A high-power, high-repetition-rate THz source for pump-probe experiments at Linac Coherent Light Source II.

Experiments using a THz pump and an X-ray probe at an X-ray free-electron laser (XFEL) facility like the Linac Coherent Light Source II (LCLS II) require frequency-tunable (3 to 20 THz), narrow bandwidth (∼10%), carrier-envelope-phase-stable THz pulses that produce high fields (>1 MV cm-1) at the repetition rate of the X-rays and are well synchronized with them. In this paper, a two-bunch scheme to generate THz radiation at LCLS II is studied: the first bunch produces THz radiation in an electromagnet wiggler immediately following the LCLS II undulator that produces X-rays from the second bunch. The initial time delay between the two bunches is optimized to compensate for the path difference in THz transport. The two-bunch beam dynamics, the THz wiggler and radiation are described, as well as the transport system bringing the THz pulses from the wiggler to the experimental hall.

Excision of both pretreatment marked positive nodes and sentinel nodes improves axillary staging after neoadjuvant systemic therapy in breast cancer.

BACKGROUND: Marking the axilla with radioactive iodine seed and sentinel lymph node (SLN) biopsy have been proposed for axillary staging after neoadjuvant systemic therapy in clinically node-positive breast cancer. This study evaluated the identification rate and detection of residual disease with combined excision of pretreatment-positive marked lymph nodes (MLNs) together with SLNs. METHODS: This was a multicentre retrospective analysis of patients with clinically node-positive breast cancer undergoing neoadjuvant systemic therapy and the combination procedure (with or without axillary lymph node dissection). The identification rate and detection of axillary residual disease were calculated for the combination procedure, and for MLNs and SLNs separately. RESULTS: At least one MLN and/or SLN(s) were identified by the combination procedure in 138 of 139 patients (identification rate 99·3 per cent). The identification rate was 92·8 per cent for MLNs alone and 87·8 per cent for SLNs alone. In 88 of 139 patients (63·3 per cent) residual axillary disease was detected by the combination procedure. Residual disease was shown only in the MLN in 20 of 88 patients (23 per cent) and only in the SLN in ten of 88 (11 per cent), whereas both the MLN and SLN contained residual disease in the remainder (58 of 88, 66 per cent). CONCLUSION: Excision of the pretreatment-positive MLN together with SLNs after neoadjuvant systemic therapy in patients with clinically node-positive disease resulted in a higher identification rate and improved detection of residual axillary disease.

ANTECEDENTES: En el cáncer de mama con ganglios positivos clínicamente tras el tratamiento neoadyuvante sistémico, se ha propuesto la utilización de iodo radioactivo (Marking Axilla with Radioactive Iodine, MARI) y de la biopsia de ganglio linfático centinela para la estadificación axilar. En este estudio se evaluó la tasa de identificación y detección de enfermedad residual cuando se combinó la exéresis de los ganglios linfáticos marcados antes del tratamiento (marked lymph nodes, MLN) junto con los ganglios centinela (sentinel lymph nodes, SLN). MÉTODOS: Se realizó un análisis retrospectivo multicéntrico de pacientes con cáncer de mama con ganglios positivos clínicamente que se sometieron a tratamiento neoadyuvante sistémico y en las que se combinaron ambas técnicas (con o sin disección axilar). Se calcularon las tasas de identificación y detección de enfermedad residual axilar para MLN y SLN por separado y en conjunto. RESULTADOS: En 138/139 pacientes se identificaron ≥ 1 MLN y/o SLN combinando ambas técnicas (tasa de identificación del 99,3%). La tasa de identificación fue de 92,8% para MLN y del 87,8% para SLN. Combinando ambas técnicas se detectó enfermedad axilar residual en 88/139 (63,3%) pacientes. Se detectó enfermedad residual en 20/88 (22,7%) pacientes utilizando únicamente MLN, en 10/88 (11,4%) pacientes utilizando únicamente SLN y en 58/88 (65,9%) combinando ambas técnicas. CONCLUSIÓN: La exéresis conjunta de los ganglios marcados con iodo radioactivo antes del tratamiento neoadyuvante sistémico y de los ganglios centinela después del tratamiento en pacientes con cN+ logró una tasa de identificación más alta y una mejor detección de la enfermedad axilar residual.

