bluuebunny/crossref_metadata_2025_split huggingface dataset:
ACCURACY: phase (P) 2 trial of AL101, a pan-Notch inhibitor, in patients (pts) with recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) with Notch activating mutations (Notchact mut).
Authors: Ferrarotto Renata , Ho Alan Loh , Wirth Lori J. , Dekel Edith , Walker Russell W. , Vergara-Silva Andrea Leninka 
Published: May 2019

TPS6098 Background: Notch signaling plays a key role in tumorigenesis. Notch cleavage by γ-secretase frees the Notch intracellular domain, which promotes the expression of target genes involved in cancer. AL101, a small molecule, is a γ-secretase inhibitor that potently inhibits Notch1-4, resulting in robust antitumor activity in vivo (PMID 26005526), including ACC xenograft models with Notchact mut (Ferrarotto, AACR 2019, Abstr 4885). Three P1 trials tested AL101 as monotherapy or in combination regimens in > 200 solid/hematologic cancer pts. In the P1 trial of AL101 monotherapy, conducted in 94 pts with advanced/metastatic solid tumors refractory to standard therapies (Tx), AL101 was generally well tolerated, with manageable AEs, and the recommended P2 dose was 4 mg IV once weekly (QW; El-Khoueiry, ASCO 2018, Abstr 2515). 4 pts had objective responses, 2 of those had Notchmut (1 of which had ACC). ACC, a rare cancer that most commonly develops in the major salivary glands, but can also arise in minor salivary glands in the trachea, lacrimal gland, and other sites, is refractory to chemotherapy, with a high recurrence rate. Notchact mut are found in a subset of ACC pts (11%–22%), with particularly aggressive disease and poor prognosis. There is no proven active treatment for R/M ACC pts (PMID 27870570). Methods: ACCURACY (NCT03691207) is an open-label, single-arm, multicenter study of AL101 (4 mg IV QW) in pts with R/M ACC (bone-exclusive disease included) with known Notch1-4act mut. Pts with disease progression within 6 months of enrollment or newly diagnosed metastatic pts are allowed; pts who received > 3 prior systemic Tx are excluded. Primary endpoint: ORR by RECIST v1.1 (or modified MDA bone criteria), by independent review committee (IRC). Secondary endpoints: ORR by investigator review (IR), duration of response by IRC and IR, PFS by IRC, OS, and safety. Per the Simon optimal design, 12 pts are enrolled in stage 1; if ≥2 pts respond, 24 additional pts are enrolled in stage 2. If ≥4 pts in stage 2 respond, the trial is deemed positive. This design yields 5% type I error rate and 80% power, if ORR is 25%. 4 of planned 36 pts have been enrolled as of 2/12/19. Clinical trial information: NCT03691207.
A phase 2 study of nivolumab (NIVO) alone or plus ipilimumab (IPI) for patients with locally advanced unresectable (laBCC) or metastatic basal cell carcinoma (mBCC).
Authors: Stein Julie E. , Brothers Patricia , Applebaum Katie , Gaskin Angela , Wang Hao , Taube Janis M. , Lipson Evan J. 
Published: May 2019

