bluuebunny/crossref_metadata_2025 huggingface dataset:
Leadership talk: From managerialism to leaderism in health care after the crash
Authors: Bresnen Mike , Hyde Paula , Hodgson Damian , Bailey Simon , Hassard John
Published: May 2015

The economic downturn that began in 2008 led to massive cuts in spending targeted at managerial activities in the UK National Health Service (NHS). Although the appellation “manager” once conferred status in the NHS, managers have borne the brunt of reform and the term itself is in danger of falling into disrepute. Drawing upon perspectives on leadership that emphasize its constitutive nature, we examine the growing alternative emergent culture of “leaderism” in the NHS and how this relates to managerial practices and identity. Empirical case study research from three hospital trusts in the UK is presented. The findings highlight not only the many tensions associated with this purported shift toward “leaderism” in practice but also how interpretative flexibility associated with the concept of leadership has itself an important bearing upon understanding attempts to bridge long-standing managerial divides within health care.
College Students as Emerging Adults
Authors: Arnett Jeffrey Jensen
Published: May 2015

In this commentary to the special issue of Emerging Adulthood edited by Reifman and Grahe, I seek to provide a broader developmental context for the studies. I begin by describing the rise in college participation over the past century, noting that even now only about 20% attend 4-year residential colleges and universities. Then, I describe some of the distinctive characteristics of these students, such as that they tend to be from higher socioeconomic status families and they are disproportionately White and female (which is true of the present student samples as well). I apply this lens briefly to the articles in the special issue, noting some of the ways the college context is important for interpreting the results. Finally, I discuss some possible future directions for this line of research, for example, in comparisons of students such as these to noncollege samples and in cross-national comparisons.
Appropriating Invention Through Concept Maps in Writing for Multimedia and the Web
Authors: Bacabac Florence Elizabeth
Published: May 2015

As an alternative approach to web preproduction, I propose the use of concept maps for invention of website projects in business and professional writing courses. This mapping device approximates our students’ initial site plans since rough ideas are formed based on a substantial exploratory technique. Incorporated in various disciplines, the construction of concept maps leads to better flowcharts and more structured wireframes for web development.
Gold Nanohole Array with Sub-1 nm Roughness by Annealing for Sensitivity Enhancement of Extraordinary Optical Transmission Biosensor
Authors: Zhang Jian , Irannejad Mehrdad , Yavuz Mustafa , Cui Bo
Published: May 2015

Nanofabrication technology plays an important role in the performance of surface plasmonic devices such as extraordinary optical transmission (EOT) sensor. In this work, a double liftoff process was developed to fabricate a series of nanohole arrays of a hole diameter between 150 and 235 nm and a period of 500 nm in a 100-nm-thick gold film on a silica substrate. To improve the surface quality of the gold film, thermal annealing was conducted, by which an ultra-smooth gold film with root-mean-square (RMS) roughness of sub-1 nm was achieved, accompanied with a hole diameter shrinkage. The surface sensitivity of the nanohole arrays was measured using a monolayer of 16-mercaptohexadecanoic acid (16-MHA) molecule, and the surface sensitivity was increased by 2.5 to 3 times upon annealing the extraordinary optical transmission (EOT) sensor.
Is mouse embryonic stem cell technology obsolete?
Authors: Skarnes William C
Published: May 2015

Injection of recombinant Cas9 protein and synthetic guide RNAs into mouse zygotes has been shown to facilitate gene disruption and knock-ins using the CRISPR system. These technologies may soon displace genetic modification using embryonic stem cells.
Connectivity and circuitry in a dish versus in a brain
Authors: Chinchalongporn Vorapin , Koppensteiner Peter , Prè Deborah , Thangnipon Wipawan , Bilo Leonilda , Arancio Ottavio
Published: May 2015

In order to understand and find therapeutic strategies for neurological disorders, disease models that recapitulate the connectivity and circuitry of patients’ brain are needed. Owing to many limitations of animal disease models, in vitro neuronal models using patient-derived stem cells are currently being developed. However, prior to employing neurons as a model in a dish, they need to be evaluated for their electrophysiological properties, including both passive and active membrane properties, dynamics of neurotransmitter release, and capacity to undergo synaptic plasticity. In this review, we survey recent attempts to study these issues in human induced pluripotent stem cell-derived neurons. Although progress has been made, there are still many hurdles to overcome before human induced pluripotent stem cell-derived neurons can fully recapitulate all of the above physiological properties of adult mature neurons. Moreover, proper integration of neurons into pre-existing circuitry still needs to be achieved. Nevertheless, in vitro neuronal stem cell-derived models hold great promise for clinical application in neurological diseases in the future.
Transplantation of mesenchymal stem cells ameliorates secondary osteoporosis through interleukin-17-impaired functions of recipient bone marrow mesenchymal stem cells in MRL/lpr mice
Authors: Ma Lan , Aijima Reona , Hoshino Yoshihiro , Yamaza Haruyoshi , Tomoda Erika , Tanaka Yosuke , Sonoda Soichiro , Song Guangtai , Zhao Wei , Nonaka Kazuaki , Shi Songtao , Yamaza Takayoshi
Published: May 2015

Introduction

Secondary osteoporosis is common in systemic lupus erythematosus and leads to a reduction in quality of life due to fragility fractures, even in patients with improvement of the primary disorder. Systemic transplantation of mesenchymal stem cells could ameliorate bone loss and autoimmune disorders in a MRL/lpr mouse systemic lupus erythematosus model, but the detailed therapeutic mechanism of bone regeneration is not fully understood. In this study, we transplanted human bone marrow mesenchymal stem cells (BMMSCs) and stem cells from exfoliated deciduous teeth (SHED) into MRL/lpr mice and explored their therapeutic mechanisms in secondary osteoporotic disorders of the systemic lupus erythematosus model mice.

