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Adjuvant therapy; Breast cancer; Olaparib Terapia adyuvante; Cáncer de mama; Olaparib Teràpia adjuvant; Càncer de mama; Olaparib Background The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI −0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals. Funding for this work, which was conducted as a collaborative partnership among the Breast International Group, NRG Oncology, Frontier Science, AstraZeneca, and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, U.S.A. (MSD), was provided by the National Institutes of Health (grant numbers: U10CA 180868, UG1CA 189867, and U10CA 180822) and by AstraZeneca as part of an alliance between AstraZeneca and MSD. Provision of olaparib and placebo was from AstraZeneca.

Supplementary Table 1 - PDF file 37K, Most Common (incidence >10%) Grade 3/4 Toxicities per Dose Group

Supplementary Table 2 - PDF file 54K, SNPs Analyzed and Genotype Frequencies

Images from social media can reflect diverse viewpoints, heated arguments, and expressions of creativity, adding new complexity to retrieval tasks. Researchers working on Content-Based Image Retrieval (CBIR) have traditionally tuned their algorithms to match filtered results with user search intent. However, we are now bombarded with composite images of unknown origin, authenticity, and even meaning. With such uncertainty, users may not have an initial idea of what the search query results should look like. For instance, hidden people, spliced objects, and subtly altered scenes can be difficult for a user to detect initially in a meme image, but may contribute significantly to its composition. It is pertinent to design systems that retrieve images with these nuanced relationships in addition to providing more traditional results, such as duplicates and near-duplicates - and to do so with enough efficiency at large scale. We propose a new approach for spatial verification that aims at modeling object-level regions using image keypoints retrieved from an image index, which is then used to accurately weight small contributing objects within the results, without the need for costly object detection steps. We call this method the Objects in Scene to Objects in Scene (OS2OS) score, and it is optimized for fast matrix operations, which can run quickly on either CPUs or GPUs. It performs comparably to state-of-the-art methods on classic CBIR problems (Oxford 5K, Paris 6K, and Google-Landmarks), and outperforms them in emerging retrieval tasks such as image composite matching in the NIST MFC2018 dataset and meme-style imagery from Reddit.

Post-mortem biometrics entails utilizing the biometric data of a deceased individual for determining or verifying human identity. Due to fundamental biological changes that occur in a person’s biometric traits after death, post-mortem data can be significantly different from ante-mortem data, introducing new challenges for biometric sensors, feature extractors and matchers. This paper surveys research to date on the problem of using iris images acquired after death for automated human recognition. A comprehensive review of existing literature is complemented by a summary of the most recent results and observations offered in these publications. This survey is unique in several elements. Firstly, it is the first publication to consider iris recognition where gallery images are acquired before death (peri-mortem images) and the probe images are acquired after death from the same subjects. Secondly, results are presented from the largest database of peri-mortem and post-mortem iris images, collected from 213 subjects by two independent institutions located in the U.S. and Poland. Thirdly, post-mortem recognition viability is assessed using more than 20 iris recognition algorithms, ranging from the classic (e.g., Gabor filtering-based) to the modern (e.g., deep learning-based). Finally, we provide a medically informed commentary on post-mortem iris, analyze the reasons for recognition failures, and identify key directions for future research.

We present the Deception Detection and Physiological Monitoring (DDPM) dataset and initial baseline results on this dataset. Our application context is an interview scenario in which the interviewee attempts to deceive the interviewer on selected responses. The interviewee is recorded in RGB, near-infrared, and long-wave infrared, along with cardiac pulse, blood oxygenation, and audio. After collection, data were annotated for interviewer/interviewee, curated, ground-truthed, and organized into train / test parts for a set of canonical deception detection experiments. Baseline experiments found random accuracy for micro-expressions as an indicator of deception, but that saccades can give a statistically significant response. We also estimated subject heart rates from face videos (remotely) with a mean absolute error as low as 3.16 bpm. The database contains almost 13 hours of recordings of 70 subjects, and over 8 million visible-light, near-infrared, and thermal video frames, along with appropriate meta, audio and pulse oximeter data. To our knowledge, this is the only collection offering recordings of five modalities in an interview scenario that can be used in both deception detection and remote photoplethysmography research., The dataset will be available for download at https://cvrl.nd.edu/projects/data/#deception-detection-and-physiological-monitoringddpm

Assumptions regarding eye morphology are implicit in iris recognition algorithms. The cornea is assumed to have little to no effect on the view of the iris texture when the eye gaze is non-frontal, the iris is assumed flat, and the eye is assumed to be imaged via an orthographic projection. If these assumptions hold, affine transformations may be used to rectify non-frontally posed images to a frontal view and the rubber sheet model may be accurately used to normalize the iris annulus to a rectangular image. This paper examines how iris recognition performance degrades when the first two assumptions are violated. Using a computer renderable eye model, a data set is created varying the presence of the cornea and a parameterized non-planarity of the iris shape across a large range of eye gaze angles. Matching scores are created using a commercial matcher. When comparing the relative impact of each assumption violation, it is observed that iris non-planarity presents a more significant problem than corneal refractive distortion with regard to iris recognition accuracy in non-frontal images.

Wellman, AD, Coad, SC, Flynn, PJ, Siam, TK, and McLellan, CP. A Comparison of preseason and in-season practice and game loads in NCAA Division I football players. J Strength Cond Res 33(4): 1020-1027, 2019-The aim of this study was to quantify the individual practice and game loads throughout the National Collegiate Athletic Association (NCAA) Division I football season to determine whether significant differences exist between the practice loads associated with the preseason training camp and those undertaken during the in-season period. Thirty-one NCAA Division I football players were monitored using the global positioning system and triaxial accelerometer (IA) (MinimaxX S5; Catapult Innovations, Melbourne, Australia) during 22 preseason practices, 36 in-season practices, and 12 competitions. The season was divided into 4 distinct phases for data analysis: preseason week 1 (preseason 1), preseason week 2 (preseason 2), preseason week 3 (preseason 3), and 12 in-season weeks. Individual IA data sets represented players from every offensive and defensive position group Wide Receiver (WR: n = 5), Offensive Line (OL: n = 4), Running Back (RB: n = 4), Quarterback (QB: n = 2), Tight End (TE: n = 3), Defensive Line (DL: n = 4), Linebacker (LB: n = 4), Defensive Back (DB: n = 5). Data were set at the practice level, where an observation for each player's maximum player load (PLMax) or mean player load (PLMean) from each training camp phase was referenced against each player's respective PL from each game, Tuesday, Wednesday, or Thursday practice session. Notable results included significantly (p ≤ 0.05) greater PLMax values attributed to preseason 1 compared with PL resulting from all in-season practices, and significantly (p ≤ 0.05) higher cumulative PL reported for preseason 1, 2, and 3 compared with every in-season week. Data from this study augment our understanding of the practice demands experienced by NCAA Division I college football players, and provide scope for the improvement of preseason practice design and physical conditioning strategies for coaches seeking to optimize performance.

Wellman, AD, Coad, SC, Flynn, PJ, Siam, TK, and McLellan, CP. Perceived wellness associated with practice and competition in National Collegiate Athletic Association Division I football players. J Strength Cond Res 33(1): 112-124, 2019-This study assessed the influence of movement demands resulting from weekly practice sessions and games, on perceived wellness measurements taken postgame (Sunday) and 48 hours pregame (Thursday) throughout the in-season period in National Collegiate Athletic Association (NCAA) Division I football players. Thirty players were monitored using global positioning system receivers (OptimEye S5; Catapult Innovations) during 12 games and 24 in-season practices. Movement variables included low-intensity distance, medium-intensity distance, high-intensity distance, sprint distance, total distance, player load, and acceleration and deceleration distance. Perceived wellness, including fatigue, soreness, sleep quality and quantity, stress, and mood, was examined using a questionnaire on a 1-5 Likert scale. Multilevel mixed linear regressions determined the differential effects of movement metrics on perceived wellness. Post hoc tests were conducted to evaluate the pairwise differentials of movement and significance for wellness ratings. Notable findings included significantly (p ≤ 0.05) less player load, low-intensity distance, medium-intensity distance, high-intensity distance, total distance, and acceleration and deceleration distance at all intensities, in those reporting more favorable (4-5) ratings of perceived fatigue and soreness on Sunday. Conversely, individuals reporting more favorable Sunday-perceived stress ratings demonstrated significantly (p ≤ 0.05) higher player load, low-intensity and medium-intensity distance, total distance, low-intensity and medium-intensity deceleration distance, and acceleration distance at all intensities than individuals reporting less favorable (1-2) perceived stress ratings. Data from this study provide a novel investigation of perceived wellness associated with college football practice and competition. Results support the use of wellness questionnaires for monitoring perceived wellness in NCAA Division I college football players.

