bluuebunny/crossref_metadata_2025 huggingface dataset:
IT strategies for tourist and service companies: analyzing challenges, approaches, and validity
Authors: Ермаков Станислав , Ermakov Stanislav , Илькевич Сергей , Ilkevich Sergey , Шлапак Вера , Shlapak Vera
Published: May 2014

The article provides an analysis of the major approaches, technologies, and challenges to molding an IT strategy for tourist and service companies. The authors touched upon the central aspects of the role which information technologies play in service and tourist management, service-focused orientation of data systems, methodological issues of service modeling, essential and viable lines of IT penetration, and the economic feasibility of strategic decisions.
ALLOTROPIC TRANSFORMATION OF COBALT IN MAGNETIC INDUCTION MELTED Fe60Al1-XCoX
Authors: Fekrache Abdelhak , Yacine Debili Mohamed , Boularas Halima , Lamrous Douniazed , Sassane Nacira
Published: May 2014

In contrast to the abundance of studies in Fe-Al and Fe-Co, those in the Fe-Al-Co ternary system are scarce. Consequently, the phase separation and phase diagram of this system remain still ambiguous. Ternary Fe0.6Al1-xCox(x values in a molar ratio of 0.05, 0.1, 0.15, and 0.2) have been elaborated by high frequency magnetic induction fusion, in order to study the effect of cobalt ternary addition on the structural behavior such as phase separation, thermal and mechanical properties of Fe-based alloy system, by means of x-ray diffraction, thermal analysis (DSC) and Vickers microhardness. An unexpected allotropic phase transformation from stable HCP to metastable FCC Cobalt has been observed in all alloys.
Zr+ ION BEAM SURFACE IRRADIATION FOR IMPROVING FATIGUE DURABILITY OF 12Cr1MoV AND 30CrMnSiNi2 STRUCTURAL STEELS
Authors: Panin Sergey , Vlasov Ilya , Sergeev Viktor , Maruschak Pavlo , Naidfeld Vasilii , Kalashnikov Mark , Bogdanov Oleg , Ovechkin Boris
Published: May 2014

A cyclic tension and alternating bending tests of 12Cr1MoV and 30CrMnSiNi2 steels specimens in as–supplied state and after surface nanostructuring by Zr+ ion beam have been carried out. Distinctions in formation of strain induced relief, as well as the cracking pattern of modified surface layer are illustrated by methods of optical microscopy and interferential profilometry. Changes to occur in subsurface layer are characterized by means of nanoindentation and fractography (scanning electron microscopy) of fracture surfaces. The description of differences of deformation behavior is carried out with use of the multilevel approach.
THE ABRASIVE WEAR BEHAVIOR OF CENOSPHERE-ALUMINIUM METAL MATRIX COMPOSITE
Authors: Varatharaju Saravanan , Pudukarai Ramaswamy Thyla , Rajarathnam Balakrishnan Sreedhara
Published: May 2014

Wear is the major parameter for various applications in automobile and aeronautical industries. Various researches are going on to improve the wear by either alloying the material or using the composite material. Current study focuses on wear improvement through composite material with aluminium as matrix and cenospheres as re-inforcement. The abrasive wear behavior of cenosphere particle reinforced aluminium alloy (AA) 6063 was investigated using pin-on-disc technique. Aluminium – cenosphere metal matrix composite was fabricated by adding various percentages of cenosphere particles using stir casting technique and its abrasive wear behavior was compared with AA6063. The uniform distribution of particles was ensured with the help of scanning electron microscopy (SEM).
INFLUENCE OF TECHNOLOGICAL PARAMETERS ON THE SPRINGBACK ANGLE OF HIGH-STRENGTH STEELS
Authors: Slota Ján , Jurčišin Miroslav , Lazarescu Lucian
Published: May 2014

The most common problem in area of sheet metal forming technology is a problem of achieving accurate and repeatable shapes of drawn and bent parts. This phenomenon is caused by the elastic springback. Springback can be defined as an elastically-driven change of shape of the deformed part upon removal of external loads. Several technological parameters influence amount of springback, between these belong friction coefficient, blankholder force, different geometry of tools, etc. In this paper is presented this topic, and also numerical simulation of this process. For an experimental process were used two high-strength steels. Steel with TRIP effect and dual phase steel DP 600. Numerical simulation was performed in the static implicit code Autoform. Results were compared and discussed.
SOME TRIBOLOGICAL ASPECTS OF Fe-Zn COATED STEEL SHEETS AT STAMPING PROCESSES
Authors: Evin Emil , Tomáš Miroslav , Kollárová Mária , Antoszewski Bogdan
Published: May 2014

Contribution presents results of study of tribological characteristics of Fe-Zn coated steel sheets. Experimental research was done using coatings with different alloying – under alloyed, optimal and slightly pre alloyed. The optimally alloyed coatings and the slightly prealloyed ones were annealed in order to reach different alloying level. Alloying level was evaluated by phase composition and % Fe in coating. Tribological properties such as surface microgeometry, abrasion, friction coefficient were analysed from the view of formability. Experimental results of strip drawn test were used for verification of strip-drawn test numerical simulation. Based on numerical simulation results, contact pressure on drawing die radius was observed.
MACROSCOPIC INVESTIGATIONS OF THE PRIMARY STRUCTURE OF CONTINUOUS CASTING INGOTS
Authors: Kudliński Zdzisław , Janiszewski Krystian
Published: May 2014

