bluuebunny/crossref_metadata_2025 huggingface dataset:
Why punishment pleases: Punitive feelings in a world of hostile solidarity
Authors: Carvalho Henrique , Chamberlen Anastasia
Published: March 2017

The argument advanced in this paper is that the motivation to punish relies on punishment producing a kind of solidarity that allows individuals to pursue emotional release together with a sense of belonging, without having to question or address why it is that they felt alienated and insecure in the first place. This raises the possibility that the reason why we believe punishment to be useful, and why we are motivated to punish, is because we derive pleasure from the utility of punishment. Simply stated, punishment pleases. It then analyses the relationship between punishment and solidarity to investigate why and how punishment pleases. We argue that the pleasure of punishment is directly linked to the specific kind of solidarity that punishment produces, which we call hostile solidarity. The paper explores the links between punishment and identity in order to examine the allure of hostile solidarity and then draws implications from this perspective and sets out an agenda for future research.
Talking Hospitality and Televising Ethno-national Boundaries in Contemporary Korea: Considering Korean TV Shows Featuring Foreigners
Authors: Kang Kyoung-Lae
Published: March 2017

This essay examines Korean television shows that feature foreigners encountering Korean society. A recent example, Non Summit, presents a series of formal “summits,” borrowing the format of an international strategic meeting. The show enables Koreans to consider issues involving cultural differences, racial discrimination, and national hospitality, particularly related to immigrants. Indeed, Korean TV shows that focus on foreigners living in Korea are increasingly popular, which surely reflects changes in the Korean racial imagination along with the increased number of immigrants entering Korea in recent years. Nevertheless, despite their stated purpose of encouraging Korea to be a more harmonious multicultural society, programs like Non Summit seem to reproduce racialized colonialism in the context of contemporary global capitalism, particularly through their selections of participants and their efforts to paper over revealed cultural tensions.
Supporting Simple Activity Engagement in Persons With Moderate to Severe Alzheimer’s Disease Through a Technology-Aided Program
Authors: Lancioni Giulio E. , Singh Nirbhay N. , O’Reilly Mark F. , Sigafoos Jeff , D’Amico Fiora , Pinto Katia , Chiapparino Claudia
Published: March 2017

Objectives:

These 2 studies assessed a technology-aided program to support mild physical exercise or simple occupational activity in participants with moderate to severe Alzheimer’s disease.

Methods:

Study 1 included 11 participants who were to perform a leg-raising response. Study 2 included 10 participants who were to sort objects into different containers. The program ensured that they received positive stimulation contingent on the responses and reminders/prompts after periods of nonresponding. Each study was carried out according to a nonconcurrent multiple baseline design across participants.

Results:

The program was successful in supporting mild physical exercise and activity with objects in the 2 groups of participants, respectively. The participants also showed signs of positive involvement (eg, smiles and verbalizations) during the sessions. Moreover, staff personnel rated the program and its impact positively.

Conclusion:

The program may be considered a practical resource for supporting positive engagement in persons with moderate to severe Alzheimer’s disease.
Overall Assessment of Human Research and Ethics Committees in the United Arab Emirates
Authors: Abdulrahman Mahera , Nair Satish Chandrasekhar
Published: March 2017

Growing demand for human health research in the United Arab Emirates (UAE) has prompted the need to develop a robust research ethics oversight. Examination of the structure, function, and practices of the human research ethics committees (HRECs), followed by evaluation of standards for measuring research output, was conducted. Results indicate that among the HRECs, 90% followed International Council for Harmonization–Good Clinical Practice guidelines, 66.6% have been in operation for more than 5 years, 95% reviewed proposals within 8 weeks, and 56% reviewed for scientific merit apart from ethics. However, systems to recognize accomplishments of researchers, funding transparency, and adverse event reporting were deployed in less than 30% of all HRECs. Research was incorporated into the vision and mission statements of many (65%) organizations. Research publications, collaborations, and recognitions were used to measure research output and report key performance indicators. In spite, resources to generate research output such as dedicated budget (20%), support staff (20%), and continuous training and mentoring program for medical residents (15%) and HREC members (25%) were somehow lacking. HREC structure and operations in the UAE are similar to other regions of the world. Systems to conduct research and report outcomes are defined in the UAE. Regulatory legislation and allocation of resources to support the clinical research enterprise will not only help to meet growing demand for clinical trials but also transform the quality of patient care in the UAE. It is anticipated that the results of this study will benefit investigators, regulators, pharmaceutical sponsors, and the policy makers in the region.
NextGenU.org’s Free, Globally Available Online Training in Lifestyle Medicine
Authors: Rossa-Roccor Verena , Malatskey Lilach , Frank Erica
Published: March 2017

NextGenU.org now uniquely offers a free, accredited, globally-available online training in Lifestyle Medicine. Courses such as Lifestyle Medicine for Primary Care Physicians, Prevention and Treatment of Alcohol Use Disorders/Tobacco Use, Substance Use Disorder Screening, Public Health Nutrition, and more are competency-based and include knowledge transfer, a web-based global peer community of practice, and local, skills-based mentorships. Trainings use existing, expert-created resources from governments, universities, and medical specialty societies thus ensuring their quality and simultaneously making them free of costs, advertisement, and geographic barriers. To offer free credits for these courses, NextGenU.org partners with universities and professional societies. NextGenU.org ’s comprehensive Lifestyle Medicine Curriculum will launch in early 2017.
Workplace trade union engagement with European Works Councils and transnational agreements: The case of Volkswagen Europe
Authors: Whittall Michael , Lucio Miguel Martínez , Mustchin Stephen , Telljohann Volker , Sánchez Fernando Rocha
Published: March 2017

