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This systematic review and meta-analysis aimed to compare the outcomes of curative therapy (resection, transplantation, ablation) for hepatocellular carcinoma (HCC) arising from non-alcoholic fatty liver disease (NAFLD) and non-NAFLD etiologies.A systematic search of PubMed, EMBASE and Cochrane Library was conducted for studies comparing survival, peri- and post-operative outcomes. Quality assessment was performed using the Newcastle-Ottawa scale.Findings for 5579 patients were pooled across 9 studies and examined. Analysis demonstrated improved disease-free survival (DFS; HR 0.85, 95% CI 0.74-0.98, p = 0.03) and overall survival (OS; HR 0.87; 95% CI 0.81-0.93; p 0.0001) in NAFLD-HCC patients undergoing liver resection as compared to non-NAFLD HCC patients. NAFLD-HCC patients undergoing all forms of curative therapy were similarly associated with improved OS (HR 0.96; 95% CI 0.86-1.06; p = 0.40) and DFS (HR 0.85; 95% CI 0.74-0.98; p = 0.03), albeit results being significant only for DFS. Only 2 studies reported higher rates of peri- and post-operative complications in patients with NAFLD-HCC. Significant inter-study heterogeneity precluded further analysis.NAFLD-HCC patients can enjoy long-term survival benefit with aggressive curative therapy. Peri- and post-operative morbidity should be mitigated with pre-operative optimization of comorbidities, and deliberately close post-operative monitoring.

Purpose: The CLASSICAL-Lung clinical trial tested the combination of pepinemab, an IgG4 humanized mAb targeting semaphorin 4D, with the PD-L1 inhibitor avelumab to assess the effects of coupling increased T-cell infiltration and reversal of immune suppression via pepinemab with sustained T-cell activation via checkpoint inhibition. Patients and Methods: This phase Ib/II, single-arm study was designed to evaluate the safety, tolerability, and efficacy of pepinemab in combination with avelumab in 62 patients with advanced non–small cell lung cancer (NSCLC), including immunotherapy-naïve (ION) patients and patients whose tumors progressed following anti-PD-1/L1 monotherapy (IOF). The main objectives were to evaluate safety/tolerability, establish a recommended phase 2 dose (RP2D), obtain a preliminary evaluation of antitumor activity, and investigate candidate biomarker activity. Results: The combination was well tolerated with no major safety signals identified. Pepinemab, 10 mg/kg with avelumab, 10 mg/kg, every 2 weeks, was selected as the RP2D. Among 21 evaluable ION patients, 5 patients experienced partial responses (PR), 4 patients evidenced clinical benefit ≥1 year, and the disease control rate (DCR) was 81%. Notably, overall response rate with the combination therapy was higher than previously reported for single-agent avelumab in the PD-L1-negative/low population. Among 29 evaluable IOF patients, the combination resulted in a DCR of 59%, including 2 PR and 7 patients with durable clinical benefit of ≥23 weeks. Biomarker analysis of biopsies demonstrated increased CD8 T-cell density correlating with RECIST response criteria. Conclusions: The combination of pepinemab with avelumab was well tolerated in NSCLC and showed signs of antitumor activity in immunotherapy-resistant and PD-L1-negative/low tumors.

Low-dose aspirin is recommended by the U.S. Preventive Services Task Force for primary prevention of colorectal cancer in certain individuals. However, broader implementation will require improved precision prevention approaches to identify those most likely to benefit. The major urinary metabolite of PGE2, 11α-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), is a biomarker for colorectal cancer risk, but it is unknown whether PGE-M is modifiable by aspirin in individuals at risk for colorectal cancer. Adults (N = 180) who recently underwent adenoma resection and did not regularly use aspirin or NSAIDs were recruited to a double-blind, placebo-controlled, randomized trial of aspirin at 81 or 325 mg/day for 8–12 weeks. The primary outcome was postintervention change in urinary PGE-M as measured by LC/MS. A total of 169 participants provided paired urine samples for analysis. Baseline PGE-M excretion was 15.9 ± 14.6 (mean ± S.D, ng/mg creatinine). Aspirin significantly reduced PGE-M excretion (−4.7 ± 14.8) compared with no decrease (0.8 ± 11.8) in the placebo group (P = 0.015; mean duration of treatment = 68.9 days). Aspirin significantly reduced PGE-M levels in participants receiving either 81 (−15%; P = 0.018) or 325 mg/day (−28%; P < 0.0001) compared with placebo. In 40% and 50% of the individuals randomized to 81 or 325 mg/day aspirin, respectively, PGE-M reduction reached a threshold expected to prevent recurrence in 10% of individuals. These results support that aspirin significantly reduces elevated levels of PGE-M in those at increased colorectal cancer risk to levels consistent with lower risk for recurrent neoplasia and underscore the potential utility of PGE-M as a precision chemoprevention biomarker. The ASPIRED trial is registered as NCT02394769.

Cerebral palsy is the most common cause of childhood motor disability, affecting 2 to 3/1000 children worldwide. Clinical abnormalities in tone, posture, and movement are the result of brain dysgenesis or injury early in life, and impairment varies in type, distribution, and in severity. The underlying brain disorder may also lead to other associated neurologic and systemic impairments. Variability in functional impairments, which can change during development, necessitates an individualized treatment plan. Treatment options are primarily symptomatic and directed toward optimizing independence, function, and/or ease of care-while limiting side effects. New promising disease-preventing and modifying treatments are emerging.

Background Chorioamnionitis (CHORIO) is a principal risk factor for preterm birth and is the most common pathological abnormality found in the placentae of preterm infants. CHORIO has a multitude of effects on the maternal–placental–fetal axis including profound inflammation. Cumulatively, these changes trigger injury in the developing immune and central nervous systems, thereby increasing susceptibility to chronic sequelae later in life. Despite this and reports of neural–immune changes in children with cerebral palsy, the extent and chronicity of the peripheral immune and neuroinflammatory changes secondary to CHORIO has not been fully characterized. Methods We examined the persistence and time course of peripheral immune hyper-reactivity in an established and translational model of perinatal brain injury (PBI) secondary to CHORIO. Pregnant Sprague–Dawley rats underwent laparotomy on embryonic day 18 (E18, preterm equivalent). Uterine arteries were occluded for 60 min, followed by intra-amniotic injection of lipopolysaccharide (LPS). Serum and peripheral blood mononuclear cells (PBMCs) were collected at young adult (postnatal day P60) and middle-aged equivalents (P120). Serum and PBMCs secretome chemokines and cytokines were assayed using multiplex electrochemiluminescent immunoassay. Multiparameter flow cytometry was performed to interrogate immune cell populations. Results Serum levels of interleukin-1β (IL-1β), IL-5, IL-6, C–X–C Motif Chemokine Ligand 1 (CXCL1), tumor necrosis factor-α (TNF-α), and C–C motif chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) were significantly higher in CHORIO animals compared to sham controls at P60. Notably, CHORIO PBMCs were primed. Specifically, they were hyper-reactive and secreted more inflammatory mediators both at baseline and when stimulated in vitro. While serum levels of cytokines normalized by P120, PBMCs remained primed, and hyper-reactive with a robust pro-inflammatory secretome concomitant with a persistent change in multiple T cell populations in CHORIO animals. Conclusions The data indicate that an in utero inflammatory insult leads to neural–immune changes that persist through adulthood, thereby conferring vulnerability to brain and immune system injury throughout the lifespan. This unique molecular and cellular immune signature including sustained peripheral immune hyper-reactivity (SPIHR) and immune cell priming may be a viable biomarker of altered inflammatory responses following in utero insults and advances our understanding of the neuroinflammatory cascade that leads to perinatal brain injury and later neurodevelopmental disorders, including cerebral palsy.