This paper presents the results of macroscopic investigations of the structure of continuous casting ingots depending on the kinetics of solidification and speed of casting of low carbon steel intended for welding wires. We have determined the Lk length of solidification path of ingots of 140 x 140 mm cross-section. We have also performed macroscopic investigations of the ingot structures together with identification of shrinkage porosity defects and axial porosities. microscopic investigations of axial ingot zones, areas of shrinkage defects and axial porosity, have demonstrated that the non-metallic phase (silicates and aluminates) presented there stands in the way of welding during the process of rolling of continuously cast ingots.
MATHEMATICAL MODELING OF SURFACE INDUCTION HEATING
Authors: Smalcerz Albert , Wieczorek Jakub , Slezok Maria
Published: May 2014

The paper presents possibilities of controlling temperature field distribution in induction heated charge. The change of the distribution was obtained with use of sequential two-frequency heating. The study was conducted as multi-variant computer simulations of strongly coupled to each other field: the electromagnetic and the temperature fields. For the analysis, the professional calculation package using the finite element method Flux 3D was used. The problem of obtaining an appropriate temperature distribution in a heated charge of, a complex shape is very important in many practical applications. A typical example is a quenching of gears. For such applications, it is required to obtain a surface and in desired depth, uniform temperature distribution on the tooth face and top land and on the bottom land of the gear. The obtained temperature should have proper distribution and value. Achieving such a defined distribution is very difficult. During the study over a dozen different calculation variants were examined.
Decentralized Procurement in Light of Strategic Inventories
Authors: Arya Anil , Frimor Hans , Mittendorf Brian
Published: May 2014

The centralization versus decentralization choice is perhaps the quintessential organizational structure decision. In the operations realm, this choice is particularly critical when it comes to the procurement function. Why firms may opt to decentralize procurement has been often studied and confirmed to be a multifaceted choice. This paper complements existing studies by detailing the trade-offs in the centralization versus decentralization decision in light of firms' strategic use of inventories to influence supplier pricing. In particular, we demonstrate that a firm's decision to cede procurement choices to its individual divisions can help moderate inventory levels and provide a natural salve on supply chain frictions.

This paper was accepted by Serguei Netessine, operations management.
Parental Adaptation to Out-of-Home Placement of a Child With Severe or Profound Developmental Disabilities
Authors: Jackson Jeffrey B. , Roper Susanne Olsen
Published: May 2014

Utilizing grounded theory qualitative research methods, a model was developed for describing parental adaptation after voluntary placement of a child with severe or profound developmental disabilities in out-of-home care. Interviews of parents from 20 families were analyzed. Parents' cognitive appraisals of placement outcomes were classified as either inducing emotional stress (i.e., guilt, sadness, fear and worry, anger and frustration, and uncertainty) or relief. Parental appraisals of responses to placement by children, extended family, and friends were identified as factors affecting the parents' adaptation to placement. The primary coping methods used by parents to decrease emotional stress and increase relief consisted of reappraisals regarding the necessity of placement, involvement in the child's life, psychotherapy, and the passage of time.
Epidemiology of Epilepsy in Older Adults With an Intellectual Disability in Ireland: Associations and Service Implications
Authors: McCarron Mary , O'Dwyer Marie , Burke Eilish , McGlinchey Eimear , McCallion Philip
Published: May 2014

There are limited studies on the prevalence of epilepsy and co-morbid conditions in older adults with an ID. To begin to address this prevalence of epilepsy was estimated for participants in the Intellectual Disability Supplement to the Irish Longitudinal Study on Ageing. Associations with demographic variables and co morbid health conditions were examined. It was found that prevalence was high (30.7%); but declined as people aged. Those with epilepsy were less likely to live with family, independently or in community settings, rates of refractory epilepsy were high and, despite medication over half of those with epilepsy still reported experiencing seizures. Given these findings, people with ID and their careers have considerable needs for information about epilepsy management, and for support from specialist ID and epilepsy services.
Individuals With 22q11.2 Deletion Syndrome Are Impaired at Explicit, But Not Implicit, Discrimination of Local Forms Embedded in Global Structures
Authors: Giersch Anne , Glaser Bronwyn , Pasca Catherine , Chabloz Mélanie , Debbané Martin , Eliez Stephan
Published: May 2014

Individuals with 22q11.2 deletion syndrome (22q11.2DS) are impaired at exploring visual information in space; however, not much is known about visual form discrimination in the syndrome. Thirty-five individuals with 22q11.2DS and 41 controls completed a form discrimination task with global forms made up of local elements. Affected individuals demonstrated clear impairment in detecting local, but not global, differences. Nevertheless, 22q11.2DS participants easily discriminated the same local elements when they were displayed in isolation, and further use of a prime demonstrated preserved facilitation of local processing in 22q11.2DS. These results did not differ by age or IQ. This study illustrates the impact of visuospatial impairments on form discrimination, and suggests how these difficulties may affect visual scanning in 22q11.2DS.
An Interactive Multimedia Program to Prevent HIV Transmission in Men With Intellectual Disability
Authors: Wells Jennifer , Clark Khaya , Sarno Karen
Published: May 2014

