bluuebunny/crossref_metadata_2025 huggingface dataset:
Heinz body–related interference with leukocyte and erythrocyte variables obtained by an automated hematology analyzer in cats
Authors: Dondi Francesco , Vasylyeva Kateryna , Serafini Federica , Gruarin Marta , Troìa Roberta , Giunti Massimo , Agnoli Chiara
Published: July 2019

Heinz bodies (HBs) are known to interfere with automated hematology in cats, particularly with the white blood cell (WBC) count. We evaluated the influence of feline HBs on the complete blood count (CBC) results obtained using a flow cytometry–based analyzer. We retrospectively selected cats with circulating HBs and reviewed the results of their CBCs, including red blood cell (RBC) indices, basophil/lobularity (Baso) WBC count (WBCB), peroxidase (Perox) WBC count (WBCP), and cytograms. Based on the presence or absence of HB-related artifacts in their Baso cytogram, cats were grouped into Baso-HBs and HBs groups, respectively, for comparison. The WBCB and WBCP were compared to manual counts of WBCs carried out on blood smears at 400× (MC-WBC). We included 32 cats in our study: 9 of 32 were in the Baso-HBs group, and 23 of 32 were in the HBs group. Baso-HBs cats had a significantly increased HB percentage ( p < 0.001), WBCB ( p < 0.001), difference between WBCB and WBCP ( p < 0.001), lymphocyte count ( p < 0.001), mean corpuscular hemoglobin concentration ( p < 0.001), and difference between calculated and measured erythrocyte hemoglobin concentrations ( p < 0.001) compared to HBs cats. In Baso-HBs cats, the WBCB was significantly higher than the WBCP ( p = 0.02); no significant difference was detected between the WBCP and the MC-WBC ( p = 0.88). Evaluation of automated CBC results raised the suspicion of HB-related interference when using a hematology analyzer in cats; hence, blood smear examination remains essential in routine practice.
Bittorio revisited: structural coupling in the Game of Life
Authors: Beer Randall D
Published: July 2019

The notion of structural coupling plays a central role in Maturana and Varela’s biology of cognition framework and strongly influenced Varela’s subsequent enactive elaboration of this framework. Building upon previous work using a glider in the Game of Life (GoL) cellular automaton as a toy model of a minimal autopoietic system with which to concretely explore these theoretical frameworks, this article presents an analysis of structural coupling between a glider and its environment. Specifically, for sufficiently small GoL universes, we completely characterize the nonautonomous dynamics of both a glider and its environment in terms of interaction graphs, derive the set of possible glider lives determined by the mutual constraints between these interaction graphs, and show how such lives are embedded in the state transition graph of the entire GoL universe.
Mixture Modeling to Characterize Anorexia Nervosa: Integrating Personality and Eating Disorder Psychopathology
Authors: Jennings Karen M. , Bodell Lindsay P. , Crosby Ross D. , Haynos Ann F. , Wildes Jennifer E.
Published: July 2019

BACKGROUND: Efforts to examine alternative classifications (e.g., personality) of anorexia nervosa (AN) using empirical techniques are crucial to elucidate diverse symptom presentations, personality traits, and psychiatric comorbidities. AIMS: The purpose of this study was to use an empirical approach (mixture modeling) to test an alternative classification of AN as categorical, dimensional, or hybrid categorical–dimensional construct based on the co-occurrence of personality psychopathology and eating disorder clinical presentation. METHODS: Patients with AN ( N = 194) completed interviews and questionnaires at treatment admission and 3-month follow-up. Mixture modeling was used to test whether indicators best classified AN as categorical, dimensional, or hybrid. RESULTS: A four-latent class, one-latent dimension mixture model that was variant across groups provided the best fit to the data. Results suggest that all classes were characterized by low self-esteem and self-harming and suicidality tendencies. Individuals assigned to Latent Class 2 (LC2; n = 21) had a greater tendency toward being impulsive and easily angered and having difficulties controlling anger compared with those in LC1 ( n = 84) and LC3 ( n = 66). Moreover, individuals assigned to LC1 and LC3 were more likely to have a poor outcome from intensive treatment compared with those in LC4 ( n = 21). Findings indicate that the dimensional aspect within each class measured frequency of specific eating disorder behaviors but did not predict treatment outcomes. CONCLUSIONS: These results emphasize the complexity of AN and the importance of considering how facets of clinical presentation beyond eating disorder behaviors may have different treatment and prognostic implications.
Identification and analysis of cell wall glycan epitopes and polyphenol oxidase in pawpaw (Asimina triloba [L.] Dunal) fruit pulp as affected by high pressure processing and refrigerated storage
Authors: Brannan Robert G , Faik Ahmed , Goelz Ryan , Pattathil Sivakumar
Published: July 2019

This research explores the cell wall composition and polyphenol oxidase activity of two pawpaw ( Asimina triloba) fruit varieties, Susquehanna and Green River Belle, that were subjected to high pressure processing and 45 days of refrigerated storage. We hypothesize that high pressure processing may inhibit enzymatic action responsible for pawpaw's deleterious postharvest tissue softening and browning. Glycome profiling uses mAb groupings that recognize 19 groups of glycan epitopes present in most major classes of cell wall glycans and was used to determine cell wall composition. Results show that both varieties have typical type I primary cell walls of flowering dicots. However, differences in the fine cell wall structure between the varieties can be inferred and the varieties behaved differently during refrigerated storage, likely indicating of a difference in cell wall-modifying enzymes present in the primary cell walls. High pressure processing treatment does not seem to be effective at eliminating polyphenol oxidase activity.
A Survey of Team Members’ Perceptions of Coaching Activities Related to Tier 1 SWPBIS Implementation
Authors: Bastable Eoin , Massar Michelle M. , McIntosh Kent
Published: July 2019

