bluuebunny/crossref_metadata_2025 huggingface dataset:
Neighbor balance and evenness of distribution of treatment replications in row‐column designs
Authors: Piepho Hans‐Peter , Michel Volker , Williams Emlyn
Published: October 2018

Row‐column designs allow error control in field experiments by blocking in two dimensions. While this strategy can capture spatial heterogeneity aligned with blocks and account for effects due to the farming operations along rows and columns, it suffers from the occasional clustered occurrence of several replications of the same treatment. This property of classical row‐column designs has hampered their more widespread use in practice. A further issue of practical importance is the degree of neighbor balance of a design, that is, the frequency of adjacencies of pairs of treatments. This paper proposes two design strategies to simultaneously optimize the evenness of spatial distribution of treatment replication as well as neighbor balance. Three examples are given to illustrate the proposed methods and demonstrate that both approaches yield comparable and satisfactory results.
Power calculation of adjusted McNemar's test based on clustered data of varying cluster size
Authors: Wu Yougui
Published: October 2018

McNemars test is often used to compare two proportions estimated from paired observations. When the observations are sampled in clusters, adjustment is needed to ensure that the size of McNemars test does not exceed the nominal level. Eliasziw and Donner (1991) developed an adjustment to McNemars test that involves first estimating the correlation between discordant pairs within a cluster, then using the estimate of the correlation to adjust the usual McNemar's test statistic. Gönen (2004) derived two approximations for calculating the power and sample size for the adjusted McNemar's test. He reported that the accuracy of the two approximations is compromised for large value of intracluster correlation and small value of proportion of discordant pairs; the error of the approximation can be higher than 10 per cent. In this paper, we extend his power formula, developed under fixed cluster size assumption, to accommodate the case where the cluster sizes are not constant. We show via simulations that the theoretical powers calculated from our proposed power formula are close to their empirical counterparts under a variety of settings. More significantly, in the case of fixed cluster size, our reduced power formula provides a more accurate power approximation than Gönen's power formula regardless of the values of intracluster correlation and the proportion of discordant pairs.
A Direct Approach for Process Development Using Single Column Experiments Results in Predictable Streamlined Multi‐Column Chromatography Bioprocesses
Authors: Utturkar Aditya , Gillette Keith , Sun Chia‐Yun , Pagkaliwangan Mark , Quesenberry Rachel , Schofield Mark
Published: October 2018

An emphasis on continuous monoclonal antibody (mAb) bioprocessing in the pharmaceutical industry necessitates effective approaches for downstream process development (PD). With a PD strategy, the process parameters are optimized to directly develop streamlined three‐step continuous chromatography processes. A design of experiment (DoE) approach with single column (batch mode) is used to simulate a multi‐column (continuous mode) purification method and characterize each chromatography step: Protein A capture, anion exchange, and mixed mode cation exchange. A novel and targeted approach to quickly characterize a DoE design space was employed and empirical modeling was used to define the capacity for multi‐column chromatography to accurately transfer the batch process to continuous mode of purification. This PD approach effectively mimics the continuous mode of operation and provides the flexibility to develop multiple continuous processes with target mAb recovery and purity. By implementing this PD strategy and the process parameters defined in batch mode, two robust and predictable continuous bioprocesses were developed within 7 weeks of investigation, which resulted in a total product yield of recovery at or above 74%, host cell protein (HCP) content below 5 ppm, and aggregate content below 1%.
Redesign of a New Manganese Peroxidase Highly Expressed in Pichia pastoris towards a Lignin‐Degrading Versatile Peroxidase
Authors: Bronikowski Agathe , Koschorreck Katja , Urlacher Vlada B.
Published: October 2018

Manganese peroxidases, lignin peroxidases, and versatile peroxidases secreted by white rot fungi are supposed to play an essential role in lignin degradation. Thus, these enzymes have attracted significant attention as potential biocatalysts. Versatile peroxidases are the most interesting ones, since they comprise activities of manganese and lignin peroxidases. Herein, we demonstrate how the properties of a new manganese peroxidase from Moniliophthora roreri, designated MrMnP1, were shifted towards those of a versatile peroxidase. MrMnP1 was cloned in Pichia pastoris X‐33 and highly expressed in a fed‐batch fermentation, yielding 132 mg L−1 of active enzyme. To extend the substrate spectrum of MrMnP1, a catalytically active tryptophan present in lignin and versatile peroxidases was first introduced. Additionally, the role of five amino acids at positions adjacent to the catalytic tryptophan was elucidated through their replacement by those found in a versatile peroxidase from Pleurotus eryngii. The resulting mutants demonstrated new activities towards high‐redox‐potential substrates, such as lignin dimers, veratryl alcohol, and the azo dye Reactive Black 5.
Implication of SLIT3‐ROBO1/ROBO2 in granulosa cell proliferation, differentiation and follicle selection in the prehierarchical follicles of hen ovary
Authors: Xu Rifu , Qin Ning , Xu Xiaoxing , Sun Xue , Chen Xiaoxia , Zhao Jinghua
Published: October 2018