TPS9595 Background: Basal cell carcinoma (BCC) is the most common human cancer. Although laBCC and mBCC are rare (<10,000 cases per year in the US), tumors are typically locally invasive and often destroy skin and surrounding structures, leading to substantial morbidity. Standard-of-care therapies include hedgehog pathway inhibitors (HhPi) (e.g., vismodegib, sonidegib), but these medications may be poorly tolerated due to side effects (e.g., muscle spasms, alopecia, dysgeusia), and anti-tumor responses often lack durability. Several published reports have described patients with advanced HhPi-refractory BCC who experienced durable, objective tumor regressions after administration of anti-PD-1, which may be better tolerated than HhPi. The purpose of this study is to evaluate the efficacy of NIVO (anti-PD-1) alone and in combination with IPI (anti-CTLA-4) in patients with laBCC or mBCC, either in the first-line setting or after HhPi therapy. Methods: NCT03521830 is an open-label, phase 2 study of NIVO alone (cohort A) and plus IPI (cohort B) for patients with laBCC or mBCC. Subjects enrolled to cohort A (treatment-naïve or after HhPi therapy) will receive NIVO 480mg IV q4 weeks for up to 48 weeks. Subjects with progressive BCC after anti-PD-1 +/- HhPi will enroll to cohort B and receive NIVO 240mg + IPI 1mg/kg IV q3 weeks x 4 doses followed by NIVO 480mg IV q4 weeks x 7 doses. The primary endpoint is objective response rate (ORR) per RECIST v1.1. Secondary endpoints are duration of response, progression-free and overall survival, and disease control rate (i.e., % of patients with stable disease lasting ≥26 weeks or complete or partial response). Exploratory studies will include assessment of changes in immune cell subsets and immune checkpoint expression in pre- and on-treatment tumor biopsies, correlated with clinical outcomes. A Simon’s two stage design is planned for each cohort, testing for 15% null vs. 40% alternative ORR for cohort A, and 5% null vs. 20% alternative ORR for cohort B. The study will enroll up to 19 patients on cohort A and 21 patients on cohort B. Subject accrual began in November 2018. Clinical trial information: NCT03521830.
KEYNOTE-629: Phase 2 study of pembrolizumab for recurrent/metastatic or locally advanced unresectable cutaneous squamous cell carcinoma (cSCC).
Authors: Grob Jean Jacques , Gonzalez Rene , Basset-Seguin Nicole , Schachter Jacob , Vornicova Olga , Bauman Jessica Ruth , Grange Florent , Meyer Nicolas , Piulats Josep M. , Zhang Eric (Pingye) , Gumuscu Burak , Swaby Ramona F. , Hughes Brett Gordon Maxwell 
Published: May 2019

TPS9598 Background: Findings from phase 1 and 2 studies suggest that targeting programmed death 1 (PD-1)/PD-L1 pathway can provide durable antitumor activity in patients with local/regionally advanced or metastatic cSCC and may be a promising treatment option. The open-label, single-arm, phase 2 KEYNOTE-629 trial (NCT03284424) will be conducted to test the clinical activity of the PD-1 inhibitor pembrolizumab in locally advanced, unresectable, and recurrent or metastatic cSCC. Methods: Patients will receive intravenous pembrolizumab 200 mg every 3 weeks for up to 35 infusions (≤24 months) or until protocol-specified treatment discontinuation. Treatment will not be stratified in this study. Eligibility criteria include age ≥18 years; locally advanced cSCC for which the patient is ineligible for resection or radiotherapy (RT) or for which the patient previously underwent RT to the index site or systemic therapy for curative intent; presence of measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1; and Eastern Cooperative Oncology Group performance status 0 or 1. Treatment will be discontinued for progressive disease, unacceptable toxicity, intercurrent illness preventing administration, investigator’s decision, patient withdrawal of consent, pregnancy, or cessation for administrative reasons. Response will be assessed by imaging 6 weeks after treatment initiation, every 6 weeks through year 1, and every 9 weeks thereafter or more frequently if clinically indicated. After disease progression or the start of new anticancer therapy, the patient will be followed up every 12 weeks until death, consent withdrawal, or study end, whichever occurs first. Safety will be monitored throughout the study and for 30 days after treatment end or 90 days if the patient experiences serious adverse events. The primary end point is objective response rate (RECIST v1.1). Secondary end points include response duration, disease control rate, progression-free survival, overall survival, and safety. Recruitment is ongoing in 10 countries and will continue until approximately 50 additional patients with locally advanced, unresectable cSCC are enrolled. Clinical trial information: NCT03284424.
Personalized response-driven adjuvant therapy after combination ipilimumab and nivolumab in high-risk resectable stage III melanoma: PRADO trial.
Authors: Reijers Irene , Rozeman Elisa A. , Menzies Alexander M. , Van De Wiel Bart A. , Eriksson Hanna , Suijkerbuijk Karijn , Van Der Veldt Astrid Aplonia Maria , Kapiteijn Ellen , Hospers Geke , Klop Willem M.C. , Spillane Andrew , Scolyer Richard A. , Svane Inge Marie , Bastholt Lars , Schmidt Henrik , Larkin James M.G. , Van Akkooi Alexander Christopher Jonathan , Long Georgina V. , Blank Christian U. 
Published: May 2019