Background We report the analysis involving patients treated on the initial CODEL design. Methods Adults (>18) with newly diagnosed 1p/19q World Health Organization (WHO) grade III oligodendroglioma were randomized to radiotherapy (RT; 5940 centigray ) alone (arm A); RT with concomitant and adjuvant temozolomide (TMZ) (arm B); or TMZ alone (arm C). Primary endpoint was overall survival (OS), arm A versus B. Secondary comparisons were performed for OS and progression-free survival (PFS), comparing pooled RT arms versus TMZ-alone arm. Results Thirty-six patients were randomized equally. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients progressed, versus 37.5% (9/24) on the RT arms. PFS was significantly shorter in TMZ-alone patients compared with RT patients (hazard ratio [HR] = 3.12; 95% CI: 1.26, 7.69; P = 0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) on the RT arms. OS did not statistically differ between arms (comparison underpowered). After adjustment for isocitrate dehydrogenase (IDH) status (mutated/wildtype) in a Cox regression model utilizing IDH and RT treatment status as covariables (arm C vs pooled arms A + B), PFS remained shorter for patients not receiving RT (HR = 3.33; 95% CI: 1.31, 8.45; P = 0.011), but not OS ((HR = 2.78; 95% CI: 0.58, 13.22, P = 0.20). Grade 3+ adverse events occurred in 25%, 42%, and 33% of patients (arms A, B, and C). There were no differences between arms in neurocognitive decline comparing baseline to 3 months. Conclusions TMZ-alone patients experienced significantly shorter PFS than patients treated on the RT arms. The ongoing CODEL trial has been redesigned to compare RT + PCV versus RT + TMZ.

BackgroundAcute Myeloid Leukemia (AML) is the most common adult leukemia and has a very poor prognosis. With a 5-year survival of under 30% (seer.cancer.gov), most people diagnosed with AML will die from the disease. AML is caused by an uncontrolled proliferation of poorly differentiated myeloid precursor cells which results from a combination of three classes of mutations that affect proliferation, differentiation and epigenetic state. For this reason, drugs targeting epigenetic modifications are being actively studied in AML. AML has been shown to avoid immune recognition though inhibiting the function of multiple cell types, especially T cells1 2 and therefore immune checkpoint blockade presents a promising therapy for any immune-targeted strategy; however, clinical trials to date have shown very modest efficacy.3–5 T cell exhaustion in cancer has been shown to be a regulated process involving transcriptional and epigenetic changes.6–9 BRD4 has been shown to be important for maintaining this exhaustion state.10 11 It stands to reason that drugs designed to target epigenetic pathways in tumors will have effects on T cell populations present in the tumor microenvironment. In these studies, we investigated the effects of the BET inhibitor (BETi) JQ1 on T cell exhaustion and checkpoint responsiveness in a murine model of AML.MethodsThe AML mouse model bears FLT3-ITD and deletion of TET2 restricted to the myeloid lineage. For in vitro studies, splenocytes were stimulated with anti-CD3 and either JQ1, anti-PD1 or both and proliferation and differentiation status were assessed by flow cytometry. For in vivo studies, treatment consisted of 2 weeks with JQ1, anti-PD1 or both.ResultsThis mouse model of AML exhibits an expansion of terminally exhausted T cells and impaired proliferative capacity after stimulation through the TCR (figure 1). Ex vivo treatment with BETi and anti-PD1 reverses CD8+ T cell exhaustion via rescue of proliferative dysfunction and expansion of more functional precursor exhausted T cells (TPEx-CD8, PD1+, TCF1+, TIM3-) (figure 2). Finally, we show that BETi synergizes with anti-PD1 in vivo leading to a reduction of tumor cells in multiple organ sites, and enrichment of CD8+ T cells in the bone marrow (figure 3).ConclusionsUsing an AML mouse model that exhibits leukemia-induced immune exhaustion, we demonstrate the pre-clinical efficacy of combining BETi and anti-PD1 therapy in the treatment of AML.ReferencesLamble AJ, Lind EF. Targeting the immune microenvironment in acute myeloid leukemia: a focus on T Cell immunity. Front Oncol 2018;8:213.Lamble AJ, Kosaka Y, Laderas T, Maffit A, Kaempf A, Brady LK, et al. Reversible suppression of T cell function in the bone marrow microenvironment of acute myeloid leukemia. Proc Natl Acad Sci U S A. 2020;117(25):14331–41.Boddu P, Kantarjian H, Garcia-Manero G, Allison J, Sharma P, Daver N. The emerging role of immune checkpoint based approaches in AML and MDS. Leuk Lymphoma 2018;59(4):790–802.Bewersdorf JP, Shallis RM, Zeidan AM. Immune checkpoint inhibition in myeloid malignancies: moving beyond the PD-1/PD-L1 and CTLA-4 pathways. Blood Rev 2020:100709.Daver N, Garcia-Manero G, Basu S, Boddu PC, Alfayez M, Cortes JE, et al. Efficacy, safety, and biomarkers of response to azacitidine and nivolumab in relapsed/Refractory acute myeloid leukemia: a nonrandomized, Open-Label, Phase II Study. Cancer Discov 2019;9(3):370–83.Beltra JC, Manne S, Abdel-Hakeem MS, Kurachi M, Giles JR, Chen Z, et al. Developmental Relationships of Four Exhausted CD8(+) T Cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity 2020;52(5):825–41 e8.Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, et al. TOX transcriptionally and epigenetically programs CD8(+) T cell exhaustion. Nature 2019;571(7764):211–8.Pauken KE, Sammons MA, Odorizzi PM, Manne S, Godec J, Khan O, et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 2016;354(6316):1160–5.Abdel-Hakeem MS, Manne S, Beltra JC, Stelekati E, Chen Z, Nzingha K, et al. Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation. Nat Immunol 2021;22(8):1008–19.Milner JJ, Toma C, Quon S, Omilusik K, Scharping NE, Dey A, et al. Bromodomain protein BRD4 directs and sustains CD8 T cell differentiation during infection. J Exp Med 2021;218(8).Kagoya Y, Nakatsugawa M, Yamashita Y, Ochi T, Guo T, Anczurowski M, et al. BET bromodomain inhibition enhances T cell persistence and function in adoptive immunotherapy models. J Clin Invest 2016;126(9):3479–94.Ethics ApprovalThis study has been approved by the OHSU IACUC committee protocol IP00000907 “Immune-based therapeutic approaches for acute myeloid leukemia” Evan Lind PI.Abstract 734 Figure 1T cell exhaustion in the AML mouse model. (A) Cytotoxic T cells show an exhausted phenotype in mice with AML. Spleen cultures from mice with AML or WT controls were stained with antibodies to CD3, CD8, TIM3, PD1, and TCF1. Left shows percent of TPEX CD8 T cells. Right panel shows TEX CD8 T cells. N = 12 animals per group. (B) Proliferative defect in T cells in mice with AML. Splenocytes were labeled with the proliferation dye CFSE. Whole spleen suspensions were stimulated with anti-CD3 or anti-CD3 and anti-CD28 for 3 days. FACs plots show proliferation of T cells in each conditionAbstract 734 Figure 2Treatment with JQ1 results in expansion of T cells with TPEX. (A) Example of proliferation (CFSE dilution) vs TCF-1 expression showing unstimulated, CD3 or CD3+JQ1 120 nM in in vitro 3-day culture. Results gated on CD8 T cells. (B) Summary of T cell proliferation from 4 independent experiments showing the percent proliferation of CD8 T cells with TPEX (PD1+ Tim-3- TCF-1+) (black line) or TEX (PD1+Tim-3+TCF1-) phenotype (red line). Statistics are unpaired T-Test for each treatment condition.Abstract 734 Figure 3In vivo treatment of FTL mice with the BETi JQ1. (A) Schematic overview of treatment protocol. (B) White blood cell counts at pre-treatment, 1 week and 2 weeks after JQ1, PD1 blockade or both. (C) Percent of CD8+ T cells of all CD3-gated T cells in the BM of treated animals. (D) A-C Percent of precursor-exhausted CD8+ T cells as a percent of all T cells in the spleen of treated animals. Results combined from 2 separate experiments n=7. D One experiment n=3.