The SLIT/ROBO pathway has been implicated in prehierarchical follicular development of hen ovary by an intrafollicular autocrine and/or paracrine fashion. SLIT3, one of the key components of the SLIT/ROBO family, serves as a ligand that potentially interacts with the four receptors, ROBO1, ROBO2, ROBO3 and ROBO4. But the exact roles and regulatory mechanism of SLIT3 in chicken ovarian follicle development remain largely unclear. The present study was conducted to investigate the potential roles and molecular regulation of SLIT3 in granulosa cell (GC) proliferation, differentiation and follicle selection within the prehierarchical follicles of hen ovary. We found that SLIT3 interacts physically with the four ROBO receptors, but the expression of the ROBO1 and ROBO2 genes are more susceptible to the regulation of SLIT3 ligand than that of the ROBO3 and ROBO4 genes. Moreover, the siRNA‐mediated knockdown of SLIT3 in the follicular GCs leads to a significant increase in cell proliferation. Conversely, overexpression of SLIT3 results in a remarkable reduction in GC proliferation. Furthermore, the overexpressed SLIT3 has notably decreased the mRNA and protein expression levels of follicle‐stimulating hormone (FSHR), growth and differentiation factor 9 (GDF9), steroidogenic acute regulatory protein (STAR) and cytochrome P450 11A1 (CYP11A1) in the GCs. These results indicated that SLIT3 may play an inhibitory effect on GC proliferation, differentiation and follicle selection, and these suppressive actions of SLIT3 in the GC proliferation can be prohibited by the siRNA‐mediated knockdown of ROBO1 and ROBO2 receptors. The current data provide a basis for further investigation of molecular mechanisms of SLIT3‐ROBO1/2 pathway in controlling the prehierarchical follicle development of the hen ovary.
Application of the MADS classification system in a “mega mammoth” stent trial: Feasibility and preliminary clinical implications
Authors: Katsikis Athanasios , Chichareon Ply , Cavalcante Rafael , Collet Carlos , Modolo Rodrigo , Onuma Yoshinobu , Stankovic Goran , Louvard Yves , Vranckx Pascal , Valgimigli Marco , Windecker Stephan , Serruys Patrick W.
Published: October 2018

Objectives and Background

We attempted to test the feasibility of application of the MADS classification system in the largest stent trial to date and evaluate the preliminary clinical implications of this approach.

Methods

In the randomized GLOBAL LEADERS trial, testing two different antiplatelet strategies in patients undergoing PCI with bivalirudin and biolimus‐eluting stents, the e‐CRF was dedicated to bifurcation treatment according to the MADS classification. Based on this e‐CRF, the techniques used for bifurcations treatment in GLOBAL LEADERS were described and compared with two large, all‐comer registries of bifurcations treatment (I‐BIGIS and COBIS), used as historical controls.

Results

Among 15,991 patients enrolled in the trial, 22,921 lesions treated at the index and staged procedure were available for analysis and 2,757 of these lesions were bifurcations and 7 were trifurcation lesions. The e‐CRF‐based MADS classification was achieved in 2,757 of these lesions (100%). 80.3% of bifurcations were treated using a single stent, 18.9% using 2 stents and 0.7% using 3 stents. Overall, the “main across side first” approach (A) was used in 77.4% with the “side branch first” approach (S) being the second most frequently used technique (10.2%). A single stent was used in the majority of the “A” approach (87.9%). A reduction in the use of 2‐stent techniques (from 33.9 to 18.9%) was observed between GLOBAL LEADERS and I‐BIGIS. The “A” approach was the most frequently used technique in GLOBAL LEADERS, while in COBIS the “S” strategy was most frequently employed.

Conclusions

Application of the MADS classification through an e‐CRF was feasible in the largest stent trial today and provided useful information about the trends observed overtime in the treatment of bifurcation lesions.
Gender and age differences in outcomes of patients with acute coronary syndromes referred for coronary angiography
Authors: Stähli Barbara E. , Wischnewsky Manfred B. , Jakob Philipp , Klingenberg Roland , Obeid Slayman , Heg Dik , Räber Lorenz , Windecker Stephan , Mach François , Gencer Baris , Nanchen David , Jüni Peter , Landmesser Ulf , Matter Christian M. , Lüscher Thomas F. , Maier Willibald
Published: October 2018

Objectives

The number of elderly patients undergoing coronary revascularization is steadily increasing, and data on the impact of gender on outcomes are scarce. This study sought to assess gender‐related differences in outcomes in elderly patients with acute coronary syndromes (ACS).

Methods

We investigated outcomes in elderly ACS patients referred for coronary angiography and prospectively enrolled in the Swiss ACS Cohort between December 2009 and October 2012. Adjudicated major adverse cardiovascular and cerebrovascular events (MACCE) included all‐cause death, non‐fatal myocardial infarction, clinically indicated repeat coronary revascularization, definite stent thrombosis, and transient ischemic attack/stroke.

Results

Among 2,168 patients recruited, 481 (22%) patients were >75 years of age (37% women). In patients >75 years, 1‐year MACCE rates were 15% and 23% in women and men (OR 0.59, 95% CI 0.36–0.97, P = 0.04), respectively, and differences remained significant after adjustments for baseline variables (adjusted OR 0.48, 95% CI 0.26–0.90, P = 0.02). Women >75 years had a lower cardiovascular mortality (6% versus 12%, adjusted OR 0.31, 95% CI 0.12–0.81, P = 0.02). In patients ≤75 years, 1‐year MACCE rates did not differ between gender (10% and 8% for women and men, adjusted OR 1.28, 95% CI 0.77–2.14, P = 0.34). Rates of TIMI major bleeding for women and men were 4% and 4% in patients >75 years (P = 0.96), and 5% and 3% in those ≤75 years (P = 0.11).

