bluuebunny/crossref_metadata_2025 huggingface dataset:
Physical Functioning, Emotional, and Behavioral Problems in Children With ADHD and Comorbid ASD: A Cross-Sectional Study
Authors: Thomas Simone , Sciberras Emma , Lycett Kate , Papadopoulos Nicole , Rinehart Nicole
Published: May 2015

Objective: To examine (a) physical and daily functioning in children with ADHD and autism spectrum disorder (ASD) compared with ADHD alone and (b) whether decreased physical quality of life (QoL) is associated with increased emotional and behavioral problems in children with ADHD-ASD. Method: Cross-sectional study comprising 392 children with confirmed ADHD (ADHD-ASD, n = 93; ADHD alone, n = 299) recruited from 21 pediatric practices in Victoria, Australia. Data were collected via parent and teacher surveys. Key measures included the Strengths and Difficulties Questionnaire (SDQ) and Pediatric Quality of Life Inventory (PedsQL). Results: Children with ADHD-ASD had poorer QoL across both psychosocial and physical health domains, and also had greater parent-reported behavioral, emotional, and peer problems, compared with children with ADHD alone. Poorer physical QoL partially mediated the relationship between comorbid ASD status and poorer emotional and behavioral functioning. Conclusion:The comorbid overlay of ASD in ADHD appears to influence not only problems in physical functioning but also the severity of problems relating to areas of emotional and behavioral functioning.
Gout and the risk of dementia: a nationwide population-based cohort study
Authors: Hong Jen-Yee , Lan Tzuo-Yun , Tang Gau-Jun , Tang Chao-Hsiun , Chen Tzeng-Ji , Lin Hsiao-Yi
Published: May 2015

Introduction

Uric acid was proposed to have anti-oxidant property and possible neuroprotective effects. We examined the association between gout and dementia with population database.

Methods

The study utilized the claims data from the nationwide representative sample of Taiwan National Health Insurance Research Database (NHIRD). We ascertained patients with gout and dementia covering vascular and non-vascular (including Alzheimer’s) subtypes using International Classification of Diseases Ninth Revision, Clinical Modification (ICD9-CM) codes. A control group matched on sex, age, and index date of gout patients was randomly sampled with a ratio of 1:4 from the same database for comparison.

Results

From 2002 to 2008, 28,769 gout patients who were older than 50 years old were identified, and 114,742 control patients was matched into the study. During follow-up, 7,119 patients developed dementia (1,214 with gout, and 5,905 without gout). After adjusting for age, sex, and relevant comorbidities, a Cox regression analysis showed that gout patients had a lower risk of developing non-vascular dementia (hazard ratio (HR): 0.77; 95% confidence interval (CI): 0.72 - 0.83; p < 0.001) and vascular dementia (HR: 0.76; 95% CI: 0.65 - 0.88; p < 0.001).

Conclusions

Patients with gout have a lower risk of developing dementia. This phenomenon exists for both non-vascular and vascular types of dementia.
Eicosapentaenoic acid and docosapentaenoic acid monoglycerides are more potent than docosahexaenoic acid monoglyceride to resolve inflammation in a rheumatoid arthritis model
Authors: Morin Caroline , Blier Pierre U , Fortin Samuel
Published: May 2015

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease of the joints and bones. Omega-3 (ω3) fatty acid supplementation has been associated with a decreased production of inflammatory cytokines and eicosanoids involved in RA pathogenesis. The aim of this study was to determine the therapeutic potential of ω3 monoglyceride (MAG-ω3) compounds in an in vivo rat model of RA induced by Complete Freund’s Adjuvant (CFA).

Method

CFA rats were untreated or treated per os with three specific compounds, namely, MAG-docosahexaenoic acid (MAG-DHA), MAG-eicosapentaenoic acid (MAG-EPA) and MAG-docosapentaenoic acid (MAG-DPA). Morphological and histological analyses, as well as pro-inflammatory marker levels were determined following MAG-ω3 treatments.

Results

Morphological and histological analyses revealed that MAG-EPA and MAG-DPA exhibited strong activity in reducing the progression and severity of arthritic disease in CFA rats. Following MAG-EPA and MAG-DPA treatments, plasma levels of the pro-inflammatory cytokines; interleukin 17A (IL-17A), IL-1β, IL-6 and tumor necrosis factor α (TNFα) were markedly lower when compared to CFA-untreated rats. Results also revealed a decreased activation of p38 mitogen-activated protein kinases (p38 MAPK) and nuclear factor-kappa B (NFκB) pathways correlated with a reduced expression of TNFα, cyclooxygenase-2 (COX-2), matrix metalloproteinase-2 (MMP-2) and MMP-9 in paw homogenates derived from MAG-EPA and MAG-DPA-treated rats. Of interest, the combined treatment of MAG-EPA and vitamin E displayed an antagonistic effect on anti-inflammatory properties of MAG-EPA in CFA rats.