The critical role of the gut microbiome in microscopic colitis (MC) is evident by the observation that fecal diversion is associated with resolution of mucosal inflammation while restoration of fecal stream is associated with recurrence of disease.1 Characterization of the composition and function of the gut microbiome in MC therefore could provide insights into disease pathogenesis.

Made available in DSpace on 2020-12-12T01:10:33Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-01-01 Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) Background: In recent years, there has been an improvement in the in vitro and in vivo methodology for the screening of anti-chagasic compounds. Millions of compounds can now have their activity evaluated (in large compound libraries) by means of high throughput in vitro screening assays. Objective: Current approaches to drug discovery for Chagas disease. Method: This review article examines the contribution of these methodological advances in medicinal chemistry in the last four years, focusing on Trypanosoma cruzi infection, obtained from the PubMed, Web of Science, and Scopus databases. Results: Here, we have shown that the promise is increasing each year for more lead compounds for the development of a new drug against Chagas disease. Conclusion: There is increased optimism among those working with the objective to find new drug candidates for optimal treatments against Chagas disease. São Paulo State University (UNESP) School of Pharmaceutical Sciences Lapdesf-Laboratory of Research and Development of Drugs São Paulo State University (UNESP) School of Pharmaceutical Sciences FAPESP: 2016/10847-9

A core goal of visual neuroscience is to predict human perceptual performance from natural signals. Performance in any natural task can be limited by at least three sources of uncertainty: stimulus variability, internal noise, and suboptimal computations. Determining the relative importance of these factors has been a focus of interest for decades but requires methods for predicting the fundamental limits imposed by stimulus variability on sensory-perceptual precision. Most successes have been limited to simple stimuli and simple tasks. But perception science ultimately aims to understand how vision works with natural stimuli. Successes in this domain have proven elusive. Here, we develop a model of humans based on an image-computable (images in, estimates out) Bayesian ideal observer. Given biological constraints, the ideal optimally uses the statistics relating local intensity patterns in moving images to speed, specifying the fundamental limits imposed by natural stimuli. Next, we propose a theoretical link between two key decision-theoretic quantities that suggests how to experimentally disentangle the impacts of internal noise and deterministic suboptimal computations. In several interlocking discrimination experiments with three male observers, we confirm this link and determine the quantitative impact of each candidate performance-limiting factor. Human performance is near-exclusively limited by natural stimulus variability and internal noise, and humans use near-optimal computations to estimate speed from naturalistic image movies. The findings indicate that the partition of behavioral variability can be predicted from a principled analysis of natural images and scenes. The approach should be extendable to studies of neural variability with natural signals.SIGNIFICANCE STATEMENTAccurate estimation of speed is critical for determining motion in the environment, but humans cannot perform this task without error. Different objects moving at the same speed cast different images on the eyes. This stimulus variability imposes fundamental external limits on the human ability to estimate speed. Predicting these limits has proven difficult. Here, by analyzing natural signals, we predict the quantitative impact of natural stimulus variability on human performance given biological constraints. With integrated experiments, we compare its impact to well-studied performance-limiting factors internal to the visual system. The results suggest that the deterministic computations humans perform are near optimal, and that behavioral responses to natural stimuli can be studied with the rigor and interpretability defining work with simpler stimuli.

The mitogen-activated protein kinase (MAPK) pathway consists of the series of protein kinases RAS-RAF-MEK-Extracellular signal-regulated kinase (ERK), and its function is important to cell proliferation, differentiation, motility, and survival. Certain mutations in the pathway, such as KRAS or BRAF V600 mutations are associated with cancer. Inhibitors of this pathway, including some MEK and BRAF inhibitors, are already being used in the clinic, but a variety of selective ERK inhibitors are still being tested in clinical studies. To date, common adverse events associated with ERK inhibitors include diarrhea, nausea, fatigue, and rash. ERK inhibitors have demonstrated preliminary antitumor activity and may be most effective against cancers with RAS, RAF, or MAPK pathway alterations. This review discusses the MAPK pathway, the biological rationale for ERK inhibitors, and clinical trials involving ERK inhibitors.

This study examined clinician experiences and attitudes toward safety planning in a large urban pediatric psychiatry department serving primarily Latino youth. A total of 46 clinicians completed a survey assessing their experience with and attitudes toward safety planning with adolescents at-risk for suicide. The majority of clinicians were female (78%), non-Latino White (54%), and aged 30-39 (52%). Clinicians' attitudes were largely positive (M = 3.69 SD = 0.47, Range = 2.42-4.42). However, many clinicians (n = 24) were not convinced that safety planning reduces the imminent risk of suicidal behavior in patients. This study provides more depth to our understanding of the way in which safety planning is perceived by clinicians.

Manuscript accepted for publication at Collabra: Psychology. In this article, we provide a toolbox of recommendations and resources for those who desire to promote the uptake of open scientific practices. Open Science encompasses a range of behaviours that aim to improve the transparency of scientific research. This paper is divided into seven sections, each devoted to different group or institution in the research ecosystem: colleagues, students, departments and faculties, universities, academic libraries, journals, and funders. We describe the behavioural influences and incentives for each of these stakeholders and changes they can make to foster Open Science. Our primary goal is to suggest actions that researchers can take to promote these behaviours, inspired by simple principles of behaviour change: make it easy, social, and attractive. In isolation, a small shift in one person’s behaviour may appear to make little difference, but when combined, many shifts can radically alter shared norms and culture. We offer this toolbox to assist individuals and institutions in cultivating a more open research culture.

Background Early childhood is a critical period for growth and development, yet the association with physical activity during this important period is unknown. The aim of this review is to critically summarize the evidence on the prospective associations between physical activity and health and development in children aged Methods A systematic search in three electronic databases (Pubmed, PsycINFO, and Sportdiscus) was conducted to identify prospective studies examining the associations between physical activity (all types; specified by quantity) and health indicators (body composition, cardiometabolic health, bone health and risks/harm) or development (motor, cognitive and social-emotional development) in young children (mean age Results Thirty-nine studies, predominantly conducted in preschoolers (ages 3–5 years), were included of which nine were rated as high methodological quality. There was moderate evidence for a positive association between physical activity and motor (n = 11 studies) and cognitive development (n = 10 studies) based on consistent findings from studies having low-to-moderate methodological quality. There was insufficient evidence for an association between physical activity and body composition (n = 15 studies), cardiometabolic health indicators (n = 7 studies), social-emotional development (n = 2 studies) and bone health (n = 2 studies) based on inconsistent findings from studies having weak-to-high methodological quality. Conclusions There is a need for more high-quality research in order to determine the dose-response relationship between physical activity and health and development in early childhood. Special attention should be paid to studies in children below the age of 3 years.

Chronic pain is prevalent in adults with cerebral palsy. We aimed to explore associations between chronic pain and somatosensory, motor, cognitive, etiologic, and environmental factors in adults with cerebral palsy. This cross-sectional study enrolled 17 adult participants with cerebral palsy (mean age 31 years; 8 female; Gross Motor Functional Classification Status levels I-V) able to self-report and 10 neurotypical adult volunteers (mean age 34 years; 9 female). Participants reported pain characteristics, demographics, and affective factors. Physical examination included somatosensory and motor evaluation. Between-group comparisons used a ranksum test, and correlation analyses estimated effect size in terms of shared variance (ρ2). Individuals with cerebral palsy reported greater pain intensity, neuropathic qualities, and nociceptive qualities than control participants. Higher pain intensity was associated with female gender (ρ2 = 16%), anxiety/depression symptoms (ρ2 = 10%), and lower household income (ρ2 = 19%). It was also associated with better communicative ability (ρ2 = 21%), spinothalamic (sharp/temperature) sensory abnormalities (ρ2 = 33%), and a greater degree of prematurity (ρ2 = 17%). This study highlights similarity of chronic pain associations in people with cerebral palsy with patterns seen in other populations with chronic pain. Spinothalamic sensory abnormalities suggest central pain mechanisms.