Conclusions

The low rates of MACCE observed in elderly women in this patient cohort suggest that with current interventional strategies the gender gap in ACS management has been attenuated.
Three‐year clinical outcomes of patients treated with everolimus‐eluting bioresorbable vascular scaffolds: Final results of the ABSORB EXTEND trial
Authors: Costa J. Ribamar , Abizaid Alexandre , Whitbourn Robert , Serruys Patrick W. , Jepson Nigel , Steinwender Clemens , Stuteville Marrianne , Ediebah Divine , Sudhir Krishnankutty , Bartorelli Antonio L. ,   on behalf of the ABSORB EXTEND investigators
Published: October 2018

Background

There is still limited data on the very long term clinical outcomes after ABSORB BRS in daily practice. We sought to evaluate the 3 year‐performance of the Absorb bioresorbable vascular scaffolds for the treatment of low/moderate complexity patients enrolled in the ABSORB EXTEND trial.

Methods

ABSORB EXTEND is a prospective, single‐arm, open‐label clinical study in which 812 patients were enrolled at 56 sites. This study allowed the treatment of lesions ≤28 mm in length and reference vessel diameter of 2.0–3.8 mm (as assessed by on‐line QCA). To determine the independent predictors of MACE, a multivariable logistic regression model was built using a stepwise (forward/backward) procedure.

Results

Average population age was 61 years and 26.5% had diabetes. Most patients had single target lesion (92.4%). Adequate scaffold deployment (PSP) was achieved in 14.2% of the cases. At three years, the composite endpoints of MACE and ischemia‐driven target vessel failure were 9.2% and 10.6%, respectively. The cumulative rate of ARC definite/probable thrombosis was 2.2%, with 1.2% of the cases occurring after the 1st year. Independent predictors of MACE were hypertension and the need for “bail out” stent.

Conclusion

At three‐year follow‐up, the use of ABSORB in low/moderate complex PCI was associated with low and acceptable rates of major adverse clinical events, despite the infrequent use of the recommended contemporary scaffold deployment technique. However, scaffold thrombosis rate was higher than reported with current generation of metallic DES. The study is registered on clinicaltrials.gov (unique identifier NCT01023789).
Anatomic and procedural associations of transcatheter heart valve displacement following Evolut R implantation
Authors: Hachinohe Daisuke , Latib Azeem , Laricchia Alessandra , Demir Ozan M. , Agricola Eustachio , Romano Vittorio , Del Sole Paolo Alberto , Leone Pier Pasquale , Ancona Marco B. , Mangieri Antonio , Regazzoli Damiano , Giannini Francesco , Mitomo Satoru , Monaco Fabrizio , Buzzatti Nicola , Montorfano Matteo , Colombo Antonio
Published: October 2018

Objectives

This study aimed to predict the displacement of self‐expanding transcatheter heart valves (THV) during final deployment.

Background

Accurate device positioning during transcatheter aortic valve implantation (TAVI) is crucial for optimal results.

Methods

At our institution, 103 patients who underwent transfemoral TAVI with Evolut R were retrospectively identified. Multiple linear regression models were created, and a predictor equation was built to quantify the factors that may affect THV behavior.

Results

Multiple linear regression analysis for THV displacement on the left coronary cusp (LCC) identified the angle between the THV and the ascending aorta (ATA), predilation, and less operator experience as independent predictors of upward displacement, whereas estimated glomerular filtration rate (eGFR) was inversely related with THV behavior (95% confidence interval: 0.219 to 0.340, 0.447 to 2.092, 0.165 to 1.757, and −0.053 to −0.011, respectively). Predictors of THV displacement on the noncoronary cusp side could not be identified using this model.

Conclusions

The ATA at the point of recapture, predilation, and less operator experience were independent predictors of upward displacement of THV on the LCC side. eGFR was an independent predictor of THV downward displacement on the LCC side. Of them, the ATA was the strongest predictor. Physicians may need to adjust this angle adequately before deployment to achieve the appropriate position.
Ablation of recurrent malignant idiopathic ventricular tachycardia: When proper diagnosis and success is a matter of contact
Authors: Giaccardi Marzia , Mascia Giuseppe , Paoletti Perini Alessandro , Giomi Andrea , Cartei Stella , Colella Andrea
Published: October 2018

Key Clinical Message

Effective and stable contact between the catheter tip and the tissue is crucial for both mapping and lesion formation during cardiac ablation procedures. Contact force catheter may be not only a therapeutic approach to arrhythmias, but also a tool for achieving accurate characterization of the arrhythmic substrate.
Environmental Catalysis: Present and Future
Authors: Rodríguez‐Padrón Daily , Puente‐Santiago Alain R. , Balu Alina M. , Muñoz‐Batista Mario J. , Luque Rafael
Published: October 2018

Environmental catalysis plays a crucial role in sustainable development by the design of novel catalytic materials and technologies. Several environmental issues are addressed by catalytic processes such as decomposition of pollutants for air, water and soil remediation, hydrogen production, CO2 reduction and biomass valorization, just to name a few. This contribution aims to provide a general overview of the main concepts and current advances in the environmental catalysis field. Special attention has been paid to photocatalysis and electrocatalysis, as sub‐areas of catalysis with tremendous potential in sustainable applications, in particular with regard to the promotion of sustainable energies. In this contribution, the partnership between Catalysis and Green Chemistry is presented, in a comprehensive way, as an open research line which is imperative and decisive for a more sustainable future.
Electrochemical Energy Conversion and Storage with Zeolitic Imidazolate Framework Derived Materials: A Perspective
Authors: Dutta Soumen , Liu Zhiming , Han HyukSu , Indra Arindam , Song Taeseup
Published: October 2018

