF1R therapeutic approaches.

Anticorrelation between ion acceleration and nonlinear coherent structures from laser-underdense plasma interaction.

In laser-plasma experiments, we observed that ion acceleration from the Coulomb explosion of the plasma channel bored by the laser is prevented when multiple plasma instabilities, such as filamentation and hosing, and nonlinear coherent structures (vortices or postsolitons) appear in the wake of an ultrashort laser pulse. The tailoring of the longitudinal plasma density ramp allows us to control the onset of these instabilities. We deduced that the laser pulse is depleted into these structures in our conditions, when a plasma at about 10% of the critical density exhibits a gradient on the order of 250 µm (Gaussian fit), thus hindering the acceleration. A promising experimental setup with a long pulse is demonstrated enabling the excitation of an isolated coherent structure for polarimetric measurements and, in further perspectives, parametric studies of ion plasma acceleration efficiency.

Development and characterization of very dense submillimetric gas jets for laser-plasma interaction.

We report on the characterization of recently developed submillimetric He gas jets with peak density higher than 10(21) atoms/cm(3) from cylindrical and slightly conical nozzles of throat diameter of less than 400 µm. Helium gas at pressure 300-400 bar has been developed for this purpose to compensate the nozzle throat diameter reduction that affects the output mass flow rate. The fast-switching electro-valve enables to operate the jet safely for multi-stage vacuum pump assembly. Such gaseous thin targets are particularly suitable for laser-plasma interaction studies in the unexplored near-critical regime.

Brunel-dominated proton acceleration with a few-cycle laser pulse.

Experimental measurements of backward accelerated protons are presented. The beam is produced when an ultrashort (5 fs) laser pulse, delivered by a kHz laser system, with a high temporal contrast (10(8)), interacts with a thick solid target. Under these conditions, proton cutoff energy dependence with laser parameters, such as pulse energy, polarization (from p to s), and pulse duration (from 5 to 500 fs), is studied. Theoretical model and two-dimensional particle-in-cell simulations, in good agreement with a large set of experimental results, indicate that proton acceleration is directly driven by Brunel electrons, in contrast to conventional target normal sheath acceleration that relies on electron thermal pressure.

Optimization of patient selection for EGFR-TKIs in advanced non-small cell lung cancer by combined analysis of KRAS, PIK3CA, MET, and non-sensitizing EGFR mutations.

BACKGROUND: We present a comprehensive analysis of KRAS, PIK3CA, MET, and non-sensitizing EGFR mutations in advanced non-small cell lung cancer (NSCLC) patients treated with tyrosine kinase inhibitors (TKIs), with the aim of clarifying the relative contribution of these molecular alterations to resistance. PATIENTS AND METHODS: One hundred and sixty-six patients with advanced NSCLC treated with EGFR-TKIs with available archival tissue specimens were included. EGFR (exons 18-21), KRAS (exons 2, 3), PIK3CA (exons 9, 20), and MET (exons 14, 15) mutations were analyzed using PCR-based sequencing. Among all the mutations evaluated, only KRAS, PIK3CA, MET, and non-sensitizing EGFR mutations, defined as "TKI non-sensitizing mutations" were used for response, time to progression (TTP), and overall survival (OS) analysis. RESULTS: TKI non-sensitizing mutations were associated with disease progression (p = 0.001), shorter TTP (p < 0.0001), and worse OS (p = 0.03). Cox's multivariate analysis including histology and performance status showed that TKI non-sensitizing mutations were independent factors for shorter TTP (p < 0.0001) and worse OS (p = 0.01). CONCLUSIONS: When KRAS, PIK3CA, MET, and non-sensitizing EGFR mutations are concomitant, up to 96.0% of NSCLC patients unlikely to respond to TKIs can be identified, and they represented independent negative prognostic factors. Comprehensive molecular dissection of EGFR signaling pathways should be considered to select advanced NSCLC patients for TKIs therapies.

Dependence on pulse duration and foil thickness in high-contrast-laser proton acceleration.

Experimental measurements of proton acceleration with high intensity and high-contrast short laser pulses have been carried out over an order of magnitude range in target thickness and laser pulse duration. The dependence of the maximum proton energy with these parameters is qualitatively supported by two-dimensional particle-in-cell simulations. They evidence that two regimes of proton acceleration can take place, depending on the ratio between the density gradient and the hot electron Debye length at the rear target surface. As this ratio can be affected by the target thickness, a complex interplay between pulse duration and target thickness is observed. Measurements and simulations support unexpected variations in the laser absorption and hot electron temperature with the pulse duration and laser intensity, for which density profile modification at the target front surface is the controlling parameter.