Purpose: GI-4000, a series of recombinant yeast expressing four different mutated RAS proteins, was evaluated in subjects with resected ras-mutated pancreas cancer. Methods: Subjects (n?=?176) received GI-4000 or placebo plus gemcitabine. Subjects' tumors were genotyped to identify which matched GI-4000 product to administer. Immune responses were measured by interferon-? (IFN?) ELISpot assay and by regulatory T cell (Treg) frequencies on treatment. Pretreatment plasma was retrospectively analyzed by matrix-assisted laser desorption/ionization-time-of-flight (MALDI-ToF) mass spectrometry for proteomic signatures predictive of GI-4000 responsiveness. Results: GI-4000 was well tolerated, with comparable safety findings between treatment groups. The GI-4000 group showed a similar pattern of median recurrence-free and overall survival (OS) compared with placebo. For the prospectively defined and stratified R1 resection subgroup, there was a trend in 1 year OS (72% vs. 56%), an improvement in OS (523.5 vs. 443.5 days [hazard ratio (HR)?=?1.06 [confidence interval (CI): 0.53?2.13], p?=?0.872), and increased frequency of immune responders (40% vs. 8%; p?=?0.062) for GI-4000 versus placebo and a 159-day improvement in OS for R1 GI-4000 immune responders versus placebo (p?=?0.810). For R0 resection subjects, no increases in IFN? responses in GI-4000?treated subjects were observed. A higher frequency of R0/R1 subjects with a reduction in Tregs (CD4+/CD45RA+/Foxp3low) was observed in GI-4000?treated subjects versus placebo (p?=?0.033). A proteomic signature was identified that predicted response to GI-4000/gemcitabine regardless of resection status. Conclusion: These results justify continued investigation of GI-4000 in studies stratified for likely responders or in combination with immune check-point inhibitors or other immunomodulators, which may provide optimal reactivation of antitumor immunity. ClinicalTrials.gov Number: NCT00300950.

Generative adversarial networks (GANs) are able to generate high resolution photo-realistic images of objects that "do not exist." These synthetic images are rather difficult to detect as fake. However, the manner in which these generative models are trained hints at a potential for information leakage from the supplied training data, especially in the context of synthetic faces. This paper presents experiments suggesting that identity information in face images can flow from the training corpus into synthetic samples without any adversarial actions when building or using the existing model. This raises privacy-related questions, but also stimulates discussions of (a) the face manifold's characteristics in the feature space and (b) how to create generative models that do not inadvertently reveal identity information of real subjects whose images were used for training. We used five different face matchers (face_recognition, FaceNet, ArcFace, SphereFace and Neurotechnology MegaMatcher) and the StyleGAN2 synthesis model, and show that this identity leakage does exist for some, but not all methods. So, can we say that these synthetically generated faces truly do not exist? Databases of real and synthetically generated faces are made available with this paper to allow full replicability of the results discussed in this work., Comment: To appear at WACV 2021

BACKGROUND The original 3-arm CODEL design included a radiotherapy (RT)-alone control arm, an RT plus temozolomide (TMZ) arm, and an exploratory TMZ-alone arm. We report the analysis involving patients treated per the initial design. METHODS Adults (18+ years) with newly-diagnosed 1p/19q codeleted WHO grade III oligodendroglioma were randomized to RT (5940 cGy) alone (Arm A); RT with concomitant and adjuvant TMZ (Arm B); or TMZ alone (Arm C). Primary endpoint was OS, Arm A vs. B. Secondary comparisons were performed for OS and PFS, comparing pooled RT arms with the TMZ-alone arm. RESULTS 36 patients were randomized equally to the three arms. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients had progressed, versus 37.5% (9/24) patients on the RT arms. PFS was shorter in TMZ-alone patients compared to RT-treated patients (HR=3.12; 95% CI: 1.26, 7.69; p=0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) of RT-treated patients. OS did not statistically differ between arms, although this comparison was underpowered. After adjustment for IDH status (mutated vs. wildtype) in a Cox regression model, with IDH status and RT treatment status as co-variables (Arm C vs pooled A and B), PFS remained shorter for patients not receiving RT (HR= 3.33; 95% CI: 1.31, 8.45; p=0.011), and OS differences remained non-significant ((HR = 2.78; 95% CI 0.58, 13.22, p=0.20). Grade 3+ adverse events occurred in 25%, 42% and 33% patients (Arms A, B and C, respectively). Neurocognitive assessments, comparing baseline and 3 month timepoints, showed no significant differences between arms. CONCLUSIONS TMZ-alone treated patients experienced significantly shorter PFS than patients treated on the pooled RT arms, which remained significant when adjusting for IDH status. CODEL has been redesigned to compare the efficacy and toxicity of RT+PCV versus RT+TMZ. Clinicaltrials.gov Identifier: NCT00887146. Support: U10CA180821, U10CA180882, https://acknowledgments.alliancefound.org.

Introduction: Multikinase inhibitors have clinical activity in radioactive iodine refractory (RAIR) differentiated thyroid cancers (DTCs) but are not curative; optimal management and salvage therapies remain unclear. This study assessed clinical effects of pazopanib therapy in RAIR-DTC patients with progressive disease, examining in parallel biomarker that might forecast/precede therapeutic response. Methods: Assessment of responses and toxicities and of any association between thyroglobulin (Tg) changes cycle 1 and RECIST (response evaluation criteria in solid tumors) response to pazopanib therapy were prospectively undertaken in Tg antibody negative RAIR-DTC patients. RECIST progressive metastatic disease 30% when the proportion of patients attaining PR whose Tg values decrease by >50% is >50% cycle 1 (one-sided α = 0.10, two sample test of proportions). Mean corpuscular volume (MCV) change or mutational status or pretreatment were also explored as early correlates of eventual RECIST response. Results: From 2009 to 2011, 60 individuals were treated and evaluated; (one additional patient withdrew; another was found ineligible before therapy initiation); 91.7% had previous systemic therapy beyond RAI. Adverse events included one death (thromboembolic) deemed possibly pazopanib associated. Twenty-two confirmed RECIST PRs resulted (36.7%, confidence interval; CI [24.6–50.1]); mean administered 4-week cycles was 10. Among 44 fully accessible patients, the Tg nadir was greater among the 20 attaining PR (median: −86.8%; interquartile range [IQR]: −90.7% to −70.9%) compared with the 28 who did not (median: −69.0%; IQR: −78.1% to −27.7%, Wilcoxon rank-sum test: p = 0.002). However, the difference in the proportion of PRs among those whose Tg fell ≥50% after cycle 1 versus those that did not were not significantly correlated (−23.5% [CI: −55.3 to 8.3]; Fisher's exact test p-value = 0.27). RECIST response was also not correlated with/predicted by early MCV change, receipt of prior therapy, or tumor mutational status. Conclusions: This trial prospectively confirmed pazopanib to have clinical activity and manageable toxicities in patients with progressive RAIR-DTC. Response to pazopanib, however, was not robustly forecast by early associated changes in Tg or MCV, by prior therapy, or by tumor mutational status. ClinicalTrials.gov NCT00625846.