Methods

The effects of systemic human mesenchymal stem cell transplantation on bone loss of MRL/lpr mice were analyzed in vivo and ex vivo. After systemic human mesenchymal stem cell transplantation, recipient BMMSC functions of MRL/lpr mice were assessed for aspects of stemness, osteogenesis and osteoclastogenesis, and a series of co-culture experiments under osteogenic or osteoclastogenic inductions were performed to examine the efficacy of interleukin (IL)-17-impaired recipient BMMSCs in the bone marrow of MRL/lpr mice.

Results

Systemic transplantation of human BMMSCs and SHED recovered the reduction in bone density and structure in MRL/lpr mice. To explore the mechanism, we found that impaired recipient BMMSCs mediated the negative bone metabolic turnover by enhanced osteoclastogenesis and suppressed osteoblastogenesis in secondary osteoporosis of MRL/lpr mice. Moreover, IL-17-dependent hyperimmune conditions in the recipient bone marrow of MRL/lpr mice damaged recipient BMMSCs to suppress osteoblast capacity and accelerate osteoclast induction. To overcome the abnormal bone metabolism, systemic transplantation of human BMMSCs and SHED into MRL/lpr mice improved the functionally impaired recipient BMMSCs through IL-17 suppression in the recipient bone marrow and then maintained a regular positive bone metabolism via the balance of osteoblasts and osteoclasts.

Conclusions

These findings indicate that IL-17 and recipient BMMSCs might be a therapeutic target for secondary osteoporosis in systemic lupus erythematosus.
Overlapping PPM for band-limited visible light communication and dimming
Authors: Gancarz John E. , Elgala Hany , Little Thomas D.C.
Published: May 2015

The synthesis of visible light communication (VLC) and lighting state control necessitates data-light modulation that can accommodate intensity control. A number of techniques that enable both optical wireless data transmission and intensity control of light-emitting diodes (LEDs) have been proposed as a response to this need. Relevant schemes leverage amplitude modulation (AM)/continuous current reduction (CCR) and/or pulse-width modulation (PWM) for dimming capability. Two-level schemes related to PWM, such as on-off keying with compensation time (OOK + CT), variable pulse position modulation (VPPM), and multiple pulse position modulation (MPPM), are most commonly investigated. In this paper, we survey and compare OOK + CT, VPPM and MPPM. Moreover, we propose a novel approach towards dimming and data transmission through the variation of codeword weights in overlapping pulse-position modulation (OPPM). The proposed approach has comparatively high spectral efficiency. Using realistic constraints of a practical VLC system, analysis reveals that OPPM can increase data rates by more than 20Mbps over expected performance of related, two-level schemes, when using LEDs suitable for lighting that have relatively low modulation bandwidths.
Long and short range order structural analysis of
In-situ
formed biphasic calcium phosphates
Authors: Kim Dong-Hyun , Hwang Kyu-Hong , Lee Ju Dong , Park Hong-Chae , Yoon Seog-Young
Published: May 2015

Background

Biphasic calcium phosphates (BCP) have attracted considerable attention as a bone graft substitute. In this study, BCP were prepared by aqueous co-precipitation and calcination method. The crystal phases of
in-situ
formed BCP consisting of hydroxyapatite (HAp) and β-tricalcium phosphate (β-TCP) were controlled by the degree of calcium deficiency of precursors. The long and short range order structures of biphasic mixtures was investigated using Rietveld refinement technique and high resolution Raman spectroscopy. The refined structural parameters of
in-situ
formed BCP confirmed that all the investigated structures have crystallized in the corresponding hexagonal (space group P63/m) and rhombohedral (space group R3c) structures.

Results

The crystal phases, Ca/P molar ratio, and lattice parameters of
in-situ
formed BCP consisting of HAp and β-TCP were controlled by the degree of calcium deficiency of calcium phosphate precursors. The significant short range order structural change of BCP was determined by Raman analysis.