The development of transition‐metal‐based materials for electrochemical energy conversion and storage has received immense interest throughout the last two decades. In this respect, zeolitic imidazolate framework (ZIF)‐derived materials are particularly important for accessing various morphologies, sizes, exposed facets, variations in the electronic structure, high surface area, and large numbers of available active sites. The properties of the ZIF‐derived materials can be tuned by applying different synthetic protocols, introducing a heteroatom in the ZIF structure or by accessing core‐shell or hollow structures. Many studies have described the beneficial effects of ZIF‐derived materials, but no critical review is available in the growing field of electrochemical energy conversion and storage. Herein, we have described the basic principles of material synthesis from ZIFs, their applications in electrochemical processes, difficulties with the synthesis, and their future development.
A Coordination Strategy for TixSn1–xO2 Solid Solution Nanocubes Wrapped by Reduced Graphene Oxide as a Candidate for Lithium‐Ion‐Battery Anodes
Authors: Dong Yutao , Cai Jialin , Li Yongsheng , Liu Yushan , Ding Jie , Li Dan , Zhang Jianmin
Published: October 2018

A series of TixSn1–xO2 (0≤x≤1) solid solution nanocubes wrapped by reduced graphene oxide (TixSn1–xO2/rGO, TSGC) were designed and synthesized for the application exploration as anode material in lithium ion batteries. When graphene oxide (GO) and K2TiO(C2O4)2 (PTO) were mixed in aqueous ambience, the TiO(C2O4)22− ions were not absorbed onto GO surface by the strong electrostatic repulsion force of the similarly negative‐charged surfaces. When Sn4+ ions were added to the mixture, they were easily adsorbed onto the GO surface. At the same time, Sn4+ ions were also easily coordinated by the carboxyl groups of the PTO species. After the followed hydrothermal and heat treatments, the desired 3D nanoarchitecture composites were obtained. Interestingly, in this TixSn1–xO2/rGO series, the Ti0.74Sn0.26O2/rGO sample exhibited the highest specific capacity of 514 mA h g−1 at 0.1 A g−1 even after 1000th cycles (nearly 100 % efficiency). Such promising electrochemical results are attributed to the 3D integrated structure by achieving better electrical contact between the active materials to shorten ion transport pathways, which highlights the synergistic effect from combining the TixSn1–xO2 nanocubes and rGO films. Additionally, the lithium storage mechanism of the as‐prepared TixSn1–xO2/rGO has been studied via in‐situ X‐ray diffraction (XRD) measurements for the first time.
5,12‐Diaminotetracenes: The Impact of Orbital Interactions between the Acene π System and Amino Groups on Their Electronic States
Authors: Uebe Masashi , Kawashima Kenji , Ito Akihiro
Published: October 2018

5,12‐Diamino‐substituted tetracenes with various N‐substituents have been prepared, and their molecular structural changes upon oxidation have been evaluated in association with their electronic structures. The N‐substituents influence both the electronic and molecular structures of the oxidized species of 5,12‐diaminotetracenes. The tetracene moiety of 5,12‐bis(N,N‐dianisylamino)tetracene retained its planarity during the course of two successive one‐electron oxidations, whereas 5,12‐bis(N,N‐dimethylamino)tetracene and 5,12‐bis(N‐anisyl‐N‐methylamino)tetracene underwent substantial structural changes into butterfly like structures through a simultaneous two‐electron oxidation process. The molecular structures in the oxidized states were closely related to the nature of the highest occupied orbitals, which were characterized by the extent of mixing between the fragment orbitals for the teracene moiety and the substituted amino groups in 5,12‐diaminotetracenes. As a consequence, the present work revealed that the extent of folding deformation of the acene moiety in the oxidized diaminoacenes could be fine‐tuned by varying the N‐substituents.
Anomalous Stoichiometry and Antiferromagnetic Ordering for the Extended Hydroxymanganese(II) Cubes/Hexacyanometalate‐Based 3D‐Structured [MnII4(OH)4][MnII(CN)6](OH2)6⋅H2O
Authors: Lapidus Saul H. , Stephens Peter W. , Kareis Christopher M. , VanNatta Peter E. , Miller Joel S.
Published: October 2018

The reaction of MnII(O2CMe)2and NaCN or LiCN in water forms a light green insoluble material. Structural solution and Rietveld refinement of high‐resolution synchrotron powder diffraction data for this unprecedented, complicated compound of previously unknown composition revealed a new alkali‐free ordered structural motif with [MnII4(μ3‐OH)4]4+cubes and octahedral [MnII(CN)6]4−ions interconnected in 3D by MnII‐N≡C‐MnIIlinkages. The composition is {[MnII(OH2)3][MnII(OH2)]3}(μ3‐OH)4][MnII(μ‐CN)2(CN)4]⋅H2O=[MnII4(μ3‐OH)4(OH2)6][MnII(μ‐CN)2(CN)4]⋅H2O, which is further simplified to [Mn4(OH)4][Mn(CN)6](OH2)7(1).1has four high‐spin (S=5/2) MnIIsites that are antiferromagnetically coupled within the cube and are antiferromagnetically coupled to six low‐spin (S=1/2) octahedral [MnII(CN)6]4−ions. Above 40 K the magnetic susceptibility,χ(T), can be fitted to the Curie–Weiss expression,χ∝(T−θ)−1, withθ=−13.4 K, indicative of significant antiferromagnetic coupling and1orders as an antiferromagnet atTc=7.8 K.
Enantioselective Synthesis of Phthalides and Isochromanones via Heck–Matsuda Arylation of Dihydrofurans
Authors: Kattela Shivashankar , de Lucca Emilio C. , Correia Carlos Roque D.
Published: October 2018