PURPOSE Adjuvant trastuzumab reduces invasive breast cancer (IBC) recurrence and risk for death in patients with HER2-amplified or overexpressing IBC. A subset of patients in the landmark trastuzumab adjuvant trials who originally tested HER2-positive but were HER2-negative by central HER2 testing appeared to possibly benefit from trastuzumab. The objective for the NSABP B-47 trial was to determine whether the addition of trastuzumab to adjuvant chemotherapy (CRx) would improve invasive disease-free survival (IDFS) in patients with HER2-negative breast cancer. PATIENTS AND METHODS A total of 3,270 women with high-risk primary IBC were randomly assigned to CRx with or without 1 year of trastuzumab. Eligibility criteria included immunohistochemistry (IHC) score 1+ or 2+ with fluorescence in situ hybridization ratio (FISH) < 2.0 or, if ratio was not performed, HER2 gene copy number < 4.0. CRx was either docetaxel plus cyclophosphamide or doxorubicin and cyclophosphamide followed by weekly paclitaxel for 12 weeks. RESULTS At a median follow-up of 46 months, the addition of trastuzumab to CRx did not improve IDFS (5-year IDFS: 89.8% with CRx plus trastuzumab [CRxT] v 89.2% with CRx alone; hazard ratio [HR], 0.98; 95% CI, 0.76 to 1.25; P = .85). These findings did not differ by level of HER2 IHC expression, lymph node involvement, or hormone-receptor status. For distant recurrence-free interval, 5-year estimates were 92.7% with CRxT compared with 93.6% for CRx alone (HR, 1.10; 95% CI, 0.81 to 1.50; P = .55) and for overall survival (OS) were 94.8% with CRxT and 96.3% in CRx alone (HR, 1.33; 95% CI, 0.90 to 1.95; P = .15). There were no unexpected toxicities from the addition of trastuzumab to CRx. CONCLUSION The addition of trastuzumab to CRx did not improve IDFS, distant recurrence-free interval, or OS in women with non-HER2–overexpressing IBC. Trastuzumab does not benefit women without IHC 3+ or FISH ratio-amplified breast cancer.

Purpose Adherence to aromatase inhibitor (AI) therapy for early-stage breast cancer is limited by AI-associated musculoskeletal symptoms (AIMSS). Duloxetine is US Food and Drug Administration approved for treatment of multiple chronic pain disorders. We hypothesized that treatment of AIMSS with duloxetine would improve average joint pain compared with placebo. Methods This randomized, double-blind, phase III trial included AI-treated postmenopausal women with early-stage breast cancer and who had average joint pain score of ≥ 4 out of 10 that developed or worsened since AI therapy initiation. Patients were randomly assigned 1:1 to duloxetine or placebo for 13 weeks. The primary end point was average joint pain through 12 weeks, examined using multivariable linear mixed models, adjusted for stratification factors (baseline pain score of 4 to 6 v 7 to 10 and prior taxane use). Clinically significant change in average pain was defined as a ≥ 2-point decrease from baseline. Results Of 299 enrolled patients, 127 patients treated with duloxetine and 128 who received placebo were evaluable for the primary analysis. By 12 weeks, the average joint pain score was 0.82 points lower for patients who received duloxetine compared with those who received placebo (95% CI, −1.24 to −0.40; P = .0002). Similar patterns were observed for worst joint pain, joint stiffness, pain interference, and functioning. Rates of adverse events of any grade were higher in the duloxetine-treated group (78% v 50%); rates of grade 3 adverse events were similar. Conclusion Results of treatment with duloxetine for AIMSS were superior to those of placebo among women with early-stage breast cancer, although it resulted in more frequent low-grade toxicities.

Background Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. Methods Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)-naive patients and patients who progressed after prior VEGFi. Results The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients. Conclusions The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63. © 2018 American Cancer Society.

Remote photoplethysmography (rPPG) is the monitoring of blood volume pulse from a camera at a distance. 3-Dimensional Convolutional Neural Networks (3DCNNs) have shown promising performance on the rPPG task, although it is critical that we understand the impact of both video and model parameters. In this paper, we explore the effect of frame rate, temporal kernel width, and – more generally – temporal receptive field on the reliability of heart rate and waveform estimation carried out by 3DCNNs. We train and evaluate 32 3DCNNs with different temporal parameters on a new large-scale database for physiological monitoring in an interview scenario. We show that previous studies reporting null effects of frame rate changes on pulse estimators may no longer be valid when using CNNs, and decreasing the frame rate may actually improve performance. In particular, we found that models trained on videos with frame rates as low as 12.9 frames per second (fps) perform better than those trained on videos recorded at a full 90 fps, perhaps due to the temporal receptive fields becoming larger in time dimension when the fps decreases. Using this insight, we propose RemotePulseNet, a novel 3DCNN architecture that exploits temporally dilated convolutions with increasing dilation rate to drastically increase the receptive field. We compare its performance with that of recent state-of-the-art pulse estimation methods, and show that both RemotePulseNet and the low frame rate 3DCNNs produce high-quality pulse signals from faces captured under a challenging interview scenario. The source code and instructions for obtaining a copy of the test data are made available with this paper.

The aims of this study were to examine the movement demands of preseason practice in National Collegiate Athletic Association Division I college football players using portable global positioning system (GPS) technology and to assess perceived wellness associated with preseason practice to determine whether GPS-derived variables from the preceding day influence perceived wellness the following day. Twenty-nine players were monitored using GPS receivers (Catapult Innovations, Melbourne, Australia) during 20 preseason practices. Individual observations (n = 550) were divided into offensive and defensive position groups. Movement variables including low-, medium-, high-intensity, and sprint distance, player load, and acceleration and deceleration distance were assessed. Perceived wellness ratings (n = 469) were examined using a questionnaire which assessed fatigue, soreness, sleep quality, sleep quantity, stress, and mood. A 1-way analysis of variance for positional movement demands and multilevel regressions for wellness measures were used, followed by post hoc testing to evaluate the relational significance between categorical outcomes of perceived wellness scores and movement variables. Results demonstrated significantly (p ≤ 0.05) greater total, high-intensity, and sprint distance, along with greater acceleration and deceleration distances for the defensive back and wide receiver position groups compared with their respective offensive and defensive counterparts. Significant (p ≤ 0.05) differences in movement variables were demonstrated for individuals who responded more or less favorably on each of the 6 factors of perceived wellness. Data from this study provide novel quantification of the position-specific physical demands and perceived wellness associated with college football preseason practice. Results support the use of position-specific training and individual monitoring of college football players.

Background: Preclinical evidence has shown that in xenograft models with estrogen receptor (ER)+/HER2+ breast cancer, signaling through the ER pathway can be enhanced in the presence of anti-HER2 treatment and lead to treatment resistance. Concurrent targeting of ER and HER2 has led to enhanced treatment efficacy and complete tumor disappearance. We hypothesized that targeting ER with endocrine therapy concurrently with chemotherapy plus dual HER2 inhibition will not be antagonistic and can overcome ER-mediated resistance and result in higher pCR as neoadjuvant treatment of ER+/HER2+ breast cancer. NRG Oncology/NSABP B-52 is a phase III, multicenter, randomized neoadjuvant therapy trial designed to determine whether the addition of estrogen deprivation to neoadjuvant therapy consisting of docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP+Est-Dep) yields a greater rate of pCR (breast and nodes) than TCHP alone. Methods: A total of 315 patients (pts) were randomly assigned between January 15, 2014 and March 17, 2016 to receive neoadjuvant therapy consisting of TCHP with or without estrogen deprivation therapy. Pts with locally advanced, hormone receptor-positive, HER2+ invasive breast cancer with no evidence of metastatic disease were eligible. Premenopausal women randomized to estrogen deprivation therapy received ovarian function suppression with goserelin (LHRH agonist) or equivalent plus an aromatase inhibitor (AI). Postmenopausal women received an AI. The determination of pCR (breast and nodes) was defined as the absence of any invasive component in the resected breast specimen and all resected lymph nodes following completion of neoadjuvant therapy. Following the intent-to-treat principle, the difference between the rates of pCR (breast and nodes) was tested using the binomial test for the difference between two proportions. The study was designed to have a statistical power of 80% to detect an increase in the pCR rate from 45% in the TCHP alone group to 60% in the TCHP+Est-Dep group. Results: The groups were balanced, with 57% clinically node positive and 50% premenopausal. Assessments for pCR were available from 308 of 315 randomized patients. The pCR (breast and nodes) for TCHP alone and TCHP+Est-Dep were 40.9% and 46.1%, respectively (p=0.36). The pCR (breast) were 44.2% and 47.4%, respectively (p=0.57). Grade 3/4 toxicities included diarrhea (23%, Conclusion: The addition of estrogen deprivation to neoadjuvant chemotherapy is not antagonistic. It improved pCR rates numerically, but the improvement was not statistically significant. The combination did not increase toxicity and may be a reasonable approach since all patients will receive endocrine therapy after neoadjuvant therapy. Correlative science studies including evaluation of residual cancer burden (RCB) and long-term outcomes will help define the role of estrogen deprivation in the treatment of HER2+ early breast cancer. Support: U10CA180868, -180822; UG1CA189867, Genentech. Citation Format: Rimawi MF, Cecchini RS, Rastogi P, Geyer, Jr CE, Fehrenbacher L, Stella PJ, Dayao Z, Rabinovitch R, Dyar SH, Flynn PJ, Baez-Diaz L, Paik S, Swain SM, Mamounas EP, Osborne CK, Wolmark N. A phase III trial evaluating pCR in patients with HR+, HER2-positive breast cancer treated with neoadjuvant docetaxel, carboplatin, trastuzumab, and pertuzumab (TCHP) +/- estrogen deprivation: NRG Oncology/NSABP B-52 [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr S3-06.