Conclusions

The long and short range order structural changes of
in-situ
formed BCP might be due to the coexistence of β-TCP and HAp crystal phases.
Probabilistic formulation of AVO modeling and AVO-attribute-based facies classification using well logs
Authors: Grana Dario , Bronston Mark
Published: May 2015

We have developed a probabilistic formulation to derive the probability density function of amplitude variation with offset (AVO) attributes given the distribution of elastic properties, in the context of AVO analysis of well log data. The proposed probabilistic formulation includes the analytical expression of the posterior distribution and contributes to the correct propagation of the uncertainty through the AVO model. When this analysis is performed in each facies, the resulting posterior probability density functions of AVO attributes, conditioned by the elastic attributes and the underlying log-facies classification, can be used in a Bayesian inversion workflow to obtain the AVO-attribute-based facies classification. This classification is then compared with the petrophysical log-facies profile and can be extended to the entire reservoir model if inverted seismic attributes are available. We demonstrate the methodology on a data set from an onshore tight-sand gas reservoir in Texas. The main results of the application are the set of probability distributions of AVO properties as a function of elastic attributes in each facies and the corresponding AVO-based facies profile at the well location. A comparison of different statistical assumptions and a sensitivity analysis on the resolution of the elastic data set are presented.
Tonality and Mutability in Rachmaninoff’s All-Night Vigil, Movement 12
Authors: Bakulina Ellen
Published: May 2015

This article offers a Schenkerian interpretation of movement 12 from Sergei Rachmaninoff’s All-Night Vigil, also known as Vespers, op. 37 (1915), from the standpoint of tonal duality, known in Russian as peremennost’, or mutability. First, I explore theoretical connections between several concepts related to tonal disunity in Russian- and English-language sources, including tonal pairing, directional tonality, and mutability, and offer my own definition of mutability, understood in Schenkerian terms. I then briefly discuss these phenomena in the style to which the Vigil belongs—the New Russian Choral School. With this theoretical and historical background, I then give a detailed analysis of movement 12, showing that (1) Rachmaninoff inherits mutability from the standard musical practice of the Russian church and (2) mutable relationships penetrate the work from the foreground to the deepest level of tonal hierarchy, at which two Ursätze in different keys are joined together at the same hierarchical level. In the process, I offer a slight adaptation of the Schenkerian background paradigms to accommodate the imperfect authentic cadence with 3^ in the soprano, which in Russian church music bears a closural function.
Schubert’s Harmonic Language and Fourier Phase Space
Authors: Yust Jason
Published: May 2015

This article introduces a type of harmonic geometry, Fourier phase space, and uses it to advance the understanding of Schubert’s tonal language and comment upon current topics in Schubert analysis. The space derives from the discrete Fourier transform on pitch-class sets developed by David Lewin and Ian Quinn but uses primarily the phases of Fourier components, unlike Lewin and Quinn, who focus more on the magnitudes. The space defined by phases of the third and fifth components closely resembles the Tonnetz and has a similar common-tone basis to its topology but is continuous and takes a wider domain of harmonic objects. A number of musical examples show how expanding the domain enables us to extend and refine some the conclusions of neo-Riemannian theory about Schubert’s harmony. Through analysis of the Trio and Adagio from Schubert’s String Quintet and other works using the geometry, the article develops a number of concepts for the analysis of chromatic harmony, including a geometric concept of interval as direction (intervallic axis), a novel approach to triadic voice leading (triadic orbits), and theories of tonal regions.
agINFRA: a research data hub for agriculture, food and the environment
Authors: Drakos Andreas , Protonotarios Vassilis , Manouselis Nikos
Published: May 2015

The agINFRA project (www.aginfra.eu) is a European Commission funded project under the 7th Framework Programme that aimed to introduce agricultural scientific communities to the vision of open and participatory data-intensive science. Working on enhancing the interoperability between heterogeneous data sources, the agINFRA project has left a set of grid- and cloud- based services that can be reused by future initiatives and adopted by existing ones, in order to facilitate the dissemination of agricultural research, educational and other types of data. On top of that, agINFRA provided a set of domain-specific recommendations for the publication of agri-food research outcomes. This paper discusses the concept of the agINFRA project and presents its major outcomes, as adopted by existing initiatives activated in the context of agricultural research and education.
Art and epistemic injustice: Ursula Biemann’s Remote Sensing and The Black Sea Files
Authors: Brown Kathryn
Published: May 2015

Having regard to two video works produced by Ursula Biemann, Remote Sensing (2001) and The Black Sea Files (2005), this article examines the portrayal of female displacement and migration in the context of Miranda Fricker’s recent discussion of ‘epistemic injustice’. Focusing on ways in which the videos demonstrate instances of testimonial injustice, it is argued that Biemann’s work requires audiences to broaden their conception of the circumstances in which such injustice might arise. The discussion shows that Remote Sensing and The Black Sea Files do not just illuminate the distinctive harm of testimonial injustice, but also deepen current debates in analytical philosophy about the ways in which social pressures, customs, and power structures impact on the provision and receipt of testimony. Instead of viewing the exercise of prejudice as the trigger for testimonial injustice, Biemann’s works show that such injustice can arise when listeners fail to have regard to the background socio-economic conditions that shape the context in which testimony is given and received. By self-consciously locating her works in a network of image circulation, Biemann also raises questions about the reliability of moving images that seek to illuminate testimonial injustice at the intersection of art and documentary.
Art, artifice and androgyny: Roxy Music’s dandy modernism
Authors: Hackett Jon
Published: May 2015