In this communication, the enantioselective synthesis of phthalides and isochromanones is described through a new palladium‐catalyzed Heck–Matsuda arylation/NaBH4‐reduction/lactonization sequence of 2,3‐ and 2,5‐dihydrofurans in good overall yields and excellent enantioselectivities (up to 98:2 er). This expeditious synthesis of chiral Heck lactol intermediates allowed the diversification of the strategy to obtain medicinally relevant chiral lactones, amines, and olefins. The natural product 3‐butylphthalide was obtained in three steps with an overall yield of 33 % yield in 98:2 er.
Optimization of Ultrasonication Process for the Degradation of Linear Alkyl Benzene Sulfonic Acid by Response Surface Methodology
Authors: Arslan Ayla , Topkaya Eylem , Veli Sevil , Bingöl Deniz
Published: October 2018

The optimization of ultrasonication process applied to linear alkyl benzene sulfonic acid (LABSA) degradation is investigated with response surface methodology in this study. Methylene blue active substance assay is used as a mean to monitor the degradation of LABSA. The effects of independent process variables (initial LABSA concentration, pH, and reaction time) on main material degradation are investigated. Among the independent variables, the greatest effect on LABSA degradation is observed for reaction time. Besides this, the effects of both reaction time and initial LABSA concentration are quite similar. The initial pH value of the solution has a lower effect on degradation performance when compared to other parameters. The predicted maximum detergent degradation was 75% at the optimal conditions of pH 7.8, initial LABSA concentration of 20 mg L−1, and reaction time of 70 min. Specific cost of LABSA degradation by ultrasonic treatment varies from 0.579 to 4.657 Euro g−1 removal LABSA. According to the results of sonication treatment applied to real wastewater, approximately 40% of the LABSA degradation is achieved at three pH values (5.27, 7.50, and 9.59). Because the original pH of the real wastewater is 9.59, it is more feasible to run experiments at this pH value.
Polyoxometalates and Their Composites as Photocatalysts for Organic Pollutants Degradation in Aqueous Media—A Review
Authors: Dehghani Ramin , Aber Soheil , Mahdizadeh Fatemeh
Published: October 2018

Polyoxometalates (POMs), eco‐friendly solid acids, are polyatomic anions containing transition metal (group 5 or group 6) oxyanions linked together through shared oxygen atoms. First, the structure, classification, synthesis, non‐photocatalytic applications, and their photocatalytic properties and applications are presented. POMs are very interesting due to their unique and remarkable characteristics. One of the most attractive characteristics of POMs is their activity as an electron relay, that is, they can undergo stepwise multi‐electron redox reactions while their construction remains intact. Based on this characteristic, POMs have been widely used as photooxidation catalysts for organic and inorganic contaminants removal. According to the literature, POMs are useful homogeneous photocatalysts for the mineralization of dyes, phenol and its derivatives, chloroacetic acids, and pesticides and wood pulp bleaching. Applications of POMs have been limited because of their high solubility in water. Immobilization and solidification of POMs using different methods and various supports for making them reusable are studied in this review. Varieties of composites of POMs are synthesized to make them photorespond to the visible light region.
pH/Redox‐Triggered Photothermal Treatment for Cancer Therapy Based on a Dual‐Responsive Cationic Polymer Dot
Authors: Mazrad Zihnil Adha Islamy , Phuong Pham Thi My , Choi Cheong A. , In Insik , Lee Kang Dae , Park Sung Young
Published: October 2018

In the present study, a pH/redox‐responsive cationic polymer dot (CD) was successfully prepared for a near‐infrared (NIR)‐mediated, simultaneously controllable photothermal temperature guided imaging off/on system to monitor therapeutic delivery. Carbonized disulfide cross‐linked branched polyethyleneimine (bPEI) was conjugated with folic acid (FA) as a targeting moiety and partially formed an ionic complex with anionic indocyanine green (ICG) to afford a bPEI‐based CD (ICG‐CD). This was responsive to mild reductive (glutathione, GSH) and acidic tumor conditions, which enabled the simultaneous biodegradation of those hydrophobic and complex sites. The ICG‐CD internalized readily into the cytoplasm of cancer cells by a FA receptor and cationic‐mediated endocytosis in the off state, whereas if ICG‐CD met intracellular GSH at high concentrations, GSH contributed partially to the recovery of fluorescence and was then internalized into acidic endosomes to induce complete restoration of fluorescence. This tumor‐sensitive degradability of the CD not only facilitated ICG release in the tumor location but also allowed controllable photothermal therapy effects of nanoparticles under NIR irradiation, which resulted in improved cancer therapy. Taken together, the results indicate great potential in tumor targeting, intracellular imaging, and controllable therapeutic delivery through a fluorescence off/on assay under the pH/redox conditions of cancer cells.
Respiratory emergency department use from diagnosis through survivorship in children, adolescents, and young adults with cancer
Authors: Ramsay Joemy M. , Ou Judy Y. , Fluchel Mark N. , Kirchhoff Anne C.
Published: October 2018

BACKGROUND

Children and adolescents and young adults (AYAs) with cancer often experience severe respiratory morbidity and mortality from the therapies used to treat their cancers. Few studies have examined respiratory outcomes among this population using emergency department (ED) visits as an objective measure of respiratory health.

