bluuebunny/crossref_metadata_2025 huggingface dataset:
Cancer incidence and risk factors in dialysis patients with human immunodeficiency virus: a cohort study
Authors: Patel Mihir , Waller Jennifer L , Baer Stephanie L , Spearman Vanessa , Kheda Mufaddal , Young Lufei , Nahman Stan , Colombo Rhonda E
Published: December 2019

Background

Patients with human immunodeficiency virus (HIV) or end-stage renal disease receiving dialysis have an increased risk of developing malignancies, but few data are available on cancer in patients with both conditions. Thus, the objective of this study was to determine the incidence of selected malignancies and identify their potential risk factors in HIV-infected dialysis patients.

Methods

This study was a nationwide cohort analysis using the US Renal Data System. Participants included all HIV-infected patients starting dialysis from 2005 to 2011. HIV status, comorbidities and malignancies were identified using International Classification of Diseases, Ninth Revision codes. Descriptive statistics and generalized linear models quantifying risk factors were performed for the overall cohort and the three most common malignancies.

Results

Overall, 6641 HIV-infected dialysis patients were identified, with 543 (8.2%) carrying a malignancy diagnosis. The most common malignancies were non-Hodgkin’s lymphoma (NHL, 25%), Kaposi sarcoma (KS, 16%) and colorectal cancer (13%). Factors increasing the risk of any malignancy diagnosis included: history of cancer [adjusted relative risk (aRR) = 5.37], two or more acquired immunodeficiency syndrome-defining opportunistic infections (ADOIs) (aRR = 3.11), one ADOI (aRR = 2.23), cirrhosis (aRR = 2.20), male sex (aRR = 1.54) and hepatitis B (aRR = 1.52). For NHL and colorectal cancer, history of cancer (aRR = 7.05 and 9.80, respectively) was the most significant risk factor. For KS, two or more ADOIs (aRR = 6.78) was the largest risk factor.

Conclusions

Over 8% of HIV-infected dialysis patients developed a malignancy. History of cancer and ADOIs were major risk factors, underscoring the significance of immune dysregulation in malignancy development.
Meso-tartrate inhibits intracellular replication of Coxiella burnetii, the causative agent of the zoonotic disease Q fever
Authors: Bitew Mebratu A , Wawegama Nadeeka K , Newton Hayley J , Sansom Fiona M
Published: December 2019

The zoonotic disease Q fever caused by the intracellular bacterium Coxiella burnetii remains a global health threat due to its high infectivity, environmental stability, the debilitating nature and the long duration of treatment. Designing new and potent drugs that target previously unexplored pathways is essential to shorten treatment time and minimise antibiotic resistance. Nicotinamide adenine dinucleotide (NAD) is an essential and ubiquitous cofactor in all living organisms. NadB, an L-aspartate oxidase catalysing the first step of the prokaryotic-specific NAD de novo biosynthetic pathway, is required for C. burnetii growth and replication inside host cells. In this study, in vitro enzyme assays utilising recombinant glutathione S-transferase tagged NadB (GST-NadB) demonstrated inhibition of the L-aspartate oxidase activity of NadB by meso-tartrate. Furthermore, meso-tartrate inhibits intracellular growth and replication of C. burnetii inside host cells in a dose-dependent manner, and has no effect on the viability of mammalian cells. Unexpectedly, meso-tartrate also inhibited growth of C. burnetii in axenic medium, and further reduces replication of the nadB mutant inside host cells, suggesting it is acting more widely than simple inhibition of NadB. Overall, these results suggest that the antibacterial activity of meso-tartrate warrants further study, including investigation of its additional target(s).
Using a custom mobile application for change management in an electronic health record implementation
Authors: Threatt Tony , Pirtle Claude J , Dzwonkowski Jennifer , Johnson Kevin B
Published: December 2019

Objectives

Institutions cite managing the modification in infrastructure, technical support, and process change as substantial barriers to a successful electronic health record (EHR) implementation. In an effort to organize and centralize the complex scheduling, task completion and communication needs of a “big-bang” EHR go-live, we developed a unified communication system with the goal of improving implementation process efficiency. Our goal was to create a platform that would work across the medical enterprise.

Materials and Methods

We employed an agile process to design the application, called Hubbl, based on initial requirements and iteratively obtained stakeholder user. The final feature set included role-specific organization, integrated communication, task and content management tooling, and embedded project information retrieval, all embedded into the end user’s day to day activities.

Results

User enrollment continually increased from launch in February of 2017 through go-live day. During the pre-go-live period, usage increased from an average of 7.37 events/user/day to 18.65 events/user/day with over 97 communications sent across all periods. 5400 unique users accessed tip sheets and information retrieval tools averaged 28.84 searches/user/day during the go-live period with an average high of 46.33 searches/user/day 5 days post-go-live. User access during go-live and post-go-live averaged 12.82 accesses/user/day and decreased from 20.42 average accesses on day one of go live to 14.07 averaged accesses on day 60 of post-go-live with over 727 tasks monitored to completion during all periods.