Conclusion

Altogether, the present data suggest that MAG-EPA, without vitamin E, represents a new potential therapeutic strategy for resolving inflammation in arthritis.
Mechanism of regulation of stem cell differentiation by matrix stiffness
Authors: Lv Hongwei , Li Lisha , Sun Meiyu , Zhang Yin , Chen Li , Rong Yue , Li Yulin
Published: May 2015

Stem cell behaviors are regulated by multiple microenvironmental cues. As an external signal, mechanical stiffness of the extracellular matrix is capable of governing stem cell fate determination, but how this biophysical cue is translated into intracellular signaling remains elusive. Here, we elucidate mechanisms by which stem cells respond to microenvironmental stiffness through the dynamics of the cytoskeletal network, leading to changes in gene expression via biophysical transduction signaling pathways in two-dimensional culture. Furthermore, a putative rapid shift from original mechanosensing to de novo cell-derived matrix sensing in more physiologically relevant three-dimensional culture is pointed out. A comprehensive understanding of stem cell responses to this stimulus is essential for designing biomaterials that mimic the physiological environment and advancing stem cell-based clinical applications for tissue engineering.
Markers of adiposity among children and adolescents: implications of the isotemporal substitution paradigm with sedentary behavior and physical activity patterns
Authors: Loprinzi Paul D. , Cardinal Bradley J. , Lee Hyo , Tudor-Locke Catrine
Published: May 2015

Background

The purpose of this study was to examine the association between daily movement patterns and dual energy X-ray absorptiometry-determined body fat percent (DXA-BF%) among children and adolescents while applying both traditional and novel analytical procedures.

Methods

Using data from the cross-sectional 2003–2006 National Health and Nutrition Examination Survey (n = 5607), physical activity was assessed via accelerometry, with the following movement patterns assessed: 1) meeting moderate-to-vigorous physical activity (MVPA) guidelines and engaging in more light-intensity physical activity (LIPA) than sedentary behavior (SB); 2) meeting MVPA guidelines, but engaging in less LIPA than SB; 3) not meeting MVPA guidelines, but engaging in more LIPA than SB; and 4) not meeting MVPA guidelines and engaging in less LIPA than SB. Various markers of adiposity (e.g., DXA-BF%) were assessed.

Results

Children in movement pattern 1 (52 %), compared to those in movement pattern 4, had significantly lower levels of BMI (∆ 2.2 kg/m2), waist circumference (∆ 6.5 cm), tricep skinfold (∆ 4.2 mm), subscapularis skinfold (∆ 2.6 mm), android BF% (∆ 7.6 %), gynoid BF% (∆ 5.1 %), and total BF% (∆ 5.2 %). Substituting 60 min/day of SB with MVPA resulted in a 4.6 % decreased estimate of total DXA-BF%. No findings were significant for adolescents.

Conclusions

The low proportion of children engaging in ≥ 60 min/day of MVPA and accumulating relatively more LIPA than SB had the lowest DXA-BF%.
Adsorbed water clusters in garnet cracks detected by impedance and Raman spectroscopies at the supercooled water phase transition
Authors: Prezas Pedro , Silva Hugo Gonçalves , Vinagre Ana , Graça Manuel Pedro F. , Moita Patrícia , Bezzeghoud Mourad
Published: May 2015

The combination of electric impedance and Raman spectroscopies at the analysis of the supercooled water phase transition enables the detection of adsorbed water clusters in garnet minerals of leucogranite samples. This transition is revealed by a change in the parameters measured by both techniques at low temperatures, [Formula: see text], and it is attributed to adsorbed water clusters in the walls of garnet cracks. The study of this transition gives important insights into the water-rock interaction, one of the most important points in the study of rock alteration. The dielectric spectra were fitted to the Havriliak-Negami model of dielectric relaxation and enabled the estimation of the activation energy of the dielectric relaxation process as [Formula: see text], which is higher than the energy attributed to water molecule reorientation in bulk ice. We determined that this energy should be related with the interaction forces between the adsorbed water clusters and the crack walls that hinder the reorientation of those molecules. The logarithmic frequency dependence of the critical transition temperature was also verified. Raman spectra allowed the identification of the water cluster vibration band, [Formula: see text], in the garnet minerals. The band disappears for temperatures around 423 K where the joint action of the laser beam and the temperature evaporates the adsorbed water clusters. This excludes the possibility that the observed supercooled phase transition could be related with structural water in chlorite minerals. The samples had low apparent porosity [Formula: see text], specific surface area, and adsorption average crack width (using the Brunauer-Emmett-Teller method) of [Formula: see text] and [Formula: see text], respectively.
Elastic full-waveform inversion using the second-generation wavelet and an adaptive-operator-length scheme
Authors: Ren Zhiming , Liu Yang
Published: May 2015

