tbuckley/cabot-search huggingface dataset:
A phase I, open-label, multicenter dose escalation study to assess the safety, tolerability, and pharmacokinetics of AZD2811 nanoparticle in patients with advanced solid tumors.
Authors: Melissa Lynne Johnson, Judy Sing-Zan Wang, Gerald Steven Falchook, Julie Charlton, Alexander MacDonald, Donald Strickland, Suzanne Fields Jones, Elizabeth J. Pease, Wolfram Brugger, Howard A. Burris
Journal: Journal of Clinical Oncology (2018)

2592 Background: Aurora kinases represent potential targets for anticancer therapy in solid tumors and hematological malignancies. The aurora B kinase inhibitor AZD1152 (barasertib) has shown benefit in patients (pts) with untreated AML versus low-dose AraC when given as a 7-day continuous infusion. AZD2811 nanoparticle is a novel, encapsulated slow release inhibitor of aurora kinase B which offers several advantages compared to AZD1152 (Ashton S et al., Sci Transl Med 2016). AZD2811 nanoparticle mimics the AZD1152 7-day continuous infusion as a 2-hr infusion on Day 1 and 4, and resulted in increased efficacy preclinically. We report the first-in-man dose-escalation of AZD2811 in pts with advanced solid tumors (NCT02579226). The objectives were to determine the MTD, safety profile, dosing schedule and preliminary efficacy of AZD2811. Methods: Adult pts with advanced solid tumors were given AZD2811 nanoparticle IV on Day 1 and 4 every 28 days. Pts were enrolled according to a standard 3+3 design. Pharmacokinetics (PK) were assessed in cycle 1. Results: 24 pts were treated in 6 cohorts: 15 mg (3 pts), 25 mg (3 pts), 38 mg (3 pts), 51 mg (3 pts), 100 mg (3 pts) and 200 mg (9 pts). Of those 24 pts, 20 pts discontinued due to disease progression, (1 pt) due to death, (1 pt) withdrew consent (1 pt), physician’s decision. Preliminary efficacy indicated one confirmed ongoing partial remission in cohort 6 at 16 months. In Cohorts 1-5, common treatment-related AEs (any grade) were diarrhea, nausea, and fatigue; in Cohort 6 (200 mg per infusion) common treatment-related AEs (any grade) were fatigue, decreased appetite, and neutropenia (5 pts, all grade 4 including 1 DLT of > 7 days without G-CSF), an expected pharmacodynamics marker of target engagement. There were no infections, fever of unknown origin or treatment-related deaths. AZD2811 total blood PK appear dose proportional with a t1/2 of 30-50 hours. Conclusions: AZD2811 nanoparticle is safe and well tolerated at a dose of 200 mg Day 1 and 4 every 28-days. A single day 1 infusion once every 21 days with G-CSF is also being investigated. Further safety and updated efficacy data will be reported at the annual meeting. Clinical trial information: NCT02579226.
<i>MDM2</i> amplification (Amp) to mediate cabozantinib resistance in patients (Pts) with advanced <i>RET</i>-rearranged lung cancers.
Authors: Romel Somwar, Roger Smith, Takuo Hayashi, Kota Ishizawa, Alexandra Snyder Charen, Inna Khodos, Marissa Mattar, Jie He, Sohail Balasubramanian, Phil Stephens, Doron Lipson, Elisa de Stanchina, Monika Davare, Vincent A. Miller, Gregory J. Riely, Charles M. Rudin, Mark G. Kris, Emily Cheng, Marc Ladanyi, Alexander E. Drilon
Journal: Journal of Clinical Oncology (2016)

9068 Background: The RET inhibitor cabozantinib is active in pts with RET-rearranged lung cancers. We previously reported an overall response rate of 38% on an ongoing phase 2 study (Drilon ASCO 2015), implying that a proportion of tumors may harbor intrinsic resistance. Furthermore, tumors that respond eventually progress due to the development of secondary resistance. Molecular mechanisms that underlie resistance to cabozantinib are poorly understood. Methods: Paired pre- and post-treatment tumor biopsies were obtained from pts with RET-rearranged lung cancers treated with cabozantinib on our phase 2 trial (NCT01639508) or off-protocol. Broad, hybrid-capture NGS (MSK-IMPACT/FoundationOne) was performed to identify concurrent genomic alterations. RET-rearranged cell lines and xenografts were treated with cabozantinib and the MDM2 inhibitors AMG232 and RG7388. Results: NGS was performed on 16 pre- and 6 post-cabozantinib tumor samples. De-novo MDM2 (p53 antagonist) amp or TP53 mutation