Coaching is an important component in multi-tiered systems of support (MTSS) such as school-wide positive behavioral interventions and supports (SWPBIS), but little is known about which coaching activities are most related to sustained implementation of this school-wide framework. A survey was developed to examine the amount of receipt and perceived importance of coaching activities delivered to SWPBIS school teams. Respondents included SWPBIS team members ( n = 264) implementing Tier 1 SWPBIS for at least 3 years in 138 districts across nine states. Partial correlations were conducted on a subsample of schools ( n = 131) using the Benchmarks of Quality (BoQ) to assess self-reported implementation fidelity to examine the extent to which each coaching activity was associated with fidelity of implementation of SWPBIS. Results indicated Assisting With Team Action Planning, Assisting With Data Collection, and Sharing Knowledge of SWPBIS Systems were perceived as most important to SWPBIS sustainability. Partial correlations showed two activities were statistically significant and positively correlated with SWPBIS fidelity of implementation: Running Data Reports for the Team and Modeling SWPBIS Implementation. Implications for assessing and differentiating coaching supports delivered to schools are discussed.
Individual and environmental determinants of burnout among nurses
Authors: Rees Clare S. , Eley Robert , Osseiran-Moisson Rebecca , Francis Karen , Cusack Lynette , Heritage Brody , Hegney Desley
Published: July 2019

Objective

Burnout is a significant problem affecting the nursing workforce and is associated with significant personal suffering and high rates of nurse turnover. Efforts to further understand the variables that explain burnout are needed. The aim of this cross-sectional study was to examine both environmental and individual factors that may explain burnout among nurses.

Method

We recruited 1848 Australian nurses to complete several online questionnaires measuring the practice environment (Practice Environment Scale of the Nursing Work Index), burnout (Professional Quality of Life Scale), trait negative affect ( Spielberger State-Trait Anxiety Inventory form Y2) and resilience (Connor Davidson Resilience Scale). Correlational analysis as well as hierarchical regression was used to determine the relative importance of variables in explaining burnout scores.

Results

All of the practice environment scales were significantly related to burnout in the negative direction, and these relationships were above .3 for all except the relationship scale ( r = –.256) and the participation in hospital affairs scale ( r = –.285). Overall, the regression model accounted for 62% of the variance in nurse burnout scores. Trait negative affect, resilience and two aspects of practice environment (Manager sub-scale and Staffing sub-scale) all explained significant variance in burnout scores. The largest contribution came from the two individual variables (resilience and trait negative affect) that together explained 55% of the variance in burnout scores.

Conclusions

Findings suggest that health service administrators should provide nursing staff with education and support to build individual resilience. Workplaces that attend to staffing and resource issues and have managers who provide high levels of support to their staff appear to be essential strategies to help prevent nurse burnout.
Students’ use of information and communication technologies in the classroom: Uses, restriction, and integration
Authors: Vahedi Zahra , Zannella Lesley , Want Stephen C
Published: July 2019

Research has frequently found that students use their information and communication technologies—such as smartphones and laptops—for non-academic uses in the classroom. These uses include sending messages as well as checking email and social media accounts. This study aimed to examine students’ in-class information and communication technology use, their motivations for it, and perceptions of it, as well as their attitudes toward restriction and integration of information and communication technologies in the classroom. It was found that students most frequently engage in non-academic information and communication technology use when they feel that they would not miss any new class content, or when they feel disengaged. Students perceived that their non-academic information and communication technology use had costs, especially distraction. However, students also reported negative attitudes toward policies that would restrict their information and communication technology use in the classroom but had positive perceptions of attempts to integrate information and communication technology use. We propose that information and communication technology integration can be an effective method of increasing student engagement—and therefore decreasing non-academic information and communication technology use.
Electromyography-based gesture recognition for quadriplegic users using hidden Markov model with improved particle swarm optimization
Authors: Sigalingging Xanno K , Budiarsa Alrezza Pradanta Bagus , Leu Jenq-Shiou , Takada Jun-ichi
Published: July 2019

People with quadriplegia cannot move their body and limbs freely, making them unable to interact normally with their environment. This article aims to improve the life quality of quadriplegia patients through a development of a system to help them interact with their surroundings. A novel algorithm to classify human gestures is proposed in this article. The algorithm is developed as the core of an assistive technology system in the form of a human interface device, which utilizes electromyograph as its sensor. The system utilizes a wearable electromyograph with a custom software as the signal capturing and processing tool. The electrodes of the electromyograph are placed on certain positions on the face, corresponding to the locations of the major muscles that govern certain facial gestures. The signals are then processed using a novel algorithm that employs hidden Markov model and improved particle swarm optimization to classify the gesture. Based on the gestures, a custom command can be assigned for different conditions. The accuracy of the system is 96.25% for five gestures classification.
Application of probabilistic approaches to the performance evaluation of building envelopes to withstand mould growth
Authors: Gradeci Klodian , Berardi Umberto
Published: July 2019

