tbuckley/cabot-search huggingface dataset:
Long NHS waiting times are harming patients, MPs warn
Authors: Matthew Limb
Journal: BMJ (2019)

Patient suffering is being overlooked as NHS performance against waiting time targets for cancer care and non-urgent care continues to “spiral downwards,” a report by MPs has warned.1

The Public Accounts Committee said that national NHS bodies seemed to “lack curiosity” and to understand little about how longer waits can harm patients.

Published on 12 June, the committee’s report found that less than half of NHS trusts and foundation trusts currently met the 18 week waiting time standard for elective treatment, and only 38% met the 62 day standard from referral to treatment for cancer patients.

Doctors’ leaders and health analysts backed the committee’s concerns that worsening waiting times were “unacceptable” and said that control must be restored.

The committee chair, Meg Hillier, said, “The impact of protracted waiting …
AB0793 LONG-TERM USE OF AMTOLMETIN GUACIL IN PATIENTS WITH OSTEOARTHRITIS, RHEUMATOID ARTHRITISAND ANKYLOSING SPONDYLITIS
Authors: Andrey Karateev, Evgeny Nasonov
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) is used to control of chronic pain in osteoarthritis (OA), rheumatoid arthritis (RA) and to prevent the progression of ankylosing spondyloarthritis (AS). Amtolmetin guacil (AMG), which has a low risk of gastrointestinal complications, may have advantages for long-term use. <h3>Objectives:</h3> To evaluate the effect and safety of long-term use of aMG. <h3>Methods:</h3> AMG 600-1800 mg/day was prescribed to 442 patients with OA (60.6 + 10.2 years, women 88.7%), 126 with RA (55.0 + 14.0 years, women 84.2%) and 73 with the aS (47.0 + 12.0 years, women 30.0%). The primary end point was the dynamics of pain on a numerical rating scale (NRS), additional for OA - WOMAC pain and HAQ, for RA - DAS28-CRP, for aS - BASDAI, BASFI and aSDAS-CRP. The result of treatment was evaluated on 3 consecutive visits after 3 months (9 months of treatment). <h3>Results:</h3> After 9 months 65.2% of OA patients, 75.3% of RA patients, and 82.2% of aS patients continued to take aMG. In end of study, the median of pain decreased with OA from 5.6 [4.1–6.9] to 3.4 [1.7–5.1], with RA from 5.8 [4.0–7.5] to 3.4 [2.0-4.8], with aS from 5.8 [4.2-7.5] to 3.1 [1.5-5.0] NRS (p &lt;0.001). In OA WOMAC pain decreased from 127 [24-159] to 13.7 [14-40], p &lt;0.001, HAQ from 0.54 ± 0.44 to 0.34 ± 0.26, p &lt;0.001. With RA, the average value of DAS28 decreased from 4.81 + 1.18 to 4.30 + 1.24, p &lt;0.05. In aS, the median BASDAI index decreased from 4.5 [1.0–8.0] to 3.0 [0–8.0], p &lt;0.001. The number of aS patients with high activity on the aSDAS-CRP index (&gt; 3.5) decreased from 76.9% to 25.8%, p &lt;0.001. The BASFI index has not changed. 77.9% of patients with OA, 77.0% of patients with RA, and 74.5% of patients with aS were satisfied with the results of aMG treatment. AMG tolerability was good. 15-25% patients had mild dyspepsia. Discontinuation of therapy due to side effects was only in 6 patients (0.93%). The development or worsening of arterial hypertension, as well as other cardiovascular complications, was not observed. <h3>Conclusion:</h3> AMG is an effective, well-tolerated NSAID, which is appropriate for long-term treatment of OA, RA and aS. <h3>Disclosure of interests:</h3> None declared
PS1402 OUTCOME IN TRANSPLANT ELIGIBLE PATIENTS WITH MULTIPLE MYELOMA IN LATIN AMERICA. AN INTERNATIONAL STUDY OF GELAMM
Authors: C. Peña, N.P. Schutz, V. Bove, F. Villano, R. Osorio, M. Chandía, D. Cardemil, C. Contreras, C.G. Contreras, J. Donoso, M. Espinoza, L.R. Gabriel, H. López‐Vidal, C. Rojas, P. Soto, P. Ochoa, P. Duarte, G. Remaggi, S. Yantorno, A. Corzo, S. Zabaljauregui, C. Shanley, S. Lopresti, S. Orlando, V. Verri, L. Quiroga, C.A. García, V. Fernández, D. Fantl, E. Riva
Journal: HemaSphere (2019)