// Nilofer S. Azad 1 , Anthony el-Khoueiry 2 , Jun Yin 3 , Ann L. Oberg 3 , Patrick Flynn 4 , Douglas Adkins 5 , Anup Sharma 1 , Daniel J. Weisenberger 2 , Thomas Brown 1 , Prakriti Medvari 1 , Peter A. Jones 6 , Hariharan Easwaran 1 , Ihab Kamel 1 , Nathan Bahary 7 , George Kim 8 , Joel Picus 9 , Henry C. Pitot 3 , Charles Erlichman 3 , Ross Donehower 1 , Hui Shen 6 , Peter W. Laird 6 , Richard Piekarz 9 , Stephen Baylin 1 and Nita Ahuja 1 1 Johns Hopkins University, Baltimore, MD, USA 2 University of Southern California, Los Angeles, CA, USA 3 Mayo Clinic, Rochestor, MN, USA 4 Metro-Minnesota CCOP, Minneapolis, MN, USA 5 Washington University, St. Louis, MO, USA 6 Van Andel Research Institute, Grand Rapids, MI, USA 7 University of Pittsburgh, Pittsburgh, PA, USA 8 Mayo Clinic, Jacksonville, FL, USA 9 Washington University, St. Louis, MO, USA 10 Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA Correspondence to: Nilofer S. Azad, email: // Keywords : epigenetics, colorectal cancer, DNA methyltransferases inhibitors, histone deacetylase inhibitors Received : August 11, 2016 Accepted : October 25, 2016 Published : February 05, 2017 Abstract Purpose: Therapy with demethylating agent 5-azacitidine and histone deacetylase inhibitor entinostat shows synergistic re-expression of tumor-suppressor genes and growth inhibition in colorectal (CRC) cell lines and in vivo studies. Experimental Design: We conducted a phase II, multi-institutional study of the combination in metastatic CRC patients. Subcutaneous azacitidine was administered at 40 mg/m2 days 1-5 and 8-10 and entinostat was given 7 mg orally on days 3 and 10. An interim analysis indicated toxicity crossed the pre-specified safety boundary but was secondary to disease. A 2 nd cohort with added eligibility restrictions was accrued: prior therapies were limited to no more than 2 or 3 (KRAS-mutated and KRAS-wildtype cancers, respectively) and

Background The addition of bevacizumab to chemotherapy improved outcomes for patients with metastatic colon cancer. E5204 was designed to test whether the addition of bevacizumab to mFOLFOX6, following neoadjuvant chemoradiation and definitive surgery, could improve overall survival (OS) in patients with stage II/III adenocarcinoma of the rectum. Subjects, Materials, and Methods Patients with stage II/III rectal cancer who had completed neoadjuvant 5-fluorouracil-based chemoradiation and had undergone complete resection were enrolled. Patients were randomized to mFOLFOX6 (Arm A) or mFOLFOX6 with bevacizumab (Arm B) administered every 2 weeks for 12 cycles. Results E5204 registered only 355 patients (17% of planned accrual goal) as it was terminated prematurely owing to poor accrual. At a median follow-up of 72 months, there was no difference in 5-year overall survival (88.3% vs. 83.7%) or 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. The rate of treatment-related grade ≥ 3 adverse events (AEs) was 68.8% on Arm A and 70.7% on Arm B. Arm B had a higher proportion of patients who discontinued therapy early as a result of AEs and patient withdrawal than did Arm A (32.4% vs. 21.5%, p = .029).The most common grade 3–4 treatment-related AEs were neutropenia, leukopenia, neuropathy, diarrhea (without prior colostomy), and fatigue. Conclusion At 17% of its planned accrual, E5204 did not meet its primary endpoint. The addition of bevacizumab to FOLFOX6 in the adjuvant setting did not significantly improve OS in patients with stage II/III rectal cancer. Implications for Practice At 17% of its planned accrual, E5204 was terminated early owing to poor accrual. At a median follow-up of 72 months, there was no significant difference in 5-year overall survival (88.3% vs. 83.7%) or in 5-year disease-free survival (71.2% vs. 76.5%) between the two arms. Despite significant advances in the treatment of rectal cancer, especially in improving local control rates, the risk of distant metastases and the need to further improve quality of life remain a challenge. Strategies combining novel agents with chemoradiation to improve both distant and local control are needed.

Purpose: To evaluate the pharmacokinetics and efficacy of imatinib in patients with recurrent oligodendroglial tumors. Methods: Patients with progressive WHO grade II-III recurrent tumors after prior RT and chemotherapy were eligible. A phase I dose-escalation study was conducted for patients on enzyme-inducing anticonvulsants (EIAC). A phase II study for non-EIAC patients utilized a fixed dose of 600mg/D. Primary efficacy endpoint was 6-month progression-free survival (PFS6). A 2-stage design was utilized, with 90% power to detect PFS6 increase from 25 to 45%. Results: In the Phase I, maximum tolerated dose was not reached at 1200mg/D. For phase II patients, overall PFS6 was 33% and median PFS 4.0months (95% CI 2.1, 5.7). Median overall survival (OS) was longer in imatinib-treated patients compared with controls (16.6 vs. 8.0months; HR = 0.64, 95% CI 0.41,1.0, p = 0.049), and longer in patients with 1p/19q-codeleted tumors (19.2 vs. 6.2months, HR = 0.43, 95% CI 0.21,0.89, p = 0.019). Confirmed response rate was 3.9% (PR = 1; REGR = 1), with stable disease observed in 52.9%. At 600mg/D, mean steady-state imatinib plasma concentration was 2513ng/ml (95% CI 1831,3195). Grade 3–4 adverse events (hematologic, fatigue, GI, hypophosphatemia, or hemorrhage) occurred in 61%. Conclusions: Although adequate plasma levels were achieved, the observed PFS6 of 33% did not reach our pre-defined threshold for success. Although OS was longer in imatinib-treated patients than controls, this finding would require forward validation in a larger cohort. Imatinib might show greater activity in a population enriched for PDGF-dependent pathway activation in tumor tissue.