Probabilistic-based approaches for the performance evaluation of building envelopes to withstand mould growth have gained significant attention in recent years. In this article, a scoping review is performed to identify some current challenges and opportunities in probabilistic-based approaches. Therefore, the performance of a highly insulated wall is evaluated by applying a probabilistic-based methodology that accounts for several uncertainties and investigates their significance. A sensitivity analysis is performed according to the Morris method to understand the influence of each parameter and simplify the system representation of this case study. Deficiencies in terms of rain penetration and air leakage are accounted for. The mould growth risk is evaluated by integrating different mould models and assessment criteria. Overall, the performance of the investigated wall is found satisfactory in most of the cases, except when wind-driven rain penetration occurs. The study demonstrates that a probabilistic-based methodology enables a systematic approach to evaluate the performance of building constructions as it accounts for the involved uncertainties, provides a clear association of the microbial growth to its probability of occurrence and enables the identification of the dominant parameters, delivering more comprehensive conclusions.
Comparison of T2*GRE and DSC-PWI for hemorrhage detection in acute ischemic stroke patients: Pooled analysis of the EPITHET, DEFUSE 2, and SENSE 3 stroke studies
Authors: Amukotuwa Shalini A , Fischbein Nancy J , Albers Gregory W , Davis Stephen , Donnan Geoffrey A , Andre Jalal B , Bammer Roland
Published: July 2019

Aims

The objective of this study was to compare the diagnostic performance of the baseline pre-contrast images of dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI) with conventional T2*gradient recalled echo (GRE) imaging for detection of hemorrhage in acute ischemic stroke patients.

Material and methods

T2*GRE and DSC-PWI from 393 magnetic resonance imaging scans from 221 patients enrolled in three prospective stroke studies were independently evaluated by two readers blinded to clinical and other imaging data. Agreement between T2*GRE and DSC-PWI for the presence of hemorrhage, and acute hemorrhagic transformation, was assessed using the kappa statistic. Inter-reader agreement was also assessed using the kappa statistic.

Results

Agreement between the baseline images of DSC-PWI and T2*GRE regarding the presence of hemorrhage was almost perfect (kreader 1 : 0.90, 95% confidence interval 0.86–0.95 and kreader 2 : 0.91, 95% confidence interval 0.87–0.96). Agreement between the sequences was still higher for detection of acute hemorrhagic transformation (kreader 1 : 0.94, 95% confidence interval 0.91–0.98 and kreader 2 : 0.95, 95% confidence interval 0.92–0.98). Inter-reader agreement for detection of hemorrhage was also almost perfect for both T2*GRE (k: 0.95, 95% confidence interval 0.91–0.98) and DSC-PWI (k: 0.96, 95% confidence interval 0.93–0.99). Acute hemorrhagic transformation detected on T2*GRE was missed on DSC-PWI by one or both readers in 5/393 (1.3%) scans.

Conclusion

The almost perfect statistical agreement between DSC-PWI and conventional T2*GRE suggests that DSC-PWI is sufficient for hemorrhage screening prior to thrombolysis in stroke patients. T2*GRE can therefore be omitted when DSC-PWI is included, thereby shortening the acute ischemic stroke magnetic resonance imaging protocol and expediting treatment. Trial registration: ClinicalTrials.gov Identifier: NCT02586415.
Regulation of lung immunity by dendritic cells: Implications for asthma, chronic obstructive pulmonary disease and infectious disease
Authors: Peters Marcus , Peters Karin , Bufe Albrecht
Published: July 2019

Since the first description of dendritic cells by Steinman and Cohn in 1973, this important cell type has gained increasing attention. Over 4000 papers have been published on this topic annually during the last few years. At the beginning, dendritic cells were recognized for their immune stimulatory properties and their importance in initiating an adaptive immune response. Later, it was found that dendritic cells do not only initiate but also regulate immune responses. This attribute makes the so-called regulatory dendritic cells highly important for the prevention of exaggerated immune responses. Immune cells make contact with different Ags every day and must be tightly controlled to prevent excessive inflammation and subsequent organ destruction, particularly in organs such as the gut and lungs. Here, we give a brief overview of our current knowledge on how immune responses are controlled by dendritic cells, highlighting how they are involved in the induction of peripheral tolerance. We focus on what is known about these processes in the lung, with a closer look at their role in the induction and control of diseases such as bronchial asthma, chronic obstructive pulmonary disease and lung infections. Finally, we summarize some current approaches to modulate the behavior of dendritic cells that may hopefully lead to future therapeutics to control exaggerated immune responses.
The endonuclease APE1 processes miR-92b formation, thereby regulating expression of the tumor suppressor LDLR in cervical cancer cells
Authors: Sun Yi , Feng Yun , Zhang Guiqian , Xu Ya
Published: July 2019

Background:

The molecular mechanisms underlying cervical cancer require elucidation to identify novel therapeutic targets. Apurinic/apyrimidinic endodeoxyribonuclease 1 (APE1) is a multifunctional apurinic/apyrimidinic (AP) endonuclease that influences the transcription of many cancer-related genes via microRNome regulation. Herein, we examine the role of miR-92b-3p (hereinafter miR-92b), whose processing may be regulated by APE1, in cervical cancer progression.

Methods:

APE1’s processing of miR-92b from its pri-miR form was measured by a quantitative reverse transcription polymerase chain reaction (qRT-PCR)-based ratio. APE1’s endonuclease activity was measured with AP-site incision assays. APE1-DROSHA interaction was studied with immunofluorescence, confocal and proximity ligation analyses. The miR-92b’s targeting of low-density lipoprotein receptor (LDLR) was investigated with luciferase reporter assays. The miR-92b mimics and shRNA-based miR-92b silencing, as well as LDLR overexpression and short interfering RNA (siRNA)-based LDLR silencing, were employed in CaSki and SiHa cervical cancer cells. Cell proliferation and chemosensitivity to paclitaxel and cisplatin were assayed. Cell-cycle progression and apoptosis were assessed by flow cytometry. Tumor growth was studied in a murine xenograft model.