This article considers glam rock’s rejection of the humdrum, spontaneity and the ‘natural’, and its embrace of costuming, camp and artificiality. With particular reference to Roxy Music, it will examine the band’s iconography, fashion and contexts during glam’s golden years – 1972 to 1974 – as well as the implications of glam style for gender and sexuality in popular music. Though some of glam’s exponents were undoubtedly much more traditional in their performance of gender identities, we can read bands like Roxy Music, within certain limits, as ‘queering’ their more meat-and-potatoes predecessors and providing an important source of identification for later pop music gender and style dissidents. The fashion and music scenes in which Roxy Music emerged are inseparable from the milieux of experimentation and innovation associated with British art and fashion schools in the 1960s onwards. To this extent, the band exemplifies the vital pathway of art school students into popular music outlined by Simon Frith and Howard Horne in Art into Pop. Through Keir Keightley’s conception of romantic and modernist authenticity in popular music and Joanne Entwhistle’s genealogy of the romantic and the dandy in fashion, we will explore how glam traces a line from the dandy via New Edwardian fashion, in which questions of gender and artifice are in a process of perpetual renegotiation.
Re-defining charity for the 21st century
Authors: Luxton Peter
Published: May 2015

Article by Peter Luxton (Professor of
Property Law, University of Sheffield) considering legislative
proposals to reform the law of charity, including a review of the
current law and issues which a new Bill must address. Published
in Amicus Curiae - Journal of the Society for Advanced Legal
Studies. The Journal is produced by the Society for Advanced
Legal Studies at the Institute of Advanced Legal Studies,
University of London.
War Crimes: a call to action
Authors: Harris Julian
Published: May 2015

Editorial by Julian Harris, Deputy General Editor of Amicus Curiae. Editorial piece from issue 77 of Amicus Curiae - Journal of the Society for Advanced Legal Studies. The Journal is produced by the Society for Advanced Legal Studies at the Institute of Advanced Legal Studies, University of London.
Greater than the sum of its parts: the growing impact of devolution on the processes of constitutional reform in the United Kingdom
Authors: Himsworth Chris
Published: May 2015

This article is the revised text of a
lecture given at the Institute of Advanced Legal Studies on
December 8, 2008, under the chairmanship of Lord Hope of
Craighead and as the firts in a series on "What's Happening in
Scotland?" Article by Chris Himsworth, Professor of
Administrative Law at the University of Edinburgh, published in
Amicus Curiae - Journal of the Society for Advanced Legal
Studies. The Journal is produced by the Society for Advanced
Legal Studies at the Institute of Advanced Legal Studies,
University of London.
Electronic evidence and the meaning of "original"
Authors: Mason Stephen
Published: May 2015

Article based on a paper given at the Tokyo Institute of Technology, Graduate School of Decision Science and Technology, Ookayama-campus, Tokyo.Article by Stephen Mason published in Amicus Curiae - Journal of the Society for Advanced Legal Studies. The Journal is produced by the Society for Advanced Legal Studies at the Institute of Advanced Legal Studies, University of London.
The South African close corporation under the Companies Act of 2008
Authors: Henning Johan J.
Published: May 2015

A review, by Professor J.J. Henning, of the South African Companies Act 71 of 2008, considering in particular the impact of its provisions on South African close corporation - a juristic person that confers on its members all the usual advantages associated with legal personality and in which all or most members are actively involved. Published in Amicus Curiae – Journal of the Society for Advanced Legal Studies at the Institute of Advanced Legal Studies. The Journal is produced by SALS at the Institute of Advanced Legal Studies, University of London.
Where should war crimes be prosecuted?
Authors: Harris Julian
Published: May 2015

Brief summary by Julian Harris (editor of Amicus Curiae) of a debate on war crimes, humanitarian law and the role of International criminal courts held at the Institute of Advanced Legal Studies in May 2010. Amicus Curiae - Journal of the Society for Advanced Legal Studies is produced by the Society for Advanced Legal Studies at the Institute of Advanced Legal Studies, University of London.
Defamation - the promise of reform
Authors: Harris Julian
Published: May 2015

Brief article by Julian Harris (Deputy General Editor, Amicus Curiae) on the impact of Lord Lester's private members's Defamation Bill in the House of Lords on May 26th, 2010 aiming to "reform English defamation law so that it strikes a fair balance between the fundamental right to freedom of expression and public information and the protection of good reputation" and moves by the Ministry of Justice to publish a draft Defamation Bill for pre-legislative scrutiny.
The German Kommanditgesellschaft auf Aktien (limited partnership with shares)
Authors: Wooldridge Frank
Published: May 2015

An overview of the German law governing limited partnership companies with shares (Kommanditgesellschaft auf Aktien). The author outlines: the historical background, applicable rules of law, formation, structure, organisation and financial provisions of a KGaA.
Urbanität durch Dichte?
Authors: Beckmann Karen
Published: May 2015

Verdichtung war die Maßgabe des Städtebaus der 1970er Jahre. Es entstanden Quartiere, die damals als modern und zukunftsweisend galten, heute jedoch überwiegend als abweisend empfunden werden. Karen Beckmann untersucht eine besonders prägnante Ausformung dieser architektonischen Strömung: Großwohnkomplexe. Im Mittelpunkt steht dabei die Suche nach den Potenzialen dieses Bautyps. Die Studie eröffnet nicht nur neue Sichtweisen auf die Architektur der 1970er Jahre, sondern zeigt auch Strategien auf, wie mit bestehenden und zukünftigen Gebäudestrukturen dieser Art umgegangen werden kann. Ihre Aktualität zeigen Projekte wie das »Interlace« in Singapur, die die Sehnsucht nach Verwirklichung der Idee von Urbanität durch Dichte neu beleben.
The relationship between adolescents’ childhood trauma experiences and empathetic tendency, social problem solving
Authors: Dereli İman Esra
Published: May 2015