Conclusion

Hubbl was an essential component of our communication, task coordination, and change management strategy, for our EHR go live. Institutions that choose a unified mobile and web-based platform during a substantial IT (information technology) implementation can feasibly ensure task completion, project coordination, and timely information dissemination.
Why Won’t You Answer the Question? Mass-Mediated Deception Detection After Journalists’ Accusations of Politicians’ Evasion
Authors: Clementson David E
Published: December 2019

Journalists often accuse politicians of dodging questions. Truth-default theory (TDT) predicts that when journalists serve as de facto deception detectors, the audience will process the messaging through a cognitive sequence that lowers the perceived trustworthiness of the politician. Conversely, the public’s perception of the media as being generally hostile and biased in their reporting could make a journalist’s allegation of evasion enhance the politician’s credibility. We constructed political TV interviews in which a journalist falsely accused a politician of evasiveness. Consistent with serial multiple mediation as proposed by TDT, in Study 1 (N = 210 U.S. voters) a journalist’s allegation triggered suspicion, which increased perceived dodging, resulting in voters distrusting the politician. Absent a journalist’s allegation, however, people remained in their truth-default state toward the politician. Study 2 (N = 429) replicated the Study 1 results, and conditional process modeling revealed that the effect was moderated by rumination.
Association mapping and genetic dissection of drought-induced canopy temperature differences in rice
Authors: Melandri Giovanni , Prashar Ankush , McCouch Susan R , van der Linden Gerard , Jones Hamlyn G , Kadam Niteen , Jagadish Krishna , Bouwmeester Harro , Ruyter-Spira Carolien
Published: December 2019

Drought-stressed plants display reduced stomatal conductance, which results in increased leaf temperature by limiting transpiration. In this study, thermal imaging was used to quantify the differences in canopy temperature under drought in a rice diversity panel consisting of 293 indica accessions. The population was grown under paddy field conditions and drought stress was imposed for 2 weeks at flowering. The canopy temperature of the accessions during stress negatively correlated with grain yield (r= –0.48) and positively with plant height (r=0.56). Temperature values were used to perform a genome-wide association (GWA) analysis using a 45K single nucleotide polynmorphism (SNP) map. A quantitative trait locus (QTL) for canopy temperature under drought was detected on chromosome 3 and fine-mapped using a high-density imputed SNP map. The candidate genes underlying the QTL point towards differences in the regulation of guard cell solute intake for stomatal opening as the possible source of temperature variation. Genetic variation for the significant markers of the QTL was present only within the tall, low-yielding landraces adapted to drought-prone environments. The absence of variation in the shorter genotypes, which showed lower leaf temperature and higher grain yield, suggests that breeding for high grain yield in rice under paddy conditions has reduced genetic variation for stomatal response under drought.
Frailty: Assessment and Associations with Outcomes
Authors: Dunlay Shannon M.
Published: December 2019

Frailty is a syndrome of decreased physiological reserve in response to stressors, which increases the vulnerability to adverse health outcomes. Although there is no standard reference test for detecting frailty before left ventricular assist device (LVAD) implantation, several screening tools can be helpful. Numerous studies have found that frailty is often present in patients scheduled to receive LVADs and is associated with longer and more complicated post-implant hospitalizations and worse long-term mortality. Contemporary data suggest that frailty is at least partially reversible with LVAD therapy in some individuals. New therapeutic strategies to improve or reverse frailty in patients receiving LVADs are needed.
The HeartWare™ HVAD™ Left Ventricular Assist Device
Authors: Hiivala Nicholas , Vassiliades Thomas
Published: December 2019

The HeartWareTM HVADTM System is an intrapericardial continuous-flow left-ventricular assist device with a centrifugal pump design capable of providing full cardiac support in patients with end-stage systolic heart failure. The inflow to the pump is inserted into the left ventricular apex and moves blood to the ascending aorta via a 10mm outflow graft and is most frequently implanted via a median sternotomy. The system is controlled by an external microprocessor unit that connects transcutaneously to the pump by way of a thin, flexible driveline and is powered by Li-ion batteries or AC/DC power. The HVAD was first implanted in man in 2006 and was subsequently approved for use in Europe in 2009 (CE Mark trial), for bridge to transplant in the United States in 2012 (ADVANCE trial), destination therapy in the United States in 2017 (ENDURANCE and ENDURANCE Supplemental trials), and implantation via a thoracotomy approach in the United States in 2018 (LATERAL trial).
Abiomed Impella Platform
Authors: Annamalai Shiva K. , Chennojwala Aditya , Foroutanjazi Sina , Karmiy Samuel J. , Razavi Allen A. , Kapur Navin K.
Published: December 2019

The Abiomed Impella platform consists of four percutaneous trans-valvular micro axial-flow acute mechanical circulatory support (AMCS) devices that provide either left or right hemodynamic support for indications of high-risk coronary intervention or cardiogenic shock. The Impella family includes: Impella 2.5, Impella CP, Impella 5.0, and Impella RP. The Impella 2.5, CP, and RP are percutaneously delivered, while Impella 5.0 requires a surgical cut-down. Like all continuous flow pumps, the fundamental principle governing the hemodynamic effect of Impella devices can be explained using the pressure head-flow (H-Q) curve where flow is directly related to rotations per minute (rpm) of the impeller and indirectly related to pressure at the inlet and outlet of the impeller. These devices work to reduce pressures and volumes within the left or right ventricle, decreasing ventricular wall stress, unloading the heart and increasing circulatory support.
Extracorporeal Membrane Oxygenation
Authors: Bohman J. Kyle , Schears Gregory J.
Published: December 2019