Results:

APE1’s endonuclease activity, via association with the DROSHA-processing complex, is necessary for processing mature miR-92b, thereby regulating expression of miR-92b’s direct target LDLR. The miR-92b promotes cell proliferation in vitro and in vivo, promotes cell-cycle progression, and reduces apoptosis and chemosensitivity. LDLR silencing recapitulated miR-92b’s transformative effects, while LDLR overexpression rescued these effects.

Conclusions:

APE1 enhances miR-92b processing, thereby suppressing LDLR expression and enhancing cervical carcinoma progression. Our identification of the novel APE1-miR-92b-LDLR axis improves our understanding of the complex pathogenesis of cervical carcinoma and reveals a novel therapeutic strategy for combating this disease.
Prediabetes: lifestyle, pharmacotherapy or regulation?
Authors: Shaw Jonathan E.
Published: July 2019

The rapidly rising number of people with diabetes worldwide has led to multiple attempts to identify effective means of preventing type 2 diabetes. Lifestyle interventions have shown impressive efficacy in multiple clinical trials of people with impaired glucose tolerance, but, as currently formulated, appear to have very little impact on impaired fasting glucose. Attempts to roll out lifestyle interventions beyond clinical trials have generally recruited too few people to have a chance of influencing the population prevalence of diabetes. Several drugs have also been shown to reduce the incidence of diabetes, but until such drugs can be shown to prevent the clinical consequences of diabetes, it is unlikely that guidelines will recommend their widespread use for diabetes prevention. Population-level interventions, including education and regulation, are attractive, as they have the potential to influence a high proportion of the population. Favourable effects of a sugar sweetened beverage tax on consumption are encouraging, but data on its influence on diabetes are not yet available.
Decomposition of Practice as an Activity for Research-Practice Partnerships
Authors: Resnick Alison Fox , Kazemi Elham
Published: July 2019

This analysis examines the process of one research-practice partnership (RPP) engaged in the activity of decomposing elementary principal practice in the context of an instructional improvement initiative in mathematics. Decomposing, or breaking apart, complex practice has been used primarily by researchers to inform the design of pre-service teacher education. We argue that decomposition is a rich activity for researchers and practitioners to collaboratively engage in to support improvement efforts where practitioners are expected to transform their day-to-day practice. We examine what can be learned from the process by which one RPP engaged in decomposing practice that might be useful for other RPPs. Our retrospective, qualitative analysis supports understanding of how RPPs might engage in decomposition and the role decomposition might play in supporting RPPs to foster educational transformation in local contexts.
The Use of Bone Grafts, Bone Graft Substitutes, and Orthobiologics for Osseous Healing in Foot and Ankle Surgery
Authors: Peterson Jonathan R. , Chen Fangyu , Nwankwo Eugene , Dekker Travis J. , Adams Samuel B.
Published: July 2019

Achieving fusion in osseous procedures about the foot and ankle presents unique challenges to the surgeon. Many patients have comorbidities that reduce osseous healing rates, and the limited space and high weightbearing demand placed on fusion sites makes the choice of bone graft, bone graft substitute, or orthobiologic agent of utmost importance. In this review, we discuss the essential characteristics of grafts, including their osteoconductive, osteoinductive, osteogenic, and angiogenic properties. Autologous bone graft remains the gold standard and contains all these properties. However, the convenience and lack of donor site morbidity of synthetic bone grafts, allografts, and orthobiologics, including growth factors and allogenic stem cells, has led to these being used commonly as augments.

Level of Evidence:

Level V, expert opinion.
Consensus criteria for diagnosis, staging, and treatment response assessment of T-cell prolymphocytic leukemia
Authors: Staber Philipp B. , Herling Marco , Bellido Mar , Jacobsen Eric D. , Davids Matthew S. , Kadia Tapan Mahendra , Shustov Andrei , Tournilhac Olivier , Bachy Emmanuel , Zaja Francesco , Porkka Kimmo , Hoermann Gregor , Simonitsch-Klupp Ingrid , Haferlach Claudia , Kubicek Stefan , Mayerhoefer Marius E. , Hopfinger Georg , Jaeger Ulrich , Dearden Claire
Published: July 2019

In a Special Report, the T-PLL International Study group presents consensus criteria for the diagnosis, staging, and treatment response assessment of patients with T-cell prolymphocytic leukemia.
Triglyceride-glucose index is associated with symptomatic coronary artery disease in patients in secondary care
Authors: da Silva Alessandra , Caldas Ana Paula Silva , Hermsdorff Helen Hermana Miranda , Bersch-Ferreira Ângela Cristine , Torreglosa Camila Ragne , Weber Bernardete , Bressan Josefina
Published: July 2019

Background

The triglyceride-glucose index (TyG index) is a tool for insulin resistance evaluation, however, little is known about its association with coronary artery disease (CAD), which is the major cardiovascular death cause, and what factors may be associated with TyG index.

Objective

To evaluate the association between the TyG index and the prevalence of CAD phases, as well as cardiovascular risk factors.

Methods

The baseline data of patients in secondary care in cardiology from Brazilian Cardioprotective Nutritional Program Trial (BALANCE Program Trial) were analyzed. Anthropometric, clinical, socio-demographic and food consumption data were collected by trained professionals. The TyG index was calculated by the formula: Ln (fasting triglycerides (mg/dl) × fasting blood glucose (mg/dl)/2) and regression models were used to evaluate the associations.

Results

We evaluated 2330 patients, which the majority was male (58.1%) and elderly (62.1%). The prevalence of symptomatic CAD was 1.16 times higher in patients classified in the last tertile of the TyG index (9.9 ± 0.5) compared to those in the first tertile (8.3 ± 0.3). Cardiometabolic risk factors were associated with TyG index, with the highlight for higher carbohydrate and lower lipid consumption in relation to recommendations that reduced the chance of being in the last TyG index tertile.