The purpose of this study was to investigate whether high school students’ childhood trauma experiences differ based on individual differences, and whether childhood trauma experiences of adolescents predict empathic tendency and social problem solving. In this study, Childhood Trauma Questionnaire, Adolescent KA-Sİ Empathic Tendency Scale, and Social Problem Solving Inventory were used. Adolescents’ physical abuse, emotional abuse-neglect, and sexual abuse sub-dimensions of childhood trauma experience scores significantly differed based on gender. Adolescents’ physical abuse, emotional abuse-neglect sub dimensions of childhood trauma experience scores significantly differed based on father education-level, number of siblings and income- level of family. Adolescents’ emotional abuse-neglect sub dimension of childhood trauma experiences scores significantly differed based on mother education-level. Also physical abuse, emotional abuse-neglect sub dimensions of childhood trauma experiences predicted cognitive empathy whereas emotional abuse-neglect, sexual abuse sub dimensions of childhood trauma experiences predicted emotional empathy. The results also indicate that adolescents’ emotional abuse-neglect sub dimensions of childhood trauma experiences predicted sub dimensions of social problem solving.
Biologic Therapies in Colorectal Cancer: Indications and Contraindications
Authors: Fakih Marwan
Published: May 2015

The role of antiangiogenic and anti-epidermal growth factor receptor (EGFR) agents has been investigated extensively in colorectal cancer in the palliative, adjuvant, and neoadjuvant settings. Although the role of biologic agents has become well-defined in the first, second, and subsequent lines of treatment of metastatic colorectal cancer (mCRC), considerable debate continues around the optimal sequencing and around optimal patient selection. The benefits from integrating bevacizumab or cetuximab in the adjuvant setting have been investigated in several randomized phase III clinical trials in stage II/III disease, all with disappointing results. Neoadjuvant approaches incorporating biologic therapy in patients with liver metastatic disease have led to mixed results. Although the current evidence does suggest increased down-staging and increased resectability with the addition of cetuximab in patients with initially unresectable or borderline resectable liver metastases, a positive effect of anti-EGFR therapy on the overall survival (OS) in this setting is not conclusive. Patients with resectable liver metastases derive no benefit and may experience potential harm from the addition of cetuximab to neoadjuvant chemotherapy. Similarly, there is neither rationale nor adequate data to support the addition of bevacizumab to neoadjuvant chemotherapy in patients with resectable liver metastases. In this review, we examine the role of antiangiogenesis and anti-EGFR therapies across the spectrum of adjuvant, neoadjuvant, and metastatic disease.
The Role of Surveillance versus Adjuvant Treatment in Stage I Germ Cell Tumors: Outcomes and Challenges
Authors: Horwich Alan
Published: May 2015

Germ cell cancers of the testis arise in young adults, and, if identified in stage I, have an excellent prognosis. Thus, we should minimize management-related toxicities. Surveillance (observation) following orchiectomy can avoid further treatment; however, patients who experience relapse receive more treatment than what would have been used during initial adjuvant therapy. For the individual patient, it is important to be aware of their particular risk of relapse, the treatment they would receive for the treatment of relapse and the alternative adjuvant approaches. For seminoma, the risk of relapse during surveillance is 15% to 20%; the size of the primary tumor and the presence of rete testis invasion are prognostic factors. Most relapses occur within 3 years; however, approximately 10% occur more than 5 years after orchiectomy. The alternative adjuvant strategies are either one cycle of carboplatin or radiotherapy (RT), which reduce recurrence risk to less than 5%. The cure rate is around 99%, regardless of which management option is implemented. For stage I nonseminoma, the risk of relapse during surveillance in unselected series is 26% to 30%. Lymphovascular invasion and the amount of embryonal carcinoma are risk factors. Most relapses occur within the first year after orchiectomy, and relapse after 3 years is rare. Ninety percent of relapse patterns are classified as “good prognosis,” and cure rates are 99%. The alternatives to surveillance include adjuvant strategies such as one cycle of adjuvant bleomycin/etoposide/cisplatin (BEP) chemotherapy; however, evidence is emerging that a single cycle is effective. There is controversy whether to offer surveillance for all patients or to offer adjuvant chemotherapy to select patients.
Triple-Negative Breast Cancer: Immune Modulation as the New Treatment Paradigm
Authors: Disis Mary L. , Stanton Sasha E.
Published: May 2015