Acute toxicity of intraoperative radiotherapy and external beam-accelerated partial breast irradiation in elderly breast cancer patients.

BACKGROUND AND PURPOSE: We investigated the acute toxicity of accelerated partial breast irradiation using external beam (EB-APBI) or intraoperative radiotherapy (IORT) techniques in elderly breast cancer patients. MATERIALS AND METHODS: Women ≥ 60 years with unifocal breast tumors of ≤ 30 mm were eligible for this prospective multi-center cohort study. IORT was applied with electrons following lumpectomy (23.3 Gy). EB-APBI was delivered using 3D-CRT or IMRT in 10 daily fractions of 3.85 Gy within 6 weeks after surgery. Acute toxicity was scored using the CTCAE v3.0 at 3 months after treatment. Patient-reported symptoms were analyzed using visual analogue scales (VAS) for pain and fatigue (scale 0-10), and single items from the EORTC QLQ-C30 and Breast Cancer questionnaires. RESULTS: In total, 267 (IORT) and 206 (EB-APBI) patients were available for toxicity analysis. More patients experienced ≥ grade 2 CTCAE acute toxicity in the IORT group (10.4% IORT and 4.9% EB-APBI; p = 0.03); grade 3 toxicity was low (3.3% IORT and 1.5% EB-APBI; ns); and no grade 4 toxicity occurred. EB-APBI patients experienced less fatigue direct postoperatively (EORTC p < 0.00, VAS p < 0.00). After 3 months only pain, according to the VAS scale, was significantly worse in the EB-APBI group (p < 0.00). CONCLUSION: Acute toxicity after IORT and EB-APBI treatment is acceptable.

Diffuse Cosmic Rays Shining in the Galactic Center: A Novel Interpretation of H.E.S.S. and Fermi-LAT γ-Ray Data.

We present a novel interpretation of the γ-ray diffuse emission measured by Fermi-LAT and H.E.S.S. in the Galactic center (GC) region and the Galactic ridge (GR). In the first part we perform a data-driven analysis based on PASS8 Fermi-LAT data: We extend down to a few GeV the spectra measured by H.E.S.S. and infer the primary cosmic-ray (CR) radial distribution between 0.1 and 3 TeV. In the second part we adopt a CR transport model based on a position-dependent diffusion coefficient. Such behavior reproduces the radial dependence of the CR spectral index recently inferred from the Fermi-LAT observations. We find that the bulk of the GR emission can be naturally explained by the interaction of the diffuse steady-state Galactic CR sea with the gas present in the central molecular zone. Although we confirm the presence of a residual radial-dependent emission associated with a central source, the relevance of the large-scale diffuse component prevents to claim a solid evidence of GC pevatrons.

Generating Single-Spike Hard X-Ray Pulses with Nonlinear Bunch Compression in Free-Electron Lasers.

A simple method for generating single-spike hard x-ray pulses in free-electron lasers (FELs) has been developed at the Linac Coherent Light Source (LCLS). This is realized by nonlinear bunch compression using 20-pC bunch charge, demonstrated in the hard x-ray regime at 5.6 and 9 keV, respectively. Measurements show about half of the FEL shots containing a single-spike spectrum. At 5.6-keV photon energy, the single-spike shots have a mean pulse energy of about 10 µJ with 70% intensity fluctuation and the pulse full width at half maximum is evaluated to be at 200-as level.

Dietary cyanidin 3-glucoside from purple corn ameliorates doxorubicin-induced cardiotoxicity in mice.

BACKGROUND AND AIMS: Anthracyclines are effective anticancer drugs that have improved prognosis of hundred thousand cancer patients worldwide and are currently the most common chemotherapeutic agents used for the treatment of blood, breast, ovarian and lung cancers. However, their use is limited because of a cumulative dose-dependent and irreversible cardiotoxicity that can cause progressive cardiomyopathy and congestive heart failure. Aim of the present study was to determine the cardioprotective activity of a dietary source of cyanidin 3-glucoside (C3G), such as purple corn, against doxorubicin (DOX)-induced cardiotoxicity in mice. METHODS AND RESULTS: In vitro studies on murine HL-1 cardiomyocytes showed that pretreatment with both pure C3G and purple corn extract improved survival upon DOX treatment. However, C3G and purple corn extract did not affect the cytotoxic effect of DOX on human cancer cell lines. We then validated in vivo the protective role of a C3G-enriched diet against DOX-induced cardiotoxicity by comparing the effect of dietary consumption of corn isogenic lines with high levels of anthocyanins (purple corn - Red diet - RD) or without anthocyanins (yellow corn - Yellow diet - YD) incorporated in standard rodent diets. Results showed that mice fed RD survived longer than mice fed YD upon injection of a toxic amount of DOX. In addition, ultrastructural analysis of hearts from mice fed RD showed reduced histopathological alterations. CONCLUSION: Dietary intake of C3G from purple corn protects mice against DOX-induced cardiotoxicity.