were identified in pre-treatment tumors from 8/16 (50%) pts. Acquired MDM2 amp was identified in post-cabozantinib recurrences from 2/4 (50%) pts with paired samples who developed resistance. In a separate group of 3,842 lung cancer pts, NGS detected concurrent MDM2 amp in 20% of tumors with RET fusions (p < 0.01). A cell line and xenograft were established from a pt with a TRIM33-RET+ tumor that developed acquired MDM2 amp after progression on cabozantinib. MDM2 inhibitors reduced cell line growth (IC50 0.07µM AMG232, 0.02µM RG7388), induced expression of p53-dependent genes, and activated caspase 3/7 in a p53- and PUMA-dependent manner. Growth was suppressed 60-90% by shRNAs targeting MDM2. Xenograft treatment with AMG232 or RG7388 resulted in 60-90% tumor volume reduction. A combination of cabozantinib and AMG232 was more effective at suppressing tumor growth than either agent alone. Ectopic MDM2 expression in NIH-3T3 cells transformed with CCDC6-RET resulted in reduced cabozantinib sensitivity. Conclusions: MDM2 amplification is a potential mechanism of primary or acquired resistance to cabozantinib. MDM2 inhibitors in clinical development can be employed as viable targeted therapeutics.
Expanding the search for significant EGFR mutations in NSCLC outside of the tyrosine kinase domain (TKD) with next-generation sequencing (NGS).
Authors: Matthew K Stein, Lindsay Kaye Morris, Jennifer Sullivan, Moon Jung Fenton, Ari M. Vanderwalde, Lee Steven Schwartzberg, Michael Gary Martin
Journal: Journal of Clinical Oncology (2017)

e20506 Background: While conventional organization of EGFR mutations in NSCLC includes classic lesions sensitive to tyrosine kinase inhibitors (TKI) and variants localized to TKD in exons 18-21, NGS raises the prospect of identifying clinically relevant variants in extra-TKD regulatory regions. Methods: Patients (pts) with lung cancer who received tumor profiling with NGS from 2013-2015 via Caris were identified. EGFR mutations were arranged based upon their known distribution relative to the TKD. In silico analysis was performed with PolyPhen-2 (Harvard) to predict nsSNPs’ pathogenicity. Results: 259 pts (248 NSCLC, 11 SC) had median age 65 years (26-85); 50% female; 64% white, 34% black; 73% with ≥20 pack-years (py), 12% non-smokers; 53% of samples were metastases. 65% NSCLC were adenocarcinoma (A), 21% squamous (S), 8% large-cell; 87% stage IV, 12% III. 44 EGFR variants were seen in 40 pts (15%; 39 NSCLC, 1 SC). While 32 pts had TKD lesions demonstrable through standard testing, 8 had extra-TKD mutations (8/44), of which 5 were extracellular domain (ECD), 1 juxtamembrane (JM) and 2 carboxy terminal (CT). Aside from pathogenic ECD mutation G598V, 5/7 extra-TKD nsSNPs were predicted-damaging (pnsSNP) with in silico (Table 1). 7/7 extra-TKD nsSNP+ pts smoked (6/7 ≥20 py) and all 6 NSCLC pts were stage IV; 50% A, 17% S; 83% male. The pt with JM R675Q had erlotinib, 150 mg daily, added following progression of stage IV NSCLC on carboplatin and paclitaxel and had a partial response for 4 months. No other pt received EGFR-directed therapy. Conclusions: 2% NSCLC cases in our cohort had EGFR pnsSNPs located outside of the TKD, representing &gt;18% of all EGFR mutations. Extra-TKD variants should be characterized collaboratively to determine TKI sensitivity and additional therapeutic targets. [Table: see text]
P01.039 Development of signaling questions assessing distress and quality of life in glioma patients - Results of 50 interviews and an expert analysis
Authors: M Renovanz, H Voß, P Scholz-Kreisel, F Ringel, S Singer, J Coburger
Journal: Neuro-Oncology (2018)

