Free-electron lasing with compact beam-driven plasma wakefield accelerator.

The possibility to accelerate electron beams to ultra-relativistic velocities over short distances by using plasma-based technology holds the potential for a revolution in the field of particle accelerators1-4. The compact nature of plasma-based accelerators would allow the realization of table-top machines capable of driving a free-electron laser (FEL)5, a formidable tool to investigate matter at the sub-atomic level by generating coherent light pulses with sub-ångström wavelengths and sub-femtosecond durations6,7. So far, however, the high-energy electron beams required to operate FELs had to be obtained through the use of conventional large-size radio-frequency (RF) accelerators, bound to a sizeable footprint as a result of their limited accelerating fields. Here we report the experimental evidence of FEL lasing by a compact (3-cm) particle-beam-driven plasma accelerator. The accelerated beams are completely characterized in the six-dimensional phase space and have high quality, comparable with state-of-the-art accelerators8. This allowed the observation of narrow-band amplified radiation in the infrared range with typical exponential growth of its intensity over six consecutive undulators. This proof-of-principle experiment represents a fundamental milestone in the use of plasma-based accelerators, contributing to the development of next-generation compact facilities for user-oriented applications9.

Incidence of persistent postoperative opioid use in patients undergoing ambulatory surgery: a retrospective cohort study.

The opioid crisis remains a major public health concern. In ambulatory surgery, persistent postoperative opioid use is poorly described and temporal trends are unknown. A population-based retrospective cohort study was undertaken in Ontario, Canada using routinely collected administrative data for adults undergoing ambulatory surgery between 1 January 2013 and 31 December 2017. The primary outcome was persistent postoperative opioid use, defined using best-practice methods. Multivariable generalised linear models were used to estimate the association of persistent postoperative opioid use with prognostic factors. Temporal trends in opioid use were examined using monthly time series, adjusting for patient-, surgical- and hospital-level variables. Of 340,013 patients, 44,224 (13.0%, 95%CI 12.9-13.1%) developed persistent postoperative opioid use after surgery. Following multivariable adjustment, the strongest predictors of persistent postoperative opioid use were pre-operative: utilisation of opioids (OR 9.51, 95%CI 8.69-10.39); opioid tolerance (OR 88.22, 95%CI 77.21-100.79); and utilisation of benzodiazepines (OR 13.75, 95%CI 12.89-14.86). The time series model demonstrated a small but significant trend towards decreasing persistent postoperative opioid use over time (adjusted percentage change per year -0.51%, 95%CI -0.83 to -0.19%, p = 0.003). More than 10% of patients who underwent ambulatory surgery experienced persistent postoperative opioid use; however, there was a temporal trend towards a reduction in persistent opioid use after surgery. Future studies are needed that focus on interventions which reduce persistent postoperative opioid use.

Stable Operation of a Free-Electron Laser Driven by a Plasma Accelerator.

The breakthrough provided by plasma-based accelerators enabled unprecedented accelerating fields by boosting electron beams to gigaelectronvolt energies within a few centimeters [1-4]. This, in turn, allows the realization of ultracompact light sources based on free-electron lasers (FELs) [5], as demonstrated by two pioneering experiments that reported the observation of self-amplified spontaneous emission (SASE) driven by plasma-accelerated beams [6,7]. However, the lack of stability and reproducibility due to the intrinsic nature of the SASE process (whose amplification starts from the shot noise of the electron beam) may hinder their effective implementation for user purposes. Here, we report a proof-of-principle experiment using plasma-accelerated beams to generate stable and reproducible FEL light seeded by an external laser. FEL radiation is emitted in the infrared range, showing the typical exponential growth of its energy over six consecutive undulators. Compared to SASE, the seeded FEL pulses have energies 2 orders of magnitude larger and stability that is 3 times higher.

Long-term outcomes and safety after reirradiation in locally recurrent nasopharyngeal carcinoma in a non-endemic area.

