bluuebunny/crossref_metadata_2025 huggingface dataset:
Dilated cardiomyopathy with endocardial fibroelastosis in a juvenile Pallas cat
Authors: Gudenschwager Erwin K. , Abbott Jonathan A. , LeRoith Tanya
Published: January 2019

Dilated cardiomyopathy (DCM) is a myocardial disease characterized by ventricular chamber dilation associated with systolic myocardial dysfunction in the absence of other cardiac lesions. DCM occasionally develops in conjunction with proliferation of fibroelastic fibers in the endocardium, producing endocardial fibroelastosis (EFE). Although early reports describe EFE as a primary disease, evidence now suggests that EFE may develop as a response to myocardial dysfunction. Echocardiographic evaluation of a 4-wk-old Pallas cat ( Otocolobus manul) with respiratory distress revealed enlargement of both atria, enlarged end-systolic left ventricular dimension, and left ventricular dilation. DCM was diagnosed, and the cat was euthanized, given the poor prognosis. Postmortem examination revealed pericardial effusion and biventricular and biatrial enlargement. The interventricular septum and free walls of ventricles were thin. Histologically, the endocardium of the left and right ventricles was diffusely thickened; Verhoeff–Van Gieson staining of the left ventricular endocardium revealed a moderate amount of endocardial accumulation of elastin and collagen. These fibers were more prominent in papillary muscles and around coronary blood vessels. Based on these findings, we diagnosed DCM with EFE. Cardiac diseases are rarely diagnosed in wild felids.
Fads or Facts? Sifting Through the Evidence to Find What Really Works
Authors: Konrad Moira , Criss Caitlin J. , Telesman Alana Oif
Published: January 2019

Despite the requirement that teachers implement evidence-based instruction in their classrooms, a significant research-to-practice gap persists. Far too often, teachers resort to quick fixes found through online searches or rely on conventional wisdom to make instructional decisions. This is no surprise as identifying evidence-based interventions can be time-consuming, overwhelming, and confusing. Indeed, claims of practices being evidence based are ubiquitous, even for practices that clearly lack evidence to support their efficacy. In addition, once an evidence-based practice is selected, the process for implementing it and evaluating its effectiveness can be an additional challenge. The purposes of this article are to distinguish between an evidence-based practice as an instructional strategy and evidence-based education as a problem-solving process and to assist teachers in identifying, implementing, and evaluating evidence-based practices in their classrooms.
Influence of Tumor Thrombus on Occurrence of Distant Venous Thromboembolism and Survival in Patients With Renal Cell Carcinoma After Surgery
Authors: Park Hyunkyung , Jeong Chang Wook , Yuk Hyeongdong , Ku Ja Hyeon , Kim Hyeon Hoe , Kwak Cheol , Kim Inho
Published: January 2019

Tumor thrombus is a unique characteristic of renal cell carcinoma (RCC). However, only a few studies have reported its clinical influence on the occurrence of venous thromboembolism (VTE). This study aimed to clarify the influence of tumor thrombus and other risk factors for VTE and to elucidate the impact of tumor thrombus on survival outcomes. We retrospectively reviewed data from patients with RCC who underwent radical or partial nephrectomy from September 1999 to August 2015 at Seoul National University Hospital. A total of 2762 patients were enrolled. The 1- and 5-year cumulative incidences of VTE were 0.5% ± 0.1% and 1.5% ± 0.3%, respectively. During a median follow-up of 39.0 months (95% confidence interval [CI], 37.1-41.0 months), deep vein thrombosis occurred in 13 patients and pulmonary embolism in 15 patients. Patients with tumor thrombus (diagnosed by surgical pathology findings) had a significantly higher incidence of VTE than those without thrombus (odds radio 8.160, 95% CI, 1.480-45.004). Older age (≥60 years) and higher preoperative C-reactive protein (>0.5 mg/dL) were also significant risk factors for VTE. Additionally, tumor thrombus was independently associated with worse progression-free survival (PFS) but not with overall survival (OS) in multivariable analysis (hazard ratio [HR] 1.916, 95% CI, 1.295-2.834 for PFS; HR 1.164, 95% CI, 0.755-1.793 for OS). In conclusion, the incidence of VTE was relatively low in patients who underwent surgery for RCC. Nevertheless, patients with tumor thrombus had an increased risk of VTE and should be closely monitored for VTE.
Inhibitory Control in Sexually Coercive Men: Behavioral Insights Using a Stop-Signal Task With Neutral, Emotional, and Erotic Stimuli
Authors: Carrier Emond Fannie , Nolet Kevin , Rochat Lucien , Rouleau Joanne-Lucine , Gagnon Jean
Published: January 2019

Response inhibition is defined as one’s ability to voluntarily override an automatic or already initiated action when that action is inappropriate. Although a core mechanism of self-control, its association with sexual coercion perpetration and the impact of erotic cues on its exertion remain unknown. According to a domain-specific perspective on impulsivity, response inhibition performances should be disproportionately hindered by sexual cues in sexual coercion perpetrators. In total, 94 male college students completed a stop-signal task that included neutral, emotional, and erotic distracters. Results showed that men who reported past use of sexual coercion obtained overall poorer stop-signal task (SST) performances. Highly arousing sexual stimuli equally hindered the performances of perpetrators and non-perpetrators, whereas moderately arousing sexual and nonsexual positive stimuli did not significantly affect performances. Results do not support a domain-specific perspective on the link between response inhibition and sexual coercion, but rather suggest generally poorer inhibitory control among sexual coercion perpetrators.
Effects of Volatiles from Clavigralla tomentosicollis Stål. (Hemiptera: Coreidae) Adults on the Host Location Behavior of the Egg Parasitoid Gryon fulviventre (Crawford) (Hymenoptera: Scelionidae)
Authors: Sanou Apolline , Traoré Fousséni , Ba Malick Niango , Dabiré-Binso Clémentine L , Pittendrigh Barry R , Sanon Antoine
Published: January 2019