Due to cognitive or physical limitations, glioma patients might not be able to validly complete self-reporting tools assessing quality of life, distress, and unmet needs. This not only impairs individual patient care and therapy monitoring but also creates bias in studies applying patient reported outcome measures (PROMs). In our study, we searched for signaling questions implementable in patient-doctor consultations in order to optimize the assessment. We performed 1) a literature research to find out the most important questions for glioma patients that are also covered by standard questionnaires. 2) After a pretest in n=10 patients, we performed structured interviews in n=50 patients in an outpatients setting and 3) an online expert survey. Inclusion criteria for the patients were cerebral glioma, understanding German language and legal capacity, exclusion criterion was aphasia. Patients and experts estimated the most important items and questions of psychosocial topics on a Likert scale (0–6). Patients responded to whether the item afflicted them during the last week or not. Further, demographic and clinical data were obtained. Applying a weighted scoring procedure based on experts’ and patients’ ratings as well as whether or not the items affected the patients, we identified the three most important main topics. From July to October 2017, n=96 eligible patients were approached and n=51 were interviewed. Mean age was 56 years (range 30–79), n=35 patients were male and n=46 patients (90%) had a high-grade glioma. Mean time of interview was 17min (range 9-35min). Patients indicated the topics “cognitive”, “mental” and “physical problems” as well as “problems concerning job and free time” to be nearly equally important with emphasis on the issues “fatigue” and “future uncertainty”. N=36 experts (neuro-oncologists) participated; we observed a tendency towards “physical” and “cognitive problems” with emphasis to “seizure” and “depressive symptoms”. Weighted scoring procedure revealed the following signaling main questions: “Has your mood worsened within the last week?”, “Are you strained by physical changes?”, “Do you have memory problems?”. Our study indicated 3 areas most important for patients with gliomas: cognitive, physical and mental problems. The corresponding signaling questions could be implemented in clinical consultation.
Abstract P017: Serum Vitamin D, Sex Hormones, and Erectile Dysfunction in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Di Zhao, Pamela Ouyang, Ian H De Boer, Pamela L Lutsey, Youssef M Farag, Eliseo Guallar, David Siscovick, Wendy S Post, Michael J Blaha, Rita R Kalyani, Kevin L Billups, Erin D Michos
Journal: Circulation (2016)

Background: Activated Vitamin D regulates testosterone (T) and estradiol (E2) synthesis. 25-hydroxyvitamin D [25(OH)D] deficiency has been associated with low T levels in men with conflicting associations described in women. Low 25(OH)D is associated with increased cardiovascular (CVD) risk and possibly with erectile dysfunction (ED) in men. We examined the association of 25(OH)D with sex hormones (SH) in men and women and with ED in men in a multi-ethnic cohort (mean age 63 yrs). Methods: 25(OH)D,T, E2, dehydroepiandrosterone (DHEA), and SH binding globulin (SHBG) levels were measured at MESA exam 1 (2000-2002), and bioavailable T calculated. Self-reported ED was recorded at exam 5 (2010-2012). Using linear regression, we evaluated the multivariable adjusted cross-sectional associations of 25(OH)D and SH separately by sex. Among men, we used logistic regression to assess the association of 25(OH)D with odds of low T&lt;10.41 nmoI/L (300 ng/dl) [9.4%] at exam 1 and with ED at exam 5. Results: After adjusting for demographic and lifestyle variables, higher 25(OH)D levels were associated with greater total T and SHBG in men and with greater E2, SHBG, and lower bioavailable T and DHEA in women [ Table ]. Compared to ≥30 ng/ml, 25(OH)D deficiency (&lt;20 ng/ml, 31% men and 32% women) was associated with increased odds of low T in men in age/race model [1.37 (1.05, 1.77)] but was attenuated after adjusting for lifestyle variables [1.19 (0.91, 1.55)]. Among 1796 men with 25(OH)D and T at exam 1, 45% were found to have ED at exam 5. Neither 25(OH)D deficiency nor low T was associated with ED. In all analyses, results were similar after further adjusting for CVD risk factors. Conclusion: Higher 25(OH)D levels were associated with higher SHBG in both men and women, greater T in men, and greater E2 and lower DHEA in women independent of adiposity and lifestyle. 25(OH)D deficiency and low T were not associated with prevalent self-reported ED assessed 10 years later. Future studies are needed to determine if treating low vitamin D can influence sex hormone levels.