Elastic full-waveform inversion (FWI) can generally yield subsurface model parameters of high spatial resolution. However, the computational and storage burden is tremendous. To mitigate this problem, we developed the following three strategies: First, we derived a time-space-domain adaptive staggered-grid finite-difference method. The size of the calculation was reduced by using smaller operator lengths for high S-wave velocities. Second, we evaluated a multiscale elastic FWI scheme based on the second-generation wavelet, by which scale decompositions of data and model space were implemented. With the scale increasing, spatial sampling intervals and time steps became larger. Therefore, the minimum computational cost could be achieved by combining the variable-operator-length scheme with the multiscale scheme. Third, to economize the memory consumption, we extended the efficient boundary storage and checkpointing schemes into elastic FWI. Only wavefields of several parts in the boundary area between two adjacent checkpoints were stored and used to reconstruct source wavefields of the inner area. Furthermore, the optimal number of checkpoints could be automatically determined by minimizing the amount of storage. We validated these new strategies for the SEG/EAGE overthrust model. The synthetic example suggested the feasibility and robustness of the new elastic FWI method in terms of improving computational efficiency and alleviating large amounts of data storage. We also analyzed the accuracy of our FWI method. The inversion results revealed that our wavelet-based method had better reconstructed structures and higher convergence rate than the conventional filtering-based multiscale FWI method.
The Novel and the Passport: Towards a Literary History of Movement Control
Authors: Gulddal Jesper
Published: May 2015

This article explores the link between the novel and the passport system as one of the defining legal institutions of modernity. The late eighteenth-century introduction of modern strategies for controlling mobility brought about a reconfiguration of political space which was now no longer freely travelable, but crisscrossed by internal and international borders. This process is crucial in terms of the history of the novel because it undid the nexus of space, mobility, and narrative characteristic of the early-modern novel and forced the genre to invent plots that better aligned with the reality of modern movement control. Taking a first step towards a literary history of movement control, this comparative study identifies three successive modalities of the novel/passport interface via readings of exemplary literary works: Schnabel's Insel Felsenburg (1731–43), Goethe's Wilhelm Meisters Lehrjahre (1795–96) as compared to Godwin's Caleb Williams (1794), and Stendhal's La Chartreuse de Parme (1839).
Celestial Asterisks: Referential Openness and the Language of “Transcendence” In Emily Dickinson, Giovanni Pascoli, and Rainer Maria Rilke
Authors: Barca Lisa A.
Published: May 2015

This essay explores how the poets Emily Dickinson (American, 1830–1886), Giovanni Pascoli (Italian, 1855–1912), and Rainer Maria Rilke (Bohemian-Austrian, 1875–1926) each use celestial imagery, such as the sun and stars, to represent the modern mystery ushered in by scientific epistemologies and the waning of religious belief. In mapping the poets' respective strategies for speaking of the “eclipse” of God, the essay analyzes the rhetorical choices each poet makes in evoking the transcendent while highlighting its unknowability. As one moves into the twentieth-century high modernism of Rilke's Sonnets to Orpheus and Duino Elegies, the possibility of a transcendence compatible with secular modernity becomes increasingly evident. Engaging a vocabulary of religious images whose authority has been attenuated but which have not been emptied of significance, the poetry reflects a modern mythos that locates the sacred in the here-and-now.
Forced Intimacies and Murky Genealogies in Hispaniola: Émile Ollivier's Mère-Solitude and Marisela Rizik's El Tiempo Del Olvido
Authors: Ramírez Dixa
Published: May 2015

In this article, I argue that two novels by writers from Hispaniola rescript the long-term idealization of heterosexual coupling in both colonial and nationalist narratives from the Caribbean and Latin America. Mère-Solitude (1983) by Haitian-Canadian Émile Ollivier and El tiempo del olvido (1996) by Dominican-American Marisela Rizik expose the sexual violence that women and other persecuted subjects have suffered historically, and which has engendered the idealized mixed-race nation in nationalist narratives. Using several shared motifs, these two novels question the reproductive optimism central to the post-independence works that imagined the nation as a large family with a powerful patriarch and ideal mixed-race children. The novels' spotlight on sexual violence and its results challenges the symbolic overlap between women's bodies and the land.
Investigation of the Cleanliness of Transferred Graphene: The First Step toward Its Application as a Window Material for Electron Microscopy and Spectroscopy
Authors: Ma Tao , Miyazaki Kotaro , Ariga Hiroko , Takakusagi Satoru , Asakura Kiyotaka
Published: May 2015

The cleanliness of transferred graphene is of significant importance for its application as the window material in environmental cells used for electron microscopy and spectroscopy. We investigated the dependence of the cleanliness of graphene on transfer routes, including FeCl3 etching, (NH4)2S2O8 etching, electrochemical delamination, and O2-bubbling, by means of transmission electron microscopy and X-ray photoelectron spectroscopy. It was found that electrochemical delamination provided the cleanest graphene with only a small amount of poly(methyl methacrylate) (PMMA) residue existing on the surface.
Mechanical Properties of Chinese Larch (Larix gmelini) Dimension Lumber
Authors: Zhou Haibin , Ren Haiqing , Lu Jianxiong
Published: May 2015

A testing program was conducted to investigate mechanical properties such as bending, tensile, and compressive strengths of Chinese larch (Larix gmelini) dimension lumber. The species was sampled in three sizes: 40 by 65, 40 by 90, and 40 by 140 mm. These lumber test samples were conditioned to a standard moisture content of 12 percent. After grading and grouping, mechanical properties were measured in full-size testing. The data developed in this study will be used to make technical submissions for the assignment of design properties of Chinese larch in the Chinese timber design code.
Welfare's forgotten past: a socio-legal history of the poor law
Authors: Charlesworth Lorie
Published: May 2015