Background: Multiple myeloma (MM) is a frequent hematologic malignancy. Despite the important advances in treatment strategies during the last decades, the gold standard remains being a proteasome inhibitor (PI)‐based induction, followed by autologous stem cell transplant (ASCT). In Latin America (LA) there is great heterogeneity in access to new drugs and ASCT, and there is scarce data regarding patient́s outcomes in the region. Aims: The aim of this study was to describe clinical characteristics and outcomes of MM transplant eligible patients in LA countries. Methods: Retrospective international multicenter cohort study. Unselected consecutive MM transplant‐ eligible patients diagnosed between 2010 and 2018 from participating centers in Chile, Argentina and Uruguay were included. Data was collected from clinical records in a standardized report form. We analyzed clinical characteristics at diagnosis and frontline therapy outcomes, including ASCT. Transplant‐eligible patients were defined as fit patients younger than 66 years old. Response to treatment was defined according to current IMWG criteria. Statistical analysis was performed by using STATA 13. Results: Six hundred and seventy one patients were included in the study, 282 from Chile, 258 from Argentina and 131 from Uruguay. The main characteristics are shown in Table 1. Significant differences in access to PI induction and ASCT were found between private and public institutions, with patients from the latter receiving suboptimal frontline therapy. Optimal response (sCR, CR and VGPR) was achieved in 51% of the patients in the CyBorD group, in 65% in the VTD group, and in 45% in the CTD group, the 3 main induction regimens used. Only 52% of patients finally underwent ASCT. With a median follow up of 33 months (range 1–109), 5 year overall survival (OS) was 58,4%, with a median survival of 73 months in the whole cohort. When analyzed according to induction treatment, 5 year OS was 74% for PI‐based, 48% for thalidomide‐based, and 23% for those not treated with novel agents ( P &lt; 0,0001). In the multivariable analysis, not undergoing ASCT ( p &lt; 0,001), renal failure (p = 0,004), hypercalcemia (p = 0,001), and achieving less than VGPR (p = 0,001) response were independent factors associated with worse outcome. Summary/Conclusion: Survival in transplant‐eligible patients is lower than the “optimal” described survival in other regions. Unequal access to PI‐based regimens and therefore to ASCT between public and private centers was observed. Reasons for 48% of candidates not being transplanted merit further analysis. image
THU0576 PROGNOSTIC FACTORS PREDICTING THE SURVIVAL OF PATIENTS WITH MACROPHAGE ACTIVATION SYNDROME
Authors: Seungmin Jung, Sungsoo Ahn, Sangwon Lee, Jason Jungsik Song, Yongbeom Park
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Macrophage activation syndrome (MAS) is a hyperinflammatory condition, which can lead to death in patients with rheumatologic disease. However, the prognosis of adult patients with MAS is largely unknown. <h3>Objectives:</h3> We aimed to investigate the mortality in patients with MAS accompanied Adult-onset Still's disease (AOSD) or systemic lupus erythematosus (SLE) and to evaluate the prognostic factors predicting the mortality in patients with MAS. <h3>Methods:</h3> We retrospectively reviewed febrile patients with AOSD or SLE admitted to Severance Hospital between 2005 and 2018. Patients who satisfied the classification criteria of MAS was included in the analysis. Cox-regression analysis was performed to evaluate the clinical factors associated with the overall mortality in patients with MAS. <h3>Results:</h3> Of the total 123 patients, 48 (39%) patients and 75 (61%) patients were diagnosed with AOSD and SLE, respectively. Forty-three patients (35%) were died from MAS during hospitalization. There was no significant difference in mortality between AOSD and SLE (<i>P</i> = 0.675). In multivariate analysis, cytopenia, and insufficient reduction of ferritin and rebound of inflammation after initial treatment with glucocorticoid were independently associated with death in patients with MAS (<i>P</i> = 0.019, &lt; 0.001, and 0.011, respectively). <h3>Conclusion:</h3> The presence of cytopenia, and treatment response after glucocorticoid treatment was closely related with death in patients with MAS. More intensive treatment should be considered in high-risk patients with poor prognostic factors. <h3>References:</h3> [1] Carter, S.J., R.S. Tattersall, and A.V. Ramanan, Macrophage activation syndrome in adults: recent advances in pathophysiology, diagnosis and treatment. Rheumatology (Oxford), 2018. [2] Grom, A.A., A. Horne, and F. De Benedetti, Macrophage activation syndrome in the era of biologic therapy. Nat Rev Rheumatol, 2016. 12(5): p.259-68. [3] Ahn, S.S., et al., Application of the 2016 EULAR/ACR/PRINTO Classification Criteria for Macrophage Activation Syndrome in Patients with Adult-onset Still Disease. J Rheumatol, 2017. 44(7): p.996-1003. [4] Ahn, S.S., et al., In-hospital mortality in febrile lupus patients based on 2016 EULAR/ACR/PRINTO classification criteria for macrophage activation syndrome. Semin Arthritis Rheum, 2017. 47(2): p.216-221. <h3>Disclosure of Interests:</h3> None declared
Integrative Cancer Pharmacogenomics to Infer Large-Scale Drug Taxonomy
Authors: Nehme El-Hachem, Deena M.A. Gendoo, Laleh Soltan Ghoraie, Zhaleh Safikhani, Petr Smirnov, Christina Chung, Kenan Deng, Ailsa Fang, Erin Birkwood, Chantal Ho, Ruth Isserlin, Gary D. Bader, Anna Goldenberg, Benjamin Haibe-Kains
Journal: Cancer Research (2017)

