Phase 2 study of intralesional PV-10 in refractory metastatic melanoma

Purpose. This international, multicenter, single-arm trial assessed efficacy and safety of intralesional rose bengal (PV-10) in 80 patients with refractory cutaneous or subcutaneous metastatic melanoma. Methods. Sixty-two stage III and 18 stage IV melanoma patients with disease refractory to a median of six prior interventions received intralesional PV-10 into up to 20 cutaneous and subcutaneous lesions up to four times over a 16-week period and were followed for 52 weeks. Objectives were to determine best overall response rate in injected target lesions and uninjected bystander lesions, assess durability of response, and characterize adverse events. Results. For target lesions, the best overall response rate was 51%, and the complete response rate was 26%. Median time to response was 1.9 months, and median duration of response was 4.0 months, with 8% of patients having no evidence of disease after 52 weeks. Response was dependent on untreated disease burden, with complete response achieved in 50% of patients receiving PV-10 to all of their disease. Response of target lesions correlated with bystander lesion regression and the occurrence of locoregional blistering. Adverse events were predominantly mild to moderate and locoregional to the treatment site, with no treatment-associated grade 4 or 5 adverse events. Conclusions. Intralesional PV-10 yielded durable local control with high rates of complete response. Toxicity was confined predominantly to the injection site. Cutaneous bystander tumor regression is consistent with an immunologic response secondary to ablation. This intralesional approach for local disease control could be complementary to current and investigational treatments for melanoma.John F. Thompson, Sanjiv S. Agarwala, B. Mark Smithers, Merrick I. Ross, Charles R. Scoggins, Brendon J. Coventry, Susan J. Neuhaus, David R. Minor, Jamie M. Singer, and Eric A. Wachte

Congenital anomalies in low- and middle-income countries: the unborn child of global surgery.

Surgically correctable congenital anomalies cause a substantial burden of global morbidity and mortality. These anomalies disproportionately affect children in low- and middle-income countries (LMICs) due to sociocultural, economic, and structural factors that limit the accessibility and quality of pediatric surgery. While data from LMICs are sparse, available evidence suggests that the true human and financial cost of congenital anomalies is grossly underestimated and that pediatric surgery is a cost-effective intervention with the potential to avert significant premature mortality and lifelong disability

keynote 412 phase iii study of pembrolizumab plus chemoradiation vs chemoradiation alone for locally advanced head and neck squamous cell carcinoma hnscc

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The novel photon detectors based on MPGD technologies for the upgrade of COMPASS RICH-1

The RICH-1 Detector of the COMPASS experiment at CERN SPS has undergone an important upgrade in 2016. Four new photon detectors, based on MPGD technology and covering a total active area larger than 1.2~$m^2$ have replaced the previously used MWPC-based photon detectors. The new detector architecture, resulting from a dedicated, eight years long, R\&D program, consists in a hybrid MPGD combination of two THGEMs and a Micromegas stage; the first THGEM, coated with a CsI layer, acts as a reflective photocathode. The signals are extracted from the anode pads by capacitive coupling and read-out by analog front-end electronics based on the APV25 chip. The new COMPASS RICH-1 photon detectors are described in detail: the detector design, the engineering aspects, the mass production, and the quality assessment are discussed. The assembly of the MPGD components and the installation of the new detectors are illustrated together with the main aspects of the commissioning. Preliminary indication of performance results are also presented.Comment: 5th International Conference on Micro-Pattern Gas Detectors (MPGD2017), speaker: F.Tessarotto (INFN -Trieste

Impact of Sequencing Targeted Therapies With High-dose Interleukin-2 Immunotherapy: An Analysis of Outcome and Survival of Patients With Metastatic Renal Cell Carcinoma From an On-going Observational IL-2 Clinical Trial: PROCLAIM