METHODS

ED visits for respiratory conditions were identified for children and AYAs diagnosed with cancer, 0‐25 years of age, from 1997 through 2012 (2535 cases) and compared with a birthdate‐matched and sex‐matched cohort without cancer drawn from the general population (7605 controls). Negative binomial regression with robust standard errors was used to estimate incidence rates, rate ratios (RRs), and 95% confidence intervals for primary respiratory ED visits, combined and by diagnosis (asthma, respiratory disease, and respiratory infection) from 1997 through 2015. Analyses were performed for new cases (0 to <5 years from diagnosis) and survivors (5‐18 years from diagnosis).

RESULTS

Subjects were followed for an average of 8 years (range, 0‐18 years). Relative to the comparison cohort, cancer cases had higher incidence rates for all types of respiratory ED visits over both follow‐up times. New cases had significantly higher RRs for any respiratory condition (RR, 4.14), respiratory disease (RR, 4.62), and respiratory infection (RR, 4.74). Among survivors, the RRs for any respiratory condition (RR, 2.00) and respiratory infection (RR, 2.10) were significantly elevated, although the magnitude tended to decline in survivorship. Demographic and clinical risk factors found to be associated with respiratory ED visits included Hispanic/other race/ethnicity, male sex, exposure to chemotherapy, diagnosis at a younger age, and a diagnosis of leukemia.

CONCLUSIONS

The results of the current study demonstrated that children and AYAs with cancer face an increased burden of respiratory complications compared with a comparison cohort without cancer from diagnosis through survivorship.
Klinefelter syndrome in males with germ cell tumors: A report from the Children's Oncology Group
Authors: Williams Lindsay A. , Pankratz Nathan , Lane John , Krailo Mark , Roesler Michelle , Richardson Michaela , Frazier A. Lindsay , Amatruda James F. , Poynter Jenny N.
Published: October 2018

BACKGROUND

Males with Klinefelter syndrome (KS) (47,XXY) may be more likely to develop germ cell tumors (GCTs), particularly mediastinal GCTs. To date, there are no reports characterizing the prevalence of KS among male GCT cases.

METHODS

The authors used array genotyping data from a Children’s Oncology Group epidemiology study to estimate the prevalence of KS in males with GCTs (433 males aged birth‐19 years). Using Fisher’s exact tests, the authors examined differences in age at diagnosis, race/ethnicity, tumor location and histology, and several birth characteristics between cases of KS‐GCT and GCT cases without chromosomal abnormalities. Using publicly available data, the authors estimated the 1‐year risk, risk ratio, and corresponding 95% confidence interval of GCTs among KS cases.

RESULTS

Based on analysis of array genotyping data, 3% of male GCT cases (13 cases) had KS. The additional X chromosome was of maternal origin in 7 of the 13 cases. Of these 13 KS cases, 5 of 9 KS‐GCT cases with parental questionnaire data (56%) reported a diagnosis of KS. No significant differences were observed with regard to patient or birth characteristics between KS‐GCT and non–KS‐GCT cases. KS‐GCT cases were significantly more likely to be diagnosed with mediastinal tumors than non–KS‐GCT cases (P<.01). The authors estimated the risk of developing a GCT among males with KS to be 0.00025, or 1 per 4000 males (risk ratio, 18.8; 95% confidence interval, 11.7‐30.0).

CONCLUSIONS

Compared with males without chromosomal abnormalities, males with KS are more likely to be diagnosed with a mediastinal GCT. The presence of KS should be considered in males with a diagnosis of mediastinal GCT. In the current study, the authors report that approximately one‐third of males with mediastinal germ cell tumors have Klinefelter syndrome, and therefore screening of these individuals for the syndrome may be warranted. Males with Klinefelter syndrome are 19 times as likely as males without Klinefelter syndrome to develop germ cell tumors.
Association between treatment of superficial bladder cancer and 10‐year mortality in older adults with multiple chronic conditions
Authors: Garg Tullika , Young Amanda J. , O’Keeffe‐Rosetti Maureen , McMullen Carmit K. , Nielsen Matthew E. , Kirchner H. Lester , Murphy Terrence E.
Published: October 2018

Background

Multiple chronic conditions (MCC) are common among older patients with cancer; however, the exclusion of these patients from clinical trials has resulted in scarce knowledge concerning outcomes, resulting in variations in treatment. Superficial bladder cancer (SBC) disproportionately affects older adults, yet to the authors’ knowledge few studies to date have examined whether treatment improves long‐term survival. In the current study, the authors evaluated the association between treatment of SBC and 10‐year mortality in medically complex older adults.

Methods

The authors identified 1800 older (aged ≥60 years) patients with SBC (American Joint Committee on Cancer stage ≤I) from 2 community‐based health systems who received treatment (bladder instillation and/or transurethral resection) or observation. Cox proportional hazards regression was performed adjusting for age, sex, race, health system, stage of disease/grade, and MCC (≥2 baseline chronic conditions). Propensity score analysis using stabilized inverse probability of treatment weights was used to compare 10‐year mortality in the 2 treatment groups with adjustment for covariates.