The efficacy of a computer-based interactive multimedia HIV/AIDS prevention program for men with intellectual disability (ID) was examined using a quasi-experimental within-subjects design. Thirty-seven men with mild to moderate intellectual disability evaluated the program. The pretest and posttest instruments assessed HIV/AIDS knowledge (high-risk fluids, HIV transmission, and condom facts) and condom application skills. All outcome measures showed statistically significant gains from pretest to posttest, with medium to large effect sizes. In addition, a second study was conducted with twelve service providers who work with men with ID. Service providers reviewed the HIV/AIDS prevention program, completed a demographics questionnaire, and a program satisfaction survey. Overall, service providers rated the program highly on several outcome measures (stimulation, relevance, and usability).
Branded: The sister arts of rhetoric and design
Authors: Engbers Susanna Kelly
Published: May 2014

This article explores the potentially fruitful relationships between design education and rhetorical education. Teachers of rhetoric and teachers of design have much to learn from one another, yet they rarely interact. One way in which design and rhetoric should be informing one another is through the related concepts of branding, familiar to designers, and ethos, well known to rhetoricians. Branding is often important in design curricula; students learn to design products whose voice people are willing to bring into their lives. And branding has obvious connections to rhetorical ethos; Aritstotle’s tripartite concept of ethos can be used to deepen discussions of both ethos and branding, particularly focusing on the ethical dimensions of both. This article surveys literature on rhetorical ethos, presents practical classroom strategies for teaching ethos and describes the possible productive relationship between teaching rhetorical ethos alongside branding.
Teaching the design of narrative visualization for financial literacy
Authors: Fry Aaron , Wilson Jennifer , Overby Carol
Published: May 2014

The authors provide a scholarly definition for metaphor-rich, story-driven ‘narrative visualization’. They argue that metaphors create a rich and emotionally resonant set of associations that frame the narrative and effectively support ‘System 1’ (or intuition-based) thinking and decision-making that Daniel Kahneman and others have identified as the primary drivers of financial behaviour. The authors then apply these observations to a case study in which they analyse student work on a financial literacy design project. They discuss best practices for teaching narrative visualization and argue for its relevance in a contemporary design education – especially its capacity to represent and reflectively explore complex financial and other concepts.
Informal peer critique and the negotiation of habitus in a design studio
Authors: Gray Colin M.
Published: May 2014

Critique is a central feature of design education, serving as both a structural mechanism to provide regular feedback, and as a high stakes assessment tool. However, this study addresses informal peer critique as an extension of this existing form, engaging students in communication outside of the formal pedagogy. The purpose of this study is to gain a greater understanding of the role of informal critique in externalizing design thinking and judgment, as analysed through Bourdieu’s habitus. Structures surrounding critique, including the role of informal vs formal spaces, objectivity vs subjectivity of critique, and differences between professor and peer feedback are addressed. Beliefs about critique are analysed as critical elements of an evolving habitus, supported by or developed in response to the culture inscribed by the formal pedagogy. Informal critique reveals tacit design thinking and conceptions of design, and outlines the co-construction of habitus between students and the formal pedagogy.
Progress in the Treatment of Advanced Prostate Cancer
Authors: Sternberg Cora N. , Petrylak Daniel P. , Madan Ravi A. , Parker Chris
Published: May 2014

The androgen receptor (AR) is the most significant target for patients with metastatic castration-resistant prostate cancer (mCRPC). There is now irrefutable evidence that the AR axis is functional in most patients throughout the history of prostate cancer, is crucial from diagnosis to death, even in patients who have received hormonal manipulation, and represents a relevant therapeutic target in all phases of the disease. The potential mechanisms of tumor escape after castration are multifold, with each mechanism today representing a therapeutic opportunity. Phase III trials have been able to demonstrate improved overall survival (OS), improved quality of life, decreased skeletal-related events, and other important clinical benefits in young and elderly patients. After the initial positive results with docetaxel chemotherapy in improving OS, further research has resulted in five new treatments in the past few years. Immunotherapy with sipuleucel-T, cabazitaxel chemotherapy, the androgen biosynthesis inhibitor abiraterone acetate, the antiandrogen enzalutamide, and the radioisotope radium-223 have all been shown to improve OS in large-scale, well-conducted clinical trials. Proper understanding of mechanisms of resistance and of cross-resistance among these agents, sequencing, and combinations is now a priority.
Ovarian Cancer: Targeting the Untargetable
Authors: Birrer Michael J.
Published: May 2014