Conclusion

The TyG index was positively associated with a higher prevalence of symptomatic CAD, with metabolic and behavioral risk factors, and could be used as a marker for atherosclerosis.

Trial registration ClinicalTrials.gov identifier: NCT01620398. Registered 15 June, 2012
Suicidal risk factors in major affective disorders
Authors: Baldessarini Ross J. , Tondo Leonardo , Pinna Marco , Nuñez Nicholas , Vázquez Gustavo H.
Published: July 2019

Background

Rates and risk factors for suicidal behaviour require updating and comparisons among mood disorders.

Aims

To identify factors associated with suicidal risk in major mood disorders.

Method

We considered risk factors before, during and after intake assessments of 3284 adults with/without suicidal acts, overall and with bipolar disorder (BD) versus major depressive disorder (MDD), using bivariate comparisons, multivariable regression modelling and receiver operating characteristic (ROC) analysis.

Results

Suicidal prevalence was greater in BD versus MDD: ideation, 29.2 versus 17.3%; attempts, 18.8 versus 4.78%; suicide, 1.73 versus 0.48%; attempts/suicide ratio indicated similar lethality, 10.9 versus 9.96. Suicidal acts were associated with familial BD or suicide, being divorced/unmarried, fewer children, early abuse/trauma, unemployment, younger onset, longer illness, more dysthymic or cyclothymic temperament, attention-deficit hyperactivity disorder (ADHD), substance misuse, mixed features, hospital admission, percentage time unwell, less antidepressants and more antipsychotics and mood stabilisers. Logistic regression found five independent factors: hospital admission, more depression at intake, BD diagnosis, onset age ≤25 years and mixed features. These factors were more associated with suicidal acts in BD than MDD: percentage time depressed/ill, alcohol misuse, >4 pre-intake depressions, more dysthymic/cyclothymic temperament and prior abuse/trauma. ADHD and total years ill were similar in BD and MDD; other factors were more associated with MDD. By ROC analysis, area under the curve was 71.3%, with optimal sensitivity (76%) and specificity (55%) with any two factors.

Conclusions

Suicidal risks were high in mood disorders: ideation was highest with BD type II, attempts and suicides (especially violent) with BD type I. Several risk factors for suicidal acts differed between BD versus MDD patients.

Declaration of interest

No author or immediate family member has financial relationships with commercial entities that might appear to represent potential conflicts of interest with the information presented.
The importance of surgical margins in dedifferentiated liposarcoma survival.
Authors: Albagoush Sara , Gootee Jonathan , Nguyen Kevin , Aurit Sarah J , Curtin Christina , Silberstein Peter T.
Published: July 2019

e22528

Background: Among the types of soft tissue sarcomas (STS), liposarcoma is the most common malignant STS. Considering therapeutic options, surgical resection is the most utilized therapeutic option. In this study, we aim to explore the effects of varying degrees of surgical margins on survival in patients with dedifferentiated liposarcoma. Methods: The National Cancer Database (NCDB) was used to select patients with dedifferentiated liposarcoma to determine if surgical margins and other variables were associated with worse overall survival after accounting for age, gender, race, Charlson-Deyo score, anatomic site, treatment approach, tumor size, tumor grade, and presence of metastases through multivariable analysis. Results: Of the 1,004 patients, 64.4% were male, 87.0% were white, and the median age was 63 years. Approximately 95% had no metastases at the time of diagnosis, and 91.5% had high grade liposarcoma. For the status of surgical margins, 50.8% had no residual tumors, 26.1% had microscopic residual tumors, and 4.3% had macroscopic residual tumors. In general, the risk of death was higher for older males (25.8% increased risk of mortality) and those with metastases (312.9% increased risk of mortality) as well as patients with high grade liposarcoma (112.4% increased risk of mortality). When compared to no residual tumor after surgery, patients with macroscopic residual tumors, had a 96.7% increased risk of death (HR 95% CI:1.24 to 3.13; p= 0.004). Conclusions: Older age, presence of metastasis, male patients, retroperitoneal/abdomen primary site, high grade tumors, and macroscopic or residual tumor present after surgery led to an increased risk of mortality.
CheckMate 384: Phase IIIb/IV trial of nivolumab (nivo) 480 mg Q4W versus 240 mg Q2W after ≤ 12 months of nivo in previously treated advanced NSCLC.
Authors: Garon Edward B. , Reinmuth Niels , Falchero Lionel , Garcia Garcia Yolanda , Hureaux José , Gore Ira , Harris Ronald P. , Bidoli Paolo , Baldini Editta , Ros Silverio , Laack Eckart , Mitchell Paul , Wolf Martin , O'Byrne Kenneth John , Zibdawi Labib , Jao Kevin , Spigel David , Li Ang , Rabindran Sridhar K. , Pichon Eric
Published: July 2019

