tbuckley/cabot-search huggingface dataset:
Synovial tissue signatures enhance clinical classification and prognostic/treatment response algorithms in early inflammatory arthritis and predict requirement for subsequent biological therapy: results from the pathobiology of early arthritis cohort (PEAC)
Authors: Gloria Lliso-Ribera, Frances Humby, Myles Lewis, Alessandra Nerviani, Daniele Mauro, Felice Rivellese, Stephen Kelly, Rebecca Hands, Fabiola Bene, Nandhini Ramamoorthi, Jason A Hackney, Alberto Cauli, Ernest H Choy, Andrew Filer, Peter C Taylor, Iain McInnes, Michael J Townsend, Costantino Pitzalis
Journal: Annals of the Rheumatic Diseases (2019)

Objective To establish whether synovial pathobiology improves current clinical classification and prognostic algorithms in early inflammatory arthritis and identify predictors of subsequent biological therapy requirement. Methods 200 treatment-naïve patients with early arthritis were classified as fulfilling RA1987 American College of Rheumatology (ACR) criteria (RA1987) or as undifferentiated arthritis (UA) and patients with UA further classified into those fulfilling RA2010 ACR/European League Against Rheumatism (EULAR) criteria. Treatment requirements at 12 months (Conventional Synthetic Disease Modifying Antirheumatic Drugs (csDMARDs) vs biologics vs no-csDMARDs treatment) were determined. Synovial tissue was retrieved by minimally invasive, ultrasound-guided biopsy and underwent processing for immunohistochemical (IHC) and molecular characterisation. Samples were analysed for macrophage, plasma-cell and B-cells and T-cells markers, pathotype classification (lympho-myeloid, diffuse-myeloid or pauci-immune) by IHC and gene expression profiling by Nanostring. Results 128/200 patients were classified as RA1987, 25 as RA2010 and 47 as UA. Patients classified as RA1987 criteria had significantly higher levels of disease activity, histological synovitis, degree of immune cell infiltration and differential upregulation of genes involved in B and T cell activation/function compared with RA2010 or UA, which shared similar clinical and pathobiological features. At 12-month follow-up, a significantly higher proportion of patients classified as lympho-myeloid pathotype required biological therapy. Performance of a clinical prediction model for biological therapy requirement was improved by the integration of synovial pathobiological markers from 78.8% to 89%–90%. Conclusion The capacity to refine early clinical classification criteria through synovial pathobiological markers offers the potential to predict disease outcome and stratify therapeutic intervention to patients most in need.
Annals Story Slam - Order From Chaos
Authors: Karen Alexander
Journal: Annals of Internal Medicine (2019)