The egg parasitoid Gryon fulviventre is a potential biological control agent of Clavigralla tomentosicollis, a coreid pod-sucking pest of Vigna unguiculata. The host location behavior of naive parasitoid females was studied using a four-armed olfactometer. Two strains of G. fulviventre parasitoids from Burkina Faso and Benin were exposed to odors provided by healthy and infested pods as well as C. tomentosicollis females and males. The time spent in each odor zone was recorded to determine the preference of parasitoid females. Results show that odors from healthy pods, infested pods, and pest females did not attract the parasitoid. However, a significantly attractive response of both strains of G. fulviventre was recorded in the presence of volatiles from males of C. tomentosicollis. Moreover, experiments testing G. fulviventre females’ behavior when simultaneously exposed to volatiles from cowpea pods (healthy and infested) and increasing numbers of C. tomentosicollis males revealed a significantly higher attraction of parasitoid females of both strains by volatiles from ten males of C. tomentosicollis. The results suggest that the males of the insect pest emit a pheromone used as kairomone by parasitoids to locate their host. The conditions determining this attractiveness at field level and its impact on host-searching efficiency are discussed.
An accurate and efficient series solution for the longitudinal vibration of elastically restrained rods with arbitrarily variable cross sections
Authors: Xu Deshui , Du Jingtao , Liu Zhigang
Published: January 2019

Longitudinal vibration of non-uniform rod has been of great significance in various engineering occasions. The existing works are usually limited to the certain area variation and/or classical boundary condition. Motivated by this limitation, an efficient accurate solution is developed for the longitudinal vibration of a general variable cross-section rod with arbitrary boundary condition. Displacement function is invariantly expressed as the summation of standard Fourier series and supplementary polynomials, with an aim to make the calculation of all derivatives more straightforwardly in the whole solving region [0, L]. Energy principle is employed for system dynamics formulation, with the elastic boundaries considered as potential energy stored in the restraining spring. Arbitrary cross-section area variation is uniformly expanded into Fourier series. Numerical examples are presented for the natural frequency and mode shapes of non-uniform rod of free and clamped boundary conditions and compared with literature data. Results show good agreement with the previous analytical solutions. Influence of cross section area variation on vibration characteristics of non-uniform rods is then studied and discussed. One of the most advantages of the proposed model is that there is no need to reformulate the problem or rewrite the codes when the cross-section area distribution and/or boundary conditions change arbitrarily.
Space, Loss and Resistance: A Haunted Pool-Map in South-Eastern Turkey
Authors: Yıldırım Umut
Published: January 2019

Based on ethnographic fieldwork (2005 to February 2007, and March and August 2008) in Diyarbakır, southeastern Turkey, this article explores the conceptual intersection of recent anthropological literature on space, neoliberalism and resistance to study the affective life of politics in the context of the war between the Partiye Karkêren Kurdistan and the Turkish State in the 1990s. Offering a contribution to regional studies on the neoliberal restructuring of the urban space and to the anthropology of resistance, this article seeks to make ‘the political’ into a conceptual thread. The article deploys this approach to think through dissonant affects at a site where uncountable deaths are woven into the neoliberal restructuring of space, yet denied through the form that such governance takes.
Environmentally friendly lightweight gypsum-based materials with waste stone dust
Authors: Krejsová J , Schneiderová Heralová R , Doleželová M , Vimmrová A
Published: January 2019

Gypsum is one of the most environmentally friendly binders and consequently its importance in building industry is increasing. New applications are being sought and new materials are being developed. A lightweight gypsum material foamed by waste stone dust was designed and tested. The amount of stone dust, a waste product formed during the cutting and polishing of decorative stones, is becoming serious problem in some countries. When the stone dust contains calcium carbonate, it can be used for gypsum foaming to produce cheap, environmentally attractive material. The physical and mechanical properties of lightweight gypsum-based materials with different amounts of stone dust were designed and tested. The material with largest amount of waste stone dust attained a bulk density under 600 kg/m3 and compressive strength of 1.1 MPa, with a thermal conductivity of 0.117 W/m.K. These properties are sufficient for use of the material as a thermal insulating plaster, as the core of thermal insulating gypsum boards or in lightweight blocks for inner walls and partitions. Life cycle cost analyses was performed for the most favourable material and was compared with aerated autoclaved concrete, which is a common commercial product with similar properties.
A practical metric for melanopic metrology
Authors: Berman SM , Clear RD
Published: January 2019

Over the past decade, there has been a growing interest in lighting research on the effects of the recently discovered melanopsin receptor (also referred to as the intrinsically photosensitive retinal ganglion cell) and its impacts on health and vision. Presently, there is not a generally accepted metrology for dealing with the spectral response of the melanopsin receptor as applied to both lighting and vision research. A proposition to handle this issue from a vision science perspective has been presented in 2014 in the journal Trends in Neurosciences and from a more lighting perspective in 2017 in Lighting Research and Technology. These propositions are complex, and do not retain the CIE standard definition of a lumen. In this paper, we propose an approach based on effective watts and melanopic/photopic ratios that is both simpler and more closely aligned with CIE standard unit definitions. In addition, we include some practical examples of how such ratios are accessible now, and can be used for both lighting and vision research as well as applications.
Medications for Early Life Epilepsy: Evidence Versus Experience?
Authors: Nickels Katherine
Published: January 2019