Creative works, whether paintings or memes, follow unique journeys that result in their final form. Understanding these journeys, a process known as "provenance analysis", provides rich insights into the use, motivation, and authenticity underlying any given work. The application of this type of study to the expanse of unregulated content on the Internet is what we consider in this paper. Provenance analysis provides a snapshot of the chronology and validity of content as it is uploaded, re-uploaded, and modified over time. Although still in its infancy, automated provenance analysis for online multimedia is already being applied to different types of content. Most current works seek to build provenance graphs based on the shared content between images or videos. This can be a computationally expensive task, especially when considering the vast influx of content that the Internet sees every day. Utilizing non-content-based information, such as timestamps, geotags, and camera IDs can help provide important insights into the path a particular image or video has traveled during its time on the Internet without large computational overhead. This paper tests the scope and applicability of metadata-based inferences for provenance graph construction in two different scenarios: digital image forensics and cultural analytics., Supplemental material for this paper can be found at https://drive.google.com/file/d/1Tbs2CQg_VQAc2PdztW5twVaiXD0G12-H/view?usp=sharing

We propose an algorithm to generate realistic face images of both real and synthetic identities (people who do not exist) with different facial yaw, shape and resolution.The synthesized images can be used to augment datasets to train CNNs or as massive distractor sets for biometric verification experiments without any privacy concerns. Additionally, law enforcement can make use of this technique to train forensic experts to recognize faces. Our method samples face components from a pool of multiple face images of real identities to generate the synthetic texture. Then, a real 3D head model compatible to the generated texture is used to render it under different facial yaw transformations. We perform multiple quantitative experiments to assess the effectiveness of our synthesis procedure in CNN training and its potential use to generate distractor face images. Additionally, we compare our method with popular GAN models in terms of visual quality and execution time., To appear in IEEE WACV 2019. Get our data (2M face images of 12K synthetic subjects, 8K 3D head models) by accessing the "Notre Dame Synthetic Face Dataset" here: https://cvrl.nd.edu/projects/data/

This paper advances the state of the art in human examination of iris images by (1) assessing the impact of different iris conditions in identity verification, and (2) introducing an annotation step that improves the accuracy of people's decisions. In a first experimental session, 114 subjects were asked to decide if pairs of iris images depict the same eye (genuine pairs) or two distinct eyes (impostor pairs). The image pairs sampled six conditions: (1) easy for algorithms to classify, (2) difficult for algorithms to classify, (3) large difference in pupil dilation, (4) disease-affected eyes, (5) identical twins, and (6) post-mortem samples. In a second session, 85 of the 114 subjects were asked to annotate matching and non-matching regions that supported their decisions. Subjects were allowed to change their initial classification as a result of the annotation process. Results suggest that: (a) people improve their identity verification accuracy when asked to annotate matching and non-matching regions between the pair of images, (b) images depicting the same eye with large difference in pupil dilation were the most challenging to subjects, but benefited well from the annotation-driven classification, (c) humans performed better than iris recognition algorithms when verifying genuine pairs of post-mortem and disease-affected eyes (i.e., samples showing deformations that go beyond the distortions of a healthy iris due to pupil dilation), and (d) annotation does not improve accuracy of analyzing images from identical twins, which remain confusing for people., Paper accepted for WACV 2019, Hawaii, USA

Although face recognition systems have achieved impressive performance in recent years, the low-resolution face recognition (LRFR) task remains challenging, especially when the LR faces are captured under non-ideal conditions, as is common in surveillance-based applications. Faces captured in such conditions are often contaminated by blur, nonuniform lighting, and nonfrontal face pose. In this paper, we analyze face recognition techniques using data captured under low-quality conditions in the wild. We provide a comprehensive analysis of experimental results for two of the most important applications in real surveillance applications, and demonstrate practical approaches to handle both cases that show promising performance. The following three contributions are made: {\em (i)} we conduct experiments to evaluate super-resolution methods for low-resolution face recognition; {\em (ii)} we study face re-identification on various public face datasets including real surveillance and low-resolution subsets of large-scale datasets, present a baseline result for several deep learning based approaches, and improve them by introducing a GAN pre-training approach and fully convolutional architecture; and {\em (iii)} we explore low-resolution face identification by employing a state-of-the-art supervised discriminative learning approach. Evaluations are conducted on challenging portions of the SCFace and UCCSface datasets.

Face recognition performance has improved remarkably in the last decade. Much of this success can be attributed to the development of deep learning techniques such as convolutional neural networks (CNNs). While CNNs have pushed the state-of-the-art forward, their training process requires a large amount of clean and correctly labelled training data. If a CNN is intended to tolerate facial pose, then we face an important question: should this training data be diverse in its pose distribution, or should face images be normalized to a single pose in a pre-processing step? To address this question, we evaluate a number of popular facial landmarking and pose correction algorithms to understand their effect on facial recognition performance. Additionally, we introduce a new, automatic, single-image frontalization scheme that exceeds the performance of current algorithms. CNNs trained using sets of different pre-processing methods are used to extract features from the Point and Shoot Challenge (PaSC) and CMU Multi-PIE datasets. We assert that the subsequent verification and recognition performance serves to quantify the effectiveness of each pose correction scheme., Comment: Accepted to WACV 2018 - Fixed title to correct working version Code available here: https://github.com/joelb92/ND_Frontalization_Project/tree/master/Release

Purpose To update guideline recommendations on the role of bone-modifying agents in multiple myeloma. Methods An update panel conducted a targeted systematic literature review by searching PubMed and the Cochrane Library for randomized controlled trials, systematic reviews, meta-analyses, clinical practice guidelines, and observational studies. Results Thirty-five relevant studies were identified, and updated evidence supports the current recommendations. Recommendations For patients with active symptomatic multiple myeloma that requires systemic therapy with or without evidence of lytic destruction of bone or compression fracture of the spine from osteopenia on plain radiograph(s) or other imaging studies, intravenous administration of pamidronate 90 mg over at least 2 hours or zoledronic acid 4 mg over at least 15 minutes every 3 to 4 weeks is recommended. Denosumab has shown to be noninferior to zoledronic acid for the prevention of skeletal-related events and provides an alternative. Fewer adverse events related to renal toxicity have been noted with denosumab compared with zoledronic acid and may be preferred in this setting. The update panel recommends that clinicians consider reducing the initial pamidronate dose in patients with preexisting renal impairment. Zoledronic acid has not been studied in patients with severe renal impairment and is not recommended in this setting. The update panel suggests that bone-modifying treatment continue for up to 2 years. Less frequent dosing has been evaluated and should be considered in patients with responsive or stable disease. Continuous use is at the discretion of the treating physician and the risk of ongoing skeletal morbidity. Retreatment should be initiated at the time of disease relapse. The update panel discusses measures regarding osteonecrosis of the jaw. Additional information is available at www.asco.org/hematologic-malignancies-guidelines and www.asco.org/guidelineswiki .

We propose a multi-scale GAN model to hallucinate realistic context (forehead, hair, neck, clothes) and background pixels automatically from a single input face mask. Instead of swapping a face on to an existing picture, our model directly generates realistic context and background pixels based on the features of the provided face mask. Unlike face inpainting algorithms, it can generate realistic hallucinations even for a large number of missing pixels. Our model is composed of a cascaded network of GAN blocks, each tasked with hallucination of missing pixels at a particular resolution while guiding the synthesis process of the next GAN block. The hallucinated full face image is made photo-realistic by using a combination of reconstruction, perceptual, adversarial and identity preserving losses at each block of the network. With a set of extensive experiments, we demonstrate the effectiveness of our model in hallucinating context and background pixels from face masks varying in facial pose, expression and lighting, collected from multiple datasets subject disjoint with our training data. We also compare our method with two popular face swapping and face completion methods in terms of visual quality and recognition performance. Additionally, we analyze our cascaded pipeline and compare it with the recently proposed progressive growing of GANs., Comment: Extended version of WACV 2020 paper

Binarized statistical image features (BSIF) have been successfully used for texture analysis in many computer vision tasks, including iris recognition and biometric presentation attack detection. One important point is that all applications of BSIF in iris recognition have used the original BSIF filters, which were trained on image patches extracted from natural images. This paper tests the question of whether domain-specific BSIF can give better performance than the default BSIF. The second important point is in the selection of image patches to use in training for BSIF. Can image patches derived from eye-tracking experiments, in which humans perform an iris recognition task, give better performance than random patches? Our results say that (1) domain-specific BSIF features can out-perform the default BSIF features, and (2) selecting image patches in a task-specific manner guided by human performance can out-perform selecting random patches. These results are important because BSIF is often regarded as a generic texture tool that does not need any domain adaptation, and human-task-guided selection of patches for training has never (to our knowledge) been done. This paper follows the reproducible research requirements, and the new iris-domain-specific BSIF filters, the patches used in filter training, the database used in testing and the source codes of the designed iris recognition method are made available along with this paper to facilitate applications of this concept., Comment: Paper accepted for WACV 2019, Hawaii, USA