Hydroxymethylnitrofurazone (NFOH) is a nitrofurazone prodrug effective in vivo during acute infections, and it has less hepatotoxicity effect than the standard drug benznidazole (BZN) which has been used during short- and long-term treatment. In the present study, we induced the indeterminate form of Chagas disease in mice with a Y strain of Trypanosoma cruzi and analysed the histopathological data about the effects of NFOH and BZN on different tissues, including the heart, skeletal muscle, liver, kidney, colon, spleen and brain. After infection, BALB/c mice were treated with NFOH (150 mg/kg) and BZN (60 mg/kg) for 60 days and then submitted to immunosuppression using dexamethasone (5 mg/kg) for 14 days. Two trained analysts, as part of a blind evaluation, examined the results using serial sections of 3 mm diameter in two different moments. The results showed reactivation of the disease only in the infected nontreated group (POS). After treatment, amastigote nests were found in the heart, colon, liver and skeletal muscle in the POS group and in the heart and liver of the BZN group. Interestingly, amastigote nests were not found in the NFOH and NEG groups. The histopathological analysis showed fewer tissue lesions and parasite infiltrates in the NFOH group when compared with the BZN and POS groups. We have not observed any increase in the levels of hepatocellular injury biomarkers (AST/ALT) in the NFOH group. These in vivo studies show the potential for NFOH as an effective and safe compound useful as an anti-T. cruzi agent.

No study to date has examined the effectiveness of integrating clinical decision support tools, like electronic health record (EHR) alerts, into the clinical care of youth at-risk for suicide. This study aimed to examine the feasibility and acceptability of using an EHR alert to increase clinicians’ use of safety planning with youth at-risk for suicide in an outpatient pediatric psychiatry clinic serving an urban low-income Latino community. An alert intervention was developed to remind clinicians to complete a safety plan whenever they documented that their patient endorsed suicidal ideation, plan, or attempt during a visit in EHR notes. The alert appeared as a separate window containing a reminder message to complete a safety plan once a clinician finished visit documentation. There were 69 at-risk patients between the ages of 13–21 in the intervention period (M = 15.71; SD = 1.86; 66.7% female) and 64 (M = 15.38; SD = 1.93; 68.6% female) in the control period. Logistic regression analyses indicated that patients in the intervention period were significantly more likely than patients in the control period to receive a safety plan (p

Purpose Agents targeting programmed death receptor 1 (PD-1) or its ligand (PD-L1) have shown antitumor activity in the treatment of metastatic breast cancer (MBC). The aim of this study was to assess the activity of avelumab, a PD-L1 inhibitor, in patients with MBC. Methods In a phase 1 trial (JAVELIN Solid Tumor; NCT01772004), patients with MBC refractory to or progressing after standard-of-care therapy received avelumab intravenously 10 mg/kg every 2 weeks. Tumors were assessed every 6 weeks by RECIST v1.1. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Membrane PD-L1 expression was assessed by immunohistochemistry (Dako PD-L1 IHC 73-10 pharmDx). Results A total of 168 patients with MBC, including 58 patients with triple-negative breast cancer (TNBC), were treated with avelumab for 2–50 weeks and followed for 6–15 months. Patients were heavily pretreated with a median of three prior therapies for metastatic or locally advanced disease. Grade ≥ 3 treatment-related AEs occurred in 13.7% of patients, including two treatment-related deaths. The confirmed objective response rate (ORR) was 3.0% overall (one complete response and four partial responses) and 5.2% in patients with TNBC. A trend toward a higher ORR was seen in patients with PD-L1+ versus PD-L1− tumor-associated immune cells in the overall population (16.7% vs. 1.6%) and in the TNBC subgroup (22.2% vs. 2.6%). Conclusion Avelumab showed an acceptable safety profile and clinical activity in a subset of patients with MBC. PD-L1 expression in tumor-associated immune cells may be associated with a higher probability of clinical response to avelumab in MBC.

Background Thymic epithelial tumors are PD-L1–expressing tumors of thymic epithelial origin characterized by varying degrees of lymphocytic infiltration and a predisposition towards development of paraneoplastic autoimmunity. PD-1–targeting antibodies have been evaluated, largely in patients with thymic carcinoma. We sought to evaluate the efficacy and safety of the anti-PD-L1 antibody, avelumab (MSB0010718C), in patients with relapsed, advanced thymic epithelial tumors and conduct correlative immunological studies. Methods Seven patients with thymoma and one patient with thymic carcinoma were enrolled in a phase I, dose-escalation trial of avelumab (MSB0010718C), and treated with avelumab at doses of 10 mg/kg to 20 mg/kg every 2 weeks until disease progression or development of intolerable side effects. Tissue and blood immunological analyses were conducted. Results Two of seven (29%) patients with thymoma had a confirmed Response Evaluation Criteria in Solid Tumors–defined partial response, two (29%) had an unconfirmed partial response and three patients (two thymoma; one thymic carcinoma) had stable disease (43%). Three of four responses were observed after a single dose of avelumab. All responders developed immune-related adverse events that resolved with immunosuppressive therapy. Only one of four patients without a clinical response developed immune-related adverse events. Responders had a higher absolute lymphocyte count, lower frequencies of B cells, regulatory T cells, conventional dendritic cells, and natural killer cells prior to therapy. Conclusion These results demonstrate anti-tumor activity of PD-L1 inhibition in patients with relapsed thymoma accompanied by a high frequency of immune-related adverse events. Pre-treatment immune cell subset populations differ between responders and non-responders. Trial registration ClinicalTrials.gov - NCT01772004. Date of registration – January 21, 2013. Electronic supplementary material The online version of this article (10.1186/s40425-019-0723-9) contains supplementary material, which is available to authorized users.

STUDY DESIGN: Pre-post, pilot study. OBJECTIVES: To characterize ventilatory (V(E)) responses to exercise following warm-up walking in individuals with chronic incomplete spinal cord injury (iSCI) during constant work rate (CWR) exercise. Secondarily, to investigate V(E) and tidal volume (V(T)) variability, and ratings of perceived exertion (RPE) before and after overground locomotor training (OLT). SETTING: Research laboratory. METHODS: A 6-min CWR walking bout at preferred pace was used as a warm-up followed by 6 min of rest and a second 6-min CWR bout at above preferred walking pace. The second CWR bout was analyzed. Breath-by-breath ventilatory data were examined using a curvilinear least squares fitting procedure with a mono-exponential model. V(E) and V(T) variability was calculated as the difference between the observed and predicted values and RPE was taken every 2 min. RESULTS: Participants (n = 3, C4–C5) achieved a hyperpneic response to exercise in V(E) and V(T). OLT resulted in faster ventilatory kinetics and reductions of 24 and 29% for V(E) and V(T) variability, respectively. A 30% reduction in RPE was concurrent with the reductions in ventilatory variability. CONCLUSIONS: OLT may improve ventilatory control during CWR in patients with cervical motor-iSCI. These data suggest that in some participants with iSCI, ventilation may influence RPE during walking. Future research should investigate mechanisms of ventilatory variability and its implications in walking performance in patients with iSCI.