Prioritizing research areas for antibiotic stewardship programmes in hospitals: a behavioural perspective consensus paper
Authors: M. Rzewuska, E. Charani, J.E. Clarkson, P.G. Davey, E.M. Duncan, J.J. Francis, K. Gillies, W.V. Kern, F. Lorencatto, C.A. Marwick, J. McEwen, R. Möhler, A.M. Morris, C.R. Ramsay, S. Rogers Van Katwyk, B. Skodvin, I. Smith, K.N. Suh, J.M. Grimshaw
Journal: Clinical Microbiology and Infection (2018)

<h2>Abstract</h2><h3>Scope</h3> Antibiotic stewardship programmes (ASPs) are necessary in hospitals to improve the judicious use of antibiotics. While ASPs require complex change of key behaviours on individual, team organization and policy levels, evidence from the behavioural sciences is underutilized in antibiotic stewardship studies across the world, including high-income countries (HICs). A consensus procedure was performed to propose research priority areas for optimizing effective implementation of ASPs in hospital settings using a behavioural perspective. <h3>Methods</h3> A workgroup for behavioural approaches to ASPs was convened in response to the fourth call for leading expert network proposals by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR). Eighteen clinical and academic specialists in antibiotic stewardship, implementation science and behaviour change from four HICs with publicly funded healthcare systems (e.g. Canada, Germany, Norway and the UK) met face-to-face to agree on broad research priority areas using a structured consensus method. <i>Question addressed and recommendations</i>: The consensus process assessing the ten identified research priority areas resulted in recommendations that need urgent scientific interest and funding to optimize effective implementation of ASPs for hospital inpatients in HICs with publicly funded healthcare systems. We suggest and detail behavioural science evidence–guided research efforts in the following areas: (a) comprehensively identifying barriers and facilitators to implementing ASPs and clinical recommendations intended to optimize antibiotic prescribing; (b) identifying actors ('who') and actions ('what needs to be done') of ASPs and clinical teams; (c) synthesizing available evidence to support future research and planning for ASPs; (d) specifying the activities in current ASPs with the purpose of defining a control group for comparison with new initiatives; (e) defining a balanced set of outcomes and measures to evaluate the effects of interventions focused on reducing unnecessary exposure to antibiotics; (f) conducting robust evaluations of ASPs with built-in process evaluations and fidelity assessments; (g) defining and designing ASPs; (h) establishing the evidence base for impact of ASPs on resistance; (i) investigating the role and impact of government and policy contexts on ASPs; and (j) understanding what matters to patients in ASPs in hospitals. <h3>Conclusions</h3> Assessment, revisions and updates of our priority-setting exercise should be considered at intervals of 2 years. To propose research priority areas in low- and middle-income countries, the methodology reported here could be applied.
Primary non-Hodgkin lymphoma of testis: Clinical and morphological features.
Authors: Sotnikova Olga, Poddubskaya Elena, Sletina Svetlana, Irina Kovalenko
Journal: Journal of Clinical Oncology (2018)

e19523 Background: Primary testis lymphoma approximately 5% of all tumors of testis and 2-4% of all extranodal lymphomas. The objective was to identify differences in the clinicomorphological features of this type lymphoma. Methods: 486 patients with primary extranodal non-Hodgkin’s lymphomas were observed in N.N.Blokhin NMCO since 2000 to 2017, 54 patients (11,1% of all extranodal lymphomas) were affected by primary lymphoma of testis. The involvement of both testicles was in 11 cases (20,4%). The diagnosis was made after orchidectomy in all cases with following immunohystochemical investigation. Results: Median of observation was 37 months. Age at time of diagnosis ranged from 21 to 79 years (the median age - 59 years). 22 patients (40,7%) were younger 60 age. The association of preceding orhitis and lymphoma has been found in 3 cases (5,6%). Bulky disease was exposed in 20 cases. Predominant histological type was diffuse large B-cell lymphoma (DLBCL) – 46 (85,2%) cases. T-cell lymphoma – 1 (1,9%), Burkitt lymphoma - 2 (3,7%), follicular type 3 = 4 (7,4%). In 1 case histological type was not determined. IV stage of disease was constituted in 20 cases (37%) including lymphomas, which were diagnosed in generalization phase –16 (29,6%) and bilateral affection. IE stage was determined in 17 cases (31,5%), IIE stage- in 10 (18,5%), IIIE – 7 clinical cases. 