100

Background: Nivo is approved as 240 mg Q2W in the EU and Japan and 240 mg Q2W or 480 mg Q4W in the US and Canada for second-line treatment (tx) of advanced NSCLC. Pharmacokinetic modeling in various tumors predicts that exposure, efficacy and safety can be maintained with less frequent Q4W dosing, which may provide a more convenient tx option. We present an interim analysis of efficacy and safety from CheckMate 384 (NCT02713867), an international, open-label, randomized phase 3b/4 trial evaluating less frequent nivo dosing (480 mg Q4W vs 240 mg Q2W) in patients (pts) with advanced NSCLC and prior Q2W nivo tx. Methods: Pts (N = 329) with previously treated histologically confirmed stage IIIB/IV or recurrent NSCLC, ECOG performance status 0–2, and prior tx with nivo 3 mg/kg or 240 mg Q2W for ≤12 mo, with ≥2 consecutive assessments of complete / partial response or stable disease, were randomized 1:1 to nivo 480 mg Q4W or 240 mg Q2W over a 30-min infusion. Co-primary endpoints: post-randomization (RND) progression-free survival rates (PFS) at 6 mo and 1 y. Secondary endpoints included safety. Due to tx landscape changes in NSCLC, statistical analyses were amended for a reduced sample size. One-sided 95% CIs were generated to compare PFS rates; presented data analyses are descriptive. Results: Of 166 and 163 pts randomized to 480 mg Q4W and 240 mg Q2W, 164 and 161 pts were treated, respectively. Median follow-up was 9.5 mo (480 mg Q4W) and 10.2 mo (240 mg Q2W). Baseline characteristics were balanced between tx arms. Stratified PFS rates post-RND were comparable between tx arms at 6 mo and 1 y (Table). Safety profiles were similar; any grade tx-related adverse events (TRAEs) and TRAEs leading to discontinuation were reported in 48% vs 61% and 6% vs 9% of pts with 480 mg Q4W vs 240 mg Q2W. No tx-related deaths were reported. Conclusions: Nivo 480 mg Q4W showed similar efficacy and safety to 240 mg Q2W in pts with disease control on nivo, supporting the potential use of 480 mg Q4W as a more convenient dosing option for second-line NSCLC tx. Clinical trial information: NCT02713867. [Table: see text]
Outcome, costs and dollar value of anticancer drugs in non-small cell lung cancer with emphasis on pembrolizumab.
Authors: Guirgis Helmy M.
Published: July 2019

104

Background: Drug outcomes were analyzed in 9 clinical studies of advanced/metastatic non-small-cell lung cancer (NSCLC). Overall survivals were not reached in some studies. Objective: Weigh hazard ratios (HR), costs and dollar value of each drug vs. its control with emphasis on pembrolizumab (pembro). Methods: Protocols were followed, and parent company costs quoted. yearly-costs of pembro, bevacizumab (bev), pemetrexed (peme) and docetaxel (doc) were calculated. Probability of survival (PoS) was defined as (1.0-HR) and dollar value as cost/PoS. Results: Doc and bev carried black box warnings with estimated grade 3/4 adverse events > 20% compared with pembro <10% and peme < 15%. Doc costs were $63,648. In second-line, estimated HR of doc versus supportive care was 0.70 and value $212,169. Pembro costs at 2mg/Kg x 80 Kg q3 weeks were $125,770. Compared with doc, pembro HR in PD-L1 > 1.0% tumor proportion score (TPS) was 0.71 and value $433,690. Using the 200mg total dose, costs were $157,213 and value $542,114. In first-line, pembro versus chemo in > 1.0% chemo demonstrated HR 0.81, and value $827,439, improving in > 50% to 0.69 and $507,139 respectively. Pembro + chemo versus chemo in < 1.0% were 0.59 and $383,446 improving in > 50% to 0.42 and $271,057. Bev costs were $132,314, HR 0.79 and value $630,067. Peme were $97,947, 0.63-0.78 and $264,722-$445,213. Conclusions: Pembro at 160 mg total dose in 80 Kg patients reduced the 200 mg costs by 20% with proportionate savings at lower weights. Pembro dollar value were enhanced by dose adjustment, PD-L1 enrichment and chemotherapy.
A phase Ia/Ib study of an anti-TIM-3 antibody (LY3321367) monotherapy or in combination with an anti-PD-L1 antibody (LY3300054): Interim safety, efficacy, and pharmacokinetic findings in advanced cancers.
Authors: Harding James J. , Patnaik Amita , Moreno Victor , Stein Mark , Jankowska Anna M. , Velez de Mendizabal Nieves , Tina Liu Zhuqing , Koneru Mythili , Calvo Emiliano
Published: July 2019

12

Background: Combined targeting of both the TIM-3 and PD-L1 immune checkpoint pathways may improve efficacy. LY3321367 mAb targets TIM-3 on immune cells and LY3300054 mAb targets PD-L1 on tumor cells and tumor-infiltrating immune cells. This analysis presents safety, efficacy, pharmacokinetic (PK) and pharmacodynamics/soluble target engagement (TE) results from LY3321367 (anti-TIM-3) monotherapy and in combination with LY3300054 (anti-PD-L1) in patients (pts) with advanced cancer. Methods: This ongoing, open-label phase 1a/1b, dose escalation and expansion study enrolled pts with histologically confirmed advanced relapsed/refractory solid tumors. Pts received IV infusions of 3mg-1200mg LY3321367 Q2W monotherapy (Arm A) or 70mg-1200mg LY3321367 + 200mg-700mg LY3300054 Q2W combination therapy (Arm B). Primary objectives assessed safety and tolerability and determined the RP2D. PK, soluble target TE, anti-drug antibodies (ADAs), and clinical efficacy (RECIST v1.1) were also evaluated. Results: At data cutoff (3 August 2018), LY3321367 monotherapy was administered to 23 pts (Arm A); 18 pts received LY3321367 combination therapy (Arm B) as phase 1a dose escalation (3 mths median follow-up). Treatment-related AEs observed in Arms A and B were mild (Gr ≤2), except for 1 pt with Gr 3 anemia in Arm B (200 mg LY3321367 + 700 mg LY3300054). No dose limiting toxicities, dose limiting-equivalent toxicities, treatment-related SAEs, or deaths were observed in Arm A or B. For LY3321367, 68.2% (Arm A) and 88.2% (Arm B) of pts were positive for treatment-emergent ADAs. Despite ADAs, no effect on PK was noted; ADA titers were low, except for 1 pt with an infusion-related reaction. LY3321367 t1/2 was ~22 days. Full TE was maintained 2 wks after 1200 mg dose; 600 mg Q2W maintained TE at steady-state. In Arm A, 2 pts had > 20% tumor regression, 1 of which was later confirmed as a PR in a post-PD-1 SCLC pt. Conclusions: LY3321367 is well tolerated as a monotherapy and in combination with LY3300054. The RP2D for LY3321367 combination therapy is 1200 mg IV infusions Q2W for cycles 1-2; 600 mg infusions Q2W starting at cycle 3 onward. Clinical trial information: NCT03099109.
Mixed response to immunotherapy in lung cancer.
Authors: Baldeo Candice , Kaleem Tasneem , Paz-Fumagalli Ricardo , Copland John A. , Menefee Michael E.
Published: July 2019