[Box: see text]
Prime-number-assisted block-based neighbor discovery protocol in wireless sensor networks
Authors: Lee Woosik , Youn Jong-Hoon , Song Teukseob
Published: January 2019

During the initial deployment time, wireless sensors continually search their neighbors. The neighbor discovery is not an one-time event because the network topology can be changed anytime due to node mobility and failure. The neighbor discovery protocol helps sensor nodes to find neighboring sensors within their communication range. This study proposes a novel neighbor discovery protocol called the prime-number-assisted block-based neighbor discovery protocol, which intelligently changes the sensor schedules based on the greater common divisor of two sensors’ discovery cycle lengths. For example, for two sensors whose duty cycles are different, if the lengths of their discovery schedules are relatively prime, the prime-number-assisted block-based neighbor discovery protocol simply uses the balanced incomplete block design–based neighbor discovery protocol without adding any additional active slots; otherwise, it changes the original balanced incomplete block design–based schedule using a prime number. In this study, we compare the performances of prime-number-assisted block-based neighbor discovery protocol and other recently proposed neighbor discovery protocols (U-Connect, Disco, SearchLight, and Hedis) using a TOSSIM simulator. The experimental results confirm the superiority of prime-number-assisted block-based neighbor discovery protocol over other neighbor discovery protocols in terms of discovery latency and energy consumptions.
A Pilot Study of Pulmonary Segmentectomy With Indocyanine Green Near-Infrared Angiography
Authors: Chen Ruiji , Ma Yongfu , Li Chengrun , Li Yunjing , Yang Bo , Guo Juntang , Feng Changjiang , Chen Siyu , Yao Jie , Liang Chaoyang , Liu Yang
Published: January 2019

Objectives. Video-assisted thoracoscopic surgery (VATS) pulmonary segmentectomy is commonly used in treating small ground-glass opacity (GGO) nodules in lung. The identification of the intersegmental plane is one of the challenges. In this pilot study, we aimed to evaluate the feasibility of indocyanine green (ICG) angiography in VATS segmentectomy. Methods. Nineteen GGO patients were enrolled, and VATS segmentectomy with ICG near-infrared angiography were performed between July 2017 and December 2017. Conventional 3-port VATS was used. ICG was injected intravenously after dominant arties were ligated. Intersegmental plane was identified and divided by stapler and electrocautery. Results. All patients had perfect intersegmental plane visualization. The mean operation time was 140.8 minutes, and the mean blood loss was 23.7 mL. No complications due to ICG occurred. The mean chest tube duration was 4.6 days. No severe complications occurred in the perioperative period. The mean chest tube drainage duration was 4.6 days. Prolonged postoperative air leak (>5 days), which required no surgical intervention, occurred in 2 cases. There were no severe complications or in-hospital deaths. Conclusions. VATS segmentectomy with ICG near-infrared angiography is a reasonable treatment option to treat small GGO in lung, especially due to its good surgical view maintenance.
Contemporary best practice in the use of neoadjuvant chemotherapy in muscle-invasive bladder cancer
Authors: Marcq Gautier , Jarry Edouard , Ouzaid Idir , Hermieu Jean-François , Henon François , Fantoni Jean-Christophe , Xylinas Evanguelos
Published: January 2019

Background:

We aimed to provide a comprehensive literature review on the best practice management of patients with nonmetastatic muscle-invasive bladder cancer (MIBC) using neoadjuvant chemotherapy (NAC).

Method:

Between July and September 2018, we conducted a systematic review using MEDLINE and EMBASE electronic bibliographic databases. The search strategy included the following terms: Neoadjuvant Therapy and Urinary Bladder Neoplasms.

Results:

There is no benefit of a single-agent platinum-based chemotherapy. Platinum-based NAC is the gold standard therapy and mainly consists of a combination of cisplatin, vinblastine, methotrexate, doxorubicin, gemcitabine or even epirubicin (MVAC). At 5 years, the absolute overall survival benefit of MVAC was 5% and the absolute disease-free survival was improved by 9%. This effect was observed independently of the type of local treatment and did not vary between subgroups of patients. Moreover, a ypT0 stage (complete pathological response) after radical cystectomy was a surrogate marker for improved oncological outcomes. High-density MVAC has been shown to decrease toxicity (with a grade 3–4 toxicity ranging from 0% to 26%) without impacting oncological outcomes. To date, there is no role for carboplatin administration in the neoadjuvant setting in patients that are unfit for cisplatin-based NAC administration. So far, there is no published trial evaluating the role of immunotherapy in a neoadjuvant setting, but many promising studies are ongoing.

Conclusion:

There is a strong level of evidence supporting the clinical use of a high-dose-intensity combination of methotrexate, vinblastine, doxorubicin and cisplatin in a neoadjuvant setting. The landscape of MIBC therapies should evolve in the near future with emerging immunotherapies.
Glycemic Variability: Risk Factors, Assessment, and Control
Authors: Kovatchev Boris
Published: January 2019