Prior art has shown it is possible to estimate, through image processing and computer vision techniques, the types and parameters of transformations that have been applied to the content of individual images to obtain new images. Given a large corpus of images and a query image, an interesting further step is to retrieve the set of original images whose content is present in the query image, as well as the detailed sequences of transformations that yield the query image given the original images. This is a problem that recently has received the name of image provenance analysis. In these times of public media manipulation ( e.g., fake news and meme sharing), obtaining the history of image transformations is relevant for fact checking and authorship verification, among many other applications. This article presents an end-to-end processing pipeline for image provenance analysis, which works at real-world scale. It employs a cutting-edge image filtering solution that is custom-tailored for the problem at hand, as well as novel techniques for obtaining the provenance graph that expresses how the images, as nodes, are ancestrally connected. A comprehensive set of experiments for each stage of the pipeline is provided, comparing the proposed solution with state-of-the-art results, employing previously published datasets. In addition, this work introduces a new dataset of real-world provenance cases from the social media site Reddit, along with baseline results., Comment: 13 pages, 6 figures

BACKGROUND: Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. METHODS: Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)–naive patients and patients who progressed after prior VEGFi. RESULTS: The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients. CONCLUSIONS: The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63. © 2018 American Cancer Society.

Two subgroups showing significantly poor survival when treated with single-agent gemcitabine have been identified; one is defined by an overexpression of ACOX1 in blood, and the other via a pain intensity threshold. Masitinib in combination with gemcitabine appears to have a positive benefit–risk ratio in both subgroups. These findings could influence future trial design in pancreatic cancer., Background Masitinib is a selective oral tyrosine–kinase inhibitor. The efficacy and safety of masitinib combined with gemcitabine was compared against single-agent gemcitabine in patients with advanced pancreatic ductal adenocarcinoma (PDAC). Patients and methods Patients with inoperable, chemotherapy-naïve, PDAC were randomized (1 : 1) to receive gemcitabine (1000 mg/m2) in combination with either masitinib (9 mg/kg/day) or a placebo. The primary endpoint was overall survival (OS) in the modified intent-to-treat population. Secondary OS analyses aimed to characterize subgroups with poor survival while receiving single-agent gemcitabine with subsequent evaluation of masitinib therapeutic benefit. These prospectively declared subgroups were based on pharmacogenomic data or a baseline characteristic. Results Three hundred and fifty-three patients were randomly assigned to receive either masitinib plus gemcitabine (N = 175) or placebo plus gemcitabine (N = 178). Median OS was similar between treatment-arms for the overall population, at respectively, 7.7 and 7.1 months, with a hazard ratio (HR) of 0.89 (95% CI [0.70; 1.13]. Secondary analyses identified two subgroups having a significantly poor survival rate when receiving single-agent gemcitabine; one defined by an overexpression of acyl–CoA oxidase-1 (ACOX1) in blood, and another via a baseline pain intensity threshold (VAS > 20 mm). These subgroups represent a critical unmet medical need as evidenced from median OS of 5.5 months in patients receiving single-agent gemcitabine, and comprise an estimated 63% of patients. A significant treatment effect was observed in these subgroups for masitinib with median OS of 11.7 months in the ‘ACOX1’ subgroup [HR = 0.23 (0.10; 0.51), P = 0.001], and 8.0 months in the ‘pain’ subgroup [HR = 0.62 (0.43; 0.89), P = 0.012]. Despite an increased toxicity of the combination as compared with single-agent gemcitabine, side-effects remained manageable. Conclusions The present data warrant initiation of a confirmatory study that may support the use of masitinib plus gemcitabine for treatment of PDAC patients with overexpression of ACOX1 or baseline pain (VAS > 20mm). Masitinib's effect in these subgroups is also supported by biological plausibility and evidence of internal clinical validation. Trial Registration ClinicalTrials.gov:NCT00789633.

Sexual problems and dysfunction are common after therapy for breast and gynecologic malignancies.1-9 Commonly reported problems are difficulties with arousal and orgasm, decreased sexual desire and sexual satisfaction, and psychological effects related to an altered body image and partner factors.4-6,8 Jensen et al reported persistent sexual dysfunction and adverse vaginal changes after radiation for cervical cancer.10 Prevalence rates for sexual problems vary by cancer type and treatment modality, but often affect 50% or more of all female cancer patients.11-13 Despite the recognized prevalence of sexual problems in survivors, there are relatively few studies that address interventions for women who have sexual complaints following cancer therapy.14 One randomized, placebo-controlled study used a nutritional supplement, ArginMax, to treat sexual arousal disorder in healthy women without a history of cancer.15-16 After 4 weeks of therapy, the women who received the supplement reported significant improvement in sexual desire and satisfaction compared with those in the placebo arm. ArginMax consists of extracts of L-arginine, ginseng, ginkgo, and damiana as well as multivitamins and minerals. Nitrous oxide is a byproduct of L-arginine metabolism and results in nitric oxide production, which triggers signaling pathways that lead to vasodilatation. Arginine is believed to be required to carry out the synthesis of nitric oxide that relaxes blood vessels and allows more blood to flow through arteries. Improving hemodynamics and genital blood flow may improve sexual response in women, as well as orgasmic and clitoral sensations.17 Given the positive results of this study and the relative lack of medical therapies for female patients with sexual dysfunction, we designed a placebo-controlled clinical trial to evaluate the use of ArginMax in female cancer survivors. We hypothesized that treatment with the supplement would improve the overall sexual functioning of study participants.

Bevacizumab or temsirolimus regimens have clinical activity in the first-line treatment of advanced renal cell carcinoma (RCC). This phase I/II trial was conducted to determine the safety of combining both agents and its efficacy in RCC patients who progressed on at least one prior anti-VEGF receptor tyrosine kinase inhibitor (RTKI) agent.In the phase I portion, eligible patients were treated with temsirolimus (25 mg IV weekly) and escalating doses of IV bevacizumab (level 1 = 5 mg/kg; level 2 = 10 mg/kg) every other week. The primary endpoint for the phase II portion (RTKI resistant patients) was the 6-month progression-free rate. Secondary endpoints were response rate, toxicity evaluation, and PFS and OS.Maximum tolerated dose was not reached at the maximum dose administered in 12 phase I patients. Forty evaluable patients were treated with the phase II recommended dose (temsirolimus 25 mg IV weekly and bevacizumab 10 mg/kg IV every 2 weeks). The 6-month progression-free rate was 40 % (16/40 pts). Median PFS was 5.9 (4-7.8) months, and median OS was 20.6 (11.5-23.7) months. Partial response, stable disease, and progressive disease were seen in 23, 63, and 14 % of patients, respectively. Most common grade 3-4 AEs included fatigue (17.8 %), hypertriglyceridemia (11.1 %), stomatitis (8.9 %), proteinuria (8.9 %), abdominal pain (6.7 %), and anemia (6.7 %). Baseline levels of serum sFLT-1 and VEGF-A were inversely correlated with PFS and OS, respectively.Temsirolimus and bevacizumab is a feasible combination in patients with advanced RCC previously exposed to oral anti-VEGF agents. The safety and efficacy results warrant further confirmatory studies in this patient population.

Acoustic metrics extracted from speech have the potential to serve as novel biomarkers for a variety of neurological and neurodevelopmental conditions, as is evidenced by the rapidly growing corpus of research articles studying the links between brain impairments and speech. In this paper, we discuss the advantages and the disadvantages of speech biomarkers and the various challenges in the design and the implementation of portable speech-based diagnostic and assessment tools. Furthermore, we provide a case study, presenting our experiences in developing an assessment tool for the detection of mild traumatic brain injuries (concussions) and discuss the challenges in obtaining and analyzing large sets of speech recordings that can be used to study the impact of brain injuries on vocal features.