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Background: Mixed response (MR) to systemic therapy is common and associated with a poor prognosis. MR often represents a therapeutic dilemma resulting in the discontinuation of a therapy to which a portion of the tumor is still sensitive, due to the emergence of resistance in other metastatic deposits. We hypothesize that discordant responses in patients receiving immunotherapy may be associated with genomic variation within discordant tumors. Methods: We defined MR with the following criteria: 1) At least one tumor has increased in size while another tumor has decreased; 2) One or more tumors have remained stable while another has increased; 3) One or more tumors have remained stable while another has decreased. 4) A new tumor has developed while other tumors have decreased or remained stable. Between 2012 and 2017, we identified 112 patients with a MR. Two patients with metastatic lung cancer, treated with nivolumab underwent paired, simultaneous sampling of discordant tumors. Results: Both patients treated with nivolumab demonstrated genomic heterogeneity between discordant tumors on next-generation sequencing, including one patient with SCLC. Conclusions: MR remains a common and challenging therapeutic quandary. Genomic heterogeneity and differences in TMB of metastatic tumors demonstrating a MR, may be factors that contribute to this phenomenon. Further characterization of genomic discrepancies in MR may provide insights into mechanisms of emerging resistance, as well as, more rational and effective combinatorial therapies.[Table: see text]
Peripheral blood TCRB chain convergence and clonal expansion following cytomegalovirus infection: Implications for the biomarker use of TCR-seq.
Authors: Looney Timothy , Zheng Jianping , Topacio-Hall Denise , Lowman Geoffrey , Hyland Fiona
Published: July 2019

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Background: Human cytomegalovirus (CMV) is a common immune-evasive herpes family virus leading to lifelong asymptomatic infection in 50 to 80% of humans. The effect of CMV infection on the T cell repertoire may be relevant given interest in identifying T cell repertoire features predictive of response to checkpoint blockade immunotherapy (CPI) for cancer. Here we sought to identify features of CMV infection using TCRB profiling of peripheral blood (PBL) total RNA. Methods: Total RNA from PBL was obtained from 35 blood donors of known CMV status, then used for TCRB sequencing via the Oncomine TCRB-LR assay (amplicon spanning CDR1, 2 and 3) and the Ion Torrent S5. In parallel, we prepared libraries via the Oncomine TCRB-SR assay (CDR3 only). Data were used to identify TCRB repertoire features correlated with CMV status and compare repertoire features across the two assays. Results: T cell clone evenness was reduced in CMV positive individuals irrespective of age, predictive of CMV status (AUC = .86, p = 2E-4, Wilcoxon), and strongly correlated between LR and SR assays (Spearman cor = .96). TCR convergence was elevated in CMV positive individuals and uncorrelated with evenness (Spearman cor = -.03) such that the combination of convergence and evenness improved the performance of a logistic regression classifier (AUC = .93). Conclusions: We identify reduced T cell evenness and elevated TCR convergence as features of chronic CMV infection. CMV infection appears to significantly alter the T cell repertoire, suggesting that CMV status may be required for proper interpretation of T cell expansion in the context of CPI for cancer.
Chemo-immunotherapy combination after PD-1 inhibitor failure improves clinical outcomes in metastatic melanoma patients.
Authors: Vera Aguilera Jesus , Paludo Jonas , Failing Jarrett , McWilliams Robert R. , Kottschade Lisa A. , Block Matthew Stephen , Markovic Svetomir , Dronca Roxana Stefania , Yan Yiyi
Published: July 2019

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Background: Clinical management of metastatic melanoma (MM) after PD-1 blockade failure remains challenging and lacks a standard of care. Chemo-immunotherapy (CIT) combinations have demonstrated favorable efficacy and safety profiles in lung cancer patients. In this study, we compared the clinical outcomes of CIT with immunotherapy or chemotherapy alone after PD-1 blockade failure. Methods: We reviewed MM patients seen at Mayo Clinic between Jan, 2012 and Jun, 2018 who failed anti-PD1 therapy and received subsequent CIT, or immune checkpoint inhibitors (ICI) or chemotherapy alone. A total of 60 patients were analyzed, the CIT cohort [n=33 (55%)] treatment consisted of carboplatin/paclitaxel (n=29), nab-paclitaxel (n=2), paclitaxel (n=1), and temozolomide (n=1). In the ICI (n=9) or chemotherapy alone cohort (n=18) [n=27 (45%)], treatment consisted of carboplatin/paclitaxel (n=11), temozolomide (n=4), nab-paclitaxel (n=3), ipilimumab/nivolumab (n=4), pembrolizumab (n=4), or nivolumab (n=1). Results: Patients in the CIT cohort had a median OS of 3.5 years (95% CI: 1.7-NR) compared to 1.8 years (95% CI: 0.9-2) in the ICI or chemotherapy alone cohort, p=0.02. The median EFS following CIT was 7.6 months (95% CI: 6-10) compared to 3.4 months (95% CI: 2.8-4.1) following either ICI or chemotherapy alone, p=0.0005. A trend towards longer median EFS with use of CIT was seen in patients with BRAF wild-type [median 9 months (95% CI: 6-12)] compared to those harboring a BRAF mutation [median 6.5 months (95% CI: 1.8-9.1), p=0.29]. Side effects were similar among both groups. Conclusions: In MM patients who have failed anti-PD-1 therapy, the CIT combination showed favorable clinical outcomes and acceptable safety profile. This regimen should be considered for MM pts in this setting who have limited treatment options. [Table: see text]
The outcome and toxicity profile of checkpoint inhibitor immunotherapy subsequent to high-dose IL-2 in the treatment of metastatic melanoma and renal cell carcinoma.
Authors: Berg Stephanie A. , Clark Joseph I. , Henry Elizabeth , Wagner Courtney Regan , Flanigan Robert Charles , Mai Hanh P.
Published: July 2019