This article examines two transnational agreements signed by the Volkswagen European and Global Works Councils, considering their interlinked implementation within subsidiaries in Britain, Italy, Spain and Germany. We demonstrate differing stances and some uncertainty towards principles of co-management, social dialogue and codetermination. These agreements have improved local industrial relations and strengthened cross-national interaction between employee representatives, despite significant differences in orientation regarding how unions should engage with management. However, the emerging international framework has not led to a clear politics of incorporation, with local trade unions being well aware of the risks of co-management and a more business-oriented relationship.
The core conditions of peer mentoring
Authors: Buck Gillian
Published: March 2017

Peer mentoring is an increasing feature of UK criminal justice, yet very little is known about the micro dynamics of this practice. Drawing upon an ethnographic study, this article identifies a number of ‘core conditions’ underpinning the practice, including caring, listening and encouraging small steps. Mentors and mentees highlight these conditions as antidotes to what they often perceive as disconnected, unhearing and technocratic criminal justice practices. Peer mentoring is claimed to release suffering, to unburden the self of grief and to explore new directions, given that mentors ‘genuinely care’ and are tolerant of slip-ups. Respondents offer valuable insight into the experience of being intervened upon and advocate for manageable shifts, which could meaningfully improve services for a range of vulnerable and stigmatized populations. However, the article also introduces tensions, including the expectation of emotional toil for little financial reward and the context of an increasingly results-driven criminal justice system.
A quasi-experimental intervention to assess the effectiveness of a physician-delivered tobacco cessation intervention in India: A detailed study protocol
Authors: Panda Rajmohan , Mahapatra Sandeep , Gaurav Kumar , Pati Sanghamitra , Mathur Manu Raj
Published: March 2017

Introduction:

Tobacco cessation is the most important, cost-effective preventive maintenance that clinicians can offer study participants who use tobacco. There is lack of preparedness among primary care physicians in delivering cessation interventions. There are also limited studies which record the effectiveness of cessation interventions in the Indian context. This study is designed to evaluate the effectiveness of brief and intensive tobacco cessation interventions delivered by trained primary care providers in two states of India.

Methods and Analysis:

A quasi-experimental study design has been adopted for the study with around 20 primary care practices, selected from four districts of two states in India (Odisha and Rajasthan). Brief (3A) and Intensive tobacco (5A) cessation intervention services will be provided to two groups of tobacco users, respectively. Both groups will be followed up for 6 months to determine the effectiveness of the cessation interventions. The cost-effectiveness of the services will also be documented at the end of the study. The entire study will be completed in 24 months, of which the final 6 months will be reserved for study participant follow-up and quit rate evaluation. When comparing the two groups, differences between proportions will be assessed by chi-square test and differences between means with t-test. The conventional significance level of 0.05 will be used in all analyses in order to reject the null hypothesis of no difference between groups. We will use difference-in-differences methods to assess the impact of the interventions on physicians’ behavior to deliver tobacco cessation in their clinical practice.

Conclusion:

The study is in participant recruitment phase.
Political Devolution
Authors: Hidayat Rachmat
Published: March 2017

The emergence of decentralization throughout the world has provoked question whether decentralization has played several important roles in fostering accountable and responsible governance. As the concept of governance expanded, so did thinking about the rationale, objectives, and forms of decentralization. Decentralization now encompasses not only the transfer of power, authority, and responsibility within the government but also the sharing of authority and resources for shaping public policy within society. One of the important reasons that drives Indonesian government to deliver a democratic decentralization is political motivation. This relates to the growing intention to local development throughout the country posed the need for political and administrative arrangement to meet the country’s diversity. This study describes and explores the nature and the process of political devolution in the context of local government in Indonesia, in particular assessing the political devolution performance in the regency of Jember. This article employs a model that combines Boex and Yilmaz and the Local Governance Barometer framework for assessing political devolution performances. The article focuses on those issues and on the opportunities for the local government to improve the most important basic needs of the people—education and health sectors in Indonesia.
School Violence Prevention
Authors: Volungis Adam M. , Goodman Katie
Published: March 2017

Although youth violence rates continue to decrease in the United States, it remains the second leading cause of death for adolescents. Furthermore, school violence remains a sociocultural concern, especially due to increasing media attention. Research consistently indicates that preventing school violence involves measures that go beyond formal protocols. One factor that has emerged from this research is that the quality of relationships between students and teachers, commonly referred to as school connectedness, may have a significant role in preventing school violence. However, there is very little literature that addresses how mental health professionals, such as school counselors, can assist teachers in fostering school connectedness with their students. This article provides a theoretical conceptualization of teacher–student relationship and communication skills that contribute to eventual school violence prevention through the development of school connectedness. The ultimate goal of this theoretical model is to provide conceptual and applied guidance in bridging the gap between research and practice.
Barriers and Facilitators to Intake of Dairy Products in Adolescent Males and Females With Different Levels of Habitual Intake
Authors: Racey Megan , Bransfield Jeanette , Capello Kathryn , Field David , Kulak Verena , Machmueller David , Preyde Michèle , Newton Genevieve
Published: March 2017