Results

Overall, 1485 patients (82.5%) and 315 patients (17.5%) received treatment and observation, respectively. In unweighted multivariable analysis, treatment was associated with a 30% reduction in death (adjusted hazard ratio [HR], 0.70; 95% confidence interval [95% CI], 0.58‐0.85 [P<.01]) and MCC with a 72% increase in death (adjusted HR, 1.72; 95% CI, 1.44‐2.05 [P<.01]). Weighted analysis with adjustment (doubly robust) also demonstrated a survival benefit for treatment (adjusted HR, 0.66; 95% CI, 0.52‐0.84 [P<.01]).

Conclusions

The results of the current study demonstrated a clinically meaningful association between cancer treatment and survival benefit in older, medically complex patients with SBC, even after adjustment for medical complexity. These data provide a foundation for future work aimed at personalizing the treatment guidance of older patients with cancer with MCC.
Salvage surgery for squamous cell carcinoma of the head and neck in the era of immunotherapy: Is it time to clarify our guidelines?
Authors: Saba Nabil F. , Mendenhall William M. , Hutcheson Kate , Suárez Carlos , Wolf Greg , Ferlito Alfio
Published: October 2018

Is salvage surgery a 1‐size‐fits‐all approach? More importantly, in this era of improved systemic therapy, what are
the criteria according to which salvage surgery for squamous cell carcinoma of the head and neck should be the uncontested modality of choice?
Will my child do better if she enrolls in a clinical trial?
Authors: Smith Malcolm A. , Joffe Steven
Published: October 2018

The question of whether children with cancer who enroll in clinical trials have superior outcomes compared with those who do not participate has been pursued for more than 4 decades, and recent studies have provided conflicting answers. Whether clinical trial participation influences outcome has important implications for how clinicians should present trial participation to patients and families. Methodological challenges limit generalizations about the impact of clinical trial participation on outcome compared with nonparticipation. Oncologists should inform patients and families that clinical trials are the engine for future progress because they identify more effective therapies and that clinical trial participation is a reasonable option to consider for children with cancer. However, as noted in by Truong and colleagues in this issue, the rationale for trial enrollment should not include an expectation of better outcomes compared with nonenrollment.
Low clinical trial accrual of patients with myelodysplastic syndromes: Causes and potential solutions
Authors: Steensma David P. , Brunner Andrew M. , DeZern Amy E. , Garcia‐Manero Guillermo , Komrokji Rami S. , Odenike Olatoyosi S. , Roboz Gail J. , Savona Michael R. , Stone Richard M. , Sekeres Mikkael A.
Published: October 2018

Despite few effective therapies, only a small percentage of patients diagnosed with myelodysplastic syndromes (MDS) in the United States are enrolled in prospective, interventional clinical trials. MDS‐specific barriers to trial accrual include a high frequency of elderly patients with comorbid conditions, atypical disease features and uncertainty regarding the diagnosis (because other nonclonal processes also can cause dysplasia and cytopenias), a history of another nonmyeloid neoplasm resulting in therapy‐related MDS, rapid disease recurrence after allogeneic stem cell transplantation, and an arbitrary division between MDS and acute myeloid leukemia. In addition, barriers to accrual that are common to other oncology populations, such as difficulty traveling to clinical trial enrollment sites and narrow trial eligibility criteria, also prevent patients with MDS from enrolling in studies. Collectively these barriers must be assessed systematically, and creative solutions are needed to improve outcomes for this needy patient population.
Changes in cardiovascular disease risk and risk factors among women with and without breast cancer
Authors: Anderson Chelsea , Nichols Hazel B. , Deal Allison M. , Park Yong‐Moon Mark , Sandler Dale P.
Published: October 2018

Background

Cardiovascular disease (CVD) risk is an important health concern among survivors of breast cancer. However, few studies to date have examined whether trajectories of CVD risk and major risk factors are worse among women with a breast cancer diagnosis compared with those without.

Methods

Changes in weight, body mass index, waist circumference, systolic blood pressure, and 10‐year CVD risk were compared between women with (813 women) and without (1049 women) an incident breast cancer diagnosis while they were enrolled in the National Institute of Environmental Health Sciences Sister Study cohort. Blood pressure and adiposity measures were collected by trained examiners at an enrollment visit (≥1 year before breast cancer diagnosis) and a second home visit 4 to 11 years later (≥1 year after breast cancer diagnosis). The non–laboratory‐based Framingham risk score, a measure of 10‐year general CVD risk, was calculated at both the enrollment and second visits. All analyses were stratified by menopausal status at the time of enrollment.

Results

Women who were premenopausal at the time of enrollment experienced moderate increases in weight, waist circumference, systolic blood pressure, and CVD risk over the study period. Those who were postmenopausal at the time of enrollment demonstrated little change in weight, but were found to have increases in waist circumference, systolic blood pressure, and CVD risk. In both groups, changes over time did not differ significantly according to breast cancer status. Neither chemotherapy nor endocrine therapy were found to be associated with greater increases in CVD risk or risk factors.

Conclusions

In the current study cohort, changes over time in CVD risk, adiposity measures, and blood pressure were similar between women who developed an incident breast cancer and those who did not.
Validating the predictors of outcomes after radical cystectomy for bladder cancer
Authors: Woldu Solomon L. , Sanli Oner , Clinton Timothy N. , Lotan Yair
Published: October 2018

Background

An assessment of surgical risk is essential for patient counseling and decision making, and it can provide rationale adjustment for patient populations as health care moves from a fee‐for‐service to a value‐based reimbursement model. The modified Frailty Index (mFI) has been proposed as a risk‐stratification tool for radical cystectomy (RC), and the objective of the current study was to validate this potential use of the mFI using an institutional cohort.