Abstract Identification of drug targets and mechanism of action (MoA) for new and uncharacterized anticancer drugs is important for optimization of treatment efficacy. Current MoA prediction largely relies on prior information including side effects, therapeutic indication, and chemoinformatics. Such information is not transferable or applicable for newly identified, previously uncharacterized small molecules. Therefore, a shift in the paradigm of MoA predictions is necessary toward development of unbiased approaches that can elucidate drug relationships and efficiently classify new compounds with basic input data. We propose here a new integrative computational pharmacogenomic approach, referred to as Drug Network Fusion (DNF), to infer scalable drug taxonomies that rely only on basic drug characteristics toward elucidating drug–drug relationships. DNF is the first framework to integrate drug structural information, high-throughput drug perturbation, and drug sensitivity profiles, enabling drug classification of new experimental compounds with minimal prior information. DNF taxonomy succeeded in identifying pertinent and novel drug–drug relationships, making it suitable for investigating experimental drugs with potential new targets or MoA. The scalability of DNF facilitated identification of key drug relationships across different drug categories, providing a flexible tool for potential clinical applications in precision medicine. Our results support DNF as a valuable resource to the cancer research community by providing new hypotheses on compound MoA and potential insights for drug repurposing. Cancer Res; 77(11); 3057–69. ©2017 AACR.
Abstract P323: Sleep Debt and Type II Diabetes Mellitus in Middle Aged and Older Women
Authors: Jonathan Z Butler, Natalie Slopen, Susan Redline, Alan M Zaslavsky, David R Williams, Aruna Pradhan, Julie Buring, Michelle A Albert
Journal: Circulation (2018)

