Abstract Relativistic electron-positron plasmas are ubiquitous in extreme astrophysical environments such as black-hole and neutron-star magnetospheres, where accretion-powered jets and pulsar winds ...are expected to be enriched with electron-positron pairs. Their role in the dynamics of such environments is in many cases believed to be fundamental, but their behavior differs significantly from typical electron-ion plasmas due to the matter-antimatter symmetry of the charged components. So far, our experimental inability to produce large yields of positrons in quasi-neutral beams has restricted the understanding of electron-positron pair plasmas to simple numerical and analytical studies, which are rather limited. We present the first experimental results confirming the generation of high-density, quasi-neutral, relativistic electron-positron pair beams using the 440 GeV/c beam at CERN’s Super Proton Synchrotron (SPS) accelerator. Monte Carlo simulations agree well with the experimental data and show that the characteristic scales necessary for collective plasma behavior, such as the Debye length and the collisionless skin depth, are exceeded by the measured size of the produced pair beams. Our work opens up the possibility of directly probing the microphysics of pair plasmas beyond quasi-linear evolution into regimes that are challenging to simulate or measure via astronomical observations.
The Galactic Centre contains a supermassive black hole with a mass of four million Suns
within an environment that differs markedly from that of the Galactic disk. Although the black hole is ...essentially quiescent in the broader context of active galactic nuclei, X-ray observations have provided evidence for energetic outbursts from its surroundings
. Also, although the levels of star formation in the Galactic Centre have been approximately constant over the past few hundred million years, there is evidence of increased short-duration bursts
, strongly influenced by the interaction of the black hole with the enhanced gas density present within the ring-like central molecular zone
at Galactic longitude |l| < 0.7 degrees and latitude |b| < 0.2 degrees. The inner 200-parsec region is characterized by large amounts of warm molecular gas
, a high cosmic-ray ionization rate
, unusual gas chemistry, enhanced synchrotron emission
, and a multitude of radio-emitting magnetized filaments
, the origin of which has not been established. Here we report radio imaging that reveals a bipolar bubble structure, with an overall span of 1 degree by 3 degrees (140 parsecs × 430 parsecs), extending above and below the Galactic plane and apparently associated with the Galactic Centre. The structure is edge-brightened and bounded, with symmetry implying creation by an energetic event in the Galactic Centre. We estimate the age of the bubbles to be a few million years, with a total energy of 7 × 10
ergs. We postulate that the progenitor event was a major contributor to the increased cosmic-ray density in the Galactic Centre, and is in turn the principal source of the relativistic particles required to power the synchrotron emission of the radio filaments within and in the vicinity of the bubble cavities.
To determine whether temozolomide is an active agent in the treatment of children with high-grade astrocytomas and whether survival is influenced by the expression of the ...O6-methylguanine-methyltransferase gene (MGMT) in these patients. In the Children's Oncology Group study ACNS0126, 107 patients with a diagnosis of anaplastic astrocytoma (AA), glioblastoma multiforme (GBM), or gliosarcoma were enrolled. All patients underwent concomitant chemoradiotherapy with temozolomide, followed by adjuvant chemotherapy with temozolomide. The outcomes were compared with those of children treated in Children's Cancer Group (CCG) study CCG-945. Formalin-fixed, paraffin-embedded tumor tissue was available in 71 cases for immunohistochemical analysis of MGMT expression. Ninety patients were deemed eligible, 31 with AA, 55 with GBM, and 4 with other eligible diagnoses. The 3-year event-free survival (EFS) and overall survival (OS) rates were 11 ± 3% and 22 ± 5%, respectively. There was no evidence that temozolomide given during radiation therapy and as adjuvant therapy resulted in improved EFS compared with that found in CCG-945 (p = 0.98). The 3-year EFS rate for AA was 13 ± 6% in ACNS0126 compared with 22 ± 5.5% in CCG-945 (p = 0.95). The 3-year EFS rate for GBM was 7 ± 4% in ACNS0126 compared with 15 ± 5% in CCG-945 (p = 0.77). The 2-year EFS rate was 17 ± 5% among patients without MGMT overexpression and 5 ± 4% among those with MGMT overexpression (p = 0.045). Temozolomide failed to improve outcome in children with high-grade astrocytomas. MGMT overexpression was adversely associated with survival.