This chapter examines the indications, applications, and complications of modern extracorporeal membrane oxygenation (ECMO). The safety profile of ECMO has improved through advancements in devices, components, and routine management, resulting in improved outcomes and an expanded range of applications. Currently, ECMO can provide cardiopulmonary support in reversible conditions, such as post-cardiotomy shock, acute respiratory failure, extracorporeal cardiopulmonary resuscitation, bridge to transplant, complex airway repairs, and massive pulmonary embolism, among others. The chapter focuses on the primary factors involved in using ECMO successfully: appropriate patient selection, optimal cannulation strategy, and availability of comprehensive medical resources (or a referral agreement with a comprehensive ECMO center) to handle emergent ECMO complications and to absorb the substantial resource requirements of treating patients with ECMO.
Postoperative Management after Assist Device Implantation
Authors: Brehm Christoph E.
Published: December 2019

Post-operative ICU management of the MCS patient represents one of the most complex challenges in the current health care environment. With increasing experience, improvements in this arena have led to dramatic improvements in the outcomes of these patients. In this chapter, we detail several of the post-operative challenges in the ICU including ventilator management, bleeding complications, hemodynamic optimization, arrhythmias, and CPR.
Gastrointestinal Bleeding in Patients with Left Ventricular Assist Devices
Authors: Kaushal Shivtej , Gaglianello Nunzio
Published: December 2019

Continuous-flow, left ventricular assist devices (CF-LVADs) offer multiple advantages over older, pulsatile left ventricular assist devices (PF-LVADs). However, the reported rate of gastrointestinal bleeding (GIB) for CF-LVADs is between 18% and 40%, which is two to four times higher than the GIB rate for PF-LVADs. Proposed pathophysiological mechanisms include the mechanics of continuous flow, abnormal platelet aggregation, and the need for therapeutic anticoagulation. Treatment can be challenging in these patients but should always be systematic and mainly involves endoscopic and medical therapy. Over the past decade, advances in both of these areas have allowed practioners to stabilize and treat these patients effectively. Given the advances in these therapies, GIB has become a manageable condition in these otherwise complex patients.
The VAD Coordinator Roles and Responsibilities in Caring for Patients with Ventricular Assist Devices
Authors: Butzler Brittany , Kiehl Kristen
Published: December 2019

An essential part of any mechanical circulatory support (MCS) program is a coordinator with an extensive knowledge of ventricular-assist devices (VAD) from a technical, clinical, and systems perspective. The VAD coordinator is the patient’s clinical liaison for the duration of MCS, from evaluation to transplant or death. These coordinators have various educational backgrounds and can have a wide variety of tasks and responsibilities. This chapter describes the primary activities and responsibilities of the VAD coordinator during each phase of MCS support, as well as other responsibilities related to troubleshooting, staff education, and tracking and maintaining VAD equipment.
Parenting in the context of chronic pain
Authors: Jordan Abbie , Jaaniste Tiina
Published: December 2019

Being a parent is rewarding, challenging, and life-changing. Parenting a child or adolescent with chronic pain poses additional, unique challenges. We present a comprehensive overview of the wide-ranging impact of paediatric chronic pain on parents and a detailed consideration of how parents respond to their child’s pain. Potential explanations for parental responses to their child’s pain are considered, including attachment, resilience, and risk factors in the context of parenting a young person with chronic pain. We review particular challenges faced by parents who themselves live with chronic pain, regarding their ability to engage with normative parenting tasks. The importance of considering the bi-directional relationship between parental and child functioning is highlighted, in addition to issues pertaining to parental involvement in paediatric chronic pain interventions. Directions for research are provided, acknowledging the importance of adopting longitudinal and dyadic perspectives in future parenting research within the chronic pain context.
Managing pain-related limitations in the workplace: The role of the employer
Authors: Main Chris J. , Shaw William S.
Published: December 2019

The main focus of this chapter is on pain-related work limitations (PWL), and in particular on the role of the employer and the challenges of implementing change in an occupational environment often focused sharply on profit and the avoidance of litigation. It will be argued that full and appropriate engagement in a healthy and motivated workforce is in everyone’s interests, although changes in the types of work, in working conditions, and in increasingly diverse work practices, represent real challenges in the design of interventions and their implementation in practice. In this chapter we begin with a description and attempted quantification of the burden of PWL. We then offer a review of the major organizational processes, the influence of management structures and prognostic factors before considering workplace interventions, and the influence of health/social policy. We conclude with a series of recommendations for an integrated approach to the management of PWL.
Pain, employment, and policy
Authors: Bevan Stephen
Published: December 2019

As we have seen, the invisibility of pain can make it very difficult for those living with it to get recognition, support, and treatment. This is not just a challenge in workplace or clinical settings, however. Chronic and work-limiting pain in the working age population can also find itself in a policy blind spot, falling between often competing policy ‘silos’ for attention, resources and—perhaps most crucially—joined up and coordinated action. In this chapter we look at the policy landscape within which those living and working with pain are often having to vie for these resources. We will look at some of the policy ‘levers’ and incentives which might be used to improve both clinical and work outcomes for those living with pain, and we will look at some international examples of initiatives which offer some hope that practical solutions can be found.
Discussion
Authors: Wainwright Elaine , Eccleston Christopher
Published: December 2019