Article based on a seminar presented by Dr
Lorie Charlesworth (Reader in Law and History at the Law School,
Liverpool John Moores University) at the IALS in February 2010 to
launch the publication of her book of the same title. The author
considers the role of the Poor Law as law, tracing the legal
underpinnings of the early system of relieving poverty in England
and Wales. 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.
Duty of care and responsibilities of the management board of a German public company
Authors: Wooldridge Frank
Published: May 2015

A consideration of the management responsibilities for duty of care in German public companies, looking particularly at the requirements which follow from paragraph 93 of the German Aktiengesetz AktG and the prohibition of competition imposed on members of the management board (board of directors) by paragraph 88 AktG.
Legislative advances in financial stability in the US - the Wall Street Reform and Consumer Protection Act 2010
Authors: Pooran Priya Nandita
Published: May 2015

This article seeks to address recent
legislative and regulatory changes in the United States in the
area of systemic risk management and to assess the impact of the
changes on financial market supervision. It also addresses
changes to the regulation of insurance markets, the enhancements
to systemic risk monitoring and the effectiveness of the proposed
consumer protection bureau. The article is by Priya Nandita
Pooran, Attorney-at-law and was 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 IALS (Institute of Advanced Legal Studies, School of
Advanced Study, University of London).
Gulf of Mexico oil disaster: some legal issues
Authors: Chatterjee Charles , Lefcovitch Anna
Published: May 2015

The aim of this article is to identify and briefly examine the legal issues that arose out of the BP oil spill (also known as Deepwater Horizon oil spill) in the Gulf of Mexico in 2010 which resulted in loss of life and adversely affected the shore of Florida, United States of America through environmental damage and cost in livelihood to firms and families.
Judges, commerce and contract law
Authors: Gava John
Published: May 2015

John Gava, Reader at Adelaide Law School,
considers the question how should judges decide commercial cases,
in particular, contract cases? He looks at the circumstances and
impact of the use of contract law, with attention on common law
contract and market needs. 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
IALS (Institute of Advanced Legal Studies, School of Advanced
Study, University of London).
Sports contracts in Italy
Authors: Serio Mario
Published: May 2015

An article by Mario Serio (Professor of Comparative Law at the University of Palermo, Italy), taken from his presentation at the International Academy of Legal Science conference held at the University of Istanbul in May 2010. The author focuses on the Italian experience of sports contracts and the way relationships between athletes and their employers may be governed in particular legal systems, including protection through implementation within sports bodies. The article is 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.
Zero Comments
Authors: Lovink Geert
Published: May 2015

In diesem dritten Band seiner kritischen Studien zur Internetkultur hinterfragt Geert Lovink den jüngsten »Web 2.0«-Hype um Blogs, Wikis oder Netzgemeinschaften. Anstatt den »Bürger-Journalismus« zu idealisieren, untersucht der Autor den »nihilistischen Impuls« der Blogs, etablierte Bedeutungsstrukturen auszuhöhlen und - voller Stolz auf ihren Insider-Charakter - das Verlinken, Indexieren und Ranking zum Hauptantrieb zu erheben. Darüber hinaus behandelt das Buch die stille Globalisierung des Internets, in der nicht mehr der Westen, sondern Länder wie Indien, China und Brasilien sich zu einflussreichen Akteuren entwickeln. Ein weiterer Schwerpunkt ist die Revision des Theoriebestands: Geert Lovink aktualisiert überholte Konzepte wie die der Globalen Internet-Zeit, der Taktischen Medien oder der Krise der Medienkunst und widmet sich dem schwierigen Verhältnis zwischen Architektur und Netz. Das Buch schließt mit spekulativen Bemerkungen zu Modellen wie Organisierte Netzwerke, Freie Kooperation und Verteilte Ästhetik.
Chemotherapy for Patients with BRCA1 and BRCA2–Mutated Ovarian Cancer: Same or Different?
Authors: Tan David S.P. , Kaye Stanley B.
Published: May 2015

Retrospective studies have shown an improved prognosis, higher response rates to platinum-containing regimens, and longer treatment-free intervals between relapses in patients with BRCA 1 and BRCA 2 ( BRCA1/2)–mutated ovarian cancer (BMOC) compared with patients who are not carriers of this mutation. These features of BMOC are attributed to homologous-recombination repair (HR) deficiency in the absence of BRCA1/2 function, which results in an impaired ability of tumor cells to repair platinum-induced double-strand breaks (DSBs), thereby conferring increased chemosensitivity and increased sensitivity to poly(ADP-ribose) polymerase (PARP) enzyme inhibition and other DNA-damaging chemotherapeutic agents such as pegylated liposomal doxorubicin (PLD). Therefore, the chemotherapeutic approach for patients with BMOC should focus on treatment with platinum-based chemotherapy at first-line and recurrent-disease settings and measures to increase the platinum-free interval following early platinum-resistant relapse (i.e., progression-free survival of less than 6 months from last platinum-based chemotherapy) by using nonplatinum cytotoxic agents, with the aim of reintroducing platinum again at a later date. The role of first-line intraperitoneal platinum-based therapy in the specific context of BMOC also merits further analysis. Other than platinum, alternative DNA-damaging agents (including PLD and trabectedin) also may have a therapeutic role in patients with recurrent BMOC. The recent approval of olaparib for clinical use in Europe and the United States will also affect chemotherapeutic strategies for these patients. Further work to clarify the precise relationship between BRCA1/2 mutation genotype and clinical phenotype is crucial to delineating the optimal therapeutic choices in the future for patients with BMOC.
Achievements and Challenges of Molecular Targeted Therapy in Melanoma
Authors: Sullivan Ryan , LoRusso Patricia , Boerner Scott , Dummer Reinhard
Published: May 2015