Methods

A retrospective review of all patients who underwent RC for bladder cancer was conducted at the authors’ institution from 2012 to 2016. In addition to detailed clinicopathologic and treatment parameters, patients were categorized according to the mFI, the Charlson Comorbidity Index (CCI), and the American Society of Anesthesiologists (ASA) classification. Covariates were analyzed to determine associations with 1‐month complication rates (according to the Clavien‐Dindo system), 3‐month readmission rates, hospitalization length, and hospitalization costs.

Results

In total, 346 patients were included in the analysis. The overall complication rate was 56.6%, the major (Clavien grade ≥3) complication rate was 19.4%, and the readmission rate was 27.9%. Receiver operating curve analysis demonstrated a weak association of all indices with major complications after RC: the area under the curve was 0.535 (95% confidence interval [CI], 0.460‐0.611) for the ASA classification; 0.565 (95% CI, 0.485‐0.645) for the CCI score; and 0.551 (95% CI, 0.471‐0.631) for the mFI. There were no significant differences in the rate of major complications when stratifying the results according to the mFI, CCI, or ASA class. Length of hospitalization and associated costs were correlated with mFI.

Conclusions

Frailty was not associated with postoperative complications and provided little additional predictive ability over the ASA classification and the CCI score. Further research is required to identify patients who are likely to suffer significant complications after RC.
FNA of epithelioid sarcoma: Curie Institute experience and critical review of the literature
Authors: Gajdzis Paweł , Laé Marick , Klijanienko Jerzy
Published: October 2018

BACKGROUND

Epithelioid sarcoma (ES) is a rare mesenchymal tumor that is divided into 2 types: classic and proximal. To the authors’ knowledge, ES has been poorly studied in cytology, with fewer than 50 cases reported to date. The objective of the current study was to analyze the cytological and immunohistochemical information regarding 5 cases of ES.

METHODS

Five cases of ES were analyzed: 4 of proximal type and 1 of classic type. The cases were taken from 4 female patients and 1 male patient. The patients ranged in age from 10 to 75 years.

RESULTS

All smears obtained from the proximal type of ES were found to be hypercellular with a necrotic and inflammatory background. Smears from classic‐type ES were hypocellular with a hemorrhagic background. Large, dispersed epithelioid cells and loosely cohesive groups of cells were most frequently noted in all cases. All cases of proximal‐type ES demonstrated rhabdoid cells and marked nuclear atypia, but in only one case were rhabdoid cells found to be dominant. ES diagnoses were confirmed by immunohistochemistry in histological material. In 4 cases, epithelial marker expression was noted, whereas CD34 was found to be positive in only the classic type of ES. In 2 cases, total loss of SMARCB1/INI1 nuclear expression was observed. In the 2 SMARCB1/INI1–positive cases, loss of SMARCA2/BRM expression was observed in one case and partial loss was observed in the other case.

CONCLUSIONS

The proximal type of ES differs from the classic type by the presence of rhabdoid cells and marked nuclear atypia. A specific immunohistochemical profile demonstrating loss of SMARCB1/INI1 or other proteins from the SWI/SNF complex also may be indicative of this diagnosis.
Molecular analysis of peripheral lung adenocarcinoma in brush cytology obtained by EBUS plus fluoroscopy‐guided bronchoscopy
Authors: Sánchez‐Font Albert , Chalela Roberto , Martín‐Ontiyuelo Clara , Albero‐González Raquel , Dalmases Alba , Longarón Raquel , Alonso‐Espinaco Virginia , Curull Víctor , Bellosillo Beatriz , Pijuan Lara
Published: October 2018

BACKGROUND

More than 60% of patients with lung cancer are diagnosed at advanced stages. The introduction of targeted therapies requires molecular diagnosis to guide treatment. The aim of this study was to evaluate the feasibility of performing mutational analysis with brushing specimens obtained by radial‐miniprobe endobronchial ultrasound (R‐EBUS) plus fluoroscopy‐guided bronchoscopy in patients with peripheral pulmonary adenocarcinoma.

METHODS

Brushing specimens were deposited on cytological slides and were conserved in Roswell Park Memorial Institute (RPMI) culture medium. DNA was isolated to perform a mutational analysis with real‐time quantitative polymerase chain reaction and Sanger sequencing for epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS).

RESULTS

Thirty patients with adenocarcinoma were prospectively included. In 100% of the patients, the molecular study was viable with brushing specimens. In 16 (53.3%), KRAS or EGFR mutations were detected: 10 KRAS mutations (33.3%) and 6 EGFR mutations (20%). In a comparison with histological samples, a correlation of 86.6% was detected, and only 2 patients with wild‐type results from brushing specimens presented with an EGFR mutation in histological samples.

CONCLUSIONS

Brushing specimens conserved in RPMI medium and obtained by R‐EBUS plus fluoroscopy‐guided bronchoscopy are valid for molecular studies. They allow the detection of EGFR/KRAS mutations in patients with peripheral adenocarcinoma. In addition, invasive techniques are avoided, the risk of complications is reduced, and the obtained samples are optimized.
The cytopathologist's expanding role in the 2018 updated molecular testing guidelines for lung cancer
Authors: Bellevicine Claudio , Troncone Giancarlo
Published: October 2018

The College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology (AMP) International joint committee has recently updated the previous 2013 molecular guidelines version. Here we summarize these changes which demonstrate that molecular cytopathology is here to stay.