Recent studies of tumor lymphocytic immune infiltrates in breast cancer have suggested an improved prognosis associated with increasing levels of tumor-infiltrating lymphocytes (TIL). Triple-negative breast cancer (TNBC) is the breast cancer subtype that has the greatest incidence of patients with a robust tumor immune infiltrate, although it is still a minority of patients. Elevated levels of either intratumoral or stromal T cells are associated with an improved overall survival (OS) and disease-free survival (DFS) in TNBC as compared with other breast cancer subtypes. TNBC may be immunogenic for several reasons. Subtypes of TNBC have a significant number of genetic mutations, and the immune system may see the aberrant proteins encoded by these mutations as foreign. Moreover, TNBC is associated with a prognostic gene signature that also includes B cells. Antibodies secreted by B cells may bind to tumor antigens and amplify the adaptive immune response that has already been initiated in the tumor. New immune modulatory agents, including immune checkpoint inhibitors, have shown activity in immunogenic tumors such as melanoma and bladder cancer and have recently been tested in TNBC. The clinical response rates observed, patterns of response, and adverse event profiles are similar to what has been described in melanoma where this class of agents has already been approved for clinical use in some cases. Lessons learned in assessing the immunogenicity of TNBC, potential mechanisms of immune stimulation, and response to immune modulatory drugs lay the foundation for the development of immune-based therapies in all subtypes of the disease.
Why Chemotherapy Should be Given Early for Men with Metastatic Prostate Cancer
Authors: Hernandez-Aya Leonel F. , Hussain Maha
Published: May 2015

Metastatic hormone-sensitive prostate cancer (mHSPC) is an incurable disease, and despite a high response rate to androgen-deprivation therapy (ADT), outcomes have not significantly changed for many decades. Earlier attempts at multitargeted strategies with the addition of cytotoxic chemotherapy to ADT did not affect survival. As more effective therapies are emerging, including cytotoxic therapy for patients with metastatic castrate-resistant prostate cancer (mCRPC), there is increasing interest for testing these drugs earlier in the disease course. The premise is that agents with clinical benefit in advanced mCRPC may have a better effect if used preemptively before the development of significant resistance and to attack earlier de novo androgen resistant/independent clones. The recent results of the phase III clinical trial E3805 investigating ADT with or without docetaxel in mHSPC provide compelling support for this strategy. Docetaxel combined with ADT significantly improved overall survival from 44 to 57.6 months (p = 0.0003), particularly in patients with high-volume disease (from 32.2 to 49.2 months; p = 0.0006). Longer follow-up is needed to assess the effect on patients with low disease burden. Further studies are needed to further maximize the antitumor effect in patients with mHSPC and to investigate the effects of advancing therapy to this disease setting on the efficacy of respective agents in the castration-resistant setting.
Immunotherapeutic Approaches in Prostate Cancer: Combinations and Clinical Integration
Authors: Slovin Susan F.
Published: May 2015

Despite multiple immunologic approaches with peptide, protein, and DNA vaccines, no single therapy has induced complete remission or maintained durability of response in patients with castration-resistant prostate cancer (CRPC). Historically, immunotherapy has had limited effect on solid tumors with the exception of melanoma and renal cell carcinomas, which have been deemed as immunologic cancers given their potential for remissions either spontaneously or after removal of the primary lesion. There is considerable excitement about using an immunotherapy in combination with biologic agents such as checkpoint inhibitors, cytokines, other vaccines, or chemotherapy. Sipuleucel-T represents one of several novel immunologic therapeutic approaches to treat prostate cancer in addition to other solid tumors. It is the first in its class of autologous cellular therapies to demonstrate safety and an overall survival benefit in patients with asymptomatic or minimally symptomatic CRPC and represents a unique treatment method that may be further enhanced with other agents. Although sipuleucel-T can be used as a foundation on which to build and enhance future immunologic clinical trials, other exciting strategies are in development that may be easily integrated into the algorithm of current care.
Expectations in the Care of Lung Cancer
Authors: Lilenbaum Rogerio , Leighl Natasha B. , Neubauer Marcus
Published: May 2015

One of the main challenges oncologists face in the care of patients with lung cancer is the decision to incorporate new clinical trial data into routine clinical practice. Beyond the question of statistical significance, which is a more objective metric, are the results meaningful and applicable to a broader population? Furthermore, in an era of value care, do the results justify a potential increase in costs? This article discusses the main points that clinicians consider in their decision-making process and illustrates the arguments with real-life examples.
Cell-of-Origin in Diffuse Large B-Cell Lymphoma: Are the Assays Ready for the Clinic?
Authors: Scott David W.
Published: May 2015

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma worldwide and consists of a heterogeneous group of cancers classified together on the basis of shared morphology, immunophenotype, and aggressive clinical behavior. It is now recognized that this malignancy comprises at least two distinct molecular subtypes identified by gene expression profiling: the activated B-cell-like (ABC) and the germinal center B-cell-like (GCB) groups—the cell-of-origin (COO) classification. These two groups have different genetic mutation landscapes, pathobiology, and outcomes following treatment. Evidence is accumulating that novel agents have selective activity in one or the other COO group, making COO a predictive biomarker. Thus, there is now a pressing need for accurate and robust methods to assign COO, to support clinical trials, and ultimately guide treatment decisions for patients. The “gold standard” methods for COO are based on gene expression profiling (GEP) of RNA from fresh frozen tissue using microarray technology, which is an impractical solution when formalin-fixed paraffin-embedded tissue (FFPET) biopsies are the standard diagnostic material. This review outlines the history of the COO classification before examining the practical implementation of COO assays applicable to FFPET biopsies. The immunohistochemistry (IHC)-based algorithms and gene expression–based assays suitable for the highly degraded RNA from FFPET are discussed. Finally, the technical and practical challenges that still need to be addressed are outlined before robust gene expression–based assays are used in the routine management of patients with DLBCL.
Smoldering Multiple Myeloma: When to Observe and When to Treat?
Authors: Mateos María-Victoria , San Miguel Jesús-F
Published: May 2015