New screening technologies and vaccination against human papillomavirus (HPV), the necessary cause of cervical cancer, may impact optimal approaches to prevent cervical cancer. We evaluated the ...cost-effectiveness of alternative screening strategies to inform cervical cancer prevention guidelines in Norway.
We leveraged the primary epidemiologic and economic data from Norway to contextualise a simulation model of HPV-induced cervical cancer. The current cytology-only screening was compared with strategies involving cytology at younger ages and primary HPV-based screening at older ages (31/34+ years), an option being actively deliberated by the Norwegian government. We varied the switch-age, screening interval, and triage strategies for women with HPV-positive results. Uncertainty was evaluated in sensitivity analysis.
Current cytology-only screening was less effective and more costly than strategies that involve switching to primary HPV testing in older ages. For unvaccinated women, switching at age 34 years to primary HPV testing every 4 years was optimal given the Norwegian cost-effectiveness threshold ($83,000 per year of life saved). For vaccinated women, a 6-year screening interval was cost-effective. When we considered a wider range of strategies, we found that an earlier switch to HPV testing (at age 31 years) may be preferred.
Strategies involving a switch to HPV testing for primary screening in older women is expected to be cost-effective compared with current recommendations in Norway.
Summary
To address uncertainty of whether clinical stage groupings (cTNM) for esophageal cancer share prognostic implications with pathologic groupings after esophagectomy alone (pTNM), we report ...data—simple descriptions of patient characteristics, cancer categories, and non–risk‐adjusted survival—for clinically staged patients from the Worldwide Esophageal Cancer Collaboration (WECC). Thirty‐three institutions from six continents submitted data using variables with standard definitions: demographics, comorbidities, clinical cancer categories, and all‐cause mortality from first management decision. Of 22,123 clinically staged patients, 8,156 had squamous cell carcinoma, 13,814 adenocarcinoma, 116 adenosquamous carcinoma, and 37 undifferentiated carcinoma. Patients were older (62 years) men (80%) with normal body mass index (18.5–25 mg/kg2, 47%), little weight loss (2.4 ± 7.8 kg), 0‐1 ECOG performance status (67%), and history of smoking (67%). Cancers were cT1 (12%), cT2 (22%), cT3 (56%), cN0 (44%), cM0 (95%), and cG2‐G3 (89%); most involved the distal esophagus (73%). Non–risk‐adjusted survival for squamous cell carcinoma was not distinctive for early cT or cN; for adenocarcinoma, it was distinctive for early versus advanced cT and for cN0 versus cN+. Patients with early cancers had worse survival and those with advanced cancers better survival than expected from equivalent pathologic categories based on prior WECC pathologic data. Thus, clinical and pathologic categories do not share prognostic implications. This makes clinically based treatment decisions difficult and pre‐treatment prognostication inaccurate. These data will be the basis for the 8th edition cancer staging manuals following risk adjustment for patient characteristics, cancer categories, and treatment characteristics and should direct 9th edition data collection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Patients with locally advanced rectal cancer (LARC) and synchronous liver metastases (sRLM) can be treated according to the liver-first approach. This study aimed to evaluate prognostic factors for ...completing treatment and in how many patients extensive lower pelvic surgery might have been omitted.
Retrospective analysis of all patients with LARC and sRLM treated at the Erasmus MC Cancer Institute according to the liver-first between 2003 and 2016.