Pain takes a significant toll on individuals, on families, and on society. In part that damage is mediated by the loss of occupation, and the unwelcome distortion of roles, of financial capability, and of purpose. We judged that the effects of work on pain, and equally of pain on work, are becoming invisible. There is too little serious academic study on what are major drivers of modern society and well-being. This book draws together leaders in their field to teach us how we can re-conceptualize our response to the current challenges in the field of pain and work. Our final chapter comprises a conceptual and analytical map of the forces of change in work, occupation, and pain management. We use this to suggest directions for research and policy and how we can innovate, as we find better solutions for managing one of the most significant health burdens of our age.
The Role of Guidelines in Breast Cancer Management in Different Resource Settings
Authors: Duggan Catherine , Eniu Alexandru , Anderson Benjamin O.
Published: December 2019

Abstract: Clinical Practice Guidelines (CPGs) translate evidence-based research into methodological standards. A variety of CPGs have been developed to guide management of breast cancer to optimize patient care. Adherence to existing guidelines in high-income countries (HICs) is associated with improved patient outcomes. However, these guidelines were developed for use in high-resource settings and assume high rates of healthcare spending and timely access to effective diagnostic and treatment modalities. There exist significant barriers to their implementation in low- and middle-income countries (LMICs). The Breast Health Global Initiative (BHGI), via a series of collaborative Global Summits from 2002 to 2013, developed a resource-stratified framework to guide all aspects of breast cancer control across all resource settings. The chapter describes CPG development, their impact on patient outcomes, and barriers to their uptake both in HICs and LMICs. It also describes BHGI resource-stratified guidelines and future directions to develop and assess implementation of these guidelines in resource-constrained settings.
The Status of Breast Pathology around the Globe
Authors: Masood Shahla , Salgado Roberto , Regitnig Peter , Pauwels Rudi
Published: December 2019

Abstract: Breast cancer has received remarkable attention at the global level, and as a result, substantial progress has been made over the past several years in the diagnosis and management of this disease. Emphasis on breast cancer screening and advances in breast imaging have led to increased early breast cancer detection. Minimally invasive sampling procedures such as fine needle aspiration biopsy and core needle biopsy have almost replaced open surgical biopsy. Breast conserving therapy and sentinel lymph node biopsy have become attractive alternatives to mastectomy and total axillary dissection. Advances in molecular diagnostics and targeted therapies have opened more effective options for individualised breast cancer therapy. In addition, discovery of breast cancer genes and recognition of breast cancer risk factors have provided opportunities for introducing various risk reduction modalities. Similarly, enhanced public awareness and the efforts of patient advocates have resulted in increased funding for breast cancer research. More importantly, integrated breast cancer care via a multidisciplinary approach has provided the foundation for the establishment of breast centres around the globe. The above-mentioned efforts have been complemented by the role that pathologists have played in the realization of these advancements. Pathologists have been central in the development, validation, implementation, and appropriateness of providing diagnostic and predictive/prognostic information. Throughout the years, pathologists have evolved from being a morphologist into becoming clinicians/scientists with in-depth understanding of integrated breast cancer care, research, and education. Currently, pathologists make the ultimate determination about the nature of a disease and help design the course of therapy for individualized patients.
Genetics
Authors: Schmidt Marjanka K , van den Broek Alexandra J. , Robson Mark E. , Campanella Ornella , Teo Soo Hwang , Andrulis Irene L. , Bleiker Eveline M. , Menko Fred H.
Published: December 2019

Abstract: About 10–30% of breast cancers are estimated to be explained by known (mostly modifiable) lifestyle and environmental factors; this is population dependent. Another 20–30% of breast cancers can be explained by germline genetics. For women with pathogenic BRCA1 and BRCA2 mutations, the risk of developing breast cancer is estimated to be between 27% and 80% by age 70 years, compared to a 4–12% lifetime risk for the general female population worldwide. Pathogenic mutations in BRCA1 increase risk for ovarian cancer as well as for a range of other tumours. After genetic testing, the gene mutation status can be used for cancer risk prediction in affected and healthy individuals. But even when no pathogenic variant in an established breast cancer gene is detected, persons can still be at increased risk of breast cancer due to a mutation in a gene that was not tested, or more likely, a probably polygenic, heritable component that is not (yet) known. With all the technical advances that have been made in sequencing in recent years, gene panel testing has been developed, enabling testing for mutations, simultaneously, in a set of multiple genes. Currently, genetic testing and breast cancer risk prediction is mainly done for high-risk individuals and families in the clinical genetic setting. However, the infrastructures for implementation of population-based genetic testing are under development.
Assessing Costs and Value for Money
Authors: Joore Manuela , Pouwels Xavier , Ramaekers Bram
Published: December 2019

Abstract: This chapter focuses on the economics of breast cancer care, describing the substantial and rising costs of breast cancer care due to increasing patient numbers and increasing costs of novel therapies. This is a major concern for stakeholders on different levels: health care providers and managers, health care insurers, and government. To assist these stakeholders in making decisions to secure the quality of breast cancer care while costs are rising and budgets are under pressure, several health economic analysis methods are available. These methods (cost-off-illness study, budget-impact analysis, and economic evaluation) provide information on the economic burden of breast cancer and the affordability and efficiency of breast cancer care, and are briefly described, while suggestions for further reading are provided.
The Economic Impact of Breast Cancer in the South-East Asian Region
Authors: Kimman Merel , Peters Sanne , Jan Stephen , Bhoo-Pathy Nirmala , Yip Cheng Har , Joore Manuela , Woodward Mark
Published: December 2019