Background: Dairy products and alternatives can contribute to overall good health including positive body composition and decreased adiposity; however, these foods are grossly underconsumed by youth, and worldwide, almost 25% of children are overweight or obese. Objective: The study investigated the barriers and facilitators toward dairy consumption by Grade 7 youth. Methods: Thirty 50-minute, audio-recorded focus groups were conducted with 134 students in eight Grade 7 classes across 5 elementary schools. Focus groups were led by trained facilitators in the elementary schools and participants were separated based on dairy consumption and gender. Recorded data were transcribed and thematically analyzed using qualitative analysis software to identify themes related to barriers and facilitators to dairy product intake by each gender. Results: Factors considered important by males and females across different levels of habitual intake include personal knowledge about dairy products and misconceptions regarding dairy foods and their associated health benefits; food characteristics, including taste; personal behaviors such as habits or routines including dairy products; social environments including parental and peer influence; physical environments factors such as availability and skipping meals; and the convenience of dairy products. Interestingly, only males noted sports as a positive influence for dairy product intake. Also, there were differences in the way males and females perceived dining out as affecting their dairy intake. Conclusion: Results suggest several potential factors that nutrition education interventions aiming to increase dairy consumption could target.
Comparative cardiovascular physiology and pathology in selected lineages of minipigs
Authors: Stricker-Krongrad Alain , Shoemake Catherine , Brocksmith Derek , Liu Jason , Hamlin Robert , Bouchard Guy
Published: March 2017

The minipig has been increasingly recognized as a valid alternative to canines and nonhuman primates in regulatory toxicity. This article presents the results of cardiovascular assessments in the Yucatan, Hanford, Sinclair, and Göttingen minipigs conducted during nonclinical investigations and control toxicity testing. Cardiac electrophysiology was obtained using clinical electrocardiogram and surgical monitor units. Peripheral vessel diameter, velocity, and flow were obtained by Doppler ultrasonography, and cardiac vessel diameter was obtained postmortem. Anatomic parameters were obtained at necropsy. Histopathology assessments were conducted on heart, blood vessels, and kidneys. Collected data were compared to published cardiovascular measurements of adult humans to illustrate similarities and differences. Each lineage of minipigs was found to have specific anatomic and physiologic characteristics that may accurately reflect response of human cardiovascular systems in clinical investigations and toxicity testing. In conclusion, the interspecies similarities between the cardiovascular systems make these lineages of minipigs suitable as models for the human counterpart. In addition, these reported differences between lineages will aid investigators in selecting a relevant lineage of minipigs if specific cardiovascular parameters are required during drug safety evaluation.
Efficacy and safety of canagliflozin in patients with type 2 diabetes based on history of cardiovascular disease or cardiovascular risk factors: a post hoc analysis of pooled data
Authors: Davies Michael J. , Merton Katherine , Vijapurkar Ujjwala , Yee Jacqueline , Qiu Rong
Published: March 2017

Background

Treatment of patients with type 2 diabetes mellitus (T2DM) and a history of cardiovascular (CV) disease or CV risk factors may present clinical challenges due to the presence of comorbid conditions and the use of concomitant medications. The sodium glucose co-transporter 2 inhibitor, canagliflozin, has been shown to improve glycaemic control and reduce body weight and blood pressure (BP) with a favourable tolerability profile in a broad range of patients with T2DM. This post hoc analysis assessed the efficacy and safety of canagliflozin in patients with T2DM based on CV disease history or CV risk factors.

Methods

Analyses were based on pooled data from four 26-week, placebo-controlled, Phase 3 studies that evaluated canagliflozin 100 and 300 mg in patients with T2DM (N = 2313; mean HbA1c, 8.0%; body weight, 89 kg; systolic BP, 128 mmHg). Changes from baseline to week 26 in HbA1c, body weight, and systolic BP were assessed based on history of CV disease, history of hypertension, baseline statin use, and number of CV risk factors. Safety was assessed based on adverse event (AE) reports.

Results

At week 26, both canagliflozin doses lowered HbA1c, body weight, and systolic BP compared with placebo in patients with and without CV disease history or risk factors. Placebo-subtracted HbA1c reductions with canagliflozin 100 and 300 mg were similar in patients with a history of CV disease (−0.95 and −1.07%) versus no history of CV disease (−0.71 and −0.90%), history of hypertension (−0.72 and −0.89%) versus no history of hypertension (−0.73 and −0.95%), baseline statin use (−0.77 and −0.99%) versus no statin use (−0.69 and −0.85%), and 0–1 CV risk factor (−0.72 and −0.87%) versus ≥2 CV risk factors (−0.74 and −1.02%). Similar body weight and systolic BP reductions were seen with canagliflozin versus placebo across subgroups. The incidence of AEs, AEs leading to discontinuation, and serious AEs was similar across subgroups.

Conclusions

The efficacy and safety of canagliflozin were generally consistent across subgroups of patients with T2DM and varying degrees of CV disease history or risk factors.

Trial registration numbers and dates ClinicalTrials.gov: NCT01081834, 4 March 2010; NCT01106625, 1 April 2010; NCT01106677, 1 April 2010; NCT01106690, 1 April 2010
Comparison of response patterns in different survey designs: a longitudinal panel with mixed-mode and online-only design
Authors: Rübsamen Nicole , Akmatov Manas K. , Castell Stefanie , Karch André , Mikolajczyk Rafael T.
Published: March 2017

Background

Increasing availability of the Internet allows using only online data collection for more epidemiological studies. We compare response patterns in a population-based health survey using two survey designs: mixed-mode (choice between paper-and-pencil and online questionnaires) and online-only design (without choice).