Early studies following perinatal hypoxic-ischemic encephalopathy (HIE) suggested expressive language deficits and academic difficulties, but there is only limited detailed study of language development in this population since the widespread adoption of therapeutic hypothermia (TH). Expressive and receptive language testing was performed as part of a larger battery with 45 children with a mean age of 26 months following perinatal HIE treated with TH. Overall cohort outcomes as well as the effects of gender, estimated household income, initial pH and base excess, and pattern of injury on neonatal brain MRI were assessed. The cohort overall demonstrated expressive language subscore, visual-reception subscore, and early learning composite scores significantly below test norms, with relative sparing of receptive language subscores. Poorer expressive language manifested as decreased vocabulary size and shorter utterances. Expressive language subscores showed a significant gender effect, and estimated socioeconomic status showed a significant effect on both receptive and expressive language subscores. Initial blood gas markers and modified Sarnat scoring did not show a significant effect on language subscores. Binarized MRI abnormality predicted a significant effect on both receptive and expressive language subscores; the presence of specific cortical/subcortical abnormalities predicted receptive language deficits. Overall, the language development profile of children following HIE in the era of hypothermia shows a relative strength in receptive language. Gender and socioeconomic status predominantly predict expressive language deficits; abnormalities detectable on MRI predominantly predict receptive language deficits.

Clinical success of autologous CD19-directed chimeric antigen receptor T cells (CAR Ts) in acute lymphoblastic leukemia and non-Hodgkin lymphoma suggests that CAR Ts may be a promising therapy for hematological malignancies, including multiple myeloma. However, autologous CAR T therapies have limitations that may impact clinical use, including lengthy vein-to-vein time and manufacturing constraints. Allogeneic CAR T (AlloCAR T) therapies may overcome these innate limitations of autologous CAR T therapies. Unlike autologous cell therapies, AlloCAR T therapies employ healthy donor T cells that are isolated in a manufacturing facility, engineered to express CARs with specificity for a tumor-associated antigen, and modified using gene-editing technology to limit T cell receptor (TCR)-mediated immune responses. Here, transcription activator-like effector nuclease (TALEN) gene editing of B cell maturation antigen (BCMA) CAR Ts was used to confer lymphodepletion resistance and reduced graft-versus-host disease (GvHD) potential. The safety profile of allogeneic BCMA CAR Ts was further enhanced by incorporating a CD20 mimotope-based intra-CAR off switch enabling effective CAR T elimination in the presence of rituximab. Allogeneic BCMA CAR Ts induced sustained antitumor responses in mice supplemented with human cytokines, and, most importantly, maintained their phenotype and potency after scale-up manufacturing. This novel off-the-shelf allogeneic BCMA CAR T product is a promising candidate for clinical evaluation.

The authors assessed the effects of forearm rotation on the proximity of the radial nerve and medial collateral ligament (MCL) to a proximal and a more distal arthroscopic anterior elbow capsulectomy. Arthroscopy was performed on 10 cadaveric specimens. Sutures were passed lateral to medial at the level of the radiocapitellar joint and at the proximal edge of the annular ligament. Dissection measured the distance to the radial nerve from the lateral starting point and to the MCL from the medial exit point in varying degrees of forearm rotation. The extent of brachialis muscle coverage of the radial nerve was documented. The distance from the starting point to the radial nerve increased in pronation at both levels. The medial extent of the capsulectomy remained a safe distance from the MCL. Brachialis muscle covered the radial nerve at both levels. Pronation increases the capsulectomy safe zone, including more distally, before encountering the radial nerve; the MCL is not at risk. [ Orthopedics . 2020;43(5):e399–e403.]

191 Background: Avelumab is a human anti–PD-L1 IgG1 monoclonal antibody that is approved for the treatment of metastatic Merkel cell carcinoma (US and EU) and advanced urothelial carcinoma progressed on platinum therapy (US). Here, we report phase 1b data for avelumab in a cohort of patients (pts) with previously treated metastatic melanoma. Methods: Pts with unresectable stage IIIC or IV melanoma progressed after ≥1 line of therapy for metastatic disease received avelumab 10 mg/kg IV Q2W until progression, unacceptable toxicity, or withdrawal. Endpoints included objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and adverse events (AEs; NCI CTCAE v4.0). Results: As of Dec 31, 2016, 51 pts were treated and followed for a median of 24.2 mo (range 16.1–31.5). Median age was 64 y (range 31–84). Site of primary tumor was cutaneous (n = 28, 54.9%), ocular (n = 16, 31.4%), mucosal (n = 2, 3.9%), or unknown (n = 5, 9.8%). Pts had received a median of 2 prior lines of therapy for advanced disease (range 0–4), including ipilimumab (n = 26, 51.0%). Confirmed ORR was 21.6% (95% CI 11.3–35.3), with complete response in 7.8% and partial response in 13.7%. In pts with cutaneous melanoma, ORR was 28.6% (95% CI 13.2–48.7). There were no objective responses in pts with ocular melanoma; however, 7 pts (43.8%) had stable disease. In pts with ≤1 (n = 25), 2 (n = 17), or ≥3 (n = 9) prior lines, ORR was 36.0% (95% CI 18.0–57.5), 11.8% (95% CI 1.5–36.4), and 0% (95% CI 0–33.6), respectively. Antitumor activity by PD-L1 status will be presented. Median duration of response was not estimable (NE) (95% CI 2.6 mo–NE). Median PFS was 3.1 mo (95% CI 1.4–6.3) and the 6-mo PFS rate was 39.2% (95% CI 25.2–52.9). Median OS was 18.5 mo (95% CI 9.3–NE) and the 12-mo OS rate was 62.3% (95% CI 46.9–74.4). 39 pts (76.5%) had a treatment-related (TR)AE, most commonly infusion-related reaction (25.5%), fatigue (17.6%), and chills (11.8%). 4 pts (7.8%) had a grade ≥3 TRAE. 5 pts (9.8%) had an immune-related AE; all were grade 1/2. No treatment-related deaths occurred. Conclusions: Avelumab showed durable responses, promising survival outcomes, and an acceptable safety profile in pts with previously treated metastatic melanoma. Clinical trial information: NCT01772004.

Importance Patients with malignant mesothelioma whose disease has progressed after platinum and pemetrexed treatment have limited options. Anti–programmed cell death 1 (PD-1) antibodies have antitumor activity in this disease, but little is known about the activity of anti–programmed cell death ligand 1 (PD-L1) antibodies in patients with mesothelioma. Objective To assess the efficacy and safety of avelumab in a cohort of patients with previously treated mesothelioma. Design, Setting, and Participants Phase 1b open-label study (JAVELIN Solid Tumor) in patients with unresectable mesothelioma that progressed after platinum and pemetrexed treatment, enrolled at 25 sites in 3 countries between September 9, 2014, and July 22, 2015. Interventions Participants received avelumab, 10 mg/kg, every 2 weeks until disease progression, unacceptable toxic effects, or withdrawal from the study. Main Outcomes and Measures Prespecified end points included confirmed best overall response based on Response Evaluation Criteria In Solid Tumors, version 1.1; duration of response; progression-free survival (PFS); overall survival (OS); PD-L1 expression–based analyses; and safety. Results Of 53 patients treated with avelumab, the median age was 67 (range, 32-84) years; 32 (60%) were male. As of December 31, 2016, median follow-up was 24.8 (range, 16.8-27.8) months. Twenty patients (38%) had 3 or more previous lines of therapy (median, 2; range, 1-8). The confirmed objective response rate (ORR) was 9% (5 patients; 95% CI, 3.1%-20.7%), with complete response in 1 patient and partial response in 4 patients. Responses were durable (median, 15.2 months; 95% CI, 11.1 to not estimable months) and occurred in patients with PD-L1–positive tumors (3 of 16; ORR, 19%; 95% CI, 4.0%-45.6%) and PD-L1–negative tumors (2 of 27; ORR, 7%; 95% CI, 0.9%-24.3%) based on a 5% or greater PD-L1 cutoff. Disease control rate was 58% (31 patients). Median PFS was 4.1 (95% CI, 1.4-6.2) months, and the 12-month PFS rate was 17.4% (95% CI, 7.7%-30.4%). Median OS was 10.7 (95% CI, 6.4-20.2) months, and the median 12-month OS rate was 43.8% (95% CI, 29.8%-57.0%). Five patients (9%) had a grade 3 or 4 treatment-related adverse event, and 3 (6%) had a grade 3 or 4 immune-related, treatment-related adverse event. There were no treatment-related deaths. Conclusions and Relevance Avelumab showed durable antitumor activity and disease control with an acceptable safety profile in a heavily pretreated cohort of patients with mesothelioma. Trial Registration ClinicalTrials.gov identifier:NCT01772004