INTRODUCTION

The premise that all tumors are targetable has been met with some controversy in the approach to epithelial ovarian cancer (EOC). Genomic analysis shows that these tumors (specifically, high-grade serous carcinomas) are genomically unstable and lack actionable driver mutations, much like HER2 in breast and gastric cancers. In this paper, Michael Birrer, MD, PhD, Massachusetts General Hospital, argues that the interpretation of genomic data in ovarian cancer requires a more thoughtful approach that necessitates a closer inspection of the data beyond the mere presence or absence of mutations. We must look at the extensive genomic alterations in DNA and, to understand more about the role of those genes affected by these changes, look beyond the tumor to the role of the stroma. As such, Dr. Birrer is arguing for the importance of translational research. This will be the key to precision medicine in ovarian cancer, as we approach drug discovery and improvements in treatment. Dr. Birrer is a world-renowned scientist who has devoted his career to the study of gynecologic cancers. He has published over 200 papers and written over 27 book chapters and reviews, served on numerous leadership positions in gynecologic oncology (including as co-chair of the National Cancer Institute's Gynecologic Cancer Steering Committee), and remains a clinician–scientist with an active lab and an active clinic. His career trajectory has shown me it is possible to be engaged as a researcher and a clinician and the work he has done has already impacted the care of patients with ovarian cancer.

Don S. Dizon, MD, ASCO Educational Book Editor
Preparing for an Epidemic: Cancer Care in an Aging Population
Authors: Shih Ya-Chen Tina , Hurria Arti
Published: May 2014

The Institute of Medicine's (IOM) Committee on Improving the Quality of Cancer Care: Addressing the Challenges of an Aging Population was charged with evaluating and proposing recommendations on how to improve the quality of cancer care, with a specific focus on the aging population. Based on their findings, the IOM committee recently released a report highlighting their 10 recommendations for improving the quality of cancer care. Based on those recommendations, this article highlights ways to improve evidence-based care and addresses rising costs in health care for older adults with cancer. The IOM highlighted three recommendations to address the current research gaps in providing evidence-based care in older adults with cancer, which included (1) studying populations which match the age and health-risk profile of the population with the disease, (2) legislative incentives for companies to include patients that are older or with multiple morbidities in new cancer drug trials, and (3) expansion of research that contributes to the depth and breadth of data available for assessing interventions. The recommendations also highlighted the need to maintain affordable and accessible care for older adults with cancer, with an emphasis on finding creative solutions within both the care delivery system and payment models in order to balance costs while preserving quality of care. The implementation of the IOM's recommendations will be a key step in moving closer to the goal of providing accessible, affordable, evidence-based, high-quality care to all patients with cancer.
Epstein-Barr Virus as a Paradigm in Nasopharyngeal Cancer: From Lab to Clinic
Authors: Raghupathy Radha , Hui Edwin Pun , Chan Anthony Tak Cheung
Published: May 2014

Nasopharyngeal carcinoma (NPC) of the undifferentiated subtype remains endemic in southern China, with a peak incidence in this region approaching 30 cases per 100,000 population per year. Despite advances in chemotherapy and radiation delivery techniques in localized disease, distant metastasis is still common and NPC remains the seventh leading cause of cancer death in the region. There is great need for early diagnosis, developing novel therapies, and identifying patients with localized disease at higher risk of future recurrence or metastasis to appropriately tailor their treatment and improve outcomes. Knowledge of the integral involvement of Epstein-Barr virus (EBV) in the pathogenesis of undifferentiated NPC has been of seminal importance in developing strategies to optimize disease management. The close association with EBV is being evaluated in multiple settings including screening of at-risk populations, disease prognostication, development of targeted therapies, optimizing adjuvant treatment, and early recurrence detection. These translational studies are likely to have an enormous effect on management of undifferentiated NPC and significantly improve the landscape of the disease in years to come.
Treating Metastatic Melanoma in 2014: What Just Happened and What Is Next?
Authors: Chapman Paul B.
Published: May 2014

INTRODUCTION

In recent years the expectation related to treating patients with metastatic melanoma has changed. Three years ago, a diagnosis of metastatic melanoma was bleak; only a small number of patients would benefit from standard treatment and the reason for treatment benefit was often unknown, leaving physicians with limited options to help their patients. Today, just 3 years later, there are proven therapies that allow physicians to expect to shrink tumors and extend the lives of their patients after diagnosis. In this article, Paul B. Chapman, MD, Memorial Sloan Kettering Cancer Center, summarizes the recent advances in the field of metastatic melanoma and looks ahead to topics such as focusing on specificity, shutting down the ERK pathway, intermittent dosing, discovering driver mutations, individualizing checkpoint inhibition, and identifying rejection antigens to identify what should occur next in order to continue to improve outcomes for a larger population of patients with metastatic melanoma. Dr. Chapman's paper reminds us of the exciting progress that has been made while focusing on the work that is left in the field.

Dr. Chapman is a physician-scientist who specializes in diagnosing and treating melanoma that has metastasized to other parts of the body. Dr. Chapman led a clinical trial that paved the way, in part, to the approval of vemurafenib—a drug that targets a BRAF mutation that is present in approximately 50% of patients with metastatic melanoma. Dr. Chapman is one of five Memorial Sloan Kettering scientists to be appointed to a melanoma “Dream Team” that focuses on identifying potential therapies for metastatic melanoma patients who do not have the mutated form of the BRAF gene. Dr. Chapman is also a professor of medicine at the Weill Cornell Medical College and is the chair of the Melanoma Research Alliance Medical Advisory Board. In addition to the above, Dr. Chapman is a sought-after mentor for medical oncology fellows and has a current research interest in identifying novel means to more durably block signaling in the MAPK pathway in melanoma cells.

