The Spectral Shape and Photon Fraction as Signatures of the GZK-Cutoff

With the prospect of measuring the fraction of arriving secondary photons, produced through photo-pion energy loss interactions of ultra high energy cosmic ray (UHECR) protons with the microwave background during propagation, we investigate how information about the local UHECR source distribution can be inferred from the primary (proton) to secondary (photon) ratio. As an aid to achieve this, we develop an analytic description for both particle populations as a function of propagation time. Through a consideration of the shape of the GZK cut-off and the corresponding photon fraction curve, we investigate the different results expected for both different maximum proton energies injected by the sources, as well as a change in the local source distribution following a perturbative deformation away from a homogeneous description. At the end of the paper, consideration is made as to how these results are modified through extra-galactic magnetic field effects on proton propagation. The paper aims to demonstrate how the shape of the cosmic ray flux in the cut-off region, along with the photon fraction, are useful indicators of the cutoff origin as well as the local UHECR source distribution.Comment: Accepted for publication in PRD, 12 pages, 9 figure

Cabozantinib and Axitinib After Vascular Endothelial Growth Factor Therapy in Patients with Advanced Renal Cell Carcinoma: A Retrospective Cohort Study from England

Background and Objective: The tyrosine kinase inhibitors cabozantinib and axitinib have been widely used in England to treat advanced renal cell carcinoma following prior vascular endothelial growth factor-targeted therapy, but data on real-world usage remain limited. Our objective was to describe the real-world treatment patterns and outcomes of patients with advanced renal cell carcinoma who received second-line or later-line (≥ 2L) cabozantinib or axitinib after vascular endothelial growth factor-targeted therapy in clinical practice in England. Methods: This retrospective cohort study used clinical practice data (collected 2011–20) from the English Cancer Analysis System database. Patient characteristics, treatment sequence and duration, and overall survival (time from initiation of cabozantinib/axitinib treatment to death) were evaluated. Results: Data from 1485 eligible adults with advanced renal cell carcinoma were analyzed: 440 received ≥ 2L cabozantinib (2L for 88.6% of them); 1045 received ≥ 2L axitinib (2L for 89.5%). The most common first-line treatments were sunitinib (2L cabozantinib subcohort, 48%; 2L axitinib subcohort, 46%) and pazopanib (46% and 54%, respectively); nivolumab was the most common third-line treatment (18% and 19%, respectively). Median (interquartile range) 2L therapy duration was 5.52 (2.73–11.74) months for cabozantinib and 4.60 (1.45–12.36) months for axitinib. Following adjustment for potential confounders using inverse probability weighting, overall survival (median [interquartile range]) was longer for ≥ 2L cabozantinib (11.2 [5.7–28.0] months) than for ≥ 2L axitinib (10.4 [4.7–22.0] months; log-rank p = 0.0034). Conclusions: The Cancer Analysis System database is a valuable research resource providing extensive real-world clinical data. Real-world overall survival was longer with ≥ 2L cabozantinib than with axitinib. Clinical Trial Registration: ClinicalTrials.gov, NCT04637204; registered November 2020

Dismantling the present and future threats of testicular cancer: a grounded theory of positive and negative adjustment trajectories

Testicular cancer commonly affects men in the prime of their lives. While survival rates are excellent, little previous research has examined men’s experiences of adjustment to survivorship. We aimed to explore this issue in younger testicular cancer survivors

Randomized phase II study investigating pazopanib versus weekly paclitaxel in relapsed or progressive urothelial cancer

Purpose: Two previous single-arm trials have drawn conflicting conclusions regarding the activity of pazopanib in urothelial cancers after failure of platinum-based chemotherapy. Patients and Methods: This randomized (1:1) open-label phase II trial compared the efficacy of pazopanib 800 mg orally with paclitaxel (80 mg/m2 days 1, 8, and 15 every 28 days) in the second-line setting. The primary end point was overall survival (OS). Results: Between August 2012 and October 2014, 131 patients, out of 140 planned, were randomly assigned. The study was terminated early on the recommendation of the independent data monitoring committee because of futility. Final analysis after the preplanned number of deaths (n = 110) occurred after a median follow-up of 18 months. One hundred fifteen deaths had occurred at the final data extract presented here. Median OS was 8.0 months for paclitaxel (80% CI, 6.9 to 9.7 months) and 4.7 months for pazopanib (80% CI, 4.2 to 6.4 months). The hazard ratio (HR) adjusted for baseline stratification factors was 1.28 (80% CI, 0.99 to 1.67; one-sided P = .89). Median progression-free survival was 4.1 months for paclitaxel (80% CI, 3.0 to 5.6 months) and 3.1 months for pazopanib (80% CI, 2.7 to 4.6 months; HR, 1.09; 80% CI, 0.85 to 1.40; one-sided P = .67). Discontinuations for toxicity occurred in 7.8% and 23.1% for paclitaxel and pazopanib, respectively. Conclusion: Pazopanib did not have greater efficacy than paclitaxel in the second-line treatment of urothelial cancers. There was a trend toward superior OS for paclitaxel

A Bayesian analysis of the 27 highest energy cosmic rays detected by the Pierre Auger Observatory