The restricted expression pattern of B-cell maturation antigen (BCMA) makes it an ideal tumor-associated antigen (TAA) for the treatment of myeloma. BCMA has been targeted by both CD3 bispecific antibody and antibody–drug conjugate (ADC) modalities, but a true comparison of modalities has yet to be performed. Here we utilized a single BCMA antibody to develop and characterize both a CD3 bispecific and 2 ADC formats (cleavable and noncleavable) and compared activity both in vitro and in vivo with the aim of generating an optimal therapeutic. Antibody affinity, but not epitope was influential in drug activity and hence a high-affinity BCMA antibody was selected. Both the bispecific and ADCs were potent in vitro and in vivo, causing dose-dependent cell killing of myeloma cell lines and tumor regression in orthotopic myeloma xenograft models. Primary patient cells were effectively lysed by both CD3 bispecific and ADCs, with the bispecific demonstrating improved potency, maximal cell killing, and consistency across patients. Safety was evaluated in cynomolgus monkey toxicity studies and both modalities were active based on on-target elimination of B lineage cells. Distinct nonclinical toxicity profiles were seen for the bispecific and ADC modalities. When taken together, results from this comparison of BCMA CD3 bispecific and ADC modalities suggest better efficacy and an improved toxicity profile might be achieved with the bispecific modality. This led to the advancement of a bispecific candidate into phase I clinical trials.

Elucidating the functions of a particular gene is paramount to the understanding of how its dysfunction contributes to disease. This is especially important when the gene is implicated in multiple different disorders. One such gene is methyl-CpG-binding protein 2 (MECP2), which has been most prominently associated with the neurodevelopmental disorder Rett syndrome, as well as major neuropsychiatric disorders such as autism and schizophrenia. Being initially identified as a transcriptional regulator that modulates gene expression and subsequently also shown to be involved in other molecular events, dysfunction of the MeCP2 protein has the potential to affect many cellular processes. In this chapter, we will briefly review the functions of the MeCP2 protein and how its mutations are implicated in Rett syndrome and other neuropsychiatric disorders. We will further discuss about the mouse models that have been generated to specifically dissect the function of MeCP2 in different cell types and brain regions. It is envisioned that such thorough and targeted examination of MeCP2 functions can aid in enlightening the role that it plays in normal and dysfunctional physiological systems.

The methyl-CpG-binding protein 2 (MECP2) gene has been implicated in multiple neuropsychiatric disorders such as autism and schizophrenia and, most notably, Rett syndrome (RTT). Mouse models of MeCP2 dysfunction that have been developed are thus important not only for examining the protein's contribution to RTT, but also for elucidating the etiologies of other MECP2-associated neuropsychiatric disorders. In this chapter, we present protocols for three behavioral assays for characterizing major functional domains of MeCP2 dysfunction-the open field test for measuring general locomotor activity and anxiety-like behavior, the three-chambered Crawley box test for assessing social preference and social novelty, and the rotarod assay for testing locomotor coordination. It is hoped that these information facilitate systematic characterization of mouse models that may aid in elucidating the role of MeCP2 in neurological disorders, as well as assessing the effects of putative mechanistic and therapeutic interventions.

Sea-surface temperature (SST) was one of the first ocean variables to be studied from earth observation satellites. Pioneering images from infrared scanning radiometers revealed the complexity of the surface temperature fields, but these were derived from radiance measurements at orbital heights and included the effects of the intervening atmosphere. Corrections for the effects of the atmosphere to make quantitative estimates of the SST became possible when radiometers with multiple infrared channels were deployed in 1979. At the same time, imaging microwave radiometers with SST capabilities were also flown. Since then, SST has been derived from infrared and microwave radiometers on polar orbiting satellites and from infrared radiometers on geostationary spacecraft. As the performances of satellite radiometers and SST retrieval algorithms improved, accurate, global, high resolution, frequently sampled SST fields became fundamental to many research and operational activities. Here we provide an overview of the physics of the derivation of SST and the history of the development of satellite instruments over half a century. As demonstrated accuracies increased, they stimulated scientific research into the oceans, the coupled ocean-atmosphere system and the climate. We provide brief overviews of the development of some applications, including the feasibility of generating Climate Data Records. We summarize the important role of the Group for High Resolution SST (GHRSST) in providing a forum for scientists and operational practitioners to discuss problems and results, and to help coordinate activities world-wide, including alignment of data formatting and protocols and research. The challenges of burgeoning data volumes, data distribution and analysis have benefited from simultaneous progress in computing power, high capacity storage, and communications over the Internet, so we summarize the development and current capabilities of data archives. We conclude with an outlook of developments anticipated in the next decade or so.

Summary Background Merkel cell carcinoma is a rare, aggressive skin cancer with poor prognosis in patients with advanced disease. Current standard care uses various cytotoxic chemotherapy regimens, but responses are seldom durable. Tumour oncogenesis is linked to Merkel cell polyomavirus integration and ultraviolet-radiation-induced mutations, providing rationale for treatment with immunotherapy antibodies that target the PD-L1/PD-1 pathway. We assessed treatment with avelumab, an anti-PD-L1 monoclonal antibody, in patients with stage IV Merkel cell carcinoma that had progressed after cytotoxic chemotherapy. Methods In this multicentre, international, prospective, single-group, open-label, phase 2 trial, patients with stage IV chemotherapy-refractory, histologically confirmed Merkel cell carcinoma (aged ≥18 years) were enrolled from 35 cancer treatment centres and academic hospitals in North America, Europe, Australia, and Asia. Key eligibility criteria were an ECOG performance status of 0 or 1, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, adequate haematological, hepatic, and renal function, and immune-competent status (patients with HIV, immunosuppression, haematological malignancies, and previous organ transplantation were excluded). Patient selection was not based on PD-L1 expression or Merkel cell polyomavirus status. Collection of biopsy material or use of archival tissue for these assessments was mandatory. Avelumab was given intravenously at a dose of 10 mg/kg every 2 weeks. The primary endpoint was confirmed objective response (complete response or partial response) assessed according to RECIST version 1.1 by an independent review committee. Safety and clinical activity were assessed in all patients who received at least one dose of study drug (the modified intention-to-treat population). This trial is registered with ClinicalTrials.gov as NCT02155647. Findings Between July 25, 2014, and Sept 3, 2015, 88 patients were enrolled and received at least one dose of avelumab. Patients were followed up for a median of 10·4 months (IQR 8·6–13·1). The proportion of patients who achieved an objective response was 28 (31·8% [95·9% CI 21·9–43·1]) of 88 patients, including eight complete responses and 20 partial responses. Responses were ongoing in 23 (82%) of 28 patients at the time of analysis. Five grade 3 treatment-related adverse events occurred in four (5%) patients: lymphopenia in two patients, blood creatine phosphokinase increase in one patient, aminotransferase increase in one patient, and blood cholesterol increase in one patient; there were no treatment-related grade 4 adverse events or treatment-related deaths. Serious treatment-related adverse events were reported in five patients (6%): enterocolitis, infusion-related reaction, aminotransferases increased, chondrocalcinosis, synovitis, and interstitial nephritis (n=1 each). Interpretation Avelumab was associated with durable responses, most of which are still ongoing, and was well tolerated; hence, avelumab represents a new therapeutic option for advanced Merkel cell carcinoma. Funding Merck KGaA, Darmstadt, Germany.