Jedd Wolchok, MD, PhD, Scientific Program Committee Chair
The Rationale for Collecting Patient-Reported Symptoms during Routine Chemotherapy
Authors: Basch Ethan
Published: May 2014

Patient-reported outcomes (PROs) such as symptoms and functional status are commonly measured in clinical trials. There is increasing interest to integrate PROs into routine clinical practice, for example during chemotherapy or postoperatively. There are several rationales for this. First, patient self-reporting improves patient-clinic communication, symptom detection, and symptom control. Second, patient-reported data may be used for quality assessment. Third, aggregated patient-reported data can be informative in comparative-effectiveness research (CER). Of particular interest is an approach that employs electronic collection of PROs with interfaces to the electronic health record (EHR) and clinician alerts for concerning symptoms. Multiple systems have been developed in oncology with these characteristics. Barriers to implementation exist, such as cost, logistics, EHR interfacing, data representation, and data interpretation, but have been largely overcome. Missing data remain a concern, but backup data collection strategies can bring self-report compliance rates up to about 85% in unselected routine care patients with advanced cancers. Overall, including patient self-reporting in routine care enhances quality of care and patient satisfaction, and is expected to become more common in the future. American Society for Clinical Oncology (ASCO) has several ongoing initiatives to develop standards and clinical practice tools in this area.
Mantle Cell Lymphoma: Biology, Clinical Presentation, and Therapeutic Approaches
Authors: Dreyling Martin
Published: May 2014

Mantle cell lymphoma is molecularly characterized by the chromosomal translocation t(11;14) (q13;q32) that results in a constitutional overexpression of the cell cycle regulator protein cyclin D1. Generally, the disease is characterized by rapid relapses and poor long-term outcome. However, a subset of patients with indolent disease has been identified. Randomized trials have demonstrated the superiority of dose intensified, cytarabine-containing induction with or without autologous stem cell transplantation in younger patients. In elderly patients, a rituximab-based maintenance has significantly prolonged progression-free and overall survival after treatment with rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, and prednisone (R-CHOP). Unfortunately, the vast majority of patients will eventually relapse. Numerous molecular targeting strategies (bortezomib, lenalidomide, temsirolimus, and especially inhibitors of the B-cell receptor pathway) have achieved high response rates in phase II studies and should be strongly considered in relapsed disease.
Fifty Years of Progress in Radiation Therapy for Breast Cancer
Authors: Harris Jay R.
Published: May 2014

Fifty years ago, radiation therapy (RT) was only used after mastectomy in patients with high-risk disease. The equipment, treatment planning, and treatment delivery were rudimentary compared to what is available today. In retrospect, the deleterious effects of the RT back then negated its benefits. The strategy of combining lesser surgery with RT (and adjuvant systemic therapy) has been successfully employed in breast-conserving therapy (BCT) and in avoiding axillary lymph node dissection in patients with 1 or 2 involved sentinel nodes. Local recurrence rates at 10 years following BCT are now similar to those following mastectomy. RT after breast-conserving surgery and after mastectomy has been demonstrated to not only decrease local-regional recurrence but also decrease distant metastases and improve long-term survival. The development of effective adjuvant systemic therapy has made RT not only more effective but also arguably more important. If systemic therapy is effective at addressing micro-metastatic disease, then obtaining local tumor control becomes even more important. Moderately hypofractionated RT (2.66 Gy per day) is just as safe and effective as conventional fractionation shortening BCT from 6 weeks to 3–4 weeks. Treatment is now given with multiple-energy linear accelerators, CT-based simulation, 3-dimensional beam modulation for much greater dose homogeneity, on-board imaging for greater daily accuracy, and various techniques to reduce cardiac dose.
Risk Stratification for Wilms Tumor: Current Approach and Future Directions
Authors: Dome Jeffrey S. , Perlman Elizabeth J. , Graf Norbert
Published: May 2014

Wilms tumor, or nephroblastoma, has provided a paradigm for progressive improvement in clinical outcomes achieved through serial cooperative group studies. With modern surgery, chemotherapy, and radiation therapy approaches, the overall survival rate for patients with Wilms tumor has reached 90%. Remarkably, the increase in survival has been achieved with a reduction in therapy for most patient subgroups, leading not only to more survivors, but also to healthier survivors. A key contributor to improved outcomes has been the development of clinical and biologic prognostic markers that have enabled risk-directed therapy. Whereas the early cooperative group studies used only tumor stage for risk stratification, current Children's Oncology Group (COG) and International Society of Pediatric Oncology (SIOP) protocols employ a multitude of prognostic factors to guide therapy. Prognostic factors used in the current generation of COG studies include stage, histology, patient age, tumor weight, completeness of lung nodule response, and loss of heterozygosity at chromosomes 1p and 16q. Future COG studies seek to incorporate gain of chromosome 1q and methylation pattern of chromosome 11p15 into the risk classification schema. Prognostic factors used in the current SIOP studies include stage, histology, tumor volume, and responsiveness to therapy. Future SIOP studies seek to incorporate absolute blastemal volume and novel molecular markers for resistant blastema into the risk stratification approach.
Fifty Years of Advances in Sarcoma Treatment: Moving the Needle from Conventional Chemotherapy to Targeted Therapy
Authors: Patel Shreyaskumar R.
Published: May 2014