Web Exclusives3 September 2019Annals Story Slam - Order From ChaosFREEKaren Alexander, PhD, RNKaren Alexander, PhD, RNSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/W19-0015 SectionsAboutVisual Abstract ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail Video. Annals Story Slam - Order From Chaos "Order From Chaos," by Karen Alexander, PhD, RN (Duration 5:09)Building on the popular Annals feature “On Being a Doctor,” storytellers share stories about the experience of doctoring on video.For more videos from and information on Annals Story Slam, visit go.annals.org/StorySlam. Comments0 CommentsSign In to Submit A Comment Author, Article, and Disclosure InformationAffiliations: PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics 3 September 2019Volume 171, Issue 5Page: SS1 ePublished: 3 September 2019 Issue Published: 3 September 2019 Copyright & PermissionsCopyright © 2019 by American College of Physicians. All Rights Reserved.Loading ...
OS9.6 Diagnosis of pseudoprogression using FET PET radiomics
Authors: P Lohmann, M A Elahmadawy, J Werner, M Rapp, G Ceccon, G R Fink, N J Shah, K Langen, N Galldiks
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Radiomics derived from different imaging modalities is gaining increasing interest in the field of neuro-oncology. Besides MRI, amino acid PET radiomics may also improve the to date challenging, clinically relevant diagnostic problem of differentiating pseudoprogression (PsP) from tumor progression (TP). To this end, we here explored the potential of O-(2-[18F]fluoroethyl)-L-tyrosine (FET) PET radiomics to discriminate between PsP and TP. MATERIAL AND METHODS Thirty-five newly diagnosed IDH-wildtype glioblastoma patients with MRI findings suspicious for TP within 12 weeks after completion of chemoradiation with temozolomide underwent an additional dynamic FET PET scan. FET PET tumor volumes were segmented using a tumor-to-brain ratio (TBR) ≥ 1.6. The static PET parameters TBRmax and TBRmean, as well as the dynamic parameter time-to-peak (TTP), were calculated. For radiomics analysis, the number of datasets for model generation was increased using data augmentation techniques. Subsequently, 70 datasets were available for model generation. Prior to further processing, patients were randomly assigned to a discovery and a validation dataset in a ratio of 70/30, with balanced distribution of PsP and TP diagnoses. Forty-two radiomics features (4 shape-based, 6 first- and 32 second-order features) were obtained using the software LifeX (lifexsoft.org). Afterwards, a z-score transformation was performed for data normalization. For feature selection, recursive feature elimination using random forest regressors was performed. For the final model generation, the number of parameters was limited to three to avoid data overfitting. Different algorithms for model calculation were compared, and the diagnostic accuracy was assessed using leave-one-out cross-validation. Finally, the resulting models were applied to the validation dataset to evaluate model robustness. RESULTS Eighteen patients were diagnosed with TP, and 17 patients had PsP. Diagnoses were based on a neuropathological confirmation or clinicoradiological follow-up (26% and 74%, respectively). The diagnostic accuracy of the best single FET PET parameter was 75% (TBRmax). Combining TBRmax and TTP increased the diagnostic accuracy to 83%. Other combinations of static and dynamic FET PET parameters, however, did not further increase the accuracy. The highest diagnostic accuracy of 92% was achieved by a three-parameter model combining the FET PET parameter TTP with two radiomics features. The model demonstrated its robustness in the validation dataset with a diagnostic accuracy of 86%. CONCLUSION The results suggest that FET PET radiomics improves the diagnostic accuracy for discerning PsP and TP considerably. Given the clinical significance of differentiating PSP and TP, prospective multicenter studies are warranted. FUNDING Wilhelm-Sander Stiftung and the DAAD GERSS Program, Germany
P14.89 What happens after 15 years? A clinical picture of a cohort of survivors of CNS tumors treated with whole-brain irradiation in a National Cancer Center
Authors: V L Espírito Santo, J Passos, T Pimentel, J Nunes, I Costa, D Salgado
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Radiotherapy (RT) is standard curative treatment for many tumours, specially brain tumours. However, RT causes damage to normal brain tissue due to genetic instability, impairment of synaptic plasticity and increased oxidative stress and inflammation. With improved treatment, patient survival also increased in years, making long-term effect of RT more evident. Late toxicities of RT are well described for pediatric survivors but there is scant literature on late toxicities in adult survivors and, in general, the adult brain is considered less susceptible to radiation damage. MATERIAL AND METHODS Retrospective analysis of adult patients treated with whole-brain RT with more than 15 years of follow-up. Clinical charts were reviewed to collect clinical, demographic and outcome data. RESULTS From 18 patients found (mean age at diagnosis of 27 years, 13 male/ 5 female), 5 were diagnosed with medulloblastoma, 5 CNS lymphoma, 5 with germinoma, 3 with ependymoma and 1 with teratocarcinoma. Most common presentations were headache (61,1%), seizure (16,7%) and dizziness (16,7%). 5 patients (27,8%) had hydrocephalus at diagnosis. All patients received whole-brain RT (mean 40Gys, varying between 21 to 60Gys), alongside with complete surgical resection in 11 patients (61,1%) and chemotherapy in 10 patients (55,6%). Mean follow-up time was 23,6 years and only 1 patient died due to lymphoma recurrence 16,7 years after the initial diagnosis. During follow-up, all patients had late RT induced changes, leukoencephalopathy in 16 patients (88,9%; mean 8,6 years after RT), ischemic stroke in 9 patients (50,0%; mean 16,0 years after RT), cerebral microbleeds in 14 patients (77,8%; mean 15,4 years after RT), cognitive decline in 12 patients (66,7%; mean 15,8 years after RT), radio-induced meningioma in 3 patients (16,7%; mean 18,1 years after RT) and epilepsy in 2 patients (11,1%; mean 10,5 years after RT). Also 1 patient had neurosensorial loss 14,2 years after RT and another one had subarachnoid haemorrhage due to ruptured aneurysm 19 years after RT. CONCLUSION Our results show that late RT induced effects are progressive and irreversible in the adult survivors, in a very similar manner as has been reported in the pediatric survivors. The impact on quality of live is increasing as patients survive longer. RT is still an important tool in neuro-oncology, but its role in curing brain tumors needs further study.
Pharmacists could be allowed to prescribe high dose statins under NHS plan
Authors: Gareth Iacobucci
Journal: BMJ (2019)