Background: The programmed death-1 receptor (PD-1) and its ligand (PD-L1) are key therapeutic targets in the reactivation of the immune response against cancer. Avelumab* (MSB0010718C) is a fully human anti-PD-L1 IgG1 antibody being investigated in clinical trials. We report clinical activity of avelumab in a cohort of patients (pts) with locally advanced (LA) or metastatic breast cancer (MBC) refractory to or progressing after standard-of-care therapy (NCT01772004). Methods: Pts received avelumab at 10 mg/kg Q2W until confirmed progression, unacceptable toxicity, or any criterion for withdrawal occurred. Tumors were assessed every 6 wks (RECIST 1.1). Unconfirmed best overall response was evaluated. Adverse events (AEs) were graded by NCI-CTCAE v4.0. Biopsy or surgical specimens were collected within 90 days prior to 1st dose of avelumab for biomarker analyses. Tumor PD-L1 expression was assessed by immunohistochemistry using various cutoff criteria. Results: As of 27 Feb 2015, 168 pts (167 female, 1 male) with MBC, including ductal (56.5%), carcinoma NOS (9.5%), lobular (3.6%), or other (30.4%), were treated with avelumab and followed for a median of 10 mo (range 6-15). Median age was 55y (range 31-81), ECOG performance status was 0 (49.4%) or 1 (50.6%), and pts had received a median of 3 prior therapies for LA/M disease (range 0-10; pts must have received prior treatment with taxane and anthracycline, unless contraindicated). Pts were HER2–/ER+ or PR+ (69 [41.1%]), triple negative (TNBC = HER2–/ER–/PR–; 57 [33.9%]), HER2+ (26 [15.5%]), or had unknown biomarker status (16 [9.5%]). Median duration of treatment was 8 wks (range 2-50), and 9 pts (5.4%) remained on avelumab. Any grade treatment-related treatment-emergent AEs (TEAEs) occurred in 120 pts (71.4%); the most common (>10%) were fatigue (33 [19.6%]), nausea (24 [14.3%]), and infusion-related reactions (20 [11.9%]). Treatment-related grade ≥3 TEAEs occurred in 24 pts (14.3%) and included (≥1%) fatigue, anemia, increased GGT, and autoimmune hepatitis (each 3 [1.8%]), and arthralgia (2 [1.2%]). There were 2 treatment-related deaths (acute liver failure, respiratory distress). Unconfirmed objective response rate (ORR) in the entire cohort was 5.4% (9 pts; 95% CI: 2.5, 9.9), with 1 CR and 8 PRs. Five of 9 responses were ongoing at time of cutoff. Stable disease was observed in additional 40 pts (23.8%), for an overall disease control rate of 29.2%. Evidence of tumor reduction by ≥30% was seen in 15 pts (8.9%). There were responders in all biomarker subgroups, including 5 PRs in TNBC (n=57 [8.8%; 95% CI: 2.9, 19.3]). PD-L1 expression was evaluable in 136 pts. Among all pts with PD-L1 expressing immune cells within the tumor, 33.3% (4 of 12) had PRs. In pts with TNBC who had PD-L1+ immune cells within the tumor, 44.4% (4 of 9) had PRs, compared with 2.6% (1 of 39) for TNBC and PD-L1– immune cells. Conclusions: Avelumab showed an acceptable safety profile and had clinical activity in a subset of pts with MBC. In pts with TNBC, presence of PD-L1 expressing immune cells within the tumor may be associated with clinical responses to avelumab. Further analyses of PD-L1 expression and clinical activity of avelumab in MBC are ongoing. *Proposed INN. Citation Format: Dirix LY, Takacs I, Nikolinakos P, Jerusalem G, Arkenau H-T, Hamilton EP, von Heydebreck A, Grote H-J, Chin K, Lippman ME. Avelumab (MSB0010718C), an anti-PD-L1 antibody, in patients with locally advanced or metastatic breast cancer: A phase Ib JAVELIN solid tumor trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S1-04.

Gas Electron Multiplier (GEM) technology is being used in various applications, particularly in high energy physics experiments. The GEM is known as a reliable detector in high radiation environment which can maintain high temporal and position resolution. GEM foil is the basic part of the detector which consists of a composite material (polyimide and copper). Large size GEM foil has complex mechanical structure and asymmetries which mainly arises due to formation of the HV sectors in the foil. These asymmetries become very relevant when large size foils are stretched to build a detector. In this article asymmetry affects are presented that define the tensile properties of a large size segmented GEM foil.

Despite progress of immune checkpoint therapies, many cases of non-small cell lung cancer (NSCLC) are refractory or acquire resistance to current therapies. Antibody blockade of semaphorin 4D (SEMA4D, CD100) can overcome resistance mechanisms of immune exclusion and myeloid suppression. Importantly, combinations of anti-SEMA4D with various immunotherapies enhanced T cell infiltration and activity, leading to durable tumor regression in preclinical models. Pepinemab (VX15/2503) is a first-in-class humanized monoclonal antibody targeting SEMA4D. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple immune activation via checkpoint inhibition with beneficial modifications of the tumor immune microenvironment via pepinemab. Here, we present interim results of the Phase 2 portion of the CLASSICAL-Lung study. This phase 1b/2, open label, single arm, first-in-human combination study is designed to evaluate the safety, tolerability and efficacy of pepinemab in combination with avelumab in 62 subjects with advanced stage (IIIB/IV) NSCLC, including immunotherapy-naïve (ION) patients and patients whose tumors progressed during or following immunotherapy (IOF). Dose escalation was successfully completed, presented previously, and no concerning safety signals have been identified to date. Among 29 evaluable IOF patients, 2 experienced confirmed partial response (PR) with 66% and 52% tumor reduction following acquired resistance to prior treatment with pembrolizumab, 15 additional patients experienced stable disease (SD), and at least 7 patients had durable clinical benefit of ≥ 23 weeks. Among 21 evaluable ION patients, 5 experienced PR, and 3 patients had clinical benefit ≥ 1 year. The disease control rate was 81%. Analysis of pre- and on-treatment biopsies demonstrated increased CD8+ T cell density correlating with response, with reduction or elimination of tumor in 10/11 biopsies from subjects with PR or SD. It was notable that 79% of patients who experienced PR or SD were reported to have tumors with negative or low PD-L1 expression. Enrollment is complete and this interim analysis suggest the combination of pepinemab plus avelumab is well tolerated and shows initial clinical signals of antitumor activity. Updated clinical response data, as well as additional immunophenotyping of both inflammatory and suppressive myeloid cells will be presented. Citation Format: Jonathan W. Goldman, Terrence L. Fisher, Elizabeth Evans, John E. Leonard, Desa Rae Pastore, Crystal Mallow, Ernest Smith, Andreas Schröeder, Kevin Chin, Michael Shafique, Thaddeus Beck, Megan A. Baumgart, Ramaswamy Govindan, Nashat Gabrail, Rachel E. Sanborn, Alexander I. Spira, Nagashree Seetharamu, Yanyan Lou, Aaron S. Mansfield, Maurice Zauderer. Interim results from CLASSICAL-Lung, phase 1b/2 study of pepinemab (VX15/2503) in combination with avelumab in advanced NSCLC [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT191.