PURPOSE: To determine outcomes and toxicities after reirradiation for locally recurrent nasopharyngeal carcinoma (rNPC) and to apply a prognostic index in a non-endemic region. METHODS: We retrospectively reported progression-free survival (PFS), overall survival (OS), and treatment-related toxicities in patients treated with curative intent for locally rNPC. We applied the prognostic model for OS and grade 5 radiotherapy (RT)-related toxicities published by Li et al. and evaluated its prognostic accuracy by receiver operating characteristic (ROC) curve analysis. RESULTS: Between 2005 and 2018, 33 patients were treated for rNPC in our institution. Median follow-up was 60 months. The mean time to local recurrence was 75 months. Six (18%) patients had a persistent grade 3 toxicity from a previous RT course. The median re-RT dose was 66 Gy. After re-RT, 13 patients had local failure and 3 patients had metastatic recurrence. Median PFS was 18 months with a 5-year PFS rate of 29%. Median OS was 35 months with a 5-year OS rate of 37%. Grade 3 or higher toxicities rate was 74%. There were 21% grade 5 toxicities. The median time to a grade 5 toxicity was less than 6 months following re-RT. The prognostic nomogram was not predictive for OS or grade 5 toxicities. CONCLUSION: Reirradiation of rNPC is an effective treatment but is associated with a high rate of life-threatening toxicity. Stratification of patients based on their risk of developing severe toxicity is needed to select patients who will most likely benefit from re-RT.

Epidemiology of systematic reviews in imaging journals: evaluation of publication trends and sustainability?

PURPOSE: To evaluate the epidemiology of systematic reviews (SRs) published in imaging journals. METHODS: A MEDLINE search identified SRs published in imaging journals from 1 January 2000-31 December 2016. Articles retrieved were screened against inclusion criteria. Demographic and methodological characteristics were extracted from studies. Temporal trends were evaluated using linear regression and Pearson's correlation coefficients. RESULTS: 921 SRs were included that reported on 27,435 primary studies, 85,276,484 patients and were cited 26,961 times. The SR publication rate increased 23-fold (r=0.92, p<0.001) while the proportion of SRs to non-SRs increased 13-fold (r = 0.94, p<0.001) from 2000 (0.10%) to 2016 (1.33%). Diagnostic test accuracy (DTA) SRs were most frequent (46.5%) followed by therapeutic SRs (16.6%). Most SRs did not report funding status (54.2%). The median author team size was five; this increased over time (r=0.20, p<0.001). Of the studies, 67.3% included an imaging specialist co-author; this decreased over time (r=-0.57, p=0.017). Most SRs included a meta-analysis (69.6%). Journal impact factor positively correlated with SR publication rates (r=0.54, p<0.001). Magnetic resonance imaging (MRI) and 'vascular and interventional radiology' were the most frequently studied imaging modality and subspecialty, respectively. The USA, UK, China, Netherlands and Canada were the top five publishing countries. CONCLUSIONS: The SR publication rate is increasing rapidly compared with the rate of growth of non-SRs; however, they still make up just over 1% of all studies. Authors, reviewers and editors should be aware of methodological and reporting standards specific to imaging systematic reviews including those for DTA and individual patient data. KEY POINTS: • Systematic review publication rate has increased 23-fold from 2000-2016. • The proportion of systematic reviews to non-systematic reviews has increased 13-fold. • The USA, UK and China are the most frequent published countries; those from the USA and China are increasing the most rapidly.

Reporting bias in imaging: higher accuracy is linked to faster publication.

OBJECTIVES: The objective of this study was to evaluate whether higher reported accuracy estimates are associated with shorter time to publication among imaging diagnostic accuracy studies. METHODS: We included primary imaging diagnostic accuracy studies, included in meta-analyses from systematic reviews published in 2015. For each primary study, we extracted accuracy estimates, participant recruitment periods and publication dates. Our primary outcome was the association between Youden's index (sensitivity + specificity - 1, a single measure of diagnostic accuracy) and time to publication. RESULTS: We included 55 systematic reviews and 781 primary studies. Study completion dates were missing for 238 (30%) studies. The median time from completion to publication in the remaining 543 studies was 20 months (IQR 14-29). Youden's index was negatively correlated with time from completion to publication (rho = -0.11, p = 0.009). This association remained significant in multivariable Cox regression analyses after adjusting for seven study characteristics: hazard ratio of publication was 1.09 (95% CI 1.03-1.16, p = 0.004) per unit increase for logit-transformed estimates of Youden's index. When dichotomizing Youden's index by a median split, time from completion to publication was 20 months (IQR 13-33) for studies with a Youden's index below the median, and 19 months (14-27) for studies with a Youden's index above the median (p = 0.104). CONCLUSION: Imaging diagnostic accuracy studies with higher accuracy estimates were weakly associated with a shorter time to publication. KEY POINTS: • Higher accuracy estimates are weakly associated with shorter time to publication. • Lag in time to publication remained significant in multivariate Cox regression analyses. • No correlation between accuracy and time from submission to publication was identified.