Methods

We used data from a longitudinal panel, the Hygiene and Behaviour Infectious Diseases Study (HaBIDS), conducted in 2014/2015 in four regions in Lower Saxony, Germany. Individuals were recruited using address-based probability sampling. In two regions, individuals could choose between paper-and-pencil and online questionnaires. In the other two regions, individuals were offered online-only participation. We compared sociodemographic characteristics of respondents who filled in all panel questionnaires between the mixed-mode group (n = 1110) and the online-only group (n = 482). Using 134 items, we performed multinomial logistic regression to compare responses between survey designs in terms of type (missing, “do not know” or valid response) and ordinal regression to compare responses in terms of content. We applied the false discovery rates (FDR) to control for multiple testing and investigated effects of adjusting for sociodemographic characteristic. For validation of the differential response patterns between mixed-mode and online-only, we compared the response patterns between paper and online mode among the respondents in the mixed-mode group in one region (n = 786).

Results

Respondents in the online-only group were older than those in the mixed-mode group, but both groups did not differ regarding sex or education. Type of response did not differ between the online-only and the mixed-mode group. Survey design was associated with different content of response in 18 of the 134 investigated items; which decreased to 11 after adjusting for sociodemographic variables. In the validation within the mixed-mode, only two of those were among the 11 significantly different items. The probability of observing by chance the same two or more significant differences in this setting was 22%.

Conclusions

We found similar response patterns in both survey designs with only few items being answered differently, likely attributable to chance. Our study supports the equivalence of the compared survey designs and suggests that, in the studied setting, using online-only design does not cause strong distortion of the results.
Horizontal resolution of multichannel analysis of surface waves
Authors: Mi Binbin , Xia Jianghai , Shen Chao , Wang Limin , Hu Yue , Cheng Feng
Published: March 2017

The multichannel analysis of surface wave (MASW) method has been effectively and widely used to determine near-surface shear-wave velocity. Horizontal resolution of the MASW method represents the minimum horizontal length of recognizable geologic anomalous bodies on a pseudo-2D S-wave velocity [Formula: see text] section. Accurately assessing the achievable lateral resolution is one of the main issues in lateral variation reconstruction using the MASW method. It is difficult to quantitatively estimate the horizontal resolution of the MASW method because of the many influencing factors, such as parameters of the observation system, the depth of an anomalous body, and the velocity contrast between the anomalous body and the surrounding rocks. We first analyzed the horizontal resolution of the MASW method based on numerical simulation experiments. According to different influencing factors of the horizontal resolution, we established different laterally heterogeneous models and observation systems and then simulated several synthetic multichannel records with a finite-difference method along a linear survey line using the roll-along acquisition mode. After the extraction of dispersion curves of Rayleigh waves and inversion for S-wave velocity profiles for each synthetic shot gather, a pseudo-2D S-wave velocity section can be generated by aligning the 1D S-wave velocity models. Ultimately, we evaluated the horizontal resolution capability of the MASW method on pseudo-2D [Formula: see text] maps. Our numerical investigation results and field data analysis indicate that [Formula: see text] values on the maps are not the same as the true [Formula: see text] values for structures whose lateral dimension is shorter than a receiver spread length and that anomalous bodies, which are larger and have high velocity contrast, are easier to distinguish on [Formula: see text] maps with a shorter receiver spread length. The horizontal resolution decreases with the increasing depth and is approximately one-half of the shortest Rayleigh wavelength that can penetrate to the depth.
Detailed seismic lithofluid distribution using Bayesian stochastic inversion for a thinly bedded reservoir: A case study over Huntington UK Central North Sea
Authors: Bellatreche Kheir-Eddine , Couch Andrew , Evans Ron
Published: March 2017

A geostatistical inversion scheme was designed and performed for reservoir characterization of the UK Central North Sea (CNS) Huntington Oil field, with the goal of increasing the resolution of the seismic inversion and derived attributes, and to provide statistical measures of the uncertainties involved in the seismic facies prediction. The aim of the study was to fully understand lithology and pore-fluid rock properties in the Forties sandstone reservoir, Late Paleocene Sele Formation fan system of the UK CNS. In the Forties, multiple sand beds are separated by thin layers of silt and shale. Reprocessed prestack seismic volumes and considerable well-log data were input to an advanced stochastic simultaneous inversion method. This method combines the strengths of geostatistical inversion with sequential Gaussian simulation and Bayesian inversion. The approach allowed the inversion to be built on a fine-scale stratigraphic grid at a reservoir scale rather than at a seismic scale, and it enabled a detailed description of facies distribution and associated uncertainty. A sufficiently large number of stochastic solutions (100 realizations) enabled probabilistic models of lithofluid distribution to be generated. Facies geobody connectivity can also be derived, but this was not part of this work. As a consequence of our study, a sidetrack water injector well location was evaluated, and a potential undrilled hydrocarbon accumulation was identified, which could extend the field life of the Huntington asset.
Impact of sarcopenia on survival outcomes in patients (pts) with metastatic gastric cancer (mGC).
Authors: Sugiyama Keiji , Narita Yukiya , Mitani Seiichiro , Honda Kazunori , Masuishi Toshiki , Taniguchi Hiroya , Kadowaki Shigenori , Ura Takashi , Ando Masashi , Tajika Masahiro , Muro Kei
Published: March 2017