Abstract: In many parts of the world, are not only the economic consequences of breast cancer a burden to society, but also patients and their families directly endure financial hardship after a breast cancer diagnosis. This chapter examines the economic consequences of breast cancer for patients and families in a low- and middle income setting. Results of a study on financial catastrophe and mortality after breast cancer diagnosis, conducted in several countries in South-East Asia, are described.
European Perspective
Authors: Wierinck Lieve , Baelus Benjamin , Hoogland Emilie , Lerda Donata , Mansel Robert , Kaufman Cary , Travado Luzia
Published: December 2019

Abstract: Cancer is a major health concern in the EU. Currently, it is the second largest cause of death in Europe, and, due to the rapidly ageing population, its prevalence is increasing. Cancer is expected to affect one in two people in the future. Given this significant impact on society, policymakers at both the European and national levels have devoted much attention to the battle against cancer. It should be noted, however, that the EU’s leverage within health policy is limited to complementing national policies through coordination or information sharing. By providing a framework for cooperation between national entities, the EU promotes efficient research and development, propagates best practices regarding cancer prevention and treatment, encourages information exchange, and regulates the use of carcinogenic substances. It facilitates coordination and cooperation by bringing stakeholders together and harmonizing the cancer policy between member states. The European quality assurance scheme for breast cancer services (the ‘European QA scheme’) covers the entire pathway of care from screening to end-of-life care, and it is person-centred and evidence-based. The European QA scheme is being developed for European countries, but its use, implementation, and impact may extend beyond geographic boundaries.
Perspectives on the Governance and Management of Breast Care Services in the USA
Authors: Tucker F. Lee , Heckel Teresa
Published: December 2019

Abstract: Improving the quality, affordability and accessibility of breast care in the USA remains a high priority among health care leadership, the lay public, and those in elected office. The formulation of public policy in the USA, including federal and state legislation, is informed by a wide variety of public and private advisory and advocacy interests. Private-sector advocacy groups positively influence access, public awareness, and research prioritization. Evolving breast-specific clinical and administrative leadership models have facilitated an emerging management focus on quantifiable attributes of service, professional performance, clinical outcomes, and value. The diversity of breast care delivery environments in the USA adds considerable complexity to the task of improving value and access to care. With robust merger and affiliation activity among hospitals and clinics, health systems and alliances are evolving regionally and nationally to provide performance-based breast-centric management models across diverse populations and geographies.
Spectral characterization of the non-thermal X-ray emission of gamma-ray pulsars
Authors: Coti Zelati Francesco , Torres Diego F , Li Jian , Viganò Daniele
Published: December 2019

We report on a detailed spectral characterization of the non-thermal X-ray emission for a large sample of gamma-ray pulsars in the second Fermi Large Area Telescope catalogue. We outline the criteria adopted for the selection of our sample, its completeness, and critically describe different approaches to estimate the spectral shape and flux of pulsars. We perform a systematic modelling of the pulsars’ X-ray spectra using archival observations with XMM–Newton, Chandra, and NuSTAR and extract the corresponding non-thermal X-ray spectral distributions. This set of data is made available online and is useful to confront with predictions of theoretical models.
Chemical abundances of Seyfert 2 AGNs – I. Comparing oxygen abundances from distinct methods using SDSS
Authors: Dors O L , Freitas-Lemes P , Amôres E B , Pérez-Montero E , Cardaci M V , Hägele G F , Armah M , Krabbe A C , Faúndez-Abans M
Published: December 2019

We compare the oxygen abundance (O/H) of the narrow-line regions (NLRs) of Seyfert 2 AGNs obtained through strong-line methods and from direct measurements of the electron temperature (Te-method). The aim of this study is to explore the effects of the use of distinct methods on the range of metallicity and on the mass–metallicity relation of active galactic nuclei (AGNs) at low redshifts (z ≲ 0.4). We used the Sloan Digital Sky Survey (SDSS) and NASA/IPAC Extragalactic Database (NED) to selected optical (3000 < λ(Å) < 7000) emission line intensities of 463 confirmed Seyfert 2 AGNs. The oxygen abundances of the NLRs were estimated using the theoretical Storchi-Bergmann et al. calibrations, the semi-empirical N2O2 calibration, the Bayesian H  ii-Chi-mistry code and the Te-method. We found that the oxygen abundance estimations via the strong-line methods differ from each other up to ∼0.8 dex, with the largest discrepancies in the low-metallicity regime ($\rm 12+\log (O/H) \: \lesssim \: 8.5$). We confirmed that the Te-method underestimates the oxygen abundance in NLRs, producing unreal subsolar values. We did not find any correlation between the stellar mass of the host galaxies and the metallicity of their AGNs. This result is independent of the method used to estimate Z.
Long-term safety and efficacy of sodium zirconium cyclosilicate for hyperkalaemia in patients with mild/moderate versus severe/end-stage chronic kidney disease: comparative results from an open-label, Phase 3 study
Authors: Roger Simon D , Lavin Philip T , Lerma Edgar V , McCullough Peter A , Butler Javed , Spinowitz Bruce S , von Haehling Stephan , Kosiborod Mikhail , Zhao June , Fishbane Steven , Packham David K
Published: December 2019

Background

Sodium zirconium cyclosilicate (SZC; formerly ZS-9) is a selective potassium (K+) binder for the treatment of adults with hyperkalaemia. This post hoc analysis of an open-label, single-arm trial (NCT02163499) compared SZC efficacy and safety >12 months among outpatients with hyperkalaemia and Stages 4 and 5 chronic kidney disease (CKD) versus those with Stages 1–3 CKD.