Smoldering multiple myeloma (SMM) is an asymptomatic disorder characterized by the presence of at least 3 g/dL of serum M-protein and/or 10% to 60% bone marrow plasma cell infiltration with no myeloma-defining event. The risk of progression to active multiple myeloma (MM) is not uniform and several markers are useful for identifying patients at high risk of progression. The definition of the disease has recently been revisited and patients with asymptomatic MM at 80% to 90% of progression risk at 2 years are now considered to have MM. Although the current standard of care is not to treat, a randomized trial in patients with high-risk SMM that compared early treatment versus observation demonstrated that early intervention resulted in substantial benefits in terms of time to progression and overall survival (OS). These findings highlight the need to follow a correct diagnosis by an accurate risk stratification to plan an optimized follow-up according to the risk of disease progression.
Multiple Myeloma: Is It Time for Biomarker-Driven Therapy?
Authors: Bhutani Manisha , Landgren Ola , Usmani Saad Z.
Published: May 2015

Remarkable strides have been made in understanding the molecular mechanisms by which multiple myeloma develops, leading to more sophisticated classification that incorporates not only the traditional diagnostic criteria, but also immunophenotype, genetic, and molecular features. However, even with this added information, considerable heterogeneity in clinical outcomes exists within the identified subtypes. The present paradigm for myeloma treatment is built on the basic step of defining transplant eligibility versus noneligibility, as determined by age, performance status, and cumulative burden of comorbidities. An incredibly complex heterogeneous disease is, therefore, treated in a generalized way with the result that large interpatient variability exists in the outcome. As antimyeloma therapeutics continue to expand it is becoming even more crucial to personalize treatment approaches that provide the most value to a specific patient. Development of biomarkers, either individually or as larger sets or patterns and ranging from analysis of blood or bone marrow to biomedical imaging, is a major focus in the field. Biomarkers such as involved serum free light chain ratio and MRI focal lesions have been implemented in the new definition of multiple myeloma and guide clinicians to initiate treatment in otherwise asymptomatic individuals. Currently, however, there is not enough evidence to support intensifying the treatment for high-risk disease or reducing the treatment for low-risk disease. Minimal residual disease-negative status is an important biomarker that holds promise for monitoring the effectiveness of response-adapted strategies. This article sheds light on the forward landscape and rear-mirror view of biomarkers in myeloma.
Addressing Barriers to Uptake of Breast Cancer Chemoprevention for Patients and Providers
Authors: Crew Katherine D.
Published: May 2015

Breast cancer is the most common malignancy among women in the United States, and the primary prevention of this disease is a major public health issue. Because there are relatively few modifiable breast cancer risk factors, pharmacologic interventions with antiestrogens have the potential to significantly affect the primary prevention setting. Breast cancer chemoprevention with selective estrogen receptor modulators (SERMs) tamoxifen and raloxifene, and with aromatase inhibitors (AIs) exemestane and anastrozole, is underutilized despite several randomized controlled trials demonstrating up to a 50% to 65% relative risk reduction in breast cancer incidence among women at high risk. An estimated 10 million women in the United States meet high-risk criteria for breast cancer and are potentially eligible for chemoprevention, but less than 5% of women at high risk who are offered antiestrogens for primary prevention agree to take it. Reasons for low chemoprevention uptake include lack of routine breast cancer risk assessment in primary care, inadequate time for counseling, insufficient knowledge about antiestrogens among patients and providers, and concerns about side effects. Interventions designed to increase chemoprevention uptake, such as decision aids and incorporating breast cancer risk assessment into clinical practice, have met with limited success. Clinicians can help women make informed decisions about chemoprevention by effectively communicating breast cancer risk and enhancing knowledge about the risks and benefits of antiestrogens. Widespread adoption of chemoprevention will require a major paradigm shift in clinical practice for primary care providers (PCPs). However, enhancing uptake and adherence to breast cancer chemoprevention holds promise for reducing the public health burden of this disease.
Decision Making in the Context of Breast Cancer Chemoprevention: Patient Perceptions and the Meaning of Risk
Authors: Holmberg Christine
Published: May 2015

Chemoprevention with selective estrogen receptor modulators (SERMs) is considered one of the most promising risk reduction options to date in the United States. Tamoxifen and raloxifene are both approved by the U.S. Food and Drug Administration (FDA) for breast cancer risk reduction. However, despite endorsement from the American Society for Clinical Oncology and the National Comprehensive Cancer Network, uptake remains low. Decision aids have been successful in improving women's understanding and knowledge about the risk–benefit trade-offs in decision making regarding SERMs. However, increased knowledge does not lead to increased uptake of chemoprevention for the purpose of reducing breast cancer risk; instead, women become more reluctant to take medication that is itself associated with risks. Reasons for this include a lack of awareness that SERMs are effective in reducing breast cancer risk, an unwillingness to increase the risk of other disease, reluctance to take a daily medication, and the perception of tamoxifen as a “cancer drug.” In studies on hypothetical decision making in the context of chemoprevention women indicate greater willingness to take a SERM when they are determined to be at risk. These findings suggest a differential understanding of what risk means among the general public, health professionals, and researchers. Feeling at risk is related to bodily signs and symptoms and not to population-derived probabilities. Such differential understanding may in part explain women's perception of the low efficacy of SERMs and their decision making regarding SERM use.
State of the Art Discovery with Tumor Profiling in Pediatric Oncology
Authors: Carroll William L. , Raetz Elizabeth , Meyer Julia
Published: May 2015