Serum dehydroepiandrosterone sulphate, psychosocial factors and musculoskeletal pain in workers.

Background: The serum level of dehydroepiandrosterone sulphate (DHEA-S) has been suggested as a biological marker of stress. Aims: To assess the association between serum DHEA-S, psychosocial factors and musculoskeletal (MS) pain in university workers. Methods: The study population included voluntary workers at the scientific departments of the University of Trieste (Italy) who underwent periodical health surveillance from January 2011 to June 2012. DHEA-S level was analysed in serum. The assessment tools included the General Health Questionnaire (GHQ) and a modified Nordic musculoskeletal symptoms questionnaire. The relation between DHEA-S, individual characteristics, pain perception and psychological factors was assessed by means of multivariable linear regression analysis. Results: There were 189 study participants. The study population was characterized by high reward and low effort. Pain perception in the neck, shoulder, upper limbs, upper back and lower back was reported by 42, 32, 19, 29 and 43% of people, respectively. In multivariable regression analysis, gender, age and pain perception in the shoulder and upper limbs were significantly related to serum DHEA-S. Effort and overcommitment were related to shoulder and neck pain but not to DHEA-S. The GHQ score was associated with pain perception in different body sites and inversely to DHEA-S but significance was lost in multivariable regression analysis. Conclusions: DHEA-S was associated with age, gender and perception of MS pain, while effort-reward imbalance dimensions and GHQ score failed to reach the statistical significance in multivariable regression analysis.

Association Between the Most Frequent Complications After Surgery for Stage I-III Colon Cancer and Short-Term Survival, Long-Term Survival, and Recurrences.

BACKGROUND: The purpose of this study was to identify the ten most frequent complications after surgery for stage I-III colon cancer and to assess the association between these complications and overall survival, conditional overall survival, and recurrences. METHODS: All patients who underwent surgery for stage I-III colon cancer in five hospitals in the Western region of the Netherlands were identified. Crude and adjusted Cox proportional hazards models were used to study the association between complications and 1-year overall survival, 5-year overall survival, 5-year conditional overall survival, and 5-year disease-free period. RESULTS: Data from 761 patients were used for the analyses. Complications were associated with decreased 1-year overall survival (hazard ratio (HR) 2.87, 95 % confidence interval (CI) 1.82-4.51; p < 0.001), 5-year overall survival (HR 1.59, 95 % CI 1.25-2.04; p < 0.001), and 5-year conditional overall survival (HR 1.34, 95 % CI 1.06-1.69; p = 0.016), whereas an increasing number of complications had no additional impact. Anastomotic leakage, excessive blood loss, and (abdominal) sepsis were associated with reduced 1-year overall survival, anastomotic leakage, delirium, abscess, and (abdominal) sepsis with reduced 5-year overall survival, and anastomotic leakage, delirium, and abscess with reduced 5-year conditional overall survival. Anastomotic leakage, electrolyte disorders, and abscess were risk factors for recurrence within five years. CONCLUSIONS: Our results demonstrate the serious impact of the most frequent complications after surgery for colon cancer on short-term and long-term outcomes. This study confirms the prolonged impact of surgery and demonstrates that complications result not only in reduced 1-year survival, but also in reduced long-term outcomes.

Optical Shaping of X-Ray Free-Electron Lasers.