Compton Scattered X-Gamma Rays with Orbital Momentum.

We study the possibility of producing x-gamma rays with orbital angular momentum by means of the inverse Compton backscattering between a high brightness electron beam and a twisted laser pulse. We use the classical electrodynamics retarded fields for evaluating the orbital angular momentum of the radiation and connecting it to that of the primary laser pulse. We then propose the dimensioning of a linearly polarized x-ray source with orbital angular momentum, starting from the parameters of operating Thomson setups.

Canine mammary tumors: a review and consensus of standard guidelines on epithelial and myoepithelial phenotype markers, HER2, and hormone receptor assessment using immunohistochemistry.

Although there have been several studies on the use of immunohistochemical biomarkers of canine mammary tumors (CMTs), the results are difficult to compare. This article provides guidelines on the most useful immunohistochemical markers to standardize their use and understand how outcomes are measured, thus ensuring reproducibility of results. We have reviewed the biomarkers of canine mammary epithelial and myoepithelial cells and identified those biomarkers that are most useful and those biomarkers for invasion and lymph node micrometastatic disease. A 10% threshold for positive reaction for most of these markers is recommended. Guidelines on immunolabeling for HER2, estrogen receptors (ERs), and progesterone receptors (PRs) are provided along with the specific recommendations for interpretation of the results for each of these biomarkers in CMTs. Only 3+ HER2-positive tumors should be considered positive, as found in human breast cancer. The lack of any known response to adjuvant endocrine therapy of ER- and PR-positive CMTs prevents the use of the biological positive/negative threshold used in human breast cancer. Immunohistochemistry results of ER and PR in CMTs should be reported as the sum of the percentage of positive cells and the intensity of immunolabeling (Allred score). Incorporation of these recommendations in future studies, either prospective or retrospective, will provide a mechanism for the direct comparison of studies and will help to determine whether these biomarkers have prognostic significance. Finally, these biomarkers may ascertain the most appropriate treatment(s) for canine malignant mammary neoplasms.

Independent and functional validation of a multi-tumour-type proliferation signature.

BACKGROUND: Previously we demonstrated that an mRNA signature reflecting cellular proliferation had strong prognostic value. As clinical applicability of signatures can be controversial, we sought to improve our marker's clinical utility by validating its biological relevance, reproducibility in independent data sets and applicability using an independent technique. METHODS: To facilitate signature evaluation with quantitative PCR (qPCR) a novel computational procedure was used to reduce the number of signature genes without significant information loss. These genes were validated in different human cancer cell lines upon serum starvation and in a 168 xenografts panel. Analyses were then extended to breast cancer and non-small-cell lung cancer (NSCLC) patient cohorts. RESULTS: Expression of the qPCR-based signature was dramatically decreased under starvation conditions and inversely correlated with tumour volume doubling time in xenografts. The signature validated in breast cancer (hazard ratio (HR)=1.63, P<0.001, n=1820) and NSCLC adenocarcinoma (HR=1.64, P<0.001, n=639) microarray data sets. Lastly, qPCR in a node-negative, non-adjuvantly treated breast cancer cohort (n=129) showed that patients assigned to the high-proliferation group had worse disease-free survival (HR=2.25, P<0.05). CONCLUSION: We have developed and validated a qPCR-based proliferation signature. This test might be used in the clinic to select (early-stage) patients for specific treatments that target proliferation.

Widely tunable, nondegenerate three-wave mixing microwave device operating near the quantum limit.

We present the first experimental realization of a widely frequency tunable, nondegenerate three-wave mixing device for quantum signals at gigahertz frequency. It is based on a new superconducting building block consisting of a ring of four Josephson junctions shunted by a cross of four linear inductances. The phase configuration of the ring remains unique over a wide range of magnetic fluxes threading the loop. It is thus possible to vary the inductance of the ring with flux while retaining a strong, dissipation-free, and noiseless nonlinearity. The device has been operated in amplifier mode, and its noise performance has been evaluated by using the noise spectrum emitted by a voltage-biased tunnel junction at finite frequency as a test signal. The unprecedented accuracy with which the crossover between zero-point fluctuations and shot noise has been measured provides an upper bound for the noise and dissipation intrinsic to the device.