3011 Background: Antibody blockade of semaphorin 4D (SEMA4D, CD100) promotes tumoral dendritic cell and CD8+ T cell infiltration and reduces function and recruitment of immunosuppressive myeloid cells. Importantly, these mechanisms to overcome immune exclusion and suppression have been shown to complement immune checkpoint therapies in preclinical models. Pepinemab is an IgG4 humanized monoclonal antibody targeting semaphorin 4D. The CLASSICAL-Lung clinical trial tests the combination of pepinemab with avelumab to couple T cell activation via checkpoint inhibition with beneficial modifications of the immune microenvironment via pepinemab. Methods: This phase 1b/2, single arm, first-in-human study is designed to evaluate the safety, tolerability and efficacy of pepinemab with avelumab in 62 patients (pts) with advanced (stage IIIB/IV) non-small cell lung cancer (NSCLC), including immunotherapy-naïve (ION) pts and pts whose tumors progressed following immunotherapy (IOF). Results: Among 21 evaluable ION pts, 5 experienced partial response (PR), 3 pts had clinical benefit ≥ 1 year, and the disease control rate (DCR) is 81%. Pts enrolled in this study were observed to have lower PD-L1 expression relative to prior single agent studies (likely due to approval of pembrolizumab for first line therapy). We, therefore, performed subgroup analysis for response by PD-L1 status. The objective tumor response (ORR) in the PD-L1 negative and low population ( < 80% TPS by Dako 73-10 assay) appears to be approximately 2-2.5 fold greater with combination therapy than with historical single agent immune checkpoint controls. Notably, 97% of pts who experienced PR or SD were reported to have tumors with negative or low PD-L1 expression. Among 29 evaluable IOF pts, the combination resulted in 59% DCR, including 2 PR and 7 patients with durable clinical benefit of ≥ 23 weeks. Biomarker analysis of pre- and on-treatment biopsies confirmed increased CD8+ T cell density correlating with response. Surprisingly, analysis of myeloid-derived suppressor cells (MDSCs) revealed a relative paucity of these cells in pretreatment NSCLC biopsies as compared to other cancer indications such as HNSCC. Conclusions: This trial is nearing completion with only 5 of 62 subjects remaining on study. Preliminary data suggest the combination is well tolerated and shows signs of increased antitumor activity, particularly in PD-L1 negative or low tumors. Updated clinical response data and immunophenotypic analyses will be presented. Clinical trial information: NCT03268057 .

75 Background: Despite progress of immune checkpoint therapies, many cases of non-small cell lung cancer (NSCLC) are refractory or acquire resistance to current therapies. Antibody blockade of semaphorin 4D (SEMA4D, CD100) can overcome resistance mechanisms of immune exclusion and myeloid suppression. Importantly, combinations of anti-SEMA4D with various immunotherapies enhanced T cell infiltration and activity, as well as durable tumor regression in preclinical models. Pepinemab (VX15/2503) is a first-in-class humanized monoclonal antibody targeting SEMA4D. Methods: The CLASSICAL-Lung clinical trial (NCT03268057) evaluates the combination of pepinemab with anti-PD-L1 antibody avelumab to couple beneficial modifications of the immune microenvironment via pepinemab with immune activation via checkpoint inhibition. This ongoing study evaluates the safety, tolerability and efficacy of the combination in patients with advanced (stage IIIB/IV) NSCLC, including immunotherapy-naïve (ION) patients and patients whose tumors progressed during or following immunotherapy (IOF). Results: The combination was well tolerated with no major safety signals identified. Among 29 evaluable IOF patients, two experienced confirmed partial response (PR) with 63% and 52% tumor reduction on study following acquired resistance to prior treatment with pembrolizumab, 15 additional patients experienced stable disease, and at least 5 patients with durable clinical benefit of ≥ 23 weeks. Among 21 evaluable ION patients, 5 experienced PR, clinical benefit ≥ 1 year was observed in 3 patients, and Disease Control Rate was 81%. Analysis of pre- and on-treatment biopsies demonstrated increased CD8+ T cell density correlating with response, reduction or elimination of tumor in 11/13 biopsies from subjects with PR or SD. Conclusions: Interim analysis suggests the combination of pepinemab plus avelumab is well tolerated and shows initial clinical signals of antitumor activity. Updated clinical response data (minimum of 6 mo. follow-up), as well as additional immunophenotyping of both inflammatory and suppressive myeloid cells will be presented. Clinical trial information: NCT03268057.

Background: \ud Patent foramen ovale (PFO) is a contributor to embolic stroke of undetermined source (ESUS). Subgroup analyses from previous studies suggest that anticoagulation could reduce recurrent stroke compared with antiplatelet therapy. We hypothesised that anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, would reduce the risk of recurrent ischaemic stroke compared with aspirin among patients with PFO enrolled in the NAVIGATE ESUS trial.\ud \ud Methods: \ud NAVIGATE ESUS was a double-blinded, randomised, phase 3 trial done at 459 centres in 31 countries that assessed the efficacy and safety of rivaroxaban versus aspirin for secondary stroke prevention in patients with ESUS. For this prespecified subgroup analysis, cohorts with and without PFO were defined on the basis of transthoracic echocardiography (TTE) and transoesophageal echocardiography (TOE). The primary efficacy outcome was time to recurrent ischaemic stroke between treatment groups. The primary safety outcome was major bleeding, according to the criteria of the International Society of Thrombosis and Haemostasis. The primary analyses were based on the intention-to-treat population. Additionally, we did a systematic review and random-effects meta-analysis of studies in which patients with cryptogenic stroke and PFO were randomly assigned to receive anticoagulant or antiplatelet therapy.\ud \ud Findings: \ud Between Dec 23, 2014, and Sept 20, 2017, 7213 participants were enrolled and assigned to receive rivaroxaban (n=3609) or aspirin (n=3604). Patients were followed up for a mean of 11 months because of early trial termination. PFO was reported as present in 534 (7·4%) patients on the basis of either TTE or TOE. Patients with PFO assigned to receive aspirin had a recurrent ischaemic stroke rate of 4·8 events per 100 person-years compared with 2·6 events per 100 person-years in those treated with rivaroxaban. Among patients with known PFO, there was insufficient evidence to support a difference in risk of recurrent ischaemic stroke between rivaroxaban and aspirin (hazard ratio [HR] 0·54; 95% CI 0·22–1·36), and the risk was similar for those without known PFO (1·06; 0·84–1·33; pinteraction=0·18). The risks of major bleeding with rivaroxaban versus aspirin were similar in patients with PFO detected (HR 2·05; 95% CI 0·51–8·18) and in those without PFO detected (HR 2·82; 95% CI 1·69–4·70; pinteraction=0·68). The random-effects meta-analysis combined data from NAVIGATE ESUS with data from two previous trials (PICSS and CLOSE) and yielded a summary odds ratio of 0·48 (95% CI 0·24–0·96; p=0·04) for ischaemic stroke in favour of anticoagulation, without evidence of heterogeneity.\ud \ud Interpretation: \ud Among patients with ESUS who have PFO, anticoagulation might reduce the risk of recurrent stroke by about half, although substantial imprecision remains. Dedicated trials of anticoagulation versus antiplatelet therapy or PFO closure, or both, are warranted.\ud \ud Funding: \ud Bayer and Janssen.

Background The increase in adiposity problems among United States adolescents has been accompanied by persistently high prevalence of unhealthy dieting behaviours (UDBs) such as fasting, taking diet pills/powders/liquids, and vomiting/taking laxatives. This study aimed to examine the associations of self-perceptions of weight status, weight change intentions (WCIs) and UDBs with sex, age and race, as well as trends of UDBs in American adolescents across the weight spectrum. Methods Data come from the biennial cross-sectional, school-based surveys, the Youth Risk Behaviour Surveillance System (1999–2013, n = 113,542). The outcome measures were the self-reported UDBs: fasting for 24 h or more; taking diet pills/powders/liquids; and vomiting/taking laxatives. Sex-stratified logistic regressions assessed relationships between weight status misperceptions across all weight statuses, race and WCIs with UDBs. Differential trends between races were assessed using race*year interaction terms. Results In males, all non-White races had higher odds of fasting and vomiting/taking laxatives than Whites (except fasting in Hispanic/Latinos), with Adjusted Odds Ratios (AORs) between 1.44 and 2.07. In females, Black/African Americans and Hispanic/Latinos had lower odds of taking diet pills/powders/liquids compared to Whites (AORs 0.50 and 0.78 respectively). Racial disparities persisted throughout the study period. Prevalence of fasting and vomiting/taking laxatives did not change between 1999 and 2013 for all races, while taking diet pills/powders/liquids decreased. Compared to individuals of normal weight who were accurate weight status perceivers, individuals of almost all other combinations of weight status and weight status perception had significantly higher odds of displaying any UDB outcome. Overestimation of weight status was found to be the strongest determinant of UDBs. Compared to individuals endorsing "not wanting to do anything" about their weight, individuals endorsing all other WCIs (including wanting to gain weight) also showed significantly higher odds for every UDB outcome, with wanting to lose weight having AORs of the greatest magnitudes. Conclusions Prevalence of UDBs is persistently high, and highest among females across all racial groups. UDBs may elevate undesired weight gain and weight loss in individuals who are obese/overweight and underweight respectively. Further research into weight status perceptions among adolescents may inform efforts to reduce UDBs.