TPS9605 Background: Adjuvant (adj) immune checkpoint inhibition (ICI) improves relapse free survival (RFS) in stage III melanoma patients (pts). However, preclinical and translational data suggest that neo-adjuvant (neoadj) treatment might be favorable due to broader immune activation. The phase 1b OpACIN study comparing neoadj to adj IPI plus NIVO demonstrated a high pathological response rate (pRR) of 78% complicated by 90% gr 3-4 immune-related adverse events (irAEs). The phase 2 OpACIN-neo trial tested safety and efficacy of three different schemes of neoadj IPI+NIVO and identified two cycles of IPI 1mg/kg + NIVO 3mg/kg as well tolerated (20% gr 3-4 irAEs), with a high pRR of 77%. In both trials, none of the pts with a pathologic response have relapsed after a median follow-up of 30 and 8.3 months. In stage IV melanoma, long-term benefit is observed in patients achieving CR with ICI, even after cessation of therapy. This raises the question of whether a therapeutic lymph node dissection (TLND) can be omitted when a deep pathologic response with neoadj IPI+NIVO is achieved. Methods: The aim of this international multi-center investigator-initiated phase 2 PRADO extension study is to confirm the pRR and toxicity of 2 cycles of neoadjuvant IPI 1mg/kg + NIVO 3mg/kg (the preferred OPACIN-neo regimen) and to test response-driven subsequent therapy i.e. omitting surgery and adjuvant ICI based on the pathological response. 100-110 pts with stage IIIB/C melanoma and a measurable lymph node (≥15mm according to RECIST 1.1) will receive two cycles of IPI 1mg/kg + NIVO 3mg/kg after marker placement into the largest lymph node metastasis. After six weeks, pts will undergo resection of the index lymph node. For pCR/near pCR, pts will not undergo TLND; For pPR, pts will undergo TLND; and for pNR, pts will undergo TLND and start adjuvant NIVO or targeted therapy +/- radiotherapy for 52 weeks. Primary endpoints are pRR of marked lymph node and RFS at 24 months. Baseline biopsies, blood samples (week 0, 6, 12) and faeces (week 0, 6) will be collected for translational research analyses. The first patient in this trial was included in October 2018; 22 patients have been enrolled. Clinical trial information: NCT02977052.
Feasibility and Rationale for Incorporating Frailty and Cognitive Screening Protocols in a Preoperative Anesthesia Clinic
Authors: Amini Shawna , Crowley Samuel , Hizel Loren , Arias Franchesca , Libon David J. , Tighe Patrick , Giordano Chris , Garvan Cynthia W. , Enneking F. Kayser , Price Catherine C. 
Published: May 2019

BACKGROUND:
Advanced age, frailty, low education level, and impaired cognition are generally reported to be associated with postoperative cognitive complications. To translate research findings into hospital-wide preoperative assessment clinical practice, we examined the feasibility of implementing a preoperative frailty and cognitive assessment for all older adults electing surgical procedures in a tertiary medical center. We examined associations among age, education, frailty, and comorbidity with the clock and 3-word memory scores, estimated the prevalence of mild to major cognitive impairment in the presurgical sample, and examined factors related to hospital length of stay.