Glycemic variability (GV) a well-established risk factor for hypoglycemia and a suspected risk factor for diabetes complications. GV is also a marker of the instability of a person’s metabolic system, expressed as frequent high and low glucose excursions and overall volatile glycemic control. In this review, the author discusses topics related to the assessment, quantification, and optimal control of diabetes, including (1) the notion that optimal control of diabetes, that is, lowering of HbA1c—the commonly accepted gold-standard outcome—can be achieved only if accompanied by simultaneous reduction of GV; (2) assessment and visualization of the two principal dimensions of GV, amplitude and time, which is now possible via continuous glucose monitoring (CGM) and various metrics quantifying GV and the risks associated with hypo- and hyperglycemic excursions; and (3) the evolution of diabetes science and technology beyond quantifying GV and into the realm of GV control via pharmacological agents, for example, GLP-1 receptor agonists and DPP-4 inhibitors, which have pronounced variability-reducing effect, or real-time automated closed-loop systems commonly referred to as the “artificial pancreas.” The author concludes that CGM allows close tracking over time, and therefore precise quantification, of glycemic variability in diabetes. The next step—optimal control of glucose fluctuations—is also taken by medications with pronounced GV-lowering effect primarily in type 2 diabetes, and by automated insulin delivery in type 1 diabetes. Contemporary CGM-based artificial pancreas systems use specific GV representations as input signals, and thus their main objective is to minimize GV and, from there, optimize glycemic control.
Using an Augmented Reality–Based Teaching Strategy to Teach Mathematics to Secondary Students With Disabilities
Authors: Kellems Ryan O. , Cacciatore Giulia , Osborne Kaitlyn
Published: January 2019

A basic understanding of math, numeracy, and related concepts are critical skills for functioning independently in society. Individuals with disabilities often struggle with basic math, which impedes their ability for independent living. Augmented reality (AR), which builds on the evidence-based principles of video modeling, is a promising teaching strategy of providing math instruction to individuals with disabilities. This article provides a practical framework (with step-by-step instructions and examples) for practitioners wishing to implement AR as a teaching strategy for secondary students with disabilities.
Potential Causal Influence of Neighborhood Disadvantage on Disordered Gambling: Evidence From a Multilevel Discordant Twin Design
Authors: Slutske Wendy S. , Piasecki Thomas M. , Deutsch Arielle R. , Statham Dixie J. , Martin Nicholas G.
Published: January 2019

The quality of the neighborhood in which one lives has been linked to disordered gambling (DG), but whether this reflects a causal relation has not yet been empirically examined. Participants were 3,450 Australian twins who completed assessments of past-year DG and personality and for whom census-derived indicators of disadvantage were used to characterize their neighborhood. Multilevel models were employed to estimate within-twin-pair and between-twin-pair effects of neighborhood disadvantage on DG, with the within-twin-pair effect representing a potentially causal association and the between-twin-pair effect representing a noncausal association. There was robust evidence for a potentially causal (as well as a noncausal) effect of neighborhood disadvantage on DG; in contrast, parallel analyses of past-year alcohol-use disorder (AUD) failed to find evidence of a potentially causal effect. These results support efforts focused on identifying the active ingredients contributing to the effect of neighborhood disadvantage on DG and developing interventions to limit their impact.
Differential attenuation of β2 integrin–dependent and –independent neutrophil migration by Ly6G ligation
Authors: Cunin Pierre , Lee Pui Y. , Kim Edy , Schmider Angela B. , Cloutier Nathalie , Pare Alexandre , Gunzer Matthias , Soberman Roy J. , Lacroix Steve , Boilard Eric , Lefort Craig T. , Nigrovic Peter A.
Published: January 2019

Antibody ligation of the murine neutrophil surface protein Ly6G disrupts neutrophil migration in some contexts but not others. We tested whether this variability reflected divergent dependence of neutrophil migration on β2 integrins, adhesion molecules that interact with Ly6G at the neutrophil surface. In integrin-dependent murine arthritis, Ly6G ligation attenuated joint inflammation, even though mice lacking Ly6G altogether developed arthritis normally. By contrast, Ly6G ligation had no impact on integrin-independent neutrophil migration into inflamed lung. In peritoneum, the role of β2 integrins varied with stimulus, proving dispensable for neutrophil entry in Escherichia coli peritonitis but contributory in interleukin 1 (IL-1)–mediated sterile peritonitis. Correspondingly, Ly6G ligation attenuated only IL-1 peritonitis, disrupting the molecular association between integrins and Ly6G and inducing cell-intrinsic blockade restricted to integrin-dependent migration. Consistent with this observation, Ly6G ligation impaired integrin-mediated postadhesion strengthening for neutrophils arresting on activated cremaster endothelium in vivo. Together, these findings identify selective inhibition of integrin-mediated neutrophil emigration through Ly6G ligation, highlighting the marked site and stimulus specificity of β2 integrin dependence in neutrophil migration.
Digital mental health apps and the therapeutic alliance: initial review
Authors: Henson Philip , Wisniewski Hannah , Hollis Chris , Keshavan Matcheri , Torous John
Published: January 2019

Background

As mental healthcare expands to smartphone apps and other technologies that may offer therapeutic interventions without a therapist involved, it is important to assess the impact of non-traditional therapeutic relationships.

Aims

To determine if there were any meaningful data regarding the digital therapeutic alliance in smartphone interventions for serious mental illnesses.

Method

A literature search was conducted in four databases (PubMed, PsycINFO, Embase and Web of Science).

Results

There were five studies that discuss the therapeutic alliance when a mobile application intervention is involved in therapy. However, in none of the studies was the digital therapeutic alliance the primary outcome. The studies looked at different mental health conditions, had different duration of technology use and used different methods for assessing the therapeutic alliance.