141

Background: Sarcopenia is a poor prognostic factor in several cancers. This study aimed to assess the predictive value of sarcopenia on survival outcomes among pts with mGC. Methods: We retrospectively analyzed 170 consecutive pts with mGC starting first-line chemotherapy at the single institution during January 2013–December 2014. Inclusion criteria were as follows: treatment with fluoropyrimidine plus platinum-based regimen, ECOG PS 0–2, and adequate organ function. Skeletal muscle index (SMI) was calculated from cross-sectional area of muscle at L3 using CT scan divided by the square of the height. Baseline sarcopenia (S) was defined as 53.4 cm2/m2 for men and 38.5 cm2/m2for women. Muscle loss after chemotherapy (L) was defined as 10% ≤ reduction in SMI. Univariate and multivariate analyses were conducted to identify whether S and L were independent prognostic factors of time to treatment failure (TTF) and overall survival (OS). Multivariate analysis included variables with p values ≤ 0.1 in univariate analyses. Results: Ninety-seven pts met the inclusion criteria; 83 (86%) were classified with S, and 39 (31%) with L. PS (0 vs. 1 and 2) and ALP (ULN> vs. ULN≤) were significantly associated with L. Overall response rate for S, non-S, L, and non-L was 60%, 63%, 63%, and 61%, respectively. S was not associated with TTF or OS. However, L was significantly associated with a shorter TTF (4.7 vs. 7.3 m, HR=1.82; 95% CI: 1.16-2.85, p=0.009) and tended toward worse OS (14.2 vs. 19.7 m, HR=1.31; 95% CI: 0.78-2.20, p=0.29). Variables with p values ≤ 0.1 in univariate analyses for TTF were L, LDH (ULN≤), ALB (ULN>), and histology (poorly differentiated). Histology was only variables with p values ≤ 0.1 for OS (p=0.002). As per multivariate analyses, only L was a significant prognostic factor of TTF. Conclusions: L is an independent negative prognostic factor of TTF in pts with mGC. Intervention for muscle loss can be a therapeutic approach for mGC. [Table: see text]
Resminostat and sorafenib combination therapy for advanced hepatocellular carcinoma in patients previously untreated with systemic chemotherapy.
Authors: Kudo Masatoshi , Ryoo Baek-Yeol , Lim Ho Yeong , Kim Do Young , Okusaka Takuji , Ikeda Masafumi , Hidaka Hisashi , Yeon Jong-Eun , Mizukoshi Eishiro , Morimoto Manabu , Lee Myung Ah , Yasui Kohichiroh , Kawaguchi Yasunori , Heo Jeong , Morita Sojiro , Kim Tae-You , Furuse Junji , Katayama Kazuhiro , Aramaki Takeshi , Tak Won-Young
Published: March 2017

252

Background: Resminostat is an oral hydroxamate-type inhibitor of class I, IIB, and IV histone deacetylases. A European Phase II study of second-line combination therapy with resminostat and sorafenib for hepatocellular carcinoma (HCC) in patients (pts) revealed a promising improvement in overall survival (OS). Here we report the findings on safety and efficacy of an Asian Phase I/II study on first-line combination therapy with sorafenib and resminostat in HCC pts. Methods: Pts with advanced or metastatic HCC considered Child-Pugh A and ECOG 0/1 were enrolled in Japan and Korea. Sorafenib was administered at 400 mg (bid) in both Phase I and II. Resminostat was administered on days 1 to 5 every 14 days. In Phase I, the dose of resminostat was escalated from 400 mg/day (DL1) to 600 mg/day (DL2). In Phase II, pts were randomly assigned to sorafenib monotherapy or sorafenib/resminostat combination therapy at a ratio of 1:1. The primary endpoint was time to progression (TTP). Tumor response was assessed according to RECIST version 1.1 every 6 weeks. Results: A total of 9 pts were enrolled in Phase I (DL1, 3 pts; DL2, 6 pts). Higher incidences of G3-4 toxicities, including one DLT (G4 thrombocytopenia), were observed at DL2. Therefore, DL1 was determined as the recommended dose for Phase II. A total of 170 pts were enrolled in Phase II. The median TTP was 2.8 months in the combination and control arm, respectively (HR: 0.984). No significant difference was observed in the median OS. Retrospective analysis revealed favorable results for the combination option in certain subgroups: for example, HBV+ (TTP: HR, 0.630; OS: HR, 0.846); no prior therapy (TTP: HR, 0.629; OS: HR, 0.590); and platelet count > = 151.000 (TTP: HR, 0.646; OS: HR, 0.509). Conclusions: Although the primary endpoint was not reached in this Phase II all-comer HCC study, the results of the subgroup analysis suggest a population-specific effect for the combination therapy, especially in one which is HBV+. This warrants the further development of this combination as first-line therapy in a well-defined subset of pts with advanced HCC. Clinical trial information: NCT02400788.
Efficacy and safety of ramucirumab (RAM) for metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma across age subgroups in two global phase 3 trials.
Authors: Muro Kei , Cho Jae Yong , Bodoky Gyorgy , Goswami Chanchal , Chao Yee , dos Santos Lucas Vieira , Shimada Yasuhiro , Topuzov Eldar , Van Cutsem Eric , Tabernero Josep , Zalcberg John Raymond , Chau Ian , Cheng Rebecca , Hsu Yanzhi , Emig Michael , Orlando Mauro , Wilke Hansjochen , Fuchs Charles S.
Published: March 2017