Much of the progress in systemic therapy for sarcomas was accomplished in the first half of the last 5 decades. Various chemotherapeutic agents were tested in the 70s through the 80s and became part of the standard of care for this patient population. During the decade of the 90s, dose intensification became feasible as a result of improved supportive care and the availability of growth factors, thus maximizing the therapeutic potential of this class of agents. However, response rates and survival plateaued and it became obvious that newer and mechanistically different agents were needed to improve the therapeutic index and gain further enhancement of outcomes. Since early 2000, primarily inspired by the experience with imatinib in gastrointestinal stromal tumors (GISTs), several targeted therapies have been tested in sarcomas with modest success. The major limitations encountered include the lack of drivers and actionable targets for bone and soft tissue sarcomas with complex genomic profiles. Continued investigations and sequencing of larger numbers of these rare and heterogeneous malignancies could shed some light on a path toward improved outcomes.
The Value of EGFRvIII as the Target for Glioma Vaccines
Authors: Lowenstein Pedro R. , Castro Maria G.
Published: May 2014

Malignant brain tumors continue to be rapidly progressive and resistant to most treatments. Even with state-of-the-art standard of care (surgery, chemotherapy, and radiotherapy) long-term survival in the last 80 years improved from 6 to 15 months. Improved imaging has also likely contributed to prolonged survival. Immunotherapy for cancer dates back to publications from 1742. The central idea is that the immune system can detect and eliminate foreign antigens, either from infectious agents or tumors, and thus could be therapeutic in brain tumors. Recent introduction of immune modulators of cytotoxic T-lymphocyte antigen (CTLA)-4 and programed cell death 1/programmed cell death 1 ligand (PD-1/PDL1) add much excitement to this field. For brain tumors, there are several ongoing phase I and III trials to determine whether any of the current immunotherapy approaches can demonstrate activity in randomized, controlled double-blinded trials—with ongoing and historical trials presented in tables within the manuscript. Immunotherapy has explored the use of various types of antigens (obtained either from homogenates of patients' tumors or synthetically produced), and various immunization procedures and adjuvants. Glioma antigens have also been isolated from the patients' own tumor, then produced in vitro (for example the glioma antigen EGFRvIII), and used to immunize patients directly, or with carriers such as dendritic cells with or without additional adjuvants. Several of these practical approaches are currently in phase III trials. Remaining challenges are how to increase the percentage of complete responses and response duration, and the enigmatic absence of an almost total lack of adverse brain inflammation following immunization of brain tumor patients, as has been observed following immunization against brain antigens in other diseases, such as Alzheimer's Disease.
National Cancer Institute's Precision Medicine Initiatives for the New National Clinical Trials Network
Authors: Abrams Jeffrey , Conley Barbara , Mooney Margaret , Zwiebel James , Chen Alice , Welch John J. , Takebe Naoko , Malik Shakun , McShane Lisa , Korn Edward , Williams Mickey , Staudt Louis , Doroshow James
Published: May 2014

The promise of precision medicine will only be fully realized if the research community can adapt its clinical trials methodology to study molecularly characterized tumors instead of the traditional histologic classification. Such trials will depend on adequate tissue collection, availability of quality controlled, high throughput molecular assays, and the ability to screen large numbers of tumors to find those with the desired molecular alterations. The National Cancer Institute's (NCI) new National Clinical Trials Network (NCTN) is well positioned to conduct such trials. The NCTN has the ability to seamlessly perform ethics review, register patients, manage data, and deliver investigational drugs across its many sites including both in cities and rural communities, academic centers, and private practices. The initial set of trials will focus on different questions: (1) Exceptional Responders Initiative—why do a minority of patients with solid tumors or lymphoma respond very well to some drugs even if the majority do not?; (2) NCI MATCH trial—can molecular markers predict response to targeted therapies in patients with advanced cancer resistant to standard treatment?; (3) ALCHEMIST trial—will targeted epidermal growth factor receptor ( EGFR) and anaplastic lymphoma kinase ( ALK) inhibitors improve survival for adenocarcinoma of the lung in the adjuvant setting?; and (4) Lung Cancer Master Protocol trial for advanced squamous cell lung cancer—is there an advantage to developing drugs for small subsets of molecularly characterized tumors in a single, multiarm trial design? These studies will hopefully spawn a new era of treatment trials that will carefully select the tumors that may respond best to investigational therapy.
Carpe Diem: Time to Seize the Opportunity for Cancer Prevention
Authors: Colditz Graham A.
Published: May 2014