Conclusions

Assessing and optimising the digital therapeutic alliance holds the potential to make tools such as smartphone apps more effective and improve adherence to their use. However, the heterogeneous nature of the five studies we identified make it challenging to draw conclusions at this time. A measure is required to evaluate the digital therapeutic alliance.
Endoscopic submucosal dissection using a novel endoscopic articulating knife for clinical staging of early esophageal neoplasia.
Authors: Genere Juan , Priyan Harshith , Wang Kenneth
Published: January 2019

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Background: Clinical staging of early esophageal neoplasia traditionally involves histological confirmation and imaging with endoscopic ultrasound (EUS), CT, and PET which have low sensitivity and specificity for staging esophageal cancer (EC). Endoscopic submucosal dissection (ESD) therapy is traditionally used for treatment, but not diagnosis as it is felt to be technically challenging and have a high risk for complications. We applied a new articulating endoscopic knife that permits safe ESD (ESD-CC) to evaluate early neoplasia with potential curative resection. Methods: We performed a retrospective study of patients undergoing ESD to stage or treat suspected early EC (cT1-T2). Clinical stage was done by EUS, CT, and PET. Two expert GI pathologists reviewed all histology. Lesions were examined with high resolution white light endoscopy and narrow band imaging. ESD was done with 1:200,000 epinephrine and methylene blue dye injection for lifting and staining the submucosal space. A 5mm, scissors-like articulated knife was used to perform ESD and hemostasis. Complications during post-ESD observation or follow-up were recorded. Results: A total of 35 patients who underwent ESD-CC were included with median age 70 (IQR 12), 26 males (74%), and followed for a median 3.4 months (IQR 6.4). This group consisted of 32 potential adenocarcinomas and 3 squamous cell cancers. The clinical Pre-ESD diagnoses were cT1 EC (24, 69%) and suspected EC in Barrett’s esophagus (BE) (11, 31%). The cT1 EC cases had ESD staged at least T1b (5, 21%), T1a (11, 46%), EC in situ (1, 4%), and dysplastic BE (7, 29%). The suspected EC cases had ESD staged at least T1b (1, 9%), T1a (2, 18%), and DBE (8, 73%). ESD-CC up-staged 4 (11%), down-staged 10 (29%), and confirmed prior diagnosis in 21 (60%). No complications including bleeding, perforation, or stricture formation regardless of size of ESD, age of patient, or co-morbidities. Conclusions: Staging of early esophageal cancer can be improved using ESD with an articulating knife, without increase in complications. ESD may be used as a staging modality in early esophageal cancer.
Prognostic value of DNA repair gene based on stratification of gastric cancer.
Authors: Chang Jinjia , Xu Midie , Sun Hui , Li Wenhua , Ye Min , Weng Weiwei , Zhu Xiaodong
Published: January 2019

12

Background: DNA repair genes can be used as prognostic biomarkers in many types of cancer. We aimed to identify prognostic DNA repair genes in patients with gastric cancer (GC) by systematically bioinformatic approaches using web-based database. Methods: Global gene expression profiles from altogether 1,325 GC patients’ samples from six independent datasets were included in the study. Clustering analysis was performed to screen potentially abnormal DNA repair genes related to the prognosis of GC, followed by unsupervised clustering analysis to identify molecular subtypes of GC. Characteristics and prognosis differences were analyzed among these molecular subtypes, and modular key genes in molecular subtypes were identified based on changes in expression correlation. Multivariate Cox proportional hazard analysis was used to find the independent prognostic gene. Kaplan-Meier method and log-rank test was used to estimate correlations of key DNA repair genes with GC patients’overall survival. Results: There were 57 key genes significantly associated to GC patients’ prognosis, and patients were stratified into three molecular clusters based on their expression profiles, in which patients in Cluster 3 showed the best survival (P < 0.05). After a three-phase training, test and validation process, the expression profile of 13 independent key DNA repair genes were identified can classify the prognostic risk of patients. Compared with patients with low-risk score, patients with high risk score in the training set had shorter overall survival (P < 0.0001). Furthermore, we verified equivalent findings by these key DNA repair genes in the test set (P < 0.0001) and the independent validation set (P = 0.0024). Conclusions: Our results suggest a great potential for the use of DNA repair gene profiling as a powerful marker in prognostication and inform treatment decisions for GC patients.
Gls-010, a novel anti-PD-1 mAb in Chinese advanced gastrointestinal tumor: Result of a phase Ib clinical trial.
Authors: Lin Shen , Gong Jifang , Xu Yingying , Zhang Xiaotian , Peng Zhi , Qi Changsong , Li Guochun , Meng Haijin , Liu Zhen , Wang Hui , Chen Chris , Li Jing , Zheng Yong , Lee Johnathan , Zhang Yan , Zhang Qiang , Jin Ge , Yang Yining , Zhao Guodong
Published: January 2019