6 patients (11,1%) had B-symptoms. In accordance to parameters of ECOG: 0-1 mark - 29%, 2 - 40%, 3 - 27,4%, 4 – 3,2%. In accordance to parameters of International Prognostic Index 21 patients (38,9%) were attributed to poor prognostic group and had high risk of progressive disease. 33 (61,1%) patients had favorable prognosis. LDG level exceeding normal index was in 24 (44,4%) cases. Level of Hb less 12g/l was in 24 cases (44,4%). Conclusions: Median of observation was only 37 months. About 1/2 of patients was younger 60 age. Predominant histological type was diffuse large B-cell lymphoma (DLBCL). In accordance to parameters of ECOG: 0-1 mark were 29% cases and 61,1% patients had favorable prognosis
PRISMA Extension for Scoping Reviews (PRISMA-ScR): Checklist and Explanation
Authors: Andrea C. Tricco, Erin Lillie, Wasifa Zarin, Kelly K. O'Brien, Heather Colquhoun, Danielle Levac, David Moher, Micah D.J. Peters, Tanya Horsley, Laura Weeks, Susanne Hempel, Elie A. Akl, Christine Chang, Jessie McGowan, Lesley Stewart, Lisa Hartling, Adrian Aldcroft, Michael G. Wilson, Chantelle Garritty, Simon Lewin, Christina M. Godfrey, Marilyn T. Macdonald, Etienne V. Langlois, Karla Soares-Weiser, Jo Moriarty, Tammy Clifford, Özge Tunçalp, Sharon E. Straus
Journal: Annals of Internal Medicine (2018)

Scoping reviews, a type of knowledge synthesis, follow a systematic approach to map evidence on a topic and identify main concepts, theories, sources, and knowledge gaps. Although more scoping reviews are being done, their methodological and reporting quality need improvement. This document presents the PRISMA-ScR (Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews) checklist and explanation. The checklist was developed by a 24-member expert panel and 2 research leads following published guidance from the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) Network. The final checklist contains 20 essential reporting items and 2 optional items. The authors provide a rationale and an example of good reporting for each item. The intent of the PRISMA-ScR is to help readers (including researchers, publishers, commissioners, policymakers, health care providers, guideline developers, and patients or consumers) develop a greater understanding of relevant terminology, core concepts, and key items to report for scoping reviews.
SAT0208 How good elderly rheumatoid arthritis patients respond at first year of treatment with certolizumab pegol?
Authors: V. Torrente-Segarra, M. Fernandez Prada, R. Expósito, N. Garrido Puñal, A. Sánchez-Andrade, J. R. Lamúa-Riazuelo, A. Olivé, J. V. Tovar
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> In rheumatoid arthritis (RA), the efficacy and safety of Certolizumab pegol (CZP) is well stablished, as reported in randomized clinical trials (RCT)<sup>1</sup> and some registries<sup>2</sup>. Only the 30% of RA patients are within the age range of 65 years or older. However, they are usually excluded from the RCT. Aging is associated with declining immune cell function and age-related comorbidities<sup>3,4</sup>. <h3>Objectives:</h3> The aim of this study was to determine the effectiveness and safety of CZP in elderly patients in a real world setting at 12 months follow-up. <h3>Methods:</h3> Observational longitudinal prospective study of RA patients from 40 sites in Spain. Variables (baseline, 3- and 12-month assessment): socio-demographics, smoking status, previous synthetic DMARD (sDMARD) and biological DMARD (bDMARD) use; TJC, SJC, ESR, CRP, DAS28. Response variables EULAR Moderate/Good Response and DAS28 remission and Safety were assessed. Low Disease Activity as DAS28 remission or mild DAS28. Descriptive, comparative and Logistic regression analyses were performed comparing &lt;65 vs. &gt;65 yr population. Kaplan-Meier survival curve was performed. <h3>Results:</h3> A total of 501 RA patients were included, 23% were aged ≥65 yr (mean age 70.8 (±4.5 SD)yr). Sociodemographics and baseline features are shown in table 1. Efficacy variables are shown in table 2. <h3>Conclusions:</h3> The effectiveness of CZP among ≥65 yr only differed from their younger counterparts from DAS28 remission rate, with a lower percentage, and side-effects (higher percentage, with higher comorbidities percentage too). However, after one year of real-life data CZP seemed as both safety and effective enough as younger RA patients in real-life scenario. <h3>References</h3> [1]Keystone E, et al. Ann Rheum Dis2014Dec;73(12):2094–100. [2]Torrente-Segarra V, et al. Mod Rheumatol2015Nov 7:1–6. [3]van Onna M, et al. BMC Musculoskelet Disord2016;17:184. [4]Cross M, et al. Ann Rheum Dis2014;73:1316–22.1. <h3>Disclosure of Interest:</h3> None declared