The treatment of melanoma has been revolutionized over the past decade with the development of effective molecular and immune targeted therapies. The great majority of patients with melanoma have mutations in oncogenes that predominantly drive signaling through the mitogen activated protein kinase (MAPK) pathway. Analytic tools have been developed that can effectively stratify patients into molecular subsets based on the identification of mutations in oncogenes and/or tumor suppressor genes that drive the MAPK pathway. At the same time, potent and selective inhibitors of mediators of the MAPK pathway such as RAF, MEK, and ERK have become available. The most dramatic example is the development of single-agent inhibitors of BRAF (vemurafenib, dabrafenib, encorafenib) and MEK (trametinib, cobimetinib, binimetinib) for patients with metastatic BRAFV600-mutant melanoma, a subset that represents 40% to 50% of patients with metastatic melanoma. More recently, the elucidation of mechanisms underlying resistance to single-agent BRAF inhibitor therapy led to a second generation of trials that demonstrated the superiority of BRAF inhibitor/MEK inhibitor combinations (dabrafenib/trametinib; vemurafenib/cobimetinib) compared to single-agent BRAF inhibitors. Moving beyond BRAFV600 targeting, a number of other molecular subsets—such as mutations in MEK, NRAS, and non-V600 BRAF and loss of function of the tumor suppressor neurofibromatosis 1 ( NF1)—are predicted to respond to MAPK pathway targeting by single-agent pan-RAF, MEK, or ERK inhibitors. As these strategies are being tested in clinical trials, preclinical and early clinical trial data are now emerging about which combinatorial approaches might be best for these patients.
Targeted and Immunotherapeutic Approaches in Brain Metastases
Authors: Ahluwalia Manmeet S. , Winkler Frank
Published: May 2015

Brain metastases are a common and devastating complication of cancer. The approach to the management of brain metastases is often multidisciplinary and includes surgery, whole-brain radiation therapy (WBRT), stereotactic radiosurgery (SRS), and systemic therapeutic agents. Until recently, systemic therapy has had a limited role in the management of brain metastases because of a lack of activity, challenges of blood-brain barrier penetration, the heterogeneous patient population, and a heavily pretreated patient population. Advances in the understanding of the biology of brain metastases and molecularly defined disease subsets have facilitated an emerging role of novel therapeutic agents, including targeted therapies and immunotherapy, in the management of brain metastases.
The Global Conduct of Cancer Clinical Trials: Challenges and Opportunities
Authors: Barrios Carlos H. , Werutsky Gustavo , Martinez-Mesa Jeovany
Published: May 2015

The nature of clinical research has changed substantially over the last 2 decades, evolving from being centered almost exclusively in developed countries to a more global scenario that is increasingly involving less developed regions of the world. Pharmaceutical companies and some academic cooperative groups have been conducting challenging, large pivotal registration studies with multinational participation. The much more needed globalization of academic research demands particular attention and represents a worthwhile subject for a more profound discussion. The requirement of large sample sizes and the potential for fast recruitment leading to a speedy completion of clinical studies are probably the most important factors that have fueled globalization of studies. Reduced operational costs and the ability to expedite the regulatory approval of drugs in various countries or regions are also important drivers. Globalization of research should be seen as having a much wider effect in the societies involved, in particular, when we consider public health, economic, social, and ethical implications. Most importantly, the process of expanding the network of clinical research sites also fosters the integration and the development of closer relationships among investigators at a global level. We consider this an essential element that should remain a prominent element in the discussion. In this article, we address the underlying reasons for globalization and we highlight some of the scientific and ethical concerns arising as a consequence. Finally, some strategies to address and mitigate the challenges of conducting multinational clinical research are proposed.
Overcoming Resistance to Anti-EGFR Therapy in Colorectal Cancer
Authors: Dienstmann Rodrigo , Salazar Ramon , Tabernero Josep
Published: May 2015