125

Background: GLS-010 is a novel fully human anti-PD-1 mAb. Phase Ia exhibited good result of tolerance and 240mg fixed dose was selected. Phase Ib is to explore efficacy and biomarkers in different types of advanced cancer. Here we report the preliminary result in Chinese gastrointestinal (GI) tumor patients (pts) from the phase Ib. Methods: All pts enrolled received GLS-010 240mg every 2 weeks. Tumor response was assessed by RECIST 1.1 every 8 weeks. Adverse events (AEs) were graded by NCI CTCAE v4.03. Several biomarkers were evaluated, including PD-L1 by IHC, tissue tumor mutation burden (tTMB) by whole exome sequencing (WES) from FFPE tissue, blood TMB (bTMB) by the multi-gene panel based next-generation sequencing (NGS) from blood ctDNA. Results: Until September 2018, 23 pts (including 10 gastric cancer or GC, 10 esophagus cancer or EC, and 3 biliary tract cancer or BTC) were enrolled in the phase 1b. The median dosing number was 4 (range: 1~16). The most common treatment related AEs included haemoglobin decreased (16/23, G1-2), leukopenia (6/23, G1-2), fever (4/23, G1), blood bilirubin increased (4/23, G1-3), ALT increased (3/23, G1), etc. Treatment–related grade 3-5 AEs include 1 multiple organ dysfunction syndrome, 1 interstitial lung disease and 1 blood bilirubin increased. 21 pts received response evaluation. Four patients achieved partial response (PR), including 1 GC (1/9), 2 EC (2/10), and 1 BTC (1/2). 2 subjects had stable disease (SD) at Week 8, and were still in treatment. No apparent correlation was observed between treatment response and PD-L1 expression. However, both tTMB and bTMB data obtained from 18 patients support positive correlation to tumor response. The tTMB level of 3 PR pts with valid data is significantly higher than that of 9 PD pts (P = 0.036). The bTMB level of 4 PR pts with valid data is significantly higher than that of 10 PD pts (P = 0.049). Conclusions: GLS-010 showed promising efficacy and acceptable safety in Chinese patients. For Chinese GI tumor TMB may be a useful biomarker to predict the treatment response to PD-1 inhibitor. Comparing to tTMB, bTMB may be of more future value due to its applicability in clinical practice.
Hyperprogressive disease (HPD) during nivolumab (Nivo) or irinotecan (IRI) as salvage line in patients with metastatic gastric cancer (MGC).
Authors: Sugimoto Naotoshi , Otsuka Tomoyuki , Hasegawa Akiko , Yagi Toshinari , Kudo Toshihiro , Fujiishi Koto , Nishio Minako , Yamamoto Sachiko , Fujisawa Fumie , Imamura Fumio
Published: January 2019

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Background: Nivo was approved in heavily treated MGC patients in September 2017 in Japan. HPD have been reported in patients with various tumor types treated with anti-PD-1/PD-L1 antibody therapy, but no data was existed in gastric cancer. Methods: We retrospectively compared tumor growth kinetics (TGK) on Nivo or IRI as salvage line and TGK on last treatment in patients with MGC in our hospital. The TGK ratio (TGKR, ratio of the slope of tumor growth before treatment and the slope of tumor growth on treatment) was calculated. HPD was defined as a TGKR ≥ 2. Results: 51 patients have been treated Nivo (n = 31) or IRI (n = 20) as salvage line before Aug 2018 in our hospital. The median age was 67 years (range 37-81) in Nivo and 68 years (range 46-80) in IRI.; 20 males and 11 females in Nivo and 16 males and 4 females in IRI; PS 0-1/2 score 19/12 in Nivo and 19/1 in IRI. Thirty-five patients (Nivo : IRI = 16:19) had target lesions according to RECIST 1.1 and performed CT pre, baseline and during treatment. HPD were observed in seven patients (44%) with Nivo. On the contrary, only one patient (5%) experienced HPD with IRI. Median PFS and OS (HPD vs. non-HPD) were 2.1 versus 3.5 months (HR: 0.29 (0.083-0.98), p = 0.046) and 5.3 versus 6.6 months (HR: 0.44 (0.078-2.5), p = 0.35) with Nivo. The rate of grade3-4 irAEs were colitis (6%), interstitial pneumonia (6%), and mytosis (3%) with Nivo. No treatment-related death and pseudo-progression were observed. Conclusions: HPD is more common with Nivo compared with IRI in patients with MGC as salvage line and associated with poor PFS in patients treated with Nivo. Further analysis will be warranted.
M1a disease should be reconsidered in esophageal cancer staging system from the perspective of treatment response and survival after definitive concurrent chemoradiotherapy.
Authors: Chung Tae Ryong , Kim Jie-Hyun , Lee Ik Jae , Cho Yona , Jung Da Hyun , Park Jae Jun , Youn Young Hoon , Park Hyojin
Published: January 2019

13

Background: M1a node involvement based on the 6th edition AJCC staging system was classified as regional node involvement in the 7th edition of esophageal squamous cell carcinoma (ESCC). However, the clinical significance of M1a node involvement based on the 6th edition staging system has not been well established. Thus, we analyzed the prognostic value of M1a node in patients of ESCC after definitive chemoradiotherapy (CCRT). Methods: A total of 188 ESCC patients had M0 disease based on the 7th edition AJCC classification, of which 31 (16.5%) of them were reclassified to the M1a patient group under the 6th edition AJCC classification. After definitive CCRT, we compared the basic characteristics of two groups, analyzed the rate of complete remission (CR), recurrence, finally assessed overall survival (OS), and disease-free survival (DFS) of each group. Results: Among 31 patients reclassified to M1a disease, 21 patients (67.7%) had subclavian nodes and 10 patients (32.3%) had celiac nodes. The median follow-up period was 18.3 months. The M1a group showed a significantly lower survival rate not only in median OS (M1a 16.4 months, M0 42.7 months, P = 0.015), but also in 5-year OS (M1a 10.8%, M0 41.2%). Three of 31 patients (9.7%) in the M1a group achieved CR, while 41 of 157 patients (26.1%) in the M0 group achieved CR ( P = 0.048). However, there was no recurrence in the M1a group after achieved CR during follow-up period. Conclusions: Among ESCC patients after completing definitive CCRT, M1a patients according to the 6th AJCC staging system showed lower CR rate and OS rate compared with M0 disease patients. M1a nodes should be differentiated from regional node involvement.
A multicenter study of trimodality therapy for patients 75 years and older with esophageal cancer.
Authors: McDonnell Niamh Anna , Lester Scott , Haddock Michael G. , Halfdanarson Thorvardur Ragnar , Mahipal Amit , Spears Grant M. , Liao Zhongxing X. , Blackmon Shanda H , Hallemeier Christopher Leigh , Lin Steven H. , Merrell Kenneth
Published: January 2019