Background The mammalian target of rapamycin (mTOR) functions within the phosphatidylinositol-3 kinase (PI3K)/Akt pathway as a critical modulator of cell survival. This clinical trial evaluated the combination of the mTOR inhibitor everolimus with conventional temozolomide (TMZ)-based chemoradiotherapy.

In this paper, we propose a novel face synthesis approach that can generate an arbitrarily large number of synthetic images of both real and synthetic identities. Thus a face image dataset can be expanded in terms of the number of identities represented and the number of images per identity using this approach, without the identity-labeling and privacy complications that come from downloading images from the web. To measure the visual fidelity and uniqueness of the synthetic face images and identities, we conducted face matching experiments with both human participants and a CNN pre-trained on a dataset of 2.6M real face images. To evaluate the stability of these synthetic faces, we trained a CNN model with an augmented dataset containing close to 200,000 synthetic faces. We used a snapshot of this trained CNN to recognize extremely challenging frontal (real) face images. Experiments showed training with the augmented faces boosted the face recognition performance of the CNN.

Patients aged ≥60 years with treatment-naive Hodgkin lymphoma (HL) have few treatment options and inferior survival due to treatment-related toxicities and comorbidities. This phase 2, nonrandomized, open-label study evaluated brentuximab vedotin (BV) monotherapy (results previously reported), BV plus dacarbazine (DTIC), and BV plus bendamustine. Patients had classical HL and were ineligible for or declined frontline chemotherapy. Twenty-two patients received 1.8 mg/kg BV and 375 mg/m2 DTIC for up to 12 cycles, and 20 more patients received 1.8 mg/kg BV plus 90 or 70 mg/m2 bendamustine for up to 6 cycles (dose reduced due to toxicity). Subsequent BV monotherapy was allowed. Approximately 30 patients were to receive BV plus bendamustine; however, the incidence of serious adverse events (65%) and 2 deaths on study led to discontinuation of bendamustine and cessation of enrollment. Most patients had stage III/IV disease, and approximately half had ≥3 comorbidities or were impaired in ≥1 aspect that significantly interfered with quality of life. For BV plus DTIC, the objective response rate (ORR) was 100% and the complete remission (CR) rate was 62%. To date, the median progression-free survival (PFS) is 17.9 months. For BV plus bendamustine, the ORR was 100% and the CR rate was 88%. Neither the median PFS nor overall survival was reached. For elderly patients with HL, BV plus DTIC may be a frontline option based on tolerability and response duration. Despite activity, BV plus bendamustine is not a tolerable regimen in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01716806.

Purpose Docetaxel and cyclophosphamide (TC) was superior to doxorubicin and cyclophosphamide (AC) in a trial in early breast cancer. However, activity of TC relative to AC regimens with a taxane (TaxAC) is unknown. Methods In a series of three adjuvant trials, women were randomly assigned to TC for six cycles (TC6) or to a standard TaxAC regimen. US Oncology Research (USOR) 06-090 compared TC6 with docetaxel, doxorubicin, and cyclophosphamide (TAC6). National Surgical Adjuvant Breast and Bowel Project (NSABP) B-46-I/USOR 07132 compared TC6, TAC6, or TC6 plus bevacizumab. NSABP B-49 compared TC6 with several standard AC and taxane combination regimens. Before any analysis of individual trials, a joint efficacy analysis of TC versus the TaxAC regimens was planned, with invasive disease-free survival (IDFS) as the primary end point. Patients who received TC6 plus bevacizumab on NSABP B-46-I/USOR 07132 were not included. A hazard ratio (HR) from a stratified Cox model that exceeded 1.18 for TC6 versus TaxAC was predefined as inferiority for TC6. The prespecified interim monitoring plan was to report for futility if the HR was > 1.18 when 334 IDFS events were observed (50% of 668 events required for definitive analysis). Results A total of 2,125 patients were randomly assigned to receive TC6 regimens and 2,117 patients were randomly assigned to receive TaxAC regimens. The median follow-up time was 3.3 years. There were 334 IDFS events, and the HR for TC6 versus TaxAC was 1.202 (95% CI, 0.97 to 1.49), which triggered early reporting for futility. The 4-year IDFS was 88.2% for TC6 and was 90.7% for TaxAC ( P = .04). Tests for treatment interaction by protocol, hormone receptor status, and nodal status were negative. Conclusion The TaxAC regimens improved IDFS in patients with high-risk human epidermal growth factor receptor 2–negative breast cancer compared with the TC6 regimen.

Deriving relationships between images and tracing back their history of modifications are at the core of Multimedia Phylogeny solutions, which aim to combat misinformation through doctored visual media. Nonetheless, most recent image phylogeny solutions cannot properly address cases of forged composite images with multiple donors, an area known as multiple parenting phylogeny (MPP). This paper presents a preliminary undirected graph construction solution for MPP, without any strict assumptions. The algorithm is underpinned by robust image representative keypoints and different geometric consistency checks among matching regions in both images to provide regions of interest for direct comparison. The paper introduces a novel technique to geometrically filter the most promising matches as well as to aid in the shared region localization task. The strength of the approach is corroborated by experiments with real-world cases, with and without image distractors (unrelated cases)., Comment: 5 pages, Accepted in International Conference on Image Processing, 2017

As image tampering becomes ever more sophisticated and commonplace, the need for image forensics algorithms that can accurately and quickly detect forgeries grows. In this paper, we revisit the ideas of image querying and retrieval to provide clues to better localize forgeries. We propose a method to perform large-scale image forensics on the order of one million images using the help of an image search algorithm and database to gather contextual clues as to where tampering may have taken place. In this vein, we introduce five new strongly invariant image comparison methods and test their effectiveness under heavy noise, rotation, and color space changes. Lastly, we show the effectiveness of these methods compared to passive image forensics using Nimble [https://www.nist.gov/itl/iad/mig/nimble-challenge], a new, state-of-the-art dataset from the National Institute of Standards and Technology (NIST)., Comment: 5 pages, 5 figures

Departing from traditional digital forensics modeling, which seeks to analyze single objects in isolation, multimedia phylogeny analyzes the evolutionary processes that influence digital objects and collections over time. One of its integral pieces is provenance filtering, which consists of searching a potentially large pool of objects for the most related ones with respect to a given query, in terms of possible ancestors (donors or contributors) and descendants. In this paper, we propose a two-tiered provenance filtering approach to find all the potential images that might have contributed to the creation process of a given query $q$. In our solution, the first (coarse) tier aims to find the most likely "host" images --- the major donor or background --- contributing to a composite/doctored image. The search is then refined in the second tier, in which we search for more specific (potentially small) parts of the query that might have been extracted from other images and spliced into the query image. Experimental results with a dataset containing more than a million images show that the two-tiered solution underpinned by the context of the query is highly useful for solving this difficult task., Comment: 5 pages, Accepted in IEEE International Conference on Image Processing (ICIP), 2017

Chemotherapy-induced peripheral neuropathy (CIPN) occurs in as high as 70 % of patients receiving certain types of chemotherapy agents. The FDA has yet to approve a therapy for CIPN. The aim of this multicenter, phase III, randomized, double-blind, placebo-controlled trial was to investigate the efficacy of 2 % ketamine plus 4 % amitriptyline (KA) cream for reducing CIPN. Cancer survivors who completed chemotherapy at least 1 month prior and had CIPN (>4 out of 10) were enrolled (N = 462). CIPN was assessed using average scores from a 7-day daily diary that asks patients to rate the average “pain, numbness, or tingling in [their] hands and feet over the past 24 h” on an 11-point numeric rating scale at baseline and 6 weeks post intervention. ANCOVA was used to measure differences in 6-week CIPN with effects including baseline CIPN, KA treatment arm, and previous taxane therapy (Y/N). The KA treatment showed no effect on 6-week CIPN scores (adjusted mean difference = −0.17, p = 0.363). This study suggests that KA cream does not decrease CIPN symptoms in cancer survivors.