It is an exciting era in pediatric oncology with the advent of new technologies to comprehensively characterize cancer genomes in childhood tumors. Defining the genetic landscape of pediatric tumors has not only provided critical insight into tumor evolution, but it has also offered promise for more effective treatment in some cases, such as Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) and anaplastic lymphoma kinase (ALK)-mutated tumors. However, several challenges remain as the field of genomic tumor profiling emerges. This new technology is costly, and the overall impact on survival has yet to be determined. Tumor heterogeneity and clonal evolution have also presented challenges in the development of targeted therapy. In this article, we review breakthroughs in gene sequencing methodology and discuss examples where genomic discoveries have resulted in the recognition of tumor susceptibility as well as incorporation of targeted therapy. We also discuss how broad scale comprehensive tumor analyses have demonstrated the convergence of individual genetic alterations on common relevant pathways. Although the impact of tumor profiling is best studied within the context of rigorously designed clinical trials, there is promise that there will be growing opportunities for the adaption of precision medicine in pediatric oncology in the future.
Adjuvant Chemotherapy for Soft Tissue Sarcoma
Authors: Casali Paolo G.
Published: May 2015

Adjuvant chemotherapy is not standard treatment in soft tissue sarcoma (STS). However, when the risk of relapse is high, it is an option for shared decision making with the patient in conditions of uncertainty. This is because available evidence is conflicting, even if several randomized clinical trials have been performed for 4 decades and also have been pooled into meta-analyses. Indeed, available meta-analyses point to a benefit in the 5% to 10% range in terms of survival and distant relapse rate. Some local benefit also was suggested by some trials. Placing chemotherapy in the preoperative setting may help gain a local advantage in terms of the quality of surgical margins or decreased sequelae. This may be done within a personalized approach according to the clinical presentation. Attempts to personalize treatment on the basis of the variegated pathology and molecular biology of STS subgroups are ongoing as well, according to what is done in the medical treatment of advanced STS. Thus, decision making for adjuvant and neoadjuvant indications deserves personalization in clinical research and in clinical practice, taking profit from all multidisciplinary clinical skills available at a sarcoma reference center, though with a degree of subjectivity because of the limitations of available evidence.
Reform of the Buy-and-Bill System for Outpatient Chemotherapy Care Is Inevitable: Perspectives from an Economist, a Realpolitik, and an Oncologist
Authors: Polite Blase , Conti Rena M. , Ward Jeffery C.
Published: May 2015

Treating patients with cancer with infused or injected oncolytics is a core component of outpatient oncology practice. Currently, practices purchase drugs and then bill insurers, colloquially called “buy and bill.” Reimbursement for these drugs is the largest source of gross revenue for oncology practices, and as the prices of cancer drugs have grown over time, these purchases have had significant impact on the financial health of practices and pose a risk that jeopardizes the ability of many practices to operate and provide patient care. Medicare Part B spending on drugs is under political scrutiny because of federal spending pressures, and the margin between buy and bill, lowered to 6% by the Medicare Modernization Act and further decreased to 4.3% by sequestration, is a convenient and popular target of budgetary discussions and proposals, scored to save billions of dollars over 10-year budget windows for each percentage-point reduction. Alternatives to the buy-and-bill system have been proposed to include invoice pricing, least costly alternative reimbursement, bundling of drugs into episode-of-care payments, shifting Part B drugs to the Medicare Part D benefit, and revision of the failed Competitive Acquisition Program. This article brings the perspectives of policy makers, health care economists, and providers together to discuss this major challenge in oncology payment reform.
Immunomodulatory effects of inosine pranobex on cytokine production by human lymphocytes
Authors: Lasek Witold , Janyst Michał , Wolny Rafał , Zapała Łukasz , Bocian Katarzyna , Drela Nadzieja
Published: May 2015

Inosine pranobex (inosine dimepranol acedoben, isoprinosine) (Inos) is an immunomodulatory and antiviral drug used in some viral infections, especially in patients with weakened immunity. In the present study, effects of Inos on the production of cytokines attributable to Th1 (IL-2, IFN-g, and TNF-a) or Th2 cells (IL-4, IL-5, and IL-10) were tested in human peripheral blood lymphocyte cultures stimulated with phytohemagglutinin (PHA). Inos enhanced TNF-a secretion significantly (in short-term - 24-hour, and prolonged term - 72-hour cultures) and IFN-g (in 72-hour cultures). Surprisingly, production of IL-10 by PHA-stimulated lymphocytes was suppressed by Inos in a dose-dependent manner in both 24-hour and 72-hour cultures. These results shed some light on immunomodulatory properties of Inos and suggest applicability of this agent in patients with a depressed function of the immune system.