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Background: Approved treatments for metastatic melanoma (MM) and metastatic renal cell carcinoma (mRCC) include targeted agents, high dose interleukin-2 (HD IL-2) and checkpoint inhibitors (CI). A subset of responders to HD-IL2 can achieve long term durable remissions (7-10%). Recently, data suggests that durable remissions are possible with CI. Thus, despite increased toxicity, first-line immunotherapy with HD-IL2 is a reasonable consideration in carefully selected patients with clear cell mRCC and MM followed by CI upon relapse. Our study explores the utility and safety of CI subsequent to HD-IL2 in patients (pts) in this population. Methods: We conducted a single institution retrospective analysis of pts with MM or mRCC who received HD-IL2 and subsequent CI from 2008-2017. Pts treated with prior targeted therapy were included. Statistical analysis was performed using Fischer's exact tests, log-rank test for KM analysis and non-parametric Wilcoxon Rank Sum tests to compare the groups. Results: We identified 34 unique pts (19 MM, 15 mRCC) from our pre-specified cohort. Pts were male (73%), Caucasian (88%), and median age=53. mRCC pts received more cancer related treatments than MM prior to CIs after HD-IL2 was given (2 vs. 1, p=0.002), had more total CI cycles administered (12 vs. 7, p=0.10) but less IL-2 doses than MM pts (20 vs. 24, p=0.26). mRCC pts tended to record higher HD-IL2 toxicity grade compared to MM pts (exact =0.04). 26% (9/34) of pts experienced a grade 2 or higher CI toxicity. Pts had higher HD IL-2 toxicities than CI toxicities during therapy but these two measures were not significantly correlated (r=0.07, p=0.73); furthermore, there was no survival difference between pts with reported grade 2 or higher CI toxicity compared to pts without any CI toxicity ( p=0.14). Conclusions: Our study suggests that CI therapy after HD-IL2 is feasible and not associated with more frequent toxicity or less clinical efficacy in pts with MM or mRCC.
Effect of radiofrequency ablation (RFA) combined with anti-CTLA-4 and anti-PD1 in a preclinical melanoma model.
Authors: Franco-Mahecha Olga L. , Christou Anna , Mauda-Havakuk Michal , Katti Prateek , Pritchard William F. , Karanian John W. , Wood Bradford J.
Published: July 2019

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Background: The aim is to characterize the effect of Radiofrequency Ablation (RFA) with anti-CTLA-4 and anti-PD1 checkpoint inhibitors, on tumor growth and immune responses against B16-OVA melanoma tumors implanted in a syngeneic mouse model. Methods: Adult c57BL/6J female mice were distributed among a non-tumor placebo group (n=5) and four experimental tumor groups: no RFA (n=10); RFA alone (n=5); CPI post-RFA (n=5); and CPI pre-and-post-RFA (n=5). On day 0, mice were inoculated SQ with 2.5x105 B16-OVA cells. RFA was performed at day 15. Three doses of anti-mouse CTLA-4 and anti-mouse PD-1 (200 µg/dose each, every 24 h) were given IP to the appropriate groups. To evaluate the effect of the therapy on a distant tumor, each tumor group was re-inoculated SQ at day 20 with 2.5x105 B16-OVA cells. Serum samples were collected to measure concentration of cytokines. Mice were euthanized at day 36. T-cell and non-T cell fractions were collected from splenocytes for co-culture and evaluation of killing in vitro. Results: Mice that received RFA alone or RFA plus CPI showed significantly smaller primary tumors and minimal growth of secondary tumors compared to untreated mice, suggesting that these therapies may have an abscopal effect. Based on the cytokine profile in serum, mice treated with CPI pre-and-post-RFA showed balanced and sustained concentrations of IFNγ and IL-2 (T cell activation) and controlled inflammatory responses. In vitro experiments showed that T cells from mice treated with CPI pre-and-post-RFA produced significantly more IFNγ when co-cultured with B16-OVA cells. However, these T cells did not demonstrate a high killing activity on the tumor cells. The killing capacity of T cells from mice treated with RFA alone or with CPI pre-and-post-RFA increased significantly when the non-T cell fraction (dendritic cells, macrophages, NK cells, and B cells) was added to the co-culture. Conclusions: RFA therapy combined with CPI given to mice bearing B16-OVA tumors may induce systemic immune responses capable of improving control of distant tumor growth. In culture, primed T cells are not able to kill B16-OVA by themselves, but the addition of the non-T cell fraction may improve T cell killing capacity.