Methods

Adults with serum K+ ≥5.1 mmol/L (measured by point-of-care i-STAT device) received SZC 10 g three times daily for 24–72 h until normokalaemia (i-STAT K+ 3.5–5.0 mmol/L) was achieved [correction phase (CP)], followed by once daily SZC 5 g for ≤12 months [maintenance phase (MP)]. Here, patients were stratified by baseline estimated glomerular filtration rate (eGFR <30 or ≥30 mL/min/1.73 m2). Study endpoints included percent achieving normokalaemia during CP and MP, mean serum K+ and bicarbonate during MP, and adverse events (AEs).

Results

Of 751 patients enrolled, 289 (39%), 453 (60%) and 9 (1%) had baseline eGFR values of <30, ≥30 mL/min/1.73 m2 or missing, respectively. During the CP, 82% of patients achieved normokalaemia in both eGFR subgroups within 24 h, and 100 and 95% with baseline eGFR <30 and ≥30 mL/min/1.73 m2, respectively, within 72 h. Corresponding proportions with normokalaemia during the MP were 82 and 90% at Day 365, respectively. Mean serum K+ reduction from baseline during the CP was sustained throughout the MP and serum bicarbonate increased. AEs during the MP were more common in the eGFR <30 ≥30 mL/min/1.73 m2 subgroup.

Conclusions

SZC corrects hyperkalaemia and maintains normokalaemia among outpatients regardless of the CKD stage.
LS1 PRACTICAL APPLICATION AND UNDERLYING BIOLOGY OF TUMOR TREATING FIELDS
Authors: Bota Daniela
Published: December 2019

Glioblastoma (GBM) is the most common and most aggressive form of brain cancer in adults. For decades, the mainstay of therapeutic intervention was based on surgical resection (when safely feasible), followed by radiotherapy (RT). In 2005, data from the landmark EORTC-NCIC trial changed the standard of care treatment for GBM. This phase III trial demonstrated a survival advantage for concomitant and adjuvant temozolomide (TMZ) chemotherapy when added to the standard course of radiation. In the group of patients assigned to radiation plus TMZ, median survival improved from 12.1 months (radiotherapy alone) to 14.6 months, but all the patient finally relapsed on TMZ. In 2015, Tumor Treating Fields (TTF, Optune) became the first FDA-approved device for the treatment of for newly diagnosed GBM. This approval was based on the EF-14 clinical trial results, in which nearly half of the patients treated with Optune in combination with maintenance temozolomide (TMZ) were alive at 2 years compared with 31% of people on TMZ alone.

Optune utilize the natural electrical properties of dividing cancer cells to disrupt mitosis and provide continuous antimitotic action against progression of GBM. TTF-treated tumor cells can exit the process of mitosis aberrantly and release cellular stress signals, such as the endoplasmic reticulum chaperonin calreticulin (CRT) and high mobility group box 1 protein (HMGB1). CRT is important to induce antitumor immune responses because CRT inhibition decreases immunogenicity. HMGB1, an endogenous chromatin-associated protein released from dying tumor cells, also plays a critical role in the activation of HMGB1-mediated toll-like receptor 2 (TLR2) immune signaling. The presence of those signals may facilitate immune activation, and immunogenic induced cell death, and eventually result in tumor destruction.

In this presentation, Daniela Bota, MD, PhD, will review the clinical results of Optune in the treatment of GBM, and will discuss the novel biological mechanisms underlying the effects of Optune in controlling tumor growth and promoting the immune responses in GBM.
LS2 METASTATIC BRAIN TUMORS / MENINGIOMAS: CURRENT CONCEPTS AND THERAPEUTIC PERSPECTIVES
Authors: Preusser Matthias
Published: December 2019

Non-glial brain tumors are the most common neoplasms affecting the central nervous system. Brain metastases are a heterogenous complication of systemic cancers. Recent research has provided insight into some important aspects of brain metastasis development, interaction of brain-metastatic tumor cells with resident cells of the CNS microenvironment and growth patterns within the brain parenchyma.Treatment choices have to consider clinical presentation, number, size and localisation of brain metastases, status of extracranial tumor burden, prior therapies, co-morbidities and histological and molecular tumor characteristics. Recent advances show that targeted therapies and immunotherapies have activity against established brain metastases and some targeted therapies are able to prevent brain metastasis development. Meningiomas are common and can be cured in 70–80% of cases by surgical resection. However, the rest of cases cannot be resected completey due to surgically inaccessibility (e.g. skull base) or show non-benign histopathological features that are associated with tumor recurrence. Meningiomas have been shown to be molecularly variable and carry distinct and reccurent genetic and epigenetic alterations that seem to enable targeted therapy and refined prognostication. Overall, significant advances in the biologcial understanding of brain metastases and meningiomas drive clinical trial design and improvement of clinical management strategies for these common tumors.
MS3-2 TREATMENT STRATEGY BASED ON THE RESULTS OF GENE PANELS
Authors: Takeda Masayuki
Published: December 2019

The advance of next-generation sequencers (NGS) has dramatically improved the performance of genomic analysis of clinical samples in cancer precision medicine. The practical use of gene panel testing for clinical applications has begun in Japan. At present, “OncomineTM Dx Target Test” is listed as a companion diagnostic system using NGS, and “FoundationOne CDx Cancer Genomic Profile” and “OncoGuide™ NCC Oncopanel System” are listed as gene panel testing under insurance coverage. Formalin-fixed paraffin-embedded specimen have been routinely used for molecular diagnosis testing, therefore quality control such as formalin fixation time and tumor contents is important to ensure validity of diagnostic results. In this presentation, the issue to obtain evaluable results of gene panel testing using formalin-fixed paraffin-embedded specimen will be discussed.