In this Letter we report the experimental demonstration of a new temporal shaping technique for x-ray free-electron lasers (FELs). This technique is based on the use of a spectrally shaped infrared (IR) laser and allows optical control of the x-ray generation process. By accurately manipulating the spectral amplitude and phase of the IR laser, we can selectively modify the electron bunch longitudinal emittance thus controlling the duration of the resulting x-ray pulse down to the femtosecond time scale. Unlike other methods currently in use, optical shaping is directly applicable to the next generation of high-average power x-ray FELs such as the Linac Coherent Light Source-II or the European X-FEL, and it enables pulse shaping of FELs at the highest repetition rates. Furthermore, this laser-shaping technique paves the way for flexible tailoring of complex multicolor FEL pulse patterns required for nonlinear multidimensional x-ray spectroscopy as well as novel multicolor diffraction imaging schemes.

Experimental demonstration of a soft x-ray self-seeded free-electron laser.

The Linac Coherent Light Source has added a self-seeding capability to the soft x-ray range using a grating monochromator system. We report the demonstration of soft x-ray self-seeding with a measured resolving power of 2000-5000, wavelength stability of 10(-4), and an increase in peak brightness by a factor of 2-5 across the photon energy range of 500-1000 eV. By avoiding the need for a monochromator at the experimental station, the self-seeded beam can deliver as much as 50-fold higher brightness to users.

Correlated energy-spread removal with space charge for high-harmonic generation.

We study the effect of longitudinal space charge on the correlated energy spread of a relativistic high-brightness electron beam that has been density modulated for the emission of coherent, high-harmonic radiation. We show that, in the case of electron bunching induced by a laser modulator followed by a dispersive chicane, longitudinal space charge forces can act to strongly reduce the induced energy modulation of the beam without a significant reduction in the harmonic bunching content. This effect may be optimized to enhance the output power and overall performance of free-electron lasers that produce coherent light through high-gain harmonic generation. It also increases the harmonic number achievable in these devices, which are otherwise gain-limited by the induced energy modulation from the laser.

Demonstration of single-crystal self-seeded two-color x-ray free-electron lasers.

A scheme for generating two simultaneous hard-x-ray free-electron laser pulses with a controllable difference in photon energy is described and then demonstrated using the self-seeding setup at the Linac Coherent Light Source (LCLS). The scheme takes advantage of the existing LCLS equipment, which allows two independent rotations of the self-seeding diamond crystal. The two degrees of freedom are used to select two nearby crystal reflections, causing two wavelengths to be present in the forward transmitted seeding x-ray pulse. The free-electron laser system must support amplification at both desired wavelengths.

Attosecond-pump attosecond-probe x-ray spectroscopy of liquid water.

Attosecond-pump/attosecond-probe experiments have long been sought as the most straightforward method for observing electron dynamics in real time. Although there has been much success with overlapped near-infrared femtosecond and extreme ultraviolet attosecond pulses combined with theory, true attosecond-pump/attosecond-probe experiments have been limited. We used a synchronized attosecond x-ray pulse pair from an x-ray free-electron laser to study the electronic response to valence ionization in liquid water through all x-ray attosecond transient absorption spectroscopy (AX-ATAS). Our analysis showed that the AX-ATAS response is confined to the subfemtosecond timescale, eliminating any hydrogen atom motion and demonstrating experimentally that the 1b1 splitting in the x-ray emission spectrum is related to dynamics and is not evidence of two structural motifs in ambient liquid water.

Evolution of clinical nature, treatment and survival of locally recurrent rectal cancer: Comparative analysis of two national cross-sectional cohorts.

BACKGROUND: In the Netherlands, use of neoadjuvant radiotherapy for rectal cancer declined after guideline revision in 2014. This decline is thought to affect the clinical nature and treatability of locally recurrent rectal cancer (LRRC). Therefore, this study compared two national cross-sectional cohorts before and after the guideline revision with the aim to determine the changes in treatment and survival of LRRC patients over time. METHODS: Patients who underwent resection of primary rectal cancer in 2011 (n = 2094) and 2016 (n = 2855) from two nationwide cohorts with a 4-year follow up were included. Main outcomes included time to LRRC, synchronous metastases at time of LRRC diagnosis, intention of treatment and 2-year overall survival after LRRC. RESULTS: Use of neoadjuvant (chemo)radiotherapy for the primary tumour decreased from 88.5% to 60.0% from 2011 to 2016. The 3-year LRRC rate was not significantly different with 5.1% in 2011 (n = 114, median time to LRRC 16 months) and 6.3% in 2016 (n = 202, median time to LRRC 16 months). Synchronous metastasis rate did not significantly differ (27.2% vs 33.7%, p = 0.257). Treatment intent of the LRRC shifted towards more curative treatment (30.4% vs. 47.0%, p = 0.009). In the curatively treated group, two-year overall survival after LRRC diagnoses increased from 47.5% to 78.7% (p = 0.013). CONCLUSION: Primary rectal cancer patients in 2016 were treated less often with neoadjuvant (chemo)radiotherapy, while LRRC rates remained similar. Those who developed LRRC were more often candidate for curative intent treatment compared to the 2011 cohort, and survival after curative intent treatment also improved substantially.