Community pharmacists could be given the power to prescribe high dose statins as part of a drive to reduce heart disease and stroke, the chief executive of NHS England has announced.

In a speech to the Health and Care Innovation Expo in Manchester on 4 September, Simon Stevens said that the NHS would carry out a review to examine the feasibility of the plan. The findings will be presented to the Medicines and Healthcare Products Regulatory Agency (MHRA) which will have the final say on the proposals.

The review will be led by chief pharmaceutical officer Keith Ridge and newly appointed director of primary care Nikki Kanani.

Stevens said: “Pharmacists are highly trained health professionals who are greatly …
Impact of poly(A)-tail G-content on Arabidopsis PAB binding and their role in enhancing translational efficiency
Authors: Taolan Zhao, Qing Huan, Jing Sun, Chunyan Liu, Xiuli Hou, Xiang Yu, Ian M. Silverman, Yi Zhang, Brian D. Gregory, Chun-Ming Liu, Wenfeng Qian, Xiaofeng Cao
Journal: Genome biology (2019)

Polyadenylation plays a key role in producing mature mRNAs in eukaryotes. It is widely believed that the poly(A)-binding proteins (PABs) uniformly bind to poly(A)-tailed mRNAs, regulating their stability and translational efficiency.We observe that the homozygous triple mutant of broadly expressed Arabidopsis thaliana PABs, AtPAB2, AtPAB4, and AtPAB8, is embryonic lethal. To understand the molecular basis, we characterize the RNA-binding landscape of these PABs. The AtPAB-binding efficiency varies over one order of magnitude among genes. To identify the sequences accounting for the variation, we perform poly(A)-seq that directly sequences the full-length poly(A) tails. More than 10% of poly(A) tails contain at least one guanosine (G); among them, the G-content varies from 0.8 to 28%. These guanosines frequently divide poly(A) tails into interspersed A-tracts and therefore cause the variation in the AtPAB-binding efficiency among genes. Ribo-seq and genome-wide RNA stability assays show that AtPAB-binding efficiency of a gene is positively correlated with translational efficiency rather than mRNA stability. Consistently, genes with stronger AtPAB binding exhibit a greater reduction in translational efficiency when AtPAB is depleted.Our study provides a new mechanism that translational efficiency of a gene can be regulated through the G-content-dependent PAB binding, paving the way for a better understanding of poly(A) tail-associated regulation of gene expression.
Engaging Community-Based Cancer Physicians: Experience of the Memorial Sloan Kettering Cancer Center Cancer Alliance
Authors: Allison Lipitz-Snyderman, Jessica Kennington, Brooke Hogan, Deborah Korenstein, Leonard Kalman, Suresh Nair, Peter Yu, Paul Sabbatini, David Pfister
Journal: Journal of the National Comprehensive Cancer Network (2019)