It is possible that ultra-high energy cosmic rays (UHECRs) are generated by active galactic nuclei (AGNs), but there is currently no conclusive evidence for this hypothesis. Several reports of correlations between the arrival directions of UHECRs and the positions of nearby AGNs have been made, the strongest detection coming from a sample of 27 UHECRs detected by the Pierre Auger Observatory (PAO). However, the PAO results were based on a statistical methodology that not only ignored some relevant information (most obviously the UHECR arrival energies but also some of the information in the arrival directions) but also involved some problematic fine-tuning of the correlation parameters. Here we present a fully Bayesian analysis of the PAO data (collected before 2007 September), which makes use of more of the available information, and find that a fraction F_AGN = 0.15^(+0.10)_(-0.07) of the UHECRs originate from known AGNs in the Veron-Cetty & Veron (VCV) catalogue. The hypothesis that all the UHECRs come from VCV AGNs is ruled out, although there remains a small possibility that the PAO-AGN correlation is coincidental (F_AGN = 0.15 is 200 times as probable as F_AGN = 0.00).Comment: MNRAS, accepted; 8 pages, 7 figure

The Lick Planet Search: Detectability and Mass Thresholds

We analyse 11 years of precise radial velocities for 76 solar type stars from the Lick survey. Eight stars in this sample have previously reported planetary-mass companions, all with mass (m sin i) less than 8 Jupiter masses (MJ). For the stars without a detected companion, we place upper limits on possible companion mass. For most stars, we can exclude companions with m sin i > 0.7 MJ (a/AU)^1/2 for orbital radii a < 5 AU. We use our results to interpret the observed masses and orbital radii of planetary-mass companions. For example, we show that the finite duration of the observations makes detection of Jupiter mass companions more and more difficult for orbital radii beyond 3 AU. Thus it is possible that the majority of solar type stars harbor Jupiter-mass companions much like our own, and if so these companions should be detectable in a few years. To search for periodicities, we adopt a "floating-mean" periodogram, which improves on the traditional Lomb-Scargle periodogram by accounting for statistical fluctuations in the mean of a sampled sinusoid. We discuss in detail the normalization of the periodogram, an issue which has been of some debate in the literature.Comment: To appear in the Astrophysical Journal (50 pages, LaTeX, including 11 figures

Posttransplant MRD and T-cell chimerism status predict outcomes in patients who received allografts for AML/MDS

Allogeneic stem-cell transplant allows for the delivery of curative graft-versus-leukemia (GVL) in patients with acute myeloid leukemia/myelodysplasia (AML/MDS). Surveillance of T-cell chimerism, measurable residual disease (MRD) and blast HLA-DR expression may inform whether GVL effectiveness is reduced. We report here the prognostic impact of these biomarkers in patients allografted for AML/MDS. One hundred eighty-seven patients from FIGARO, a randomized trial of reduced-intensity conditioning regimens in AML/MDS, were alive and relapse-free at the first MRD time-point and provided monitoring samples for flow cytometric MRD and T-cell chimerism, requested to month+12. Twenty-nine (15.5%) patients had at least 1 MRD-positive result posttransplant. MRD-positivity was associated with reduced overall survival (OS) (hazard ratio [HR], 2.18; P = .0028) as a time-varying Cox variable and remained significant irrespective of pretransplant MRD status in multivariate analyses (P < .001). Ninety-four patients had sequential MRD with T-cell chimerism results at months+3/+6. Patients with full donor T-cell chimerism (FDTC) had an improved OS as compared with patients with mixed donor T-cell chimerism (MDTC) (adjusted HR=0.4; P = .0019). In patients with MDTC (month+3 or +6), MRD-positivity was associated with a decreased 2-year OS (34.3%) vs MRD-negativity (71.4%) (P = .001). In contrast, in the group with FDTC, MRD was infrequent and did not affect the outcome. Among patients with posttransplant MRD-positivity, decreased HLA-DR expression on blasts significantly reduced OS, supporting this as a mechanism for GVL escape. In conclusion, posttransplant MRD is an important predictor of the outcome in patients allografted for AML/MDS and is most informative when combined with T-cell chimerism results, underlining the importance of a GVL effect in AML/MDS

Genomic evolution and transcriptional changes in the evolution of prostate cancer into neuroendocrine and ductal carcinoma types

Prostate cancer is typically of acinar adenocarcinoma type but can occasionally present as neuroendocrine and/or ductal type carcinoma. These are associated with clinically aggressive disease, and the former often arises on a background of androgen deprivation therapy, although it can also arise de novo. Two prostate cancer cases were sequenced by exome capture from archival tissue. Case 1 was de novo small cell neuroendocrine carcinoma and ductal adenocarcinoma with three longitudinal samples over 5 years. Case 2 was a single time point after the development of treatment-related neuroendocrine prostate carcinoma. Case 1 showed whole genome doubling in all samples and focal amplification of AR in all samples except the first time point. Phylogenetic analysis revealed a common ancestry for ductal and small cell carcinoma. Case 2 showed 13q loss (involving RB1) in both adenocarcinoma and small cell carcinoma regions, and 3p gain, 4p loss, and 17p loss (involving TP53) in the latter. By using highly curated samples, we demonstrate for the first time that small-cell neuroendocrine and ductal prostatic carcinoma can have a common ancestry. We highlight whole genome doubling in a patient with prostate cancer relapse, reinforcing its poor prognostic nature