INTRODUCTION

In his plea for increased resources to implement cancer prevention strategies, Graham Colditz, MD, states that half or more of cancers in the U.S. and other high-income countries are preventable with information already available. He describes the data-driven possibilites: screening, vaccination, exercise, smoking cessation, sun protection, safe sexual practices, and moderate to no alcohol intake, as well as approaches to implement these strategies and makes a compelling case for using resources for this purpose. Dr. Colditz is Associate Director of Prevention and Control in the Alvin J. Siteman Cancer Center, and Niess-Gain Professor in the Department of Surgery at the Washington University School of Medicine. He received his PhD in epidemiology from Harvard University, and his Internal Medicine Training at the Royal Brisbane Hospital in Australia. Dr. Colditz has an enormous volume of publications, with over 800 original research articles. He has worked to identify lifestyle and environmental factors that affect people's health, and to develop and teach cancer prevention strategies at the individual and community levels. His research also powers a website— www.yourdiseaserisk.wustl.edu —that helps people assess their risk of developing cancer, diabetes and other diseases as well as suggesting ways to lead longer, healthier lives. His work is inspirational in combining excellent scientific investigation with dedication to making results available and useful to non-scientists.

Gini F. Fleming, MD, Cancer Education Committee Chair
Fifty Years of Systemic Therapy for Breast Cancer: From One Size Fits All to Tailored Therapy
Authors: Burstein Harold J.
Published: May 2014

Breast cancer treatment has evolved dramatically in the past 50 years. In addition to innovations in medical therapy—including widespread use of endocrine treatments, chemotherapy, and anti-HER2 agents—medical advances in genetic testing, imaging, and screening have revolutionized care. As profound as these changes in medical treatment have been, however, they are matched by a cultural transformation in the way society understands, discusses, and cares about breast cancer. Breast cancer has evolved from an unnamed affliction to a disease that is regularly featured on the front page of the newspapers, and is discussed in countless forums in traditional and social media. Clinical specialization in breast cancer among oncologists has given patients access to dedicated specialists around the country. These transformations will be highlighted through the analysis of a patient, Rachel Carson, who died 50 years ago from breast cancer.
Optimal Management of the Premenopausal Patient with Estrogen Receptor–Positive Breast Cancer
Authors: Chojecki Aleksander , Wong Serena , Toppmeyer Deborah
Published: May 2014

Tamoxifen is the standard of care in the adjuvant treatment of premenopausal women with estrogen receptor–positive (ER+) breast cancer. Ovarian suppression (OS) is another method of endocrine therapy and has been shown to decrease the risk of recurrence and confer a survival advantage when used as the sole source of hormone therapy. However, there is no evidence that OS is superior to treatment with tamoxifen. Studies comparing OS with or without tamoxifen compared with chemotherapy have demonstrated comparable effects. There does not appear to be any additional benefit when OS is combined with chemotherapy, although there is a suggestion that there may be an effect in the subgroup of young women (aged younger than 40 years) who are least likely to experience chemotherapy-induced cessation of ovarian function. Interpretation of existing data is hampered by the lack of studies incorporating modern chemotherapy regimens and the absence of molecular analyses that would allow us to better define populations most likely to benefit from endocrine therapy. Last, the role of aromatase inhibitors (AI) in the premenopausal setting remains undefined. Two recent studies, SOFT and TEXT, aim to shed light on the effect of OS and AI in premenopausal ER+ breast cancer and are pending analysis.
New Directions in Perioperative Management of Locally Advanced Esophagogastric Cancer
Authors: Burtness Barbara , Ilson David , Iqbal Syma
Published: May 2014

Cancers of the esophagus arise as adenocarcinomas and squamous cell carcinomas; these represent distinct diseases, with differing prognosis, yet they are often studied in common trials. With surgery alone, 5 year survival for T2-T3N0 disease is less than 30% to 40%, and declines to less than 25% with nodal involvement. The CROSS randomly assigned patients to surgery alone or to weekly carboplatin/paclitaxel X 5 and 41.4 Gy concurrent radiotherapy, followed by surgery. Seventy-five percent of enrolled patients had adenocarcinoma. Preoperative combined-modality therapy improved R0 resection from 69% to 92% (p < 0.001 and improved median survival from 24 months to 49.4 months (p < 0.003). This regimen reduced both locoregional recurrence (34% to 14%; p < 0.001) and the development of peritoneal carcinomatosis (14% to 4%; p < 0.001). Systemic perioperative therapy may have a greater effect on distant disease, the predominant mode of failure for these patients, and current trials compare preoperative chemoradiation with periooperative systemic therapy. PET scan response during preoperative chemotherapy without radiotherapy correlates with improvements in pathologic response and with improved survival. Nonresponse on early PET scan allows identifıcation of patients for earlier surgery and discontinuation of ineffective preoperative chemotherapy, without survival detriment. There is no predictive benefıt for early PET scan during the course of chemotherapy followed by chemoradiotherapy. The use of early PET scan during induction chemotherapy is being evaluated in CALGB/Alliance trial (NCT01333033). Molecular profıling has identifıed somatic gene mutations and pathways that may be oncogenic in upper gastrointestinal cancers. Potential targets include the epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor (VEGFR), HER2, mammalian target of rapamycin (mTOR), fıbroblast growth factor receptor (FGFR), MEK, and others. Targeted therapies with known survival benefit in esophagogastric cancer are currently limited to trastuzumab for HER2 overexpressing cancers, or ramicirumab.
Molecular Characterization and Clinical Utility of Circulating Tumor Cells in the Treatment of Prostate Cancer
Authors: Lorente David , Mateo Joaquin , de Bono Johann S.
Published: May 2014