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Background: Trimodality therapy is the standard of care for patients with resectable cancer of the esophagus. However, patients ≥75 years have been underrepresented or excluded from landmark clinical trials to date. We investigated the feasibility and safety of treatment of esophageal cancer with trimodality therapy in patients’ ≥ 75 years. Methods: We performed a retrospective review of all patients ≥75 years who received trimodality therapy for esophageal cancer in 3 high volume tertiary cancer institutions from June 2007 to June 2013. All patients received neoadjuvant radiation with concomitant chemotherapy followed by esophagectomy. Toxicities and clinical outcomes were abstracted from the electronic medical record and partially from a prospectively maintained database. Overall and disease-free survival were estimated using the Kaplan-Meier method. Results: Five hundred seventy patients were treated with trimodality therapy for esophageal cancer from 2007-2013. Of these, 38 patients (7%) were 75 or older at the time of diagnosis. At diagnosis, comorbidities included coronary artery disease (32%), atrial fibrillation (11%) and COPD (13%). The majority of patients (87%) received 50.4Gy/28 fractions. 5-fluorouracil (5-FU)/cisplatin was the most common chemotherapy regimen (37%), followed by 5-FU/docetaxel (24%). A total of 13 patients (34%) developed acute grade ≥3 toxicity associated with neoadjuvant therapy. The most common acute grade 3 toxicities were haematological (10%), nausea (8%), esophagitis (5%) and fatigue (5%). Significant postoperative complications included respiratory (empyema, ARDS, pleural effusion) (39%), arrhythmia (32%), anastomotic leak (5%), and ileus (5%). There were 2 deaths (5%) within 90 days of surgery: one was secondary to empyema, the other developed DIC and sepsis. Median overall survival and disease free survival were 4.4 and 2.3 years respectively. Conclusions: Trimodality treatment is a reasonable approach for management of carefully selected elderly patients with esophageal cancer, with similar rates of cancer outcomes, and treatment related morbidity and mortality as compared to younger patients.
Impact of double-flap technique for reconstruction after proximal gastrectomy.
Authors: Asanuma Kazuki , Kawakubo Hirofumi , Mayanagi Shuhei , Nakamura Rieko , Irino Tomoyuki , Fukuda Kazumasa , Wada Norihito , Kitagawa Yuko
Published: January 2019

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Background: Proximal gastrectomy (PG) has been performed for proximal early gastric cancer as a minimally invasive procedure. In PG, gastroesophageal reflux disease (GERD) becomes problem, thus several techniques have been reported to reduce GERD. So far, we have mainly performed the method of anastomosis based on double stapling technique (DST) using a trans-oral anvil delivery system for reconstruction after PG. For preventing GERD, we recently introduced double-flap technique (DFT) reported to be more physiological anti-reflux reconstruction which can prevent GERD. So, this study shows superiority of DFT compared to DST. Methods: Patients who have undergone PG for proximal gastric cancer during Jan. 2012 to Jul. 2017 in our hospital were reviewed as candidates. Operation time, blood loss, postoperative anastomotic complication, postoperative hospital stay, postoperative reflux symptom or endoscopic findings, intake of proton pump inhibitor (PPI) at 1 year after the operation, and postoperative nutritional status were retrospectively investigated. Results: DFT was performed in 26 patients whereas DST was performed in 38 patients. Average operation time and postoperative hospital stay was not significant in both groups (DFT group; 275.8±41.4 minutes, 13.6±8.9 days, DST group; 252.2±82.9 minutes, 15.2±7.2 days, respectively). As for postoperative complications higher than Clavien-Dindo Grade III, one case of suture failure was observed in DFT group. Postoperative reflux symptoms and endoscopic findings of gastroesophageal reflux were significantly frequent in DST group compared to DFT group (Reflux symptoms, DFT group : DST group = 0 : 7(p = 0.03), Endoscopic findings, DFT group : DST group = 1 : 11(p < 0.01) , respectively). There were significantly more cases of PPI taking one year after the operation in DST group(DFT group : DST group = 8 : 28 (p < 0.01) ). Average weight loss at one year after the operation and serum level of albumin of in DFT group were 6.0±4.7kg and 4.11±0.29 g/dL, respectively and DST group were 7.6±5.3kg and 3.95±0.39 g/dL, respectively and there were no significance between two groups. Conclusions: DFT is superior to DST as a reconstruction method after PG in terms of suppressing GERD.
Reliability of endoscopic biopsy compared with endoscopic submucosal dissection histopathologic diagnosis.
Authors: Lee Kyuwon , Kim Tae Ho
Published: January 2019

15

Background: Endoscopic biopsy is the most convenient and simple method for approaching gastric neoplasm. Aim of our study was to determine the diagnostic accuracy of biopsy during screening endoscopy compared to endoscopic submucosal dissection (ESD). Methods: 175 patients who underwent both screening endoscopic biopsy and ESD from 2015.01 to 2017.12 in Bucheon St. Mary’s hospital were retrospectively reviewed. Results: Seventeen lesions had different histopathological ESD findings compared with endoscopic biopsy. Among six endoscopic biopsies that showed atypia, four were diagnosed with adenocarcinoma and two maintained the results. 64 out of the 175 lesions showed low grade dysplasia by endoscopic biopsy. After ESD, two cases were diagnosed with high grade dysplasia and two cases were diagnosed with adenocarcinoma. Of 12 lesions which showed high grade dysplasia on endoscopic biopsy, four lesions turned out to be adenocarcinoma (three well differentiated, one moderately differentiated) after ESD. Of 91 adenocarcinoma lesions on endoscopic biopsy, three lesions had discrepancy on differentiation level and one lesion turned out to be signet ring cell carcinoma after all. Patients who were infected with Helicobacter pylori (H. pylori) had tendency to have discrepancy between initial biopsy and ESD histopathology result. (OR 3.68, 95% CI 1.08-11.955, P = 0.018). Conclusions: Discrepancy between endoscopic biopsy and post-ESD histopathology were found. Possibility of coexistence or progression to high grade neoplasm should be considered regarding endoscopic biopsy results especially if infected with H. pylori and active ESD histopathological confirmation needs to be done if necessary.
Predictive biomarkers for the efficacy of nivolumab as ≥ third-line therapy in patients with advanced gastric cancer (AGC): From a subset analysis of ATTRACTION-2 phase III trial.
Authors: Kim Jwa Hoon , Ryu Min-Hee , Park Young Soo , Ma Jungeun , Lee Sun Young , Kim Deokhoon , Kang Yoon-Koo
Published: January 2019