METHODS:
Medical staff screened adults ≥65 years of age for frailty, general cognition (via the clock-drawing test command and copy, 3-word memory test), and obtained years of education. Feasibility was studied in 2 phases: (1) a pilot phase involving 4 advanced nurse practitioners and (2) a 2-month implementation phase involving all preoperative staff. We tracked sources of missing data, investigated associations of study variables with measures of cognition, and used 2 approaches to estimate the likelihood of dementia in our sample (ie, using extant data and logistic regression modeling and using Mini-Cog cut scores). We explored which protocol variables related to hospital length of stay.

RESULTS:
The final implementation phase sample included 678 patients. Clock and 3-word memory scores were significantly associated with age, frailty, and education. Education, clock scores, and 3-word scores were not significantly different by surgery type. Likelihood of preoperative cognitive impairment was approximately 20%, with no difference by surgery type. Length of stay was significantly associated with preoperative comorbidity and performance on the clock copy condition.

CONCLUSIONS:
Frailty and cognitive screening protocols are feasible and provide information for perioperative care planning. Challenges to clinical adaptation include staff training, missing data, and additional administration time. These challenges appear minimal relative to the benefits of identifying frailty and cognitive impairment in a group at risk for negative postoperative cognitive outcome.
A função do Código de Defesa do Usuário de Serviços Públicos (Lei nº 13.460/2017) no modelo brasileiro de controle dos serviços públicos
Authors: Carvalho André Castro , Venturini Otavio 
Published: May 2019

The purpose of the Public Service User Defense Code (Federal Law No. 13.460/2017) in the Brazilian model of the control of public services O estudo pretende analisar a função do Código de Defesa do Usuário de Serviços Públicos (Lei nº 13.460/17) no modelo brasileiro de controle dos serviços públicos. Para tanto, inicialmente, analisam-se duas chaves distintivas relacionadas com modelos teóricos do controle dos serviços públicos (litigância × regulação) e da posição jurídica dos usuários dos serviços públicos (cidadão-contribuinte e cidadão-cliente). Em um segundo momento, realiza-se uma leitura do contexto brasileiro, com base na nossa evolução normativa e em pesquisas empíricas sobre o perfil e a efetividade do controle dos serviços públicos no Brasil. Por fim, busca-se compreender a função e o encaixe normativo que a Lei nº 13.460/2017 (Código de Defesa do Usuário de Serviços Públicos) poderá ter no nosso complexo modelo de controle dos serviços públicos. This article aims to present a study on the Brazilian Public Service User Defense Code (Law No. 13.460/17). In order to do so, two distinctive topics related to the theoretical models of the control of public services (litigation × regulation) and the legal position of the users of public services (citizen-centred service × customer-centred service) are analyzed. Secondly, a review of the Brazilian context based on its normative evolution and empirical research on the profile and effectiveness of the control of non- Brazilian public services is made. Lastly, the article examines the purpose of Law No. 13.460/2017 (Public Service User Defense Code) in midst of the complex model of control of public services in Brazil.
PROCESSO DE TERRITORIALIZAÇÃO NA INTEGRAÇÃO ENSINO-SERVIÇO-COMUNIDADE
Authors: MAEYAMA Marcos Aurélio , VIVAN Júlia Boron , ZAPPELINI NETTO Antônio Renor , SCHNORRENBERGER Bruna Luiza , PASSOS João Pedro Berardi , ZENONI Daniela de Araújo , VEIGA Mariana Vilela , CAMPOS Viviane dos Santos , BUENO Jéssica Lüders , COSTA Camila Bentes 
Published: May 2019