Our understanding of the genetic and nongenetic molecular alterations associated with anti–epidermal growth factor receptor (EGFR) therapy resistance in colorectal cancer (CRC) has markedly expanded in recent years. Mutations in RAS genes ( KRAS/ NRAS exons 2, 3, or 4) predict a lack of clinical benefit when anti-EGFR monoclonal antibodies (mAbs) are added to chemotherapy. Genetic events in additional nodes of the mitogen-activated protein kinase (MAPK)–phosphoinositide 3-kinase (PI3K) pathways that bypass EGFR signaling, such as BRAF or PIK3CA mutations or KRAS, ERBB2, or MET amplifications, also may confer resistance to cetuximab or panitumumab. Polymorphisms that block antibody binding as a result of EGFR extracellular domain mutations have been reported. Nongenetic mechanisms, including compensatory activation of receptor tyrosine kinases HER3 and MET, together with high expression of the ligands amphiregulin, transforming growth factor alpha heregulin, and hepatocyte growth factor in the tumor microenvironment also are thought to be involved in resistance. In one-third of the samples, more than one genetic event can be found, and nongenetic events most likely coexist with gene alterations. Furthermore, activation of a gene expression signature of epithelial-mesenchymal transition has been associated with reduced cellular dependence on EGFR signaling. Collectively, this body of work provides convincing evidence that the molecular heterogeneity of CRC plays an important role in the context of resistance to anti-EGFR therapy. Herein, we discuss how this knowledge has been translated into drug development strategies to overcome primary and acquired anti-EGFR resistance, with rational combinations of targeted agents in genomically selected populations, second-generation EGFR inhibitors, and other agents expected to boost the immune response at the tumor site.
Resistance to Anti-HER2 Therapies in Breast Cancer
Authors: Rimawi Mothaffar F. , De Angelis Carmine , Schiff Rachel
Published: May 2015

HER2 is amplified or overexpressed in 20% to 25% of breast cancers. HER2 is a redundant, robust, and powerful signaling pathway that represents an attractive therapeutic target. Anti-HER2 therapy in the clinic has resulted in significant improvements in patient outcomes and, in recent years, combinations of anti-HER2 therapies have been explored and carry great promise. However, treatment resistance remains a problem. Resistance can be mediated, among others, by pathway redundancy, reactivation, or the utilization of escape pathways. Understanding mechanisms of resistance can lead to better therapeutic strategies to overcome resistance and optimize outcomes.
Treatment of Peritoneal Carcinomatosis of Colorectal Origin
Authors: Cercek Andrea , James C. Jr  , Ryan David P.
Published: May 2015

The management of peritoneal carcinomatosis from colon cancer remains a controversial issue. Peritoneal carcinomatosis is associated with worse survival and has led to an aggressive treatment that combines surgery and intraperitoneal chemotherapy (IPC). This review will describe the rationale behind this treatment and the current controversy surrounding it.
Germ Cell Tumors: Looking to the Future
Authors: Bosl George J.
Published: May 2015

Our knowledge about the management of men with germ cell tumors (GCTs) and its tumor biology continues to evolve. Vascular disease, metabolic syndrome, second malignant neoplasms, and hypogonadism occur after treatment for GCTs and the latency pattern resembles that seen in patients treated for Hodgkin lymphoma. Patients receiving treatment for GCTs should be informed not only of the near-term toxicity (experienced during or shortly after administration), but also the delayed and late effects of chemotherapy and the need for lifelong surveillance for all late outcomes, including late relapse. Recent data suggest that the treatment outcome of patients with intermediate-risk, poor-risk, and relapsed GCTs can be improved through multicenter trials that include the general oncology community. Finally, GCTs are a malignancy of primordial germ cells. Programmed differentiation is clinically evident in vivo and probably related to chemotherapy resistance. This biology has much clinical relevance, some of which is already in use.
Radium 223: How Can We Optimize This New Tool for Metastatic Castration-Resistant Prostate Cancer?
Authors: Dorff Tanya Barauskas , Gross Mitchell E.
Published: May 2015

Radium 223 is an alpha-emitting intravenous radiotherapy approved for the treatment of men with metastatic castration-resistant prostate cancer (mCRPC). The approved indication covers men with pain from bony metastatic disease and no visceral involvement; however, questions remain as to optimal patient selection and timing of this treatment relative to other life-extending therapies for mCRPC. Limited data exist to guide clinicians on how to position radium 223 in the therapeutic sequence, however, some theoretical considerations and data derived from the ALSYMPCA trial populations pre- and postdocetaxel will be outlined. Subgroup analyses may provide some insight into patient selection.
Evolving Immunotherapy Strategies in Urothelial Cancer
Authors: Brancato Sam J. , Lewi Keidren , Agarwal Piyush K.
Published: May 2015

The treatment of nonmuscle-invasive urothelial carcinoma with bacillus Calmette-Guérin (BCG) represents the importance of immunotherapy in the treatment of cancer. Despite its clinical efficacy, up to 30% of patients will ultimately experience progression to muscle-invasive disease. This, along with an improved understanding of the biologic pathways involved, has led to efforts to improve, enhance, or alter the immune response in the treatment of urothelial carcinoma. A number of novel therapeutic approaches currently are being pursued, including recombinant BCG to induce T helper type 1 (Th1) immune responses, nonlive Mycobacterium agents, targeted agents toward cancer-associated antigens, immune-modulating vaccines, and adoptive T-cell therapies. Here, we review the current and future immunotherapy treatment options for patients with urothelial cancer.
Epithelial Ovarian Cancer in Older Women: Defining the Best Management Approach
Authors: Duska Linda R. , Tew William P. , Moore Kathleen N.
Published: May 2015