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Background: ATTRACTION-2 phase III trial proved the clinical efficacy of nivolumab (Nivo) in AGC patients (pts) treated with ≥ 2 previous chemotherapy regimens. However, the benefits of Nivo seem to be limited to a subset of pts and there is a need to identify predictive markers to select pts who would benefit from Nivo. Methods: Clinical data and tumor samples of AGC pts enrolled from Asan Medical Center in ATTRACTION-2 study were retrospectively analyzed. PD-L1 (+) was defined as combined positive score of ≥ 1%. EBV and MSI status were determined by EBV-encoded small RNA in situ hybridization and IHC for MLH-1, MSH-2, PMS-2, and MSH-6, respectively. Tumor mutation burden (TMB) was acquired by targeted next-generation sequencing using the NextSeq platform with OncoPanel. Results: A total of 45 pts (28/17 in Nivo/placebo arms) were eligible for the analysis. Baseline neutrophil-lymphocyte ratio (NLR) was median 2.9 and 7 pts had hyponatremia ( < 135). In 36 pts with available tissues, there were PD-L1 (+) (N = 13, 36.1%), EBV (+) (N = 6, 16.7%), and no MSI-high. TMB data could be acquired in 29 pts and median TMB was 8.2/Mb (0.0-21.3). With a median follow-up of 28.3 months (mo) in surviving pts, objective response rate, median progression-free survival (PFS), and overall survival (OS) were 16.7%, 1.6 mo, and 8.1 mo in Nivo arm and 0%, 1.6 mo and 6.5 mo in placebo arm. In Nivo arm with measurable lesions, PD-L1 (+) pts had significantly higher disease control rate than PD-L1 (-) pts (87.5% vs. 20%, p = 0.015). In multivariate model adjusted for important factors (age, sex, Nivo vs. placebo, treatment line, NLR, Na, and PD-L1), NLR ≤ 2.9 and PD-L1 (+) were significant factors for PFS (Hazard Ratio [HR] 0.47, p = 0.037 and HR 0.32, p = 0.006, respectively) and PD-L1 (+) was a significant factor for OS (HR, 0.44, p = 0.012). With adjusting these factors with TMB, PD-L1 (+) remained favorable for PFS and OS. Pts with NLR ≤ 2.9 or PD-L1 (+) or Na > 135 significantly favored Nivo compared to placebo in terms of PFS and OS. Conclusions: Baseline NLR and PD-L1 status may be relevant predictive markers to select pts with AGC who would benefit from Nivo.
The real-world data in patients with advanced gastric cancer treated with ramucirumab combination chemotherapy.
Authors: Kimura Akie , Sakai Daisuke , Kudo Toshihiro , Nishida Naohiro , Katou Aya , Inagaki Chiaki , Otsuru Toru , Tanaka Koji , Miyazaki Yasuhiro , Makino Tomoki , Takahashi Tsuyoshi , Kurokawa Yukinori , Yamasaki Makoto , Doki Yuichiro , Mori Masaki , Satoh Taroh
Published: January 2019

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Background: Ramucirumab with paclitaxel or ramucirumab monotherapy have shown the efficacy and safety in second-line chemotherapy for advanced gastric cancer. The previous reports have shown that neutrophil-lymphocyte ratio (NLR) was the prognostic factor for progression free survival. Methods: We conducted a retrospective review of clinical data from patients treated with ramucirumab at our institution between April 2015 to August 2018. Results: Of 90 patients, 81 received ramucirumab plus paclitaxel, and 9 received ramucirumab monotherapy. There was a significant difference of treatment line between combination therapy and monotherapy (mean 2.5 vs. 3.9, p = 0.00127). Response rate among the patients with target lesions was 18.8% (13/69), and disease control rate was 62.3% (43/69). On the other hand, response rate among the patients previously treated with nivolumab or pembrolizumab was 57.1% (4/7). Median overall survival (OS) for combination therapy and monotherapy was 10.8 months (95% confidence interval [CI] 7.1-11.9) and 5.5 months (95% CI 0.89-9.5), respectively. Grade 3 or 4 neutropenia was more common with combination therapy than with monotherapy (53.1 vs. 11.1%). Of 69 patients who received ramucirumab plus paclitaxel as second or third-line chemotherapy, high NLR (> 3) was the significant factor for poor PFS (median PFS, 2.7 vs. 5.4 months, p = 0.00103), but didn’t show the difference about OS (median OS, 9.7 vs. 11.9 months, p = 0.27). Conclusions: In our analysis, efficacy data was comparable with previous reports. In subgroup analysis, good response was observed in the group of prior nivolumab or pembrolizumab. NLR was prognostic factor for PFS, while it wasn’t show the relevance to OS because of the influence of after ramucirumab therapy.