Anti-vascular endothelial growth factor (VEGF) therapy has failed to improve survival in patients with breast cancer (BC). Potential mechanisms of resistance to anti-VEGF therapy include the up-regulation of alternative angiogenic and proinflammatory factors. Obesity is associated with hypoxic adipose tissues, including those in the breast, resulting in increased production of some of the aforementioned factors. Hence, we hypothesized that obesity could contribute to anti-VEGF therapy's lack of efficacy. We found that BC patients with obesity harbored increased systemic concentrations of interleukin-6 (IL-6) and/or fibroblast growth factor 2 (FGF-2), and their tumor vasculature was less sensitive to anti-VEGF treatment. Mouse models revealed that obesity impairs the effects of anti-VEGF on angiogenesis, tumor growth, and metastasis. In one murine BC model, obesity was associated with increased IL-6 production from adipocytes and myeloid cells within tumors. IL-6 blockade abrogated the obesity-induced resistance to anti-VEGF therapy in primary and metastatic sites by directly affecting tumor cell proliferation, normalizing tumor vasculature, alleviating hypoxia, and reducing immunosuppression. Similarly, in a second mouse model, where obesity was associated with increased FGF-2, normalization of FGF-2 expression by metformin or specific FGF receptor inhibition decreased vessel density and restored tumor sensitivity to anti-VEGF therapy in obese mice. Collectively, our data indicate that obesity fuels BC resistance to anti-VEGF therapy via the production of inflammatory and angiogenic factors.

The immature coagulation system during infancy has age-related physiological differences in proteins that contribute to significant variation in heparin responsiveness through alterations in heparin-enhanced thrombin inhibition. The primary aim of this study was to evaluate the relationship between preoperative antithrombin (AT) activity and heparin responsiveness in neonates and infants undergoing congenital cardiac surgery. In this retrospective cohort study, neonates (aged 0-28 days) and infants (aged 29-365 days) undergoing congenital cardiac surgery in the 12-month period from October 2013 to 2014 were studied. The two age groups were compared for the primary endpoint of heparin response measured by the heparin sensitivity index (HSI), with heparin loading doses and heparin resistance being secondary endpoints. Multivariable linear regression analyses were used to explore the relationship between AT activity and heparin response measured by HSI. There were 122 infants and 19 neonates included in the study. After adjusting for low-molecular-weight heparin, unfractionated heparin, and platelet count, there was a significant relationship between AT activity and HSI (r = 0.44; P = 0.009). The median [interquartile range] HSI did not differ between neonates and infants (0.76 [0.69- 0.98] vs 0.89 [0.70-1.10] sec·unit−1·kg−1, respectively; median difference, 0.08; 95% confidence interval [CI], −0.01 to 0.17; P = 0.182), despite the mean (standard deviation) AT activity differing between age groups [60 (16)% vs 84 (18)%, respectively; mean difference, 24; 95% CI, 15 to 32; P < 0.001]. There was a moderate relationship between AT activity and heparin response measured by HSI. Comparing neonates and infants, there was similar heparin responsiveness measured by HSI despite differing AT activity levels. These findings should help guide the perioperative administration of exogenous AT to neonates and infants and suggest that, outside the neonatal period, preoperative AT activity may be used to identify children at risk of decreased heparin responsiveness.

Removal of acidic gases such as H2S and CO2 is performed during the purification of raw natural gas, most commonly using amine gas treatment. However, this industrially entrenched method is limited by significant shortcomings including low operational capture efficiency, amine pipeline corrosion and a large energy penalty due to the sorbent regeneration process. To address these shortcomings, we have studied the use of perfluorinated silica-stabilized dry alkanolamines (DAf) for CO2 capture. Due to their micronized liquid domains, DAf display high operational CO2 capture efficiency. Further, to minimize energy requirements for sorbent regeneration, microwave-assisted regeneration of the spent DAf sorbent was also studied and shown to decrease the energy requirements by about ten times. In contrast to very recent work, our results show that the use of DAf exhibits extraordinary recyclability, with a negligible decrease in absorption capacity over at least ten absorption–regeneration cycles, indicating the potential of this material for gas treatment applications.

Pudendal nerve terminal motor latency (PNTML) testing is a standard recommendation for the evaluation of fecal incontinence. Its role in guiding therapy for fecal incontinence has been previously questioned. The aim of this study was to evaluate the relationship between PNTML testing and anorectal dysfunction. This was a retrospective analysis of data collected prospectively from patients who presented to a pelvic floor disorder center from 2007 to 2015. The relationship between PNTML (normal versus delayed) and anorectal manometry, fecal incontinence severity, and fecal incontinence-related quality of life scores was assessed using the Wilcoxon-Mann-Whitney test. Two hundred sixty-nine patients underwent PNTML testing, and 91.1% were female (N = 245) (median age 62.2 years). Normal PNTML was seen in 234 (87.0%) patients. Among 268 patients who underwent anorectal manometry, delayed PNTML was only significantly associated with median maximum anal squeeze pressure (P = 0.04). Delayed PNTML was not associated with a decrease in median fecal incontinence severity or fecal incontinence-related quality of life scores (N = 99). PNTML was only associated with median maximum anal squeeze pressure, and it was not associated with patient-reported severity of symptoms of fecal incontinence, changes in quality of life attributable to fecal incontinence, median mean resting anal pressure, or median maximum resting anal pressure. PNTML testing may not be relevant to current therapeutic algorithms for fecal incontinence and its routine use should be questioned.

There is a wide range in the reported photon tenth value distance (TVD) in the maze of high‐energy linear accelerator vaults. In order to gain insight into the appropriate use of the TVD value during door design, we performed measurements of the photon dose in the maze of four vaults. In addition, our study represents the first to describe a scenario where an inner borated polyethylene (BPE) door for neutron shielding is installed in the maze downstream to Point A, the point on the maze centerline that is just visible from the isocenter. The measurements were made along the maze centerline at 1 m above the floor. In all cases, the accelerator operated at a nominal energy of 15 MV. Of the four vaults, three were equipped with an inner BPE door at a distance of 1.0–2.1 m downstream to Point A. The door was made of 10.16 cm (4″) BPE sandwiched between two 0.635 cm (1/4″) steel face plates. The photon dose in the maze without a BPE door decreases exponentially with a characteristic TVD of 6 m beyond a distance of 2.5 m from Point A. The presence of a BPE door in an identical vault not only reduces the photon intensity in the maze by about an order of magnitude, but also softens the energy spectrum with a shortened TVD of 4.7 m, significantly lessening the shielding burden at the outer maze entrance. In contrast to the common use of Point A as the reference point to specify distance, the photon dose in the maze with a BPE door located downstream to Point A can be satisfactorily described as exponential functions of the distance measured from the door, which shows good consistency among the three vaults of different room parameters.