Epithelial ovarian cancer is a cancer of older women. In fact, almost half of women diagnosed with ovarian cancer will be older than age 64, and 25% will be older than age 74. Therefore, it is crucial to examine the available data in older populations to optimize the therapeutic approach without negatively affecting the quality of life permanently. Unfortunately, little prospective data are available in this under-represented population of women. Although ovarian cancer traditionally has been approached with aggressive cytoreductive surgery, older patients may benefit from a less aggressive surgical approach and, in some cases, may be candidates for neoadjuvant chemotherapy followed by an interval cytoreduction. Modalities do exist for assessing an older woman's ability to tolerate surgery and chemotherapy, and these tools should be familiar to clinicians who are caring for this population of women in making treatment decisions. Ongoing planned trials to evaluate pretreatment assessment for older patients will provide objective, feasible, clinical tools for applying our treatment-based knowledge. Future trials of both surgery and chemotherapy, including a focus on the sequence of these two treatment modalities, are crucial to guide decision making in this vulnerable population and to improve outcomes for all.
Research Progress in Head and Neck Squamous Cell Carcinoma: Best Abstracts of ICHNO 2015
Authors: Economopoulou Panagiota , Bourhis Jean , Psyrri Amanda
Published: May 2015

Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous group of tumors that develop via one of the two primary carcinogenic pathways: chemical carcinogenesis through exposure to tobacco and alcohol or virally induced tumorigenesis. HPV-negative (HPV–) and HPV-positive (HPV+) HNSCCs represent distinct disease entities, and the latter is associated with a substantially improved outcome. Differences in molecular pathogenesis account for these different outcomes; their staging classification and therapeutic regimens also are currently being re-evaluated, and re-evaluation would be significantly facilitated by robust biomarkers for patient stratification. Through the past years, with the advent of the omics era, a better understanding of the biology of HNSCC has been accompanied by the exploration of a large and rapidly expanding number of targeted agents, which might be incorporated into standard management in the future. In the era of personalized medicine, and with a view to improve the outcomes and quality of life of patients, current research efforts also are focused on the identification of specific biomarkers for treatment selection. Treatment of HNSCC is expected to change in the next decade if molecular biology continues to evolve. Herein, we highlight research progress in HNSCC presented at the fifth International Conference on Innovative Approaches in Head and Neck Oncology (ICHNO).
Comparative Effectiveness Research in Cancer with Observational Data
Authors: Giordano Sharon H.
Published: May 2015

Observational studies are increasingly being used for comparative effectiveness research. These studies can have the greatest impact when randomized trials are not feasible or when randomized studies have not included the population or outcomes of interest. However, careful attention must be paid to study design to minimize the likelihood of selection biases. Analytic techniques, such as multivariable regression modeling, propensity score analysis, and instrumental variable analysis, also can also be used to help address confounding. Oncology has many existing large and clinically rich observational databases that can be used for comparative effectiveness research. With careful study design, observational studies can produce valid results to assess the benefits and harms of a treatment or intervention in representative real-world populations.
Cancer Care Quality: Current State and Future Directions
Authors: Shulman Lawrence N.
Published: May 2015

Delivery of high-quality medicine is essential in all fields, but it is particularly crucial in cancer medicine in which therapies can be toxic and life-threatening and appropriate treatment can lead to long-term remissions or cure, and when poor therapy compromises survival. Variability in postoperative mortality has been demonstrated for several complex cancer surgeries, depending on surgical expertise and volumes. Systemic therapy, including both cytotoxic and targeted therapies (which are the backbones of many curative regimens), can have severe toxicities. Small upward errors in dosing or schedule can result in unnecessary morbidity and mortality, and they can result in reduced efficacy and poor outcomes. Similarly, radiation therapy is a critical modality in the treatment of so many cancers, but clinically important morbidity and mortality can be associated with it. Methods to continually assess quality in ways that lead to interventions to improve care are essential in cancer medicine today, and they can be viewed as an obligation of our profession.
New Targeted Therapies for Indolent B-Cell Malignancies in Older Patients
Authors: Krem Maxwell M. , Gopal Ajay K.
Published: May 2015

Molecularly targeted agents have become an established component of the treatment of indolent B-cell malignancies (iNHL). iNHL disproportionately affects older adults, so treatments that have excellent tolerability and efficacy across multiple lines of therapy are in demand. The numbers and classes of targeted therapies for iNHL have proliferated rapidly in recent years; classes of agents that show promise for older patients with iNHL include anti-CD20 antibodies, phosphatidyl-3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway inhibitors, immunomodulators, proteasome inhibitors, epigenetic modulators, and immunotherapies. Here, we review the proposed mechanisms of action, efficacy, and tolerability of novel agents for iNHL, with an emphasis on their applicability to older patients.
Current Therapies and Their Indications for the Philadelphia-Negative Myeloproliferative Neoplasms
Authors: Kiladjian Jean-Jacques
Published: May 2015