Background: Sleep disturbances can be both a cause and consequence of circadian disruption resulting in cardiometabolic dysregulation. However, little is known about sleep debt, defined as the average sleep duration difference &gt;=2 hours between weekend versus weekday and type II diabetes (T2D) mellitus particularly in older women. Methods and Results: We analyzed 25,335 women free of cardiovascular disease (CVD) in the ongoing follow-up cohort from the Women’s Health Study (WHS). Utilizing the WHS stress questionnaire (2012-13) that assessed sleep duration among other chronic and acute stress measures, we computed sleep debt as the average sleep duration difference &gt;=2 hours between weekend versus weekday. Of the 2539 women with physician confirmed T2D at the time of questionnaire administration, 216 women had sleep debt. Mean age for women with sleep debt and T2D versus no sleep debt and diabetes were 69.3 ± 4.4 and 72.7 +/- 6.1 years old respectively. Women with sleep debt and T2D were younger, more likely to have hypertension and hypercholesterolemia, use alcohol, be current smokers, had higher body mass index and be anxious or depressed. In logistic regression analyses, women with sleep debt had a 47% higher odds of T2D independent of age, race/ethnicity, and socioeconomic status (income and education) [odds ratio (OR): 1.47, 95% confidence interval (CI): 1.25 to 1.72, P&lt;0.0001]. Adjustment for CVD risk factors, depression and anxiety symptoms resulted in attenuation of the relationship which maintained statistical significance [OR: 1.31, 95% CI: 1.10 to 1.55, P= 0.0002]. When cumulative psychological stress (combination of chronic and acute stressors: e.g., life events, job stress, discrimination) was accounted for, the observed relationship between sleep debt and T2D persisted [OR: 1.28, 95% CI 1.09 to 1.53, P= 0.004]. (Table 1) Conclusion: Sleep debt was associated with higher odds of type 2 diabetes prevalence in middle-aged and older women.
Laser brain cancer surgery in a xenograft model guided by optical coherence tomography
Authors: Nitesh Katta, Arnold D Estrada, Austin B McElroy, Aleksandra Gruslova, Meagan Oglesby, Andrew G Cabe, Marc D Feldman, RY Declan Fleming, Andrew J Brenner, Thomas E Milner
Journal: Theranostics (2019)

Higher precision surgical devices are needed for tumor resections near critical brain structures.The goal of this study is to demonstrate feasibility of a system capable of precise and bloodless tumor ablation.An image-guided laser surgical system is presented for excision of brain tumors in vivo in a murine xenograft model.The system combines optical coherence tomography (OCT) guidance with surgical lasers for high-precision tumor ablation (Er:YAG) and microcirculation coagulation (Thulium (Tm) fiber laser).Methods: A fluorescent human glioblastoma cell line was injected into mice and allowed to grow four weeks.Craniotomies were performed and tumors were imaged with confocal fluorescence microscopy.The mice were subsequently OCT imaged prior, during and after laser coagulation and/or ablation.The prior OCT images were used to compute three-dimensional tumor margin and angiography images, which guided the coagulation and ablation steps.Histology of the treated regions was then compared to post-treatment OCT images.Results: Tumor sizing based on OCT margin detection matched histology to within experimental error.Although fluorescence microscopy imaging showed the tumors were collocated with OCT imaging, margin assessment using confocal microscopy failed to see the extent of the tumor beyond ~ 250 µm in depth, as verified by OCT and histology.The two-laser approach to surgery utilizing Tm wavelength for coagulation and Er:YAG for ablation yielded bloodless resection of tumor regions with minimal residual damage as seen in histology. Conclusion:Precise and bloodless tumor resection under OCT image guidance is demonstrated in the murine xenograft brain cancer model.Tumor margins and vasculature are accurately made visible without need for exogenous contrast agents.
PS1193 CHARACTERISTICS AND OUTCOMES OF THE TREATMENT PATIENTS WITH T315I MUTATION CML
Authors: J. Vlasova, E. Morozova, M. Barabanshikova, T. Gindina, A. Alyanskiy, E. Darskaya, B. Afanasyev
Journal: HemaSphere (2019)