3

Background: REGARD and RAINBOW are two phase 3 studies which demonstrated significant survival benefits and manageable toxicity in patients with advanced gastric cancer (GC) randomized in the second-line setting to receive RAM or placebo. We examined outcomes by age (≤45, 45-70, ≥70, ≥75 years). Methods: Patients were randomized 2:1 to receive RAM 8 mg/kg + best-supportive care (BSC) or placebo (PL) + BSC (REGARD); or 1:1 RAM 8 mg/kg + paclitaxel (PTX) or PL + PTX (RAINBOW). Kaplan-Meier analysis and Cox proportional hazards regression were performed for overall survival (OS) and progression-free survival (PFS). Subpopulation treatment effect pattern plot (STEPP) assessed efficacy and the incidence of adverse events (AEs) across age subgroups. Results: Baseline characteristics were generally well balanced between arms amongst the age subgroups. Efficacy outcomes are summarized in the Table. STEPP analysis revealed no obvious patterns for differential risks in terms of efficacy and AEs (any grade or grade ≥3) according to age. Conclusions: Compared with PL, the efficacy of RAM was maintained in all age groups, with similar rates of toxicity. Despite some limitations regarding patient numbers in some age subgroups, this exploratory subgroup analysis supports the use of RAM for the treatment of GC, irrespective of age. Clinical trial information: NCT00917384 and NCT01170663. [Table: see text]
Results from a phase 2b, randomized, multicenter study of GVAX pancreas and CRS-207 compared to chemotherapy in adults with previously-treated metastatic pancreatic adenocarcinoma (ECLIPSE Study).
Authors: Le Dung T. , Ko Andrew H. , Wainberg Zev A. , Picozzi Vincent J. , Kindler Hedy L. , Wang-Gillam Andrea , Oberstein Paul Eliezer , Morse Michael , Zeh Herbert , Weekes Colin D. , Reid Tony R. , Murphy Aimee , McDougall Katherine , Whiting Chan C. , Nair Nitya , Enstrom Amanda , Ferber Sandy , Dubensky Thomas Walter , Brockstedt Dirk G. , Jaffee Elizabeth M.
Published: March 2017

345

Background: GVAX is composed of irradiated, allogeneic pancreatic cancer cells modified to express GM-CSF and induce broad tumor antigen responses. Low-dose cyclophosphamide (CY) is administered with GVAX to inhibit regulatory T cells. CRS-207 is live, attenuated, double-deleted Listeria monocytogenes(LADD) engineered to express mesothelin. CRS-207 boosts T cell responses against mesothelin and stimulates innate and adaptive immunity. In an earlier Phase 2 study in patients with mPDA, CY/GVAX + CRS-207 resulted in a significant improvement in overall survival (OS) compared to CY/GVAX alone. Methods: Patients with previously-treated mPDA were randomized 1:1:1 to receive 2 doses of CY/GVAX + 4 doses of CRS-207 (Arm A), 6 doses of CRS-207 alone (Arm B), or physician’s choice of single-agent chemotherapy (Arm C). Two cohorts were included based on number of prior lines of therapy; the primary cohort (PC) represented those with ≥ 2 prior lines. The primary objective was to compare OS between Arms A and C in the PC. Additional objectives include OS analyses between all treatment arms, safety, tumor responses and immune analyses. Results: 303 patients were enrolled: 213 in the PC and 90 in an exploratory 2nd-line cohort (SC). Common AEs associated with CRS-207 treatment included transient fevers, chills, and nausea. High dropout rates were observed in Arm C prior to treatment (40% in PC, 63% in SC). Clinical trial information: NCT02004262 . Subset and immune analyses, as well as OS data from SC, will be presented at the meeting. Conclusions: The combination of CY/GVAX + CRS-207 did not show a survival benefit over chemotherapy in patients with previously-treated mPDA, although survival of patients receiving CRS-207 alone appeared similar to chemotherapy. The regimens were well tolerated with no new significant safety findings. The high dropout rate in the chemotherapy arm demonstrates a potential challenge for conventional controls in immunotherapy trials. [Table: see text]
Updated results of a phase 1 study combining the matrix metalloproteinase 9 inhibitor GS-5745 with gemcitabine and nab-paclitaxel in patients with advanced pancreatic cancer.
Authors: Bendell Johanna C. , Patel Manish R. , Brachmann Carrie Baker , Huang Xi , Maltzman Julia D. , Smith Victoria , Vosganian Gregory Sumpao , Wainberg Zev A. , Starodub Alexander
Published: March 2017

363

Background: GS-5745 is a monoclonal antibody inhibitor of matrix metalloproteinase 9 (MMP9), an extracellular enzyme involved in matrix remodeling, tumor growth, and metastasis. We present data from patients (pts) with advanced pancreatic adenocarcinoma enrolled in an ongoing multi-indication phase 1 study (NCT01803282) evaluating GS-5745. Methods: Following a monotherapy dose finding stage, pts with locally advanced or metastatic pancreatic cancer received gemcitabine (G) + nab-paclitaxel (Abraxane, A) and GS-5745 800 mg IV every 2 weeks. Treatment continued until disease progression, unacceptable toxicity or withdrawal of consent. Response was assessed every 8 weeks per RECIST version 1.1 criteria. Results: As of April 2016, 36 pts were enrolled (1 continues to receive GS-5745). The most frequently observed adverse events (AEs) of any grade include fatigue (75%), alopecia (55.6%), peripheral edema (55.6%) and nausea (50%). Grade ≥ 3 AEs observed in ≥ 10% of pts included neutropenia (25%), anemia (19.4%) and fatigue (13.9%). The median progression free survival (PFS) for all pts is 7.8 (90% confidence interval (CI) = [6.1, 11]) months (mos), median duration of response (DOR) is 5.8 mos and the objective response rate (ORR) is 44.4%. Of the 31 pts who were treatment naïve in the metastatic setting, median PFS is 9.2 (90% CI = [6.1, 11]) mos, median DOR 5.8 mos and the ORR 51.6%. Median baseline circulating MMP9 was 44.3 (range 12.4-549.6) ng/mL and 31 of 32 patients with post-baseline samples had undetectable MMP9 levels within 8 weeks. Conclusions: GS-5745+GA demonstrated numerically higher ORR and PFS compared to historical data without additional toxicity. Additionally, reductions in circulating MMP9 levels post treatment suggest target engagement by GS-5745 . These results suggest this combination may warrant additional study in first line metastatic pancreatic adenocarcinoma. Clinical trial information: NCT01803282.
Randomized, open-label trial of gemcitabine/nab-paclitaxel (G/NP) ± pamrevlumab (P) as neoadjuvant chemotherapy in locally advanced, unresectable pancreatic cancer (LAPC).
Authors: Picozzi Vincent J. , Rocha Flavio G. , Helton Scott , Pishvaian Michael J. , Jackson Patrick G , Mody Kabir , Asbun Horacio , Carney Mairead , Etheridge Tina , Neff Thomas B , Porter Seth , Zhong Ming , Valone Frank , Kouchakji Elias , Imperial Joanne C. , Carrier Ewa
Published: March 2017