Background: The proliferation of relationships between community health systems and academic medical centers has created a need to identify effective components of these models. This article reports on frontline physician experiences, with one such relationship established through the Memorial Sloan Kettering Cancer Center (MSK) Cancer Alliance. MSK created the Alliance with the goals of rapidly bringing the newest standards of care into community settings and increasing patient access to clinical trials in their local communities. Methods: Alliance leadership administered a 10-question anonymous survey to physicians treating patients with cancer across the 3 Alliance member health systems: Hartford HealthCare Cancer Institute, Lehigh Valley Cancer Institute, and Miami Cancer Institute at Baptist Health South Florida. The purpose of the survey was to identify opportunities to improve physician engagement. Results: There were 103 clinician respondents across Alliance members, of which 87 reported participation in a disease management team and were included in the final analysis. Most respondents reported high value from Alliance activities, such as attending MSK tumor boards (94%) and lecture series (96%), among those who reported them applicable. Across all respondents, most reported satisfaction with engagement opportunities, such as MSK physician participation in their institution’s meetings (76%). When asked where they would like to see increased engagement, the most commonly reported response was for more lecture series (45%). Most respondents (88%) reported that the Alliance led to practice change, either for themselves or for other clinicians at their institution. Many attributed this practice change to MSK disease-specific process measures. Conclusions: The activities most valued by community physicians were heavily physician relationship–based. The encouraging experience of the MSK Cancer Alliance suggests that activities involving physician investment may be effective for promoting practice change in the context of cross-institution relationships. Future research is needed in this area.
P14.125 Retrospective analysis of long-term response to bevacizumab in combination with irinotecan for recurrent glioblastoma: identification of prognostic factors
Authors: C Besson, M Morisse, H Brut, W Waissi, G Noel, B Chauffert, D Prébay, R Schott, N Etienne-Selloum
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND In absence of standard treatment for recurrent glioblastoma (rGBM), numerous prospective and retrospective studies have evaluated the off-label combination of bevacizumab (BEV) with irinotecan (IRI) in patients with rGBM. We report here our single center experience with this combination and we investigated prognostic factors for long-term response. MATERIAL AND METHODS We performed a retrospective analysis of consecutive patients treated initially by Stupp protocol and with BEV-IRI for a rGBM between 2007 and 2017. Times to progression and overall survival, as well as toxicities, were investigated and analysed. Patients without progression at least 12 month after the first administration of BEV-IRI were considered as long-term responders. The primary end-point was overall survival post-BEV-IRI (OS-BEV-IRI). RESULTS One-hundred eleven patients were eligible for the analysis. Median age at the diagnosis was 57 years and the value of WHO Performance Status (PS) at the recurrence was 0 to 1 for 67,5% of patients. Kaplan-Meier median progression-free survival (PFS-BEV-IRI) and overall survival (OS-BEV-IRI) at recurrence estimates (calculated from start of BEV-IRI) were 6.51 and 10.41 months, respectively. The median OS (calculated from diagnosis) was 22,4 months. Twenty-Three patients (20,7%) were long-term responders to BEV-IRI regimen. This subgroup was not significantly different than the short-term responders according to age or PS distribution, but the relative proportion of biopsy in comparison to other surgery modalities was significantly increased in long-term responders (p&lt;0,0001). Univariate analysis showed that PS 0–1 (p=0,007), biopsy (p=0,0022) are significantly associated with a better prognosis, but not age. Eighty three patients (75%) had toxicities, mainly grade 1 and 2 (92%), such as hypertension, proteinuria, haemorrhage, thrombosis, nausea, diarrhoea, fatigue or neutropenia. Most of the grade 3 and grade 4 toxicities were related to BEV treatment. Adverse events were significantly more frequent in long-term responders (p=0,0096). CONCLUSION BEV-IRI Combination is well tolerated and may offer some clinical benefits in recurrent GBM patients, more particularly if only biopsy was performed instead of surgery. Our results strengthened the role of these agents for the treatment of recurrent GBM.
Attendees of Manchester’s Lung Health Check pilot express a preference for community-based lung cancer screening
Authors: Haval Balata, Janet Tonge, Phil V Barber, Denis Colligan, Peter Elton, Matthew Evison, Marie Kirwan, Juliette Novasio, Anna Sharman, Kathryn Slevin, Sarah Taylor, Sara Waplington, Richard Booton, Phil A Crosbie
Journal: Thorax (2019)