A criação do Sistema Único de Saúde traz consigo o ordenamento parareorientação dos serviços de saúde a partir do conceito ampliado de saúde. Nesse sentido, o conhecimento dos determinantes sociais de uma população é fundamental para o processo de planejamento das ações para abordagem integral do processo saúdedoença. O objetivo deste trabalho foi relatar a experiência da integração ensino-serviçocomunidade no processo de territorialização de uma área de abrangência de uma equipe de Saúde da Família. A coleta de dados foi realizada a partir da saída a campo, entrevista com informantes-chaves e sistemas de informação. Os resultados demonstraram que a população do território tem acesso a alguns determinantes sociais e privação de outros, que potencialmente podem ser determinantes para a situação da saúde atual e futura, devendo ser objeto de discussão e ação da equipe de saúde local no planejamento de ações.
Rectal Aberrant Crypt Foci in Humans Are Not Surrogate Markers for Colorectal Cancer Risk
Authors: Quintanilla Isabel , López-Cerón María , Jimeno Mireya , Cuatrecasas Miriam , Zabalza Michel , Moreira Leticia , Alonso Virginia , Rodríguez de Miguel Cristina , Muñoz Jennifer , Castellvi-Bel Sergi , Llach Josep , Castells Antoni , Balaguer Francesc , Camps Jordi , Pellisé Maria 
Published: May 2019

INTRODUCTION:
Over the past 20 years, aberrant crypt foci (ACF) have emerged as potential precursors and biomarkers for colorectal cancer (CRC). However, data regarding their molecular pathogenesis, as well as their endoscopic and histological identification, remain inconsistent.

METHODS:
A wide cohort of ACF from 100 control subjects and 100 case patients, including patients with adenoma and CRC, were characterized for endoscopic, morphologic, and molecular features.

RESULTS:
We observed that among all the endoscopic features evaluated, only the number of large ACF correlated with CRC risk (P = 0.003), whereas the histological classification, as assessed by 2 different pathologists, was inconsistent and did not differ between control and case patients. Moreover, only a few APC and BRAF mutations and no microsatellite instability were detected in our samples. KRAS mutations were detected in 16.3% of ACF samples, which also exhibited increased MGMT hypermethylation. However, none of those events were found to be predictive of CRC risk.

DISCUSSION:
Although ACF might be preneoplastic lesions of the colon, they are not suitable biomarkers for assessing CRC progression.
Short-term effect of Tramadol injection on the serum levels of Follicle Stimulating Hormone, Luteinizing Hormone and Testosterone in Male Sahel Goats in Maiduguri, Nigeria
Authors: Bako Babagana , Malami Sani , Uthman Sadiq Garba , Gana Ashiekh Lawan 
Published: May 2019

Tramadol is a synthetic analogue of codeine. Its mood elevation property and sex enhancement potentials are the main reason for its abuse. The aim of the study was to determine the short-term effect of tramadol administration on Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH) and Testosterone (TEST) levels in Male Sahel Goats. This was an experimental study conducted from 1st October 2017 to 12th November 2017 at the Livestock Teaching and Research Farm, University of Maiduguri, Maiduguri, Borno State Nigeria involving 20 Male Sahel Goats. The goats were divided in to 4 groups of 5 each; group 1 served as control and groups 2, 3 and 4 were injected intramuscularly with 4 mg/kg (low dose), 8 mg/kg (medium dose) and 12 mg/kg (high dose) of Tramadol respectively. The injections were given intramuscularly, 3 times a week for 4 weeks. Blood samples were collected to determine the serum levels of FSH, LH and TEST at 0, 1 week, 2 weeks, 3 weeks and 4 weeks of tramadol injections. The MeanÂ±SD of the hormones were computed using SPSS 20. The difference in mean was compared using t test and ANOVA with p < 0.05 set for statistical significance. The baseline levels of FSH, LH and TEST in Male Sahel Goat in Maiduguri were 2.91Â±5.74 Miu/ml, 0.29Â±0.72 Miu/ml and 3.92Â±6.39 ng/ml respectively. Only the goats in group 4 showed a significant increase in serum FSH and LH by the 4th week (P=0.01 and 0.03 respectively) while no significant change was noted in the other groups. The was a decline in the level of Testosterone from 1st week through 4th week in all the experimental group but the level in the control group remain fairly constant throughout the experiment. The decline is inversely proportional to the dose of tramadol injection and most marked in group 4.High dose and prolonged used of Tramadol should be avoided because of side effects of Hypergonadotrophic hypogonadism.Â Â
Nation and Negation (Terrible Rage)
Authors: Rebellato Dan 
Published: May 2019