365

Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by dense stroma and connective tissue growth factor (CTGF) overexpression. Although prolonged overall survival (OS) can be achieved through resection, only approximately 15% to 20% of patients are treated with surgery. Previously, pamrevlumab (P), a fully human monoclonal antibody blocking CTGF, was combined with gemcitabine/erlotinib (G/E) in a study of advanced PDAC. P plasma levels of > 150 μg/mL and low baseline CTGF levels resulted in prolonged OS. We hypothesize that neoadjuvant (NA) treatment of LAPC with P + G/nab-paclitaxel (NP) may alter LAPC’s stroma, increase R0 resectability, and improve OS similar to that of patients resectable at presentation. Methods: LAPC subjects, confirmed by NCCN criteria and staging laparoscopy, were randomized 2:1 to G/NP ± P for 6-cycle/24-week treatment. Safety and efficacy (resection rate, OS, progression-free survival, tumor response) were assessed. Resection was performed in subjects who met protocol-defined criteria with no contraindications. Results: As of 26 Sep 2016, 25 subjects were enrolled. Of 14 subjects in Arm A (G/NP + P), 7 completed, 2 discontinued. Of 11 subjects in Arm B (G/NP), 4 completed, 4 discontinued. 6 subjects (43%) in Arm A and 4 (36%) in Arm B experienced SAEs; no P-related SAEs were reported. Out of 7 eligible Arm A subjects, 3 were not resected. Successful resection was achieved in 4 Arm A subjects (3 R0, 1 R1) and 1 Arm B subject (R0) (Table). Conclusions: The combination of G/NP + P is feasible and well-tolerated with no incremental safety signals in this study. The addition of P suggests a trend toward increased resectability among LAPC subjects. Clinical trial information: NCT02210559. [Table: see text]
Pertuzumab + trastuzumab for HER2-positive metastatic biliary cancer: Preliminary data from MyPathway.
Authors: Javle Milind M. , Hainsworth John D. , Swanton Charles , Burris Howard A. , Kurzrock Razelle , Sweeney Christopher , Meric-Bernstam Funda , Spigel David R. , Bose Ron , Guo Shuangli , Bernaards Coen , Beattie Mary Stanley , Scappaticci Frank A. , Hurwitz Herbert
Published: March 2017

402

Background: Biliary cancers have a high mortality rate, with limited treatment options. While HER2 is overexpressed in 9-20% of biliary cancers, it has not been fully explored as a therapeutic target. MyPathway is a multi-basket study evaluating the efficacy and safety of targeted therapies in non-indicated tumor types harboring relevant genetic alterations. We present preliminary data for patients with HER2-positive metastatic biliary cancer receiving HER2-targeted treatment with pertuzumab + trastuzumab. Methods: MyPathway (NCT02091141) is an open-label, multicenter, phase IIA study. Patients in this subset analysis had refractory metastatic biliary cancer with HER2 amplification/overexpression or putative activating mutations by gene sequencing, FISH, or IHC. Patients received standard doses of pertuzumab + trastuzumab until disease progression or unacceptable toxicity. The primary endpoint is investigator-assessed overall response rate (RECIST v1.1). Results: As of July 31, 2016, 11 patients with HER2-positive biliary cancer (HER2-amplified/overexpressed, n = 8; HER2-mutated, n = 3 [D277Y, S310F, and A775-G776insYVMA]) have been enrolled. At a median follow-up of 4.2 (range 2.0–12.0) months, 4 patients had partial responses (PR) and 3 had stable disease (SD) for > 4 months (Table). Safety was consistent with the package inserts. Conclusions: Preliminary results indicate that pertuzumab + trastuzumab has activity in HER2 amplified/overexpressed/mutated metastatic biliary tumors, suggesting HER2 as a therapeutic target for these rare cancers. Accrual to MyPathway is ongoing. Clinical trial information: NCT02091141. [Table: see text]
Comparative effectiveness of initiating colorectal cancer (CRC) screening (Scr) at age 45.
Authors: Barzi Afsaneh , Siegel Rebecca , Fedewa Stacey A. , Lenz Heinz-Josef , Quinn David I. , Jemal Ahmedin , Sadeghi Sarmad
Published: March 2017