The groundbreaking discovery of the Janus-associated kinase 2 (JAK2) V617F mutation 10 years ago resulted in an unprecedented intensive basic and clinical research in Philadelphia-negative myeloproliferative neoplasms (MPNs). During these years, many new potential targets for therapy were identified that opened the era of targeted therapy for these diseases. However, only one new drug (ruxolitinib) has been approved during the past 40 years, and, although promising new therapies are evaluated, the armamentarium to treat MPN still relies on conventional drugs, like cytotoxic agents and anagrelide. The exact role of interferon (IFN) alfa still needs to be clarified in randomized studies, although it has been shown to be effective in MPNs for more than 25 years. The current therapeutic strategy for MPNs is based on the risk of vascular complication, which is the main cause of mortality and mortality in the medium term. However, the long-term outcome may be different, with an increasing risk of transformation to myelodysplastic syndrome or acute leukemia during follow-up times. Medicines able to change this natural history have not been clearly identified yet, and allogeneic stem cell transplantation currently remains the unique curative approach, which is only justified for patients with high-risk myelofibrosis or for patients with MPNs that have transformed to myelodysplasia or acute leukemia.
Beyond “Second-Line” in Non–Small Cell Lung Cancer: Therapy and Supportive Care
Authors: Martins Renato G. , Reynolds Craig H. , Riely Gregory J.
Published: May 2015

Although there once was a single algorithm for the treatment of patients with advanced lung cancer, the modern treatment of advanced lung cancer has multiple treatment pathways that depend on multiple factors, including histology and molecular subtype of disease. New molecular targets, targeted agents, and modes of therapy for patients, including immunotherapy, are being identified at an accelerating pace. These advances are changing outcomes and the treatment landscape, but they also highlight situations with inadequate data to support the use of cytotoxic chemotherapy. In this article, we provide an overview of data regarding cytotoxic chemotherapy and targeted therapy and their value after second line, review the critical role of supportive care and palliative care, and emphasize the importance of advance care planning with our patients. Although this article focuses primarily on NSCLC, the comments about palliative care and advanced care planning also apply to patients with small cell lung cancer.
The Latest in Surgical Management of Stage IIIA Non–Small Cell Lung Cancer: Video-Assisted Thoracic Surgery and Tumor Molecular Profiling
Authors: Woodard Gavitt A. , Jablons David M.
Published: May 2015

Stage IIIA non–small cell lung cancer (NSCLC) remains a treatment challenge and requires a multidisciplinary care team to optimize survival outcomes. Thoracic surgeons play an important role in selecting operative candidates and assisting with pathologic mediastinal staging via cervical mediastinoscopy, endobronchial ultrasound, or esophageal ultrasound with fine needle aspiration. The majority of patients with stage IIIA disease will receive induction therapy followed by repeat staging before undergoing lobectomy or pneumonectomy; occasionally, a patient with an incidentally found, single-station microscopic IIIA tumor will undergo resection as the primary initial therapy. Multiple large clinical trials, including SWOG-8805, EORTC-8941, INT-0139, and ANITA, have shown 5-year overall survival rates of up to 30% to 40% using triple-modality treatments, and the best outcomes repeatedly are seen among patients who respond to induction treatment or who have tumors amenable to lobectomy instead of pneumonectomy. The need for a pneumonectomy is not a reason to deny patients an operation, because current operative mortality and morbidity rates are acceptably low at 5% and 30%, respectively. In select patients with stage IIIA disease, video-assisted thoracic surgery and open resections have been shown to have comparable rates of local recurrence and long-term survival. New developments in genetic profiling and personalized medicine are exciting areas of research, and early data suggest that molecular profiling of stage IIIA NSCLC tumors can accurately stratify patients by risk within this stage and predict survival outcomes. Future advances in treating stage IIIA disease will involve developing better systemic therapies and customizing treatment plans on the basis of an individual tumor's genetic profile.
Chemotherapy-Induced Peripheral Neurotoxicity in Cancer Survivors: An Underdiagnosed Clinical Entity?
Authors: Cavaletti Guido , Alberti Paola , Marmiroli Paola
Published: May 2015

Systemic chemotherapy is a cornerstone of the modern medical management of cancer, although its use is limited by toxicity on normal tissues and organs, including the nervous system. Long-surviving or cured people strongly require a high level of wellness in addition to prolongation of life (the concept of the quality of survival), but neurologic dysfunction can severely affect daily life activities. Chemotherapy-related peripheral neurotoxicity is becoming one of the most worrisome long-term side effects in patients affected by a neoplasm. The central nervous system has a limited capacity to recover from injuries, and it is not surprising that severe damage can determine long-term or permanent neurologic dysfunction. However, the peripheral nervous system also can be permanently damaged by anticancer treatments despite its better regeneration capacities, and the effect on patients' daily life activities might be extremely severe. However, only recently, the paradigms of peripheral neurotoxicity reversibility have been scientifically challenged, and studies have been performed to capture the patients' perspectives on this issue and to measure the effect of peripheral neurotoxicity on their daily life activities. Despite these efforts, knowledge about this problem is still largely incomplete, and further studies are necessary to clarify the several still-unsettled aspects of long-term peripheral neurotoxicity of conventional and targeted anticancer chemotherapy.