Circulating tumor cells (CTCs) are rare cancer cells that can be detected in the blood of patients with solid malignancies. The Veridex CellSearch Assay was analytically and clinically validated, and has received U.S. Food and Drug Administration (FDA) clearance for the enumeration of CTCs in breast, colorectal, and prostate cancer. A number of alternative assays, with potential advantages, are currently undergoing clinical and/or analytic validation before their routine use can be established. In prostate cancer, high pretreatment CTC counts have been associated with worse survival, and changes in CTC counts in response to treatment have been established as indicators of response to treatment. Additional analyses are ongoing to establish the value of CTC counts as a surrogate of survival in prospective, phase III trials, which could influence the process of drug development and regulatory approval. Additionally, CTCs have a potential role in the molecular characterization of prostate cancer, serving as “liquid biopsies” to determine the molecular characteristics of the disease. The study of androgen receptor (AR) mutations or amplification, chromosomal rearrangements, or the determination of DNA repair biomarkers has been evaluated in clinical trials. CTCs have a wide range of potential applications, from their prognostic use in stratification of patients in clinical trials or the assessment of response to treatment, to the pharmacodynamic evaluation of novel agents, or the discovery and use of predictive biomarkers that can aid in the development of personalized medicine.
Treating the Two Extremes in Renal Cell Carcinoma: Management of Small Renal Masses and Cytoreductive Nephrectomy in Metastatic Disease
Authors: Kim Dae Y. , Wood Christopher G. , Karam Jose A.
Published: May 2014

OVERVIEW:

The incidental renal mass represents a heterogeneous group that contains both benign and malignant pathologies. The majority of renal cell carcinomas are discovered incidentally, without the presence of symptoms directly related to the mass, and are closely associated with the term small renal masses because of the discovery before the onset of symptoms. In general, small renal masses are defined as 4 cm or smaller, and may account for greater than half of renal cell carcinoma diagnosis. The use of renal mass biopsy may offer additional pathological information but the clinician must be reminded of the technical and diagnostic limitations of renal mass biopsy. Patient-dependent factors, such as life expectancy and comorbidities, guide the management of small renal masses, which include active surveillance, partial nephrectomy, radical nephrectomy, and ablative techniques (cryoablation and radiofrequency ablation). Partial nephrectomy has demonstrated durable oncologic control for small renal masses while preserving renal function and, if feasible, is the current treatment of choice. In the other extreme of the renal cell carcinomas spectrum and in the presence of metastatic disease, the removal of the renal primary tumor is termed cytoreductive nephrectomy. Two randomized trials (SWOG 8949 and EORTC 30947) have demonstrated a survival benefit with cytoreductive nephrectomy before the initiation of immunotherapy. These two studies have also been the motivation to perform cytoreductive nephrectomy in the targeted therapy era. Currently, there are two ongoing randomized prospective trials accruing to investigate the timing and relevance of cytoreductive nephrectomy in the contemporary setting of targeted therapy.
New Agents and New Targets for Renal Cell Carcinoma
Authors: Philips George K. , Atkins Michael B.
Published: May 2014

The vascular endothelial growth factor (VEGF) pathway blockers and mammalian target of rapamycin (mTOR) inhibitors have dramatically improved the treatment options and outcome for patients with advanced renal cell carcinoma (RCC). However, because the vast majority of patients will still succumb to their disease, novel treatment approaches are still necessary. Efforts to identify novel therapeutic target treatments are focused on better understanding unique aspects of tumor cell biology guided the Cancer Genome Atlas analyses and the interaction of the tumor with its microenvironment. Areas of promising investigation include a) the identification of mechanisms of acquired resistance to VEGF pathway inhibition and developing agents targeting these in combination with VEGF receptor (VEGFR) pathway blockade; b) the identification of novel therapeutic targets, particularly for patients with VEGF pathway blocker refractory disease; and c) the development of novel immunotherapies, particularly those involving checkpoint inhibitors used alone or in combination with other immunotherapies of VEGF pathway blockers. Specific targets or agents of interest include angiopoietins (trebaninib), c-Met (cabozantinib), activin receptor-like kinase-1 (ALK-1; dalantercept), interleukin (IL)-8, and HDM2 for acquired resistance to VEGF pathway inhibition; hypoxia inducible factor-2 alpha (HIF-2 alpha), TORC1/2, and the Hippo pathway for novel targets, and PD1 and PDL1 antibodies given either alone or in combination with other checkpoint inhibitors, other immunotherapies, or VEGF pathway blockers for novel immunotherapies. In addition, the application of genetic, immunologic, or other biomarkers developed in the context of this research has the potential to select patients with specific tumor types for therapy targeted to specific vulnerabilities within the tumor or tumor microenvironment. Together, these developments should enable the transition to a new era of rational and more effective therapy for patients with advanced RCC.