Learning from clinical trials of neoadjuvant checkpoint blockade

Neoadjuvant checkpoint inhibition, in which the therapy is administered before surgery, is a promising new approach to managing bulky but resectable melanoma, and is also being explored in other cancers. This strategy has a high pathologic response rate, which correlates with survival outcomes. The fact that biopsies are routinely available provides a unique opportunity for understanding the responses to therapy and carrying out reverse translation in which these data are used to select therapies in the clinic or in trials that are more likely to improve patient outcomes. In this Perspective, we discuss the rationale for neoadjuvant immunotherapy in resectable solid tumors based on preclinical and human translational data, summarize the results of recent clinical trials and ongoing research, and focus on future directions for enhancing reverse translation.</p

Using Scalars to Probe Theories of Low Scale Quantum Gravity

Arkani-Hamed, Dimopoulos and Dvali have recently suggested that gravity may become strong at energies near 1 TeV which would remove the hierarchy problem. Such a scenario can be tested at present and future colliders since the exchange of towers of Kaluza-Klein gravitons leads to a set of new dimension-8 operators that can play important phenomenological roles. In this paper we examine how the production of pairs of scalars at $e^+e^-$, $\gamma \gamma$ and hadron colliders can be used to further probe the effects of graviton tower exchange. In particular we examine the tree-level production of pairs of identical Higgs fields which occurs only at the loop level in both the Standard Model and its extension to the Minimal Supersymmetric Standard Model. Cross sections for such processes are found to be potentially large at the LHC and the next generation of linear colliders. For the $\gamma\gamma$ case the role of polarization in improving sensitivity to graviton exchange is emphasized.Comment: 32 pages, 12 figures, latex, remarks added to tex

Effect of nivolumab (NIVO) on quality of life (QoL) in patients (pts) with treatment-naïve advanced melanoma (MEL): results of a phase III study (CheckMate 066)

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Coronal Shock Waves, EUV Waves, and Their Relation to CMEs. III. Shock-Associated CME/EUV Wave in an Event with a Two-Component EUV Transient

On 17 January 2010, STEREO-B observed in extreme ultraviolet (EUV) and white light a large-scale dome-shaped expanding coronal transient with perfectly connected off-limb and on-disk signatures. Veronig et al. (2010, ApJL 716, 57) concluded that the dome was formed by a weak shock wave. We have revealed two EUV components, one of which corresponded to this transient. All of its properties found from EUV, white light, and a metric type II burst match expectations for a freely expanding coronal shock wave including correspondence to the fast-mode speed distribution, while the transient sweeping over the solar surface had a speed typical of EUV waves. The shock wave was presumably excited by an abrupt filament eruption. Both a weak shock approximation and a power-law fit match kinematics of the transient near the Sun. Moreover, the power-law fit matches expansion of the CME leading edge up to 24 solar radii. The second, quasi-stationary EUV component near the dimming was presumably associated with a stretched CME structure; no indications of opening magnetic fields have been detected far from the eruption region.Comment: 18 pages, 10 figures. Solar Physics, published online. The final publication is available at http://www.springerlink.co

Coronal Shock Waves, EUV waves, and Their Relation to CMEs. I. Reconciliation of "EIT waves", Type II Radio Bursts, and Leading Edges of CMEs

We show examples of excitation of coronal waves by flare-related abrupt eruptions of magnetic rope structures. The waves presumably rapidly steepened into shocks and freely propagated afterwards like decelerating blast waves that showed up as Moreton waves and EUV waves. We propose a simple quantitative description for such shock waves to reconcile their observed propagation with drift rates of metric type II bursts and kinematics of leading edges of coronal mass ejections (CMEs). Taking account of different plasma density falloffs for propagation of a wave up and along the solar surface, we demonstrate a close correspondence between drift rates of type II bursts and speeds of EUV waves, Moreton waves, and CMEs observed in a few known events.Comment: 30 pages, 15 figures. Solar Physics, published online. The final publication is available at http://www.springerlink.co

Accretion, Outflows, and Winds of Magnetized Stars

Many types of stars have strong magnetic fields that can dynamically influence the flow of circumstellar matter. In stars with accretion disks, the stellar magnetic field can truncate the inner disk and determine the paths that matter can take to flow onto the star. These paths are different in stars with different magnetospheres and periods of rotation. External field lines of the magnetosphere may inflate and produce favorable conditions for outflows from the disk-magnetosphere boundary. Outflows can be particularly strong in the propeller regime, wherein a star rotates more rapidly than the inner disk. Outflows may also form at the disk-magnetosphere boundary of slowly rotating stars, if the magnetosphere is compressed by the accreting matter. In isolated, strongly magnetized stars, the magnetic field can influence formation and/or propagation of stellar wind outflows. Winds from low-mass, solar-type stars may be either thermally or magnetically driven, while winds from massive, luminous O and B type stars are radiatively driven. In all of these cases, the magnetic field influences matter flow from the stars and determines many observational properties. In this chapter we review recent studies of accretion, outflows, and winds of magnetized stars with a focus on three main topics: (1) accretion onto magnetized stars; (2) outflows from the disk-magnetosphere boundary; and (3) winds from isolated massive magnetized stars. We show results obtained from global magnetohydrodynamic simulations and, in a number of cases compare global simulations with observations.Comment: 60 pages, 44 figure

The New Urban Revival in the United States

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/68657/2/10.1080_00420989320081901.pd

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results

Jet size dependence of single jet suppression in lead-lead collisions at sqrt(s(NN)) = 2.76 TeV with the ATLAS detector at the LHC

Measurements of inclusive jet suppression in heavy ion collisions at the LHC provide direct sensitivity to the physics of jet quenching. In a sample of lead-lead collisions at sqrt(s) = 2.76 TeV corresponding to an integrated luminosity of approximately 7 inverse microbarns, ATLAS has measured jets with a calorimeter over the pseudorapidity interval |eta| < 2.1 and over the transverse momentum range 38 < pT < 210 GeV. Jets were reconstructed using the anti-kt algorithm with values for the distance parameter that determines the nominal jet radius of R = 0.2, 0.3, 0.4 and 0.5. The centrality dependence of the jet yield is characterized by the jet "central-to-peripheral ratio," Rcp. Jet production is found to be suppressed by approximately a factor of two in the 10% most central collisions relative to peripheral collisions. Rcp varies smoothly with centrality as characterized by the number of participating nucleons. The observed suppression is only weakly dependent on jet radius and transverse momentum. These results provide the first direct measurement of inclusive jet suppression in heavy ion collisions and complement previous measurements of dijet transverse energy imbalance at the LHC.Comment: 15 pages plus author list (30 pages total), 8 figures, 2 tables, submitted to Physics Letters B. All figures including auxiliary figures are available at http://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/HION-2011-02

Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy

Background: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy.Patients and methods: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately.Results: Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors.Conclusions: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.</p