Abstract
The aftermath of the Brexit referendum has revealed a deeply divided Britain, with anger on both sides and seemingly little desire to seek compromise or mutual understanding. Remainers denounce Leavers as ignorant bigots. Leavers denounce Remainers as metropolitan elitists. Theresa May went even further, characterizing supporters of open borders and free movement as ‘citizens of nowhere’ whose lack of attachment to nation suggests they simply don’t understand what citizenship means. Given the UK’s regional correlation between high levels of theatregoing and high support for Remain, this is a challenge for theatremakers and scholars. One strong feature of contemporary British playwriting is a detachment from place; in numerous recent plays, place is estranged, unspecified, annulled, orphaned, globalized, generalized, combined, relativized and scenographically anonymized. Does this represent an absence of nation? No, because this would be to accept the rigid oppositions of the Leave campaign between nations and open borders, between the local and the global. Instead, there is a restless deconstructive movement within the very identification of nation that moves to transcend it and this is captured and embodied in the heterotopic ambiguities of the spatially specific performance of the placeless play.
“Can I Tell You about It?”: England, Austerity and “Radical Optimism” in the Theatre of Anders Lustgarten
Authors: Megson Chris 
Published: May 2019

Abstract
Over the past decade, the plays of Anders Lustgarten have taken a prominent place in the English theatre repertoire. Performed by companies including Red Ladder, Cardboard Citizens, and the Royal Shakespeare Company, Lustgarten’s dramatic writing places social and political issues centrestage, ranging from the housing crisis and the electoral ascendancy of far-right parties to the alienation of the urban working class and the racist scapegoating of immigrants. This article focuses on Lustgarten’s landmark play inspired by the Occupy movement, If You Don’t Let Us Dream, We Won’t Let You Sleep (Royal Court Theatre, 2013). I explore how the play engages with, and reflects on, economic austerity, forms of contemporary mass protest, and, indirectly, evolving conceptions of English nationhood. I also examine Lustgarten’s notion of “Radical Optimism” – a term he identifies with the global anti-austerity protests following the 2007-8 financial crisis – and consider its importance to what he calls “anti-prop” political theatre. The first part of the article probes the relationship between If You Don’t Let Us Dream and the established “tradition” of state-of-the-nation playwriting; the second part identifies the play’s challenge to this “tradition,” which is informed by its proximity to the Occupy protests.
Theatricalizing the National Housing Crisis in Mike Bartlett’s Game and Philip Ridley’s Radiant Vermin
Authors: Boles William C. 
Published: May 2019

Abstract
Since the start of the new millennia, the words ‘national crisis’ have not been far removed from many of the plays on the British stage. The aftermath of 9/11 and the British government’s decision to aid George Bush’s Middle East invasion plans sparked plays by David Hare, Roy Williams, and the Tricycle Theatre’s The Great Game as well as verbatim theatre pieces. The Great Recession unleashed works by David Hare (again), Laura Wade, and Lucy Prebble, among others. The increasing threats of floods across Great Britain and Europe placed the crisis of climate change front and centre in plays by Mike Bartlett and Steve Waters. The housing crisis, while not as provocative a theatrical topic as the ones above, has also inspired theatrical responses, including Mike Bartlett’s Game and Philip Ridley’s Radiant Vermin, and these two works are the focus of my paper. More specifically, I will examine each playwright’s focus on the role of the homeless in regards to the housing crisis. Interestingly, both playwrights posit that the victimization of the homeless is the crucial solution to not only solving the housing crisis in Britain, but also maintaining the status quo of Britain’s affluent population.