Due to evolution of detection technologies, we can detect gene mutation with high sensitivity. Detection of gene mutation in circulating tumor DNA is feasible approach for diagnostic testing in cancer treatment. Liquid biopsy has been approved as a companion diagnostic testing to detect EGFR mutations in NSCLC. Examples of the clinical utility of plasma testing in cancer treatment will be presented.
EL2 CHANGES IN JAPANESE ACADEMIC CLINICAL TRIALS AND FRAMEWORKS FOR PLANNING CLINICAL TRIALS
Authors: Nakamura Kenichi
Published: December 2019

After the enforcement of the Japanese Clinical Trials Act, the number of investigator-initiated registration-directed trials (IIRDT, Chiken) is increasing while the number of non-registration academic trials is decreasing. Pharmaceutical companies tend to make an investment in IIRDT because the data derived from IIRDT can be utilized for new drug application for PMDA, which means the goals and return are clear for industries. On the other hand, the reason of the decrease of non-registration academic trials is the burden of cost and procedures specified in the Clinical Trials Act. In order to start academic trials, certain amount of research budget is indispensable due to the cost for certified review board and clinical trial insurance. Also, even minor changes of site information in jRCT should be submitted to certified review board and the hospital directors of all participating sites, which is one of the most serious burden for investigators. Confirmation of COI declaration in participating sites is another burden for investigators/sites. Under these circumstances, the number of non-registration academic trials will be decreasing for the time being.

In the Clinical Trials Act era, investigators must prepare some budget to start clinical trials. In order to obtain public funding, social/scientific value and scientific validity are substantially important. To express the social value sufficiently, the purpose of the trial should focus not on the researcher’s interest but on the contribution for patients. In terms of scientific validity, the framework of PICO is useful; PICO means Patient, Intervention, Control and Outcome. Utilization of this framework and the consistency of these four factors are essential to make the trial design sound.
CBMS-08 INVESTIGATION FOR NICOTINIC EFFECTS ON STEM CELL’S PROPERTY IN HSV-TK/GCV GENE THERAPY
Authors: Kenmochi Hiroaki , Yamasaki Tomohiro , Oishi Tomoya , Horikawa Makoto , Yamamoto Taisuke , Koizumi Shinichiro , Sameshima Tetsuro , Namba Hiroki
Published: December 2019

BACKGROUND

Herpes simplex virus-thymidine kinase/ganciclovir (HSV-tk/GCV) system is one of feasible therapeutic strategies for defeating malignant gliomas. Stem cells with intrinsic tumor tropism are used for suicide gene vehicles, which make this therapy further realistic. Nicotine is known to affect cellular migration capacity in variety types of cells but whether nicotine impacts on stem cells’ migration capacity to gliomas is not scrutinized. In this research, we investigated nicotinic impact on stem cells’ properties including tumor tropism and gap junctional intercellular communication (GJIC), which is crucial to this therapeutic strategy.

METHODS

Mouse induced pluripotent stem cell (iPSC)-derived neural stem cells (miPS-NSCs) and human dental pulp mesenchymal stem cells (hDPSCs) were used. Nicotine cytotoxicity for 24 hours was evaluated by MTT assay for stem cells and glioma cells; GS-9L and C6 (rat), GL261 (mouse), U251 and U87 (human). Tumor tropism to glioma-conditioned medium (CM) with or without non-toxic nicotine concentrations was assessed using Matrigel Invasion Chamber. Nicotine effect on GJIC was assessed with scrape loading/dye transfer assay (SL/DT assay) for co-culture of stem cells and glioma cells (stem cell/glioma cell) or parachute assay for glioma cells alone using high-content analysis.

RESULTS

MTT assay revealed 1 μM of nicotine, equivalent to serum nicotine concentration in habitual smoking, is the maximum safe concentration for stem cells and glioma cells. Tumor tropism (miPS-NSCs to GL261-CM, hDPSCs to U251- or U87-CM) and GJIC of co-culture of stem cells and glioma cells (miPS-NSC/GL261, hDPSC/U251) or glioma cells alone (GS-9L, C6, GL261 and U251) were not affected by 1 μM of nicotine.