Using the relativistic two-stream instability for the generation of soft-x-ray attosecond radiation pulses.

In this Letter we discuss a novel method for generating ultrashort radiation pulses using a broadband two-stream instability in an intense relativistic electron beam. This method relies on an electron beam having two distinct two-energy bands. The use of this new high brightness electron beam scenario, in combination with ultrashort soft x-ray pulses from high harmonic generation in gas, allows the production of high power attosecond pulses for ultrafast pump and probe experiments.

Single-shot coherent diffraction imaging of microbunched relativistic electron beams for free-electron laser applications.

With the advent of coherent x rays provided by the x-ray free-electron laser (FEL), strong interest has been kindled in sophisticated diffraction imaging techniques. In this Letter, we exploit such techniques for the diagnosis of the density distribution of the intense electron beams typically utilized in an x-ray FEL itself. We have implemented this method by analyzing the far-field coherent transition radiation emitted by an inverse-FEL microbunched electron beam. This analysis utilizes an oversampling phase retrieval method on the transition radiation angular spectrum to reconstruct the transverse spatial distribution of the electron beam. This application of diffraction imaging represents a significant advance in electron beam physics, having critical applications to the diagnosis of high-brightness beams, as well as the collective microbunching instabilities afflicting these systems.

Generation of coherent broadband photon pulses with a cascaded longitudinal space-charge amplifier.

The longitudinal space-charge amplifier has been recently proposed by Schneidmiller and Yurkov as an alternative to the free-electron laser instability for the generation of intense broadband radiation pulses [Phys. Rev. ST Accel. Beams 13, 110701 (2010)]. In this Letter, we report on the experimental demonstration of a cascaded longitudinal space-charge amplifier at optical wavelengths. Although seeded by electron beam shot noise, the strong compression of the electron beam along the three amplification stages leads to emission of coherent undulator radiation pulses exhibiting a single spectral spike and a single transverse mode. The on-axis gain is estimated to exceed 4 orders of magnitude with respect to spontaneous emission.

Multicolor operation and spectral control in a gain-modulated x-ray free-electron laser.

We show that the spectral properties of a self-amplified spontaneous emission x-ray free-electron laser can be controlled by modulating the gain in magnetic undulators, thus producing one or several spectral lines within a single few femtosecond pulse. By varying the magnetic field along the undulator and the electron beam transport line, the system we demonstrate can tailor the x-ray spectrum to optimally meet numerous experimental requirements for multicolor operation.

Echo-enabled x-ray vortex generation.

A technique to generate high-brightness electromagnetic vortices with tunable topological charge at extreme ultraviolet and x-ray wavelengths is described. Based on a modified version of echo-enabled harmonic generation for free-electron lasers, the technique uses two lasers and two chicanes to produce high-harmonic microbunching of a relativistic electron beam with a corkscrew distribution that matches the instantaneous helical phase structure of the x-ray vortex. The strongly correlated electron distribution emerges from an efficient three-dimensional recoherence effect in the echo-enabled harmonic generation transport line and can emit fully coherent vortices in a downstream radiator for access to new research in x-ray science.

Nonlinear longitudinal space charge oscillations in relativistic electron beams.

In this Letter we study the evolution of an initial periodic modulation in the temporal profile of a relativistic electron beam under the effect of longitudinal space-charge forces. Linear theory predicts a periodic exchange of the modulation between the density and the energy profiles at the beam plasma frequency. For large enough initial modulations, wave breaking occurs after 1/2 period of plasma oscillation leading to the formation of short current spikes. We confirm this effect by direct measurements on a ps-modulated electron beam from an rf photoinjector. These results are useful for the generation of intense electron pulse trains for advanced accelerator applications.