BACKGROUND: This analysis describes the outcome for patients who received targeted therapy (TT) prior to or following high-dose interleukin-2 (HD IL-2). PATIENTS AND METHODS: Patients with renal cell carcinoma (n = 352) receiving HD IL-2 were enrolled in Proleukin RESULTS: Overall, there were 4% complete response (CR), 13% partial response (PR), 39% stable disease (SD), and 43% progressive disease (PD) with HD IL-2. The median overall survival (mOS) was not reached in patients with CR, PR, or SD, and was 15.5 months in patients with PD (median follow-up, 21 months). Sixty-one patients had prior TT before HD IL-2 with an overall response rate (ORR) to HD IL-2 of 19% (1 CR, 9 PR) and an mOS of 22.1 months. One hundred forty-nine patients received TT only after HD IL-2 with an mOS of 35.5 months. One hundred forty-two patients had no TT before or after HD IL-2, and mOS was not reached. The mOS was 8.5 months in PD patients who received HD IL-2 without follow-on TT and 29.7 months in PD patients who received follow-on TT after HD IL-2. CONCLUSIONS: HD IL-2 as sole front-line therapy, in the absence of added TT, shows extended clinical benefit (CR, PR, and SD). Patients with PD after HD IL-2 appear to benefit from follow-on TT. Patients who progressed on TT and received follow-on HD IL-2 experienced major clinical benefit. HD IL-2 therapy should be considered in eligible patients

Combination of searches for heavy spin-1 resonances using 139 fb − 1 of proton-proton collision data at s = 13 TeV with the ATLAS detector

A combination of searches for new heavy spin-1 resonances decaying into different pairings of W, Z, or Higgs bosons, as well as directly into leptons or quarks, is presented. The data sample used corresponds to 139 fb−1 of proton-proton collisions at s = 13 TeV collected during 2015–2018 with the ATLAS detector at the CERN Large Hadron Collider. Analyses selecting quark pairs (qq, bb, tt¯, and tb) or third-generation leptons (τν and ττ) are included in this kind of combination for the first time. A simplified model predicting a spin-1 heavy vector-boson triplet is used. Cross-section limits are set at the 95% confidence level and are compared with predictions for the benchmark model. These limits are also expressed in terms of constraints on couplings of the heavy vector-boson triplet to quarks, leptons, and the Higgs boson. The complementarity of the various analyses increases the sensitivity to new physics, and the resulting constraints are stronger than those from any individual analysis considered. The data exclude a heavy vector-boson triplet with mass below 5.8 TeV in a weakly coupled scenario, below 4.4 TeV in a strongly coupled scenario, and up to 1.5 TeV in the case of production via vector-boson fusion

Search for new phenomena with top-quark pairs and large missing transverse momentum using 140 fb − 1 of pp collision data at s = 13 TeV with the ATLAS detector

A search is conducted for new phenomena in events with a top quark pair and large missing transverse momentum, where the top quark pair is reconstructed in final states with one isolated electron or muon and multiple jets. The search is performed using the Large Hadron Collider proton-proton collision data sample at a centre-of-mass energy of s = 13 TeV recorded by the ATLAS detector that corresponds to an integrated luminosity of 140 fb−1. An analysis based on neural network classifiers is optimised to search for directly produced pairs of supersymmetric partners of the top quark (stop), and to search for spin-0 mediators, produced in association with a pair of top quarks, that decay into dark-matter particles. In the stop search, the analysis is designed to target models in which the mass difference between the stop and the neutralino from the stop decay is close to the top quark mass. This new search is combined with previously published searches in final states with different lepton multiplicities. No significant excess above the Standard Model background is observed, and limits at 95% confidence level are set. Models with neutralinos with masses up to 570 GeV are excluded, while for small neutralino masses models are excluded for stop masses up to 1230 GeV. Scalar (pseudoscalar) dark matter mediator masses as large as 350 (370) GeV are excluded when the coupling strengths of the mediator to Standard Model and dark-matter particles are both set to one. At lower mediator masses, models with production cross-sections as small as 0.15 (0.16) times the nominal predictions are excluded. Results of this search are also used to set constraints on effective four-fermion contact interactions between top quarks and neutrinos