In total 129 consecutive patients were included. In 90 patients (70%) the liver-first was completed. Ten patients had a (near) complete response (ypT0-1N0) of their primary tumour. In 36 out of 39 patients not completing the liver-first protocol palliative rectum resection was withheld. Optimal cut-offs for CEA level (53.15 μg/L), size (3.85 cm) and number (4) of RLMs were identified. A preoperative CEA level above 53.15 μg/L was an independent predictor for non-completion of the liver-first protocol (p = 0.005).
Ten patients had a (near) complete response of their primary tumour and, in retrospect, rectum sparing therapies could have been considered. Together with 36 patient in whom palliative rectum resection was not necessary this entails that nearly 40% patients with LARC and sRLM might be spared major pelvic surgery if the liver-first approach is applied. A predictor (CEA) was found for non-completion of the liver-first protocol. The majority of patients underwent resection of both primary tumour and hepatic metastasis with curative intent. These findings together entail that the liver-first approach may be considered in patients with LARC and sRLM.
Background
Abdominoperineal resection (APR) carries a high risk of perineal wound morbidity. Perineal wound closure using autologous tissue flaps has been shown to be advantageous, but there is no ...consensus as to the optimal method. The aim of this study was to evaluate the feasibility of a novel gluteal turnover flap (GT-flap) without donor site scar for perineal closure after APR.
Methods
Consecutive patients who underwent APR for primary or recurrent rectal cancer were included in a prospective non-randomised pilot study in two academic centres. Perineal reconstruction consisted of a unilateral subcutaneous GT-flap, followed by midline closure. Feasibility was defined as uncomplicated perineal wound healing at 30 days in at least five patients, and a maximum of two flap failures.
Results
Out of 17 potentially eligible patients, 10 patients underwent APR with GT-flap-assisted perineal wound closure. Seven patients had pre-operative radiotherapy. Median-added theatre time was 38 min (range 35–44 min). Two patients developed a superficial perineal wound dehiscence, most likely because of the excessive width of the skin island. Two other patients developed purulent discharge and excessive serosanguinous discharge, respectively, resulting in four complicated wounds at 30 days. No flap failure occurred, and no radiological or surgical reinterventions were performed. Median length of hospital stay was 10 days (IQR 8–12 days).
Conclusions
The GT-flap for routine perineal wound closure after APR seems feasible with limited additional theatre time, but success seems to depend on correct planning of the width of the flap. The potential for reducing perineal morbidity should be evaluated in a randomised controlled trial.
Aims
Everolimus is a drug from the class of mammalian target of rapamycin inhibitors used for both immunosuppressant and oncological indications. We postulate that there is room for improvement of ...dosing, as the optimal immunosuppressive dose in calcineurin‐free regimens is unknown and since the once daily dosing regimen for oncological indications is often associated with treatment‐limiting toxicity.
Methods
We developed a mechanistic population pharmacokinetic model for everolimus in cancer and transplant patients and explored alternative dosing regimens.
Results
We found that formulation did not influence bioavailability and that use of >20 mg prednisolone daily increased everolimus clearance. In transplant patients, the approved dose of 0.75–1 mg twice daily (BID) results in subtherapeutic trough levels (<6 μg l–1) and that a higher starting dose of 2.25–3 mg BID is required.
Conclusion
For oncological indications, our results encourage the investigation of dosing everolimus 3.75 mg BID in terms of superiority in safety and noninferiority in efficacy.
Gradient and curvature drift play a key role in the modulation of cosmic rays. Reduction in the drift coefficient due to turbulence has been demonstrated unambiguously through direct numerical ...simulations, but a theory that can explain these results is still lacking. We introduce a parameterized form of the drift coefficient based on direct numerical simulations and show that good agreement with observed proton energy spectra at Earth can be found when it is used in a numerical modulation model. We show that the turbulence ultrascale, for which no observations currently exist, plays an important role in drift reduction. The magnitude at Earth and spatial dependence of this quantity required to fit cosmic-ray observations at Earth are argued to be plausible based on the required properties of the two-dimensional turbulence spectrum at large scales.
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