CONCLUSIONS

Physiological nicotine presence did not affect (1) stem cell’s tumor tropism to gliomas and (2) GJIC between stem cells and glioma cells or within glioma cells. HSV-tk/GCV therapy may retain its therapeutic efficacy against gliomas even under physiological nicotine concentrations.
CBMS-10 FUNCTIONAL ROLE OF MYCN IN SHH TYPE TP53 MUTATED MB’S METABOLISM
Authors: Yokogami Kiyotaka , Watanabe Takashi , Yamashita Shinji , Mizuguchi Asako , Takeshima Hideo
Published: December 2019

BACKGROUND

Medulloblastoma is classified in 4 subgroups. Prognosis and therapeutic option were different from each subgroups. Thus, we need subgroup-specific in vitro models for investigating new therapeutic targets. Little established medulloblastoma cell-lines, which have been subgrouped is available. Especially, commercially available SHH type TP53 mutated cell-line is only DAOY. We established new cell lines 505CSC / 507FBS from the patient with SHH type with TP53 mutated MB. This matched pair cell line showed high expression of MYCN in serum free conditioned medium. To know the functional role of N-MYC in MB, we used 507CSC and DAOY.

MATERIAL AND METHODS

Using chemical inhibitor of MYCN in 507CSC and DAOY, proliferation assay, mRNA expression and measurements of ex-vivo metabolic phenotype were performed.

RESULTS

MYCN inhibition leads to cell death in both cell lines. MYCN regulated glucose, glutamine and methionine metabolism. Especially the targets were PKM2, GLS2, MAT2A, DNMT1 and 3A.

CONCLUSION

MYCN is a target of therapy in a patient with SHH type TP53 mutated medulloblastoma.
CBMS-12 PENTAMIDINE; TRANSLATIONAL RESEARCH FOR A NEW CHEMOTHERAPY TARGETING ON GLIOMA CELLS AND GLIOMA STEM CELLS USING DRUG REPOSITIONING
Authors: Tamai Sho , Hemragul Sabit , Shabierjiang Jiapaer , Zhang Guangtao , Zhang Jiakang , Wang Yi , Tanaka Shingo , Kinoshita Masashi , Hirao Atsushi , Nakada Mitsutoshi
Published: December 2019

INTRODUCTION

Glioblastoma (GBM) is primary malignant brain tumor with poor prognosis. Despite aggressive chemoradiotherapies, GBM has resistance and finally relapses. Recently, it is revealed that glioma stem cells (GSCs) are forming tumors and induce the recurrence. However, there is no effective therapy for GSCs. Herein, we newly identified pentamidine, an antiprotozoal drug, is effective for not only glioma cells but also GSCs by using drug repositioning approach.

METHOD

We used two glioma cell lines, A172 and T98, and patient-derived glioma stem cell lines KGS01, KGS07 which were established at Kanazawa University. We investigated proliferation ability, stemness and intracellular signal change by proliferation assay, sphere forming assay and western blotting, respectively. RESULT Proliferation ability was prohibited by pentamidine in both glioma cell lines and GSC lines. The half maximal inhibitory concentrations were 5–10 μM in glioma cell lines and 1–5 μM in GSC lines. Sphere forming assay revealed that size and number of spheres were reduced in both GSC lines, depending on concentration of pentamidine. In all cell lines, phosphorylation of extracellular signal-related kinase (ERK) and signal transducer and activator of transcription 3 (STAT3) were suppressed by pentamidine.

DISCUSSION

Pentamidine is known as the therapeutic drug for pneumocystis jirovecii. In this study, pentamidine suppressed proliferation activity in all cell lines, and stemness in both GSCs. Previous papers revealed pentamidine had anti-tumor effects for some types of tumor cell lines, however, therapeutic effect for tumor stem cells have never been mentioned.

CONCLUSION

These results suggest that pentamidine would be therapeutic drug for not only glioma cells but also GSCs by suppressing phosphorylation of ERK and STAT3.
GEN-06 CLINICAL COURSE AFTER TUMOR RECURRENCE OF MGMT HYPERMETHYLATED GLIOBLASTOMA
Authors: Adachi Junichi , Shirahata Mitsuaki , Suzuki Tomonari , Mishima Kazuhiko , Fujimaki Takamitsu , Nishikawa Ryo
Published: December 2019

MGMT methylation in glioblastoma is a biomarker for determining treatment responsiveness and predicting prognosis. We analyzed whether there were differences in the prognosis between glioblastoma with MGMT hypermethylation and other glioblastomas after tumor recurrence. We enrolled 184 patients who underwent radiation therapy and temozolomide chemotherapy after tumor resection for newly diagnosed glioblastoma. MGMT methylation was quantitatively analyzed using methylation-specific high resolution melting analysis. The cut-off value for MGMT methylation had a difference of 35% from the previous values. The subjects were split into three groups according to their MGMT methylation levels, 122 in the low (L) methylation group (levels of 0–34%), 40 in the medium (M) methylation group (levels of 35–69%), and 22 in the high (H) methylation group (levels of 70% or more). We mainly focused on and compared the progression after recurrence. The progression-free survival (PFS) rate and overall survival (OS) rate were significantly longer in the M and H groups than in the L group. There was no difference in PFS between group M and group H, but OS was significantly longer in group H. The details of treatment for the 16 of 22 patients who had recurrences in group H are as follows: temozolomide, n = 1; bevacizumab, n = 8; investigational drugs (peptide vaccines and immune checkpoint inhibitors), n = 3; and supportive care, n = 4. The median survival rate for these 16 patients after recurrence was 18 months. Even patients who received only supportive care had a median survival time ranging between 9 and 17 months. Our results indicate that MGMT hypermethylation in glioblastoma is effective to a certain degree with other treatments even after recurrence. Even patients who underwent only supportive care survived for a relatively longer period of time. Biologically, MGMT hypermethylation may be associated with a moderately slow-growing tumor.