Colorectal hamartomatous polyposis and ganglioneuromatosis in a dog.

A 5-month-old female Great Dane puppy was treated for hematochezia, tenesmus, and rectal prolapse by resection of a 10-cm-long segment of colon and rectum. Grossly, the colorectal segment had diffuse mucosal and submucosal thickening with multiple polypoid nodules. The histologic diagnosis was colorectal hamartomatous polyps with ganglioneuromatosis. Duplication of PTEN was detected by quantitative multiplex polymerase chain reaction testing. The presence of 2 hamartomatous colorectal lesions with PTEN mutation is similar to human Cowden syndrome.

Characterizing most irregular small-scale structures in turbulence using local Hölder exponents.

Two scalar fields characterizing respectively pseudo-Hölder exponents and local energy transfers are used to capture the topology and the dynamics of the velocity fields in areas of lesser regularity. The present analysis is conducted using velocity fields from two direct numerical simulations of the Navier-Stokes equations in a triply periodic domain. A typical irregular structure is obtained by averaging over the 213 most irregular events. Such structure is similar to a Burgers vortex, with nonaxisymmetric corrections. A possible explanation for such asymmetry is provided by a detailed time-resolved analysis of birth and death of the irregular structures, which shows that they are connected to vortex interactions, possibly vortex reconnection.

[Individualization of dose and fractionation of radiotherapy for head and neck cancers]. / Personnalisation de la dose et du fractionnement de la radiothérapie des cancers de la tête et du cou.

Head and neck cancers comprise a variety of tumours depending on the sub-site, for which target volumes and the prescribed doses need to be individualized according to each patient's history and presentation. This article aims at describing the main factors involved in decision-making regarding dose and volume, as well as ongoing research. Contouring and treatment guidelines, use of altered fractionation, major prognostic factors, the role of Human papillomavirus and of functional imaging will be presented and discussed.

Local estimates of Hölder exponents in turbulent vector fields.

It is still not known whether solutions to the Navier-Stokes equation can develop singularities from regular initial conditions. In particular, a classical and unsolved problem is to prove that the velocity field is Hölder continuous with some exponent h<1 (i.e., not necessarily differentiable) at small scales. Different methods have already been proposed to explore the regularity properties of the velocity field and the estimate of its Hölder exponent h. A first method is to detect potential singularities via extrema of an "inertial" dissipation D*=lim_{ℓ→0}D_{ℓ}^{I} that is independent of viscosity [Duchon and Robert, Nonlinearity 13, 249 (2000)0951-771510.1088/0951-7715/13/1/312]. Another possibility is to use the concept of multifractal analysis that provides fractal dimensions of the subspace of exponents h. However, the multifractal analysis is a global statistical method that only provides global information about local Hölder exponents, via their probability of occurrence. In order to explore the local regularity properties of a velocity field, we have developed a local statistical analysis that estimates locally the Hölder continuity. We have compared outcomes of our analysis with results using the inertial energy dissipation D_{ℓ}^{I}. We observe that the dissipation term indeed gets bigger for velocity fields that are less regular according to our estimates. The exact spatial distribution of the local Hölder exponents however shows nontrivial behavior and does not exactly match the distribution of the inertial dissipation.

Interactions between cancer-associated fibroblasts and tumor cells promote MCL-1 dependency in estrogen receptor-positive breast cancers.

Selective inhibition of BCL-2 is expected to enhance therapeutic vulnerability in luminal estrogen receptor-positive breast cancers. We show here that the BCL-2 dependency of luminal tumor cells is nevertheless mitigated by breast cancer-associated fibroblasts (bCAFs) in a manner that defines MCL-1 as another critical therapeutic target. bCAFs favor MCL-1 expression and apoptotic resistance in luminal cancer cells in a IL-6 dependent manner while their own, robust, survival also relies on MCL-1. Studies based on ex vivo cultures of human luminal breast cancer tissues further argue that the contribution of stroma-derived signals to MCL-1 expression shapes BCL-2 dependency. Thus, MCL-1 inhibitors are beneficial for targeted apoptosis of breast tumor ecosystems, even in a subtype where MCL-1 dependency is not intrinsically driven by oncogenic pathways.