Manchester’s ‘Lung Health Check’ pilot utilised mobile CT scanners in convenient retail locations to deliver lung cancer screening to socioeconomically disadvantaged communities. We assessed whether screening location was an important factor for those attending the service. Location was important for 74.7% (n=701/938) and 23% (n=216/938) reported being less likely to attend an equivalent hospital-based programme. This preference was most common in current smokers (27% current smokers vs 19% former smokers; Adj OR 1.46, 95% CI 1.03 to 2.08, p=0.036) and those in the lowest deprivation quartile (25% lowest quartile vs 17.6% highest quartile; Adj OR 2.0, 95% CI 1.24 to 3.24, p=0.005). Practical issues related to travel were most important in those less willing to attend a hospital-based service, with 83.3% citing at least one travel related barrier to non-attendance. A convenient community-based screening programme may reduce inequalities in screening adherence especially in those at high risk of lung cancer in deprived areas.
Safety and efficacy of AMG 714 in adults with coeliac disease exposed to gluten challenge: a phase 2a, randomised, double-blind, placebo-controlled study
Authors: Marja-Leena Lähdeaho, Mika Scheinin, Pekka Vuotikka, Juha Taavela, Alina Popp, Johanna Laukkarinen, Jukka Koffert, Olli-Pekka Koivurova, Marko Pesu, Laura Kivelä, Zsófia Lovró, Joni Keisala, Jorma Isola, Jane R Parnes, Francisco Leon, Markku Mäki
Journal: The Lancet. Gastroenterology & hepatology (2019)
P11.35 Fluorine-18-labeled PET radiotracers for imaging tryptophan uptake and metabolism in brain tumors
Authors: O Muzik, F John, S Mittal, C Juhasz
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Abnormal metabolism of tryptophan via the serotonin and kynurenine pathways plays a key role in multiple disease processes including cancer. Upregulation of key enzymes of the kynurenine pathway (such as indoleamine 2,3-dioxygenase [IDO] and tryptophan 2,3-dioxygenase [TDO]) plays an important role in immune resistance in human brain tumors. IDO inhibitors have recently entered in human clinical trials, and their use can benefit from molecular imaging evaluating IDO activity. Imaging tryptophan uptake and metabolism in vivo can be achieved with tryptophan derivative PET radiotracers. Human studies with such tracers showed promise but have been confined to carbon-11-labeled compounds (such as alpha-[11C]methyl-L-tryptophan). Preclinical development of fluorine-18-labeled tryptophan-based radiotracers has surged only in recent years. We performed a systematic review of studies reporting on such tracers and summarized their biological characteristics and their potential for imaging key enzymes of the kynurenine pathway. MATERIAL AND METHODS A PubMed search using the key words “tryptophan” and “PET”/”positron emission tomography” was performed. English language original articles including data on the preparation and/or radiochemical or biological characteristics of fluorine-18-labeled tryptophan derivative radiotracers have been reviewed. RESULTS Nineteen original papers identified by the search included data on 15 unique fluorine-18-labeled tryptophan-derived radiotracers. Automated synthesis was reported for 1-(2-[18F]fluoroethyl)-L-tryptophan, the most extensively evaluated tracer among the 15. Biodistribution studies showed high uptake in the pancreas, and the L-type amino acid transporter was the dominant transport mechanism for most of the reported radiotracers. Multiple tracers showed accumulation in various tumor cell lines, including glioma cell lines, in vitro and in xenografts in vivo, with favorable tumor-to-background uptake ratios in comparison to clinically used fluorine-18-labeled radiotracers (such as glucose and non-tryptophan amino acid analogs). Five of the 15 tracers showed promise for imaging IDO activity, including a fluorine-18-labeled analog of alpha-[11C]methyl-L-tryptophan. Two of the 15 radiotracers were metabolized by TDO but showed rapid defluorination in vivo. CONCLUSION Most fluorine-18-labeled tryptophan derivative PET tracers share common transport mechanisms and biodistribution characteristics. Several of these radiotracers show promise for imaging IDO activity in vivo, and, therefore, could be leading candidates for testing and validation toward human tumor PET imaging applications.