Background: Resistance to tyrosine kinase inhibitors (TKI) in patients with chronic myeloid leukemia (CML) is frequently caused by point mutations in the BCR‐ABL kinase domain, including the gatekeeper mutant T315I, which confers a high degree of resistance to all currently approved tyrosine kinase inhibitors except ponatinib. Aims: To evaluate the results of different treatments in CML patients with mutation T315I. Methods: Retrospective analysis of 79 BCR‐ABL T315I ‐positive CML patients (pts) was done. Allogeneic bone marrow transplantation (allo‐HSCT) was made in 20 pts, 59 pts received only pharmacological therapy (41 pts received TKI as monotherapy or in combination with other drugs, 10‐ α‐IF, other 8 pts received hydroxyurea or chemotherapy). At the time of allo‐HSCT 6 pts were in CP 1, 7‐ CP≥2, 6 pts had AP and 3 pts were in BC. Median (Me) age at the time of mutation detected was 42 years (13–75) (38 years in HSCT‐group). In allo‐HSCT group 13 pts had unrelated donors, 13(65%) pts received more than 2 lines TKIs before HSCT. The number of points on EBMT scale: 3–4 points ‐ 16 pts, 5–7 points ‐ 6 pts. Conditioning regimen in 13 (70%) pts had reduced intensity. Me time to HSCT after T315I detection was 7 months (0–72). Results: Me follow‐up time after T315I detection was 21 months (1–100). 5‐years OS in whole group was 42%. According to multivariate analysis only CML phase at the time of mutation detection significantly affect to survival in whole group. All pts in BC (n = 7), 3 in HSCT group and 4 in non‐HSCT group, died within first year after T315I indication wherein Me survival time was 1,3 month. 5‐years OS in non‐HSCT group (n = 59) was 42% with Me survival time 2,8 years. 5‐years OS after allo‐HSCT (n = 20) was 37% with Me survival time 5 months. However, 7 pts live more than 2 years after allo‐HSCT, 2 ‐ more than 6 years. All living patients after allo‐HSCT are in deep molecular response. Pts in the 2nd CP have OS 47% (CI 95% 29–53%), p = 0.46. There was no significant difference in 5‐years OS between TKI (n = 41) and non‐TKI (n = 18) pharmacological therapy (non‐HSCT) groups (42% and 47% respectively, p = 0,53). In the group that received α‐interferon in the combination with other drugs (n = 10), the 5‐year OS is higher than in the group that did not receive interferon therapy (n = 49), 72% vs 45%, respectively (p = 0.21). Summary/Conclusion: Detection of T315I mutation in TKI‐resistant patients is extremely unfavorable factor for survival, and it is a great reason for switching to ponatinib or other new potential investigated drugs if possible. Allo‐HSCT is an effective method of treatment for this group of patients in case of good selection taking into consideration transplant risk, especially for patients in CP ≥2. The administration of pharmacological therapy in the 1 st CP is an effective method of treatment, which allows to control the disease for a long time.
Recurrent Gene Duplication Leads to Diverse Repertoires of Centromeric Histones in Drosophila Species
Authors: Lisa E. Kursel, Harmit S. Malik
Journal: Molecular Biology and Evolution (2017)

Despite their essential role in the process of chromosome segregation in most eukaryotes, centromeric histones show remarkable evolutionary lability. Not only have they been lost in multiple insect lineages, but they have also undergone gene duplication in multiple plant lineages. Based on detailed study of a handful of model organisms including Drosophila melanogaster, centromeric histone duplication is considered to be rare in animals. Using a detailed phylogenomic study, we find that Cid, the centromeric histone gene, has undergone at least four independent gene duplications during Drosophila evolution. We find duplicate Cid genes in D. eugracilis (Cid2), in the montium species subgroup (Cid3, Cid4) and in the entire Drosophila subgenus (Cid5). We show that Cid3, Cid4, and Cid5 all localize to centromeres in their respective species. Some Cid duplicates are primarily expressed in the male germline. With rare exceptions, Cid duplicates have been strictly retained after birth, suggesting that they perform nonredundant centromeric functions, independent from the ancestral Cid. Indeed, each duplicate encodes a distinct N-terminal tail, which may provide the basis for distinct protein–protein interactions. Finally, we show some Cid duplicates evolve under positive selection whereas others do not. Taken together, our results support the hypothesis that Drosophila Cid duplicates have subfunctionalized. Thus, these gene duplications provide an unprecedented opportunity to dissect the multiple roles of centromeric histones.
Abstract P031: Weight Changes and Their Predictors Among 11,140 Patients With Type 2 Diabetes in The Advance Trial
Authors: Susan van Dieren, Andre Pascal Kengne, John Chalmers, Joline Beulens, Yvonne van der Schouw, Sophia Zoungas
Journal: Circulation (2012)