[Patients' preferences and decision-making: state of the art and applications in cancer]. / Préférences des patients et prise de décision : état des lieux et retour d'expérience en cancérologie.

BACKGROUND: This paper deals with the physician-patient encounter. In France, the current legal framework allows patients to be informed (patients' rights to health information) and to participate to decisions regarding their own health. In such a context, this paper aims to give the reader the broad key components of the so-called 'patient treatment preferences elicitation process' in breast cancer, our research area. METHODS AND RESULTS: We first present the general context, with a definition of the different physician-patient models. We then present decision aids, tools that aim to provide high-quality information to patients in the decision-making process. Finally, based on our previous studies and on examples drawn from the international literature, we present the empirical process of patients' preferences elicitation, which not only increases patients' knowledge of and satisfaction with the decision made, but also allows patients to be part of their disease management. CONCLUSION: Far from being a phenomenon in the air supported by a legal system, this method developed in the 90s allows patients and more generally healthcare users to be autonomous without constraining them to a choice.

[New developments in the management of nasopharyngeal carcinoma]. / Nouveautés dans la prise en charge des carcinomes nasopharyngés.

Nasopharyngeal carcinoma is a rare condition, with less than 300 cases occurring per year in France. Its treatment can be difficult due to the importance of side effects, but tumor control is usually excellent following a well conducted chemoradiotherapy. This article summarizes the recent advances in nasopharyngeal cancer diagnosis, classification, treatment, surveillance and management of recurrences. Chemotherapy timing is discussed, along with arguments in favor of induction chemotherapy in locally advanced cases. As a survival advantage has been suggested for when patients are treated in high volume center it seems reasonable to refer these young patients for treatment to tertiary expert centers, especially given the low incidence of the disease.

[Preoperative treatments of rectal cancers]. / Traitements préopératoires des cancers rectaux.

Surgery alone is no longer appropriate to the treatment of T3-T4 resecable rectal cancer. Preoperative chemoradiotherapy has recently been approved as the new standard treatment. This approach improves local control with local failure rate raranging now around 6-8%. However, it does not impact on overall survival. It becomes urgent to develop new concepts and a basic research in the understanding of the biological mechanisms that may explain the resistance of the micrometastatic process.

Production and characterization of monoclonal antibodies specific for canine CD138 (syndecan-1) for nuclear medicine preclinical trials on spontaneous tumours.

We isolated 11 antibodies specific for canine CD138 (cCD138) to validate the interest of CD138 antigen targeting in dogs with spontaneous mammary carcinoma. The affinity of the monoclonal antibodies in the nanomolar range is suitable for immunohistochemistry and nuclear medicine applications. Four distinct epitopes were recognized on cCD138 by this panel of antibodies. CD138 expression in canine healthy tissues is comparable to that reported in humans. CD138 is frequently expressed in canine mammary carcinomas corresponding to the human triple negative breast cancer subtype, with cytoplasmic and membranous expression. In canine diffuse large B-cell lymphoma, CD138 expression is associated with the 'non-germinal center' phenotype corresponding to the most aggressive subtype in humans. This homology of CD138 expression between dogs and humans confirms the relevance of tumour-bearing dogs as spontaneous models for nuclear medicine applications, especially for the evaluation of new tumour targeting strategies for diagnosis by phenotypic imaging and radio-immunotherapy.

Polymorphonuclear functions in Hodgkin's disease patients at diagnosis, in remission, and in relapse.

Five tests investigating different aspects of the nonspecific defense mechanisms including capillary tube random migration, particle ingestion activity, quantitative and histochemical nitroblue tetrazolium dye reduction by polymorphonuclear neutrophils, and serum lysozyme concentrations were performed in 46 patients with Hodgkin's disease. The anomalies observed in the active stage of the disease consisted of a decreased random migration, a high level of serum lysozyme, and an increased nitroblue tetrazolium reduction by resting phagocytes associated with a decrease in nitroblue tetrazolium reduction by stimulated phagocytes. The particle ingestion activity was normal. The serum lysozyme assay was the only test observed to normalize in the group of patients in remission. Its determination, therefore, offers an additional means of evaluating disease activity.