531

Background: The incidence of CRC in age group 45-50 is rising based on SEER data. We investigated the outcomes of lowering Scr age to 45 from a societal perspective. Methods: A Markov model was built to represent the natural history and incidence of CRC in US general population (GP). Individual level simulation was used to compare 14 Scr strategies (ST). Effectiveness in life years (LY) & number of prevented (Prev) CRCs, and costs in US$ ($) inclusive of CRC Scr and treatment were measured. LY and $ were discounted at 3%. Incremental cost effectiveness ratios (ICERs) were calculated. Individuals in a cohort of GP aged 45-75 were followed for up to 35 years with Scr starting at age 50 (@50) or 45 (@45). Results: Colonoscopy (CS) @50 ranked 1 with the highest LY and lowest $ & ICER followed by CS @45 (ranked 2) with an ICER of $23074. All other STs had lower LY & higher $ and were dominated by CS. By starting Scr @45, the number of Prev CRC increased favoring Scr @45. LY changes were minimal but favored Scr @45. When CS was removed from Scr options, Fecal Occult Blood Test (FOBT) @45, CT Colonography (CT) every 10 years @50 and CT every 5 years @45 dominated remaining STs with ICERs of $0, $5585, and $31058, respectively. When CT and FOBT were removed from Scr options, FOBT+FS @45 and DNA @45 dominated remaining STs with ICERs of $0 and $650790, respectively. Results remained stable in sensitivity analyses. Conclusions: LY, Prev CRC improved as a result of Scr @45. When dominating STs were sequentially removed, STs beginning @ 45 remained cost effective with ICERs of <$50,000. The advantages of @45 are the result of earlier start and longer duration of Scr. Of note, DNA was not cost effective with ICER of >$650K after CS and CT were removed from calculations. [Table: see text]
Rectal versus left-sided colon cancers: Clinicopathological differences observed in a pooled analysis of 4,182 patients enrolled to 8 clinical trials from the ARCAD database.
Authors: Salem Mohamed E. , Yin Jun , Renfro Lindsay A. , Weinberg Benjamin Adam , Maughan Tim , Adams Richard , Van Cutsem Eric , Falcone Alfredo , Tebbutt Niall C. , Seymour Matthew T. , Diaz-Rubio Eduardo , Aranda Enrique , Bokemeyer Carsten , Heinemann Volker , De Gramont Aimery , Grothey Axel , Marshall John , Sargent Daniel J.
Published: March 2017

675

Background: Recent retrospective analysis of CALGB/SWOG 80405 showed that left-sided colon cancers (LCC) respond differently to biological therapy compared with right-sided tumors. However, differences between rectal cancers (RC) and LCC remain undefined. Herein, we report our exploration of differences between these two groups. Methods: Individual patient data from 4182 patients (pts) with metastatic colorectal cancers, enrolled onto 8 first-line randomized trials, were pooled. Only pts with tumor locations that were clearly defined as LCC (splenic flexure to sigmoid) or RC were included in this analysis. Differences in pt characteristics and disease factors according to LCC vs. RC were identified. The prognostic effect of primary tumor location on OS and PFS was quantified via multivariable Cox proportional hazards modeling stratified by treatment arm within each study and adjusting for age, sex, performance status, and prior surgery. Results: In total, 2,479 (59%) pts with LCC and 1,703 (41%) pts with RC were identified. Pts with RC, compared with LCC, were more likely to be male (68% vs. 62%, p < 0.001), have lung metastases (mets) (56% vs. 37%, p < 0.001), and have 2 or more metastatic sites (64% vs. 60%, p < 0.02), whereas pts with LCC were more likely to have liver mets (84% vs. 76%, p < 0.001). RC had a greater frequency of KRAS mutations (41% vs. 37%, p = 0.04) than LCC but there were no differences in the frequency of BRAF mutations (5% vs. 4%, p = 0.2). In multivariable analysis, no differences in OS or PFS were observed between pts with LCC vs. RC. While risk of death did not differ by primary tumor location, across all pts with LCC or RC, those with liver mets had a 17% increased risk of death compared to those with lung mets (HR = 1.17, p = 0.03) after adjusting for effects of other variables. Forthcoming prognostic analysis of LCC vs. RC within grouped backbone treatments (e.g., FOLFOX and FOLFIRI) is underway. Conclusions: Tumors arising in the rectum may carry clinical and molecular features that are distinct from LCC. Further investigations are warranted to determine whether RC should be treated with the same chemo backbone and biological therapy as LCC.
Optimal prophylactic method of venous thromboembolism for gastrectomy in Korean patients: Prospective randomized controlled trial.
Authors: Jung Yoon Ju , Song Kyo Young , Seo Ho Seok , Park Cho Hyun
Published: March 2017

7

Background: This study was conducted to evaluate the incidence of VTE after surgery gastric cancer patients and determined the optimal method of thromboembolic prophylaxis in Korean patients. Methods: In this trial, 682 patients were assigned to 2 groups; an intermittent pneumatic compression (IPC) with or without 40 mg of enoxaparin. The primary outcome was VTE incidence within 30 days of surgery; defined as deep vein thrombosis (DVT) or documented pulmonary thromboembolism (PTE). The duration of follow-up was 6 months. Results: The primary outcome was assessed in 666 patients. The overall incidence of VTE was 2.10%; that of IPC group was significantly higher than the IPC plus enoxaparin group. Among 14 patients with VTE; 13(92.8%) patients were diagnosed with asymptomatic DVT, 1 patient was diagnosed with PTE. The incidence of bleeding complication was significantly higher in IPC plus enoxaparin group. By month 6, no patient died. Conclusions: Although the incidence of VTE was significantly lower in IPC plus enoxaparin group, symptomatic event was extremely rare and no mortality was observed. In Korean patient with gastric cancer does not need conventional prophylaxis using heparin because of the extremely lower incidence of symptomatic VTE and relatively higher incidence of bleeding complication. Clinical trial information: NCT01448746. [Table: see text]