RNA Methylation by the MIS Complex Regulates a Cell Fate Decision in Yeast

For the yeast Saccharomyces cerevisiae, nutrient limitation is a key developmental signal causing diploid cells to switch from yeast-form budding to either foraging pseudohyphal (PH) growth or meiosis and sporulation. Prolonged starvation leads to lineage restriction, such that cells exiting meiotic prophase are committed to complete sporulation even if nutrients are restored. Here, we have identified an earlier commitment point in the starvation program. After this point, cells, returned to nutrient-rich medium, entered a form of synchronous PH development that was morphologically and genetically indistinguishable from starvation-induced PH growth. We show that lineage restriction during this time was, in part, dependent on the mRNA methyltransferase activity of Ime4, which played separable roles in meiotic induction and suppression of the PH program. Normal levels of meiotic mRNA methylation required the catalytic domain of Ime4, as well as two meiotic proteins, Mum2 and Slz1, which interacted and co-immunoprecipitated with Ime4. This MIS complex (Mum2, Ime4, and Slz1) functioned in both starvation pathways. Together, our results support the notion that the yeast starvation response is an extended process that progressively restricts cell fate and reveal a broad role of post-transcriptional RNA methylation in these decisions

People Efficiently Explore the Solution Space of the Computationally Intractable Traveling Salesman Problem to Find Near-Optimal Tours

Humans need to solve computationally intractable problems such as visual search, categorization, and simultaneous learning and acting, yet an increasing body of evidence suggests that their solutions to instantiations of these problems are near optimal. Computational complexity advances an explanation to this apparent paradox: (1) only a small portion of instances of such problems are actually hard, and (2) successful heuristics exploit structural properties of the typical instance to selectively improve parts that are likely to be sub-optimal. We hypothesize that these two ideas largely account for the good performance of humans on computationally hard problems. We tested part of this hypothesis by studying the solutions of 28 participants to 28 instances of the Euclidean Traveling Salesman Problem (TSP). Participants were provided feedback on the cost of their solutions and were allowed unlimited solution attempts (trials). We found a significant improvement between the first and last trials and that solutions are significantly different from random tours that follow the convex hull and do not have self-crossings. More importantly, we found that participants modified their current better solutions in such a way that edges belonging to the optimal solution (“good” edges) were significantly more likely to stay than other edges (“bad” edges), a hallmark of structural exploitation. We found, however, that more trials harmed the participants' ability to tell good from bad edges, suggesting that after too many trials the participants “ran out of ideas.” In sum, we provide the first demonstration of significant performance improvement on the TSP under repetition and feedback and evidence that human problem-solving may exploit the structure of hard problems paralleling behavior of state-of-the-art heuristics

Viewpoint-Free Photography for Virtual Reality

Viewpoint-free photography, i.e., interactively controlling the viewpoint of a photograph after capture, is a standing challenge. In this thesis, we investigate algorithms to enable viewpoint-free photography for virtual reality (VR) from casual capture, i.e., from footage easily captured with consumer cameras. We build on an extensive body of work in image-based rendering (IBR). Given images of an object or scene, IBR methods aim to predict the appearance of an image taken from a novel perspective. Most IBR methods focus on full or near-interpolation, where the output viewpoints either lie directly between captured images, or nearby. These methods are not suitable for VR, where the user has significant range of motion and can look in all directions. Thus, it is essential to create viewpoint-free photos with a wide field-of-view and sufficient positional freedom to cover the range of motion a user might experience in VR. We focus on two VR experiences: 1) Seated VR experiences, where the user can lean in different directions. This simplifies the problem, as the scene is only observed from a small range of viewpoints. Thus, we focus on easy capture, showing how to turn panorama-style capture into 3D photos, a simple representation for viewpoint-free photos, and also how to speed up processing so users can see the final result on-site. 2) Room-scale VR experiences, where the user can explore vastly different perspectives. This is challenging: More input footage is needed, maintaining real-time display rates becomes difficult, view-dependent appearance and object backsides need to be modelled, all while preventing noticeable mistakes. We address these challenges by: (1) creating refined geometry for each input photograph, (2) using a fast tiled rendering algorithm to achieve real-time display rates, and (3) using a convolutional neural network to hide visual mistakes during compositing. Overall, we provide evidence that viewpoint-free photography is feasible from casual capture. We thoroughly compare with the state-of-the-art, showing that our methods achieve both a numerical improvement and a clear increase in visual quality for both seated and room-scale VR experiences