Background/Aim: To determine the baseline characteristics and glucose lowering therapies associated with weight change among subjects with type 2 diabetes. Methods: 11,140 participants in the ADVANCE trial, were randomly assigned to an intensive (aiming for an HbA 1c ≤ 6.5%) or a standard blood glucose control strategy. Weight was measured at baseline and every 6 months over a median follow-up of 5 years. Multivariable linear regression and linear mixed effect models were used to examine predictors of weight change. Results: The mean difference in weight between the intensive and standard glucose control arm during follow-up was 0.75 kg (95% CI: 0.56 to 0.94), p-value&lt;0.001. The mean weight decreased by 0.70 kg (95% CI: 0.53 to 0.87), p &lt;0.001 by the end of follow-up in the standard arm but remained stable in the intensive arm, with a non-significant gain of 0.16 kg (95% CI: -0.02 to 0.34), p=0.075. Baseline factors associated with weight gain were younger age, higher HbA 1c , Caucasian ethnicity and number of glucose lowering medications. Treatment combinations including insulin [3.20 kg (95% CI: 2.90 to 3.50)] and thiazolidinediones [3.05 kg (95% CI: 2.68 to 3.42)] were associated with the greatest weight gain whilst treatment combinations including sulphonylureas were associated with less weight gain [0.71 kg (95%CI: 0.39 to 1.03)] (Figure 1). Conclusion: Intensive glucose control regimens are not necessarily associated with substantial weight gain. Patient characteristic associated with weight change were age, ethnicity, smoking and HbA1c. The main treatment strategies predicting weight gain were the use of insulin and thiazolidinediones. Acknowledgements: This research was supported by a program grant from the National Health and Medical Research Council of Australia, the Center for Translational Molecular Medicine (CTMM) and the Netherlands Heart Foundation, Dutch Diabetes Research Foundation and Dutch Kidney Foundation (PREDICCt).
Human Ocular Angiogenesis‐Inspired Vascular Models on an Injection‐Molded Microfluidic Chip
Authors: Jihoon Ko, Younggyun Lee, Somin Lee, Seung‐Ryeol Lee, Noo Li Jeon
Journal: Advanced Healthcare Materials (2019)

Angiogenic sprouting, which is the growth of new blood vessels from pre-existing vessels, is orchestrated by cues from the cellular microenvironment, such as spatially controlled gradients of angiogenic factors. However, current in vitro models are less scalable for in-depth studies of angiogenesis. In this study, a plastic-based microfluidic chip is developed to reconstruct in vitro 3D vascular networks. The main disadvantages of the preexisting system are identified, namely, the low productivity and difficulty of experiments, and a breakthrough is suggested while minimizing disadvantages. The selection of plastic materials contributes to the productivity and usability of in vitro devices. By adopting this material, this chip offers simple fluid patterning, facilitating the construction of a cell-culture microenvironment. Compared with previous systems, the chip, which can form both inward and outwardly radial vascular sprouting, demonstrates the growth of functional, morphologically integral microvessels. The developed angiogenic model yields dose-dependent results for antiangiogenic drug screening. This model may contribute significantly not only to vascular studies under normal and pathological conditions, but also to fundamental research on the ocular neovascularization. Furthermore, it can be applied as a tool for more practical, extended preclinical research, providing an alternative to animal experiments.