tbuckley/cabot-search huggingface dataset:
Diagnostic performance of <sup>18</sup>F-DCFPyL in the OSPREY Trial: A prospective phase 2/3 multicenter study of <sup>18</sup>F-DCFPyL PET/CT imaging in patients (Pts) with known or suspected metastatic prostate cancer (mPC).
Authors: Michael J. Morris, Jeremy C. Durack, Ajjai Shivaram Alva, Hebert Alberto Vargas, Morand Piert, Russell Kent Pachynski, Frederic Pouliot, Jean-Mathieu Beauregard, Mark A. Preston, Atish Dipankar Choudhury, Lawrence Saperstein, Peter Carroll, Steven P. Rowe, Kenneth J. Pienta, Tess Lin, Vivien Wong, Melissa Nichols, Jessica Donato Jensen, Barry A. Siegel
Journal: Journal of Clinical Oncology (2019)

5012 Background: Accurate detection of prostate cancer is imperative to patient management, yet standard imaging methods perform poorly in accurately detecting mPC. 18 F-DCFPyL is a novel PET imaging agent that selectively binds to prostate-specific membrane antigen, a recognized target for prostate cancer. OSPREY was a prospective, multicenter study in pts with either newly diagnosed high-risk prostate cancer (cohort A), or known or suspected mPC (cohort B). Here we focus on Cohort B. Methods: 117 men planned for biopsy of recurrent or mPC received 18 F-DCFPyL. Pts underwent image-guided biopsy. Sensitivity, positive predictive value (PPV), and safety of 18 F-DCFPyL PET/CT were the key endpoints for Cohort B. 18 F-DCFPyL PET/CT scans were evaluated by three independent, blinded central readers; and results were compared to histopathology as the truth standard. Results: The sensitivity and PPV of 18 F-DCFPyL PET/CT as compared to histopathology ranged from 92.9-98.6% (lower bound of 95% CI: 84.0-91.6%) and 81.2-87.8%, respectively. Diagnostic performance by anatomic location showed high sensitivity and high PPV in all sites of disease (Table). Only two (1.7%) cohort B pts experienced ≥1 drug-related AE (dysgeusia and generalized rash), both were mild (Grade 1) in severity. Conclusions: 18 F-DCFPyL PET/CT was well tolerated and demonstrated high sensitivity and PPV in accurately detecting nodal, bone, and visceral/soft tissue metastases. A positive 18 F-DCFPyL PET/CT scan is highly likely to represent pathologically proven distant disease, demonstrating the potential of 18 F-DCFPyL as a PET imaging agent to favorably influence treatment planning. Clinical trial information: NCT02981368. [Table: see text]
Letter to the Editor: Suggestions for Rational Management of Nonalcoholic Fatty Liver Disease
Authors: Lei Luo, Huaibin Zou, Sujun Zheng, Zhongping Duan, Yu Chen
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. To the Editor: We read with great interest the article by Allen et al.1 about the health care cost of nonalcoholic fatty liver disease (NAFLD). The real‐world data derived from OptumLabs Data Warehouse showed higher costs occurred from the first year to the subsequent 5 years among NAFLD patients than among the matched controls cohort. Although the extra expenses aimed mainly at liver biopsies and imaging were lack of long‐term benefits and cost‐effectiveness, an effective solution remains to be determined; thus, we have some suggestions for the rational management of NAFLD. NAFLD is identified as a liver manifestation of metabolic syndrome rather than isolated liver disease.2 In a long‐term follow‐up study, cardiovascular disease (CVD) predominated the cause of death in NAFLD patients, which was much higher than liver‐related mortality (48% vs. 7%).3 However, the conventional tests for NAFLD merely directed at the liver could not reflect the metabolic disorder comprehensively. Therefore, it would be of great interest whether the investigators could compare the CVD mortality and all‐cause mortality of NAFLD patients with various expenses for liver‐related tests. If the higher cost did not reduce the death rate during follow‐up, this result might be educational for primary care physicians, who covered most outpatient visits and made up the large burden of NAFLD costs. Meanwhile, it is essential for primary care physicians to be aware of the latent fatal CVD risk after newly diagnosed cases of NAFLD. Framingham Risk Score, a scale for calculating the incidence of CVD over the next 10 years, has been widely used in cardiology.4 Introducing this assessment as a routine method could be helpful to screen out the high cardiac risk cases without additional costs. Moreover, statin therapy for this subgroup will bring a dual benefit for both cardiovascular and liver enzymology.5 In conclusion, the complexity of NAFLD dictates the need for multidisciplinary integrated management. Cooperation from hepatologists, cardiologists, and primary care physicians would be helpful to formulate a rational method for managing NAFLD.
Clinical utility of custom-designed NGS panel testing in pediatric tumors
Authors: Lea F. Surrey, Suzanne P. MacFarland, Fengqi Chang, Kajia Cao, Komal S. Rathi, Gozde T. Akgumus, Daniel Gallo, Fumin Lin, Adam Gleason, Pichai Raman, Richard Aplenc, Rochelle Bagatell, Jane Minturn, Yael Mosse, Mariarita Santi, Sarah K. Tasian, Angela J. Waanders, Mahdi Sarmady, John M. Maris, Stephen P. Hunger, Marilyn M. Li
Journal: Genome Medicine (2019)

Somatic genetic testing is rapidly becoming the standard of care in many adult and pediatric cancers. Previously, the standard approach was single-gene or focused multigene testing, but many centers have moved towards broad-based next-generation sequencing (NGS) panels. Here, we report the laboratory validation and clinical utility of a large cohort of clinical NGS somatic sequencing results in diagnosis, prognosis, and treatment of a wide range of pediatric cancers. Subjects were accrued retrospectively at a single pediatric quaternary-care hospital. Sequence analyses were performed on 367 pediatric cancer samples using custom-designed NGS panels over a 15-month period. Cases were profiled for mutations, copy number variations, and fusions identified through sequencing, and their clinical impact on diagnosis, prognosis, and therapy was assessed. NGS panel testing was incorporated meaningfully into clinical care in 88.7% of leukemia/lymphomas, 90.6% of central nervous system (CNS) tumors, and 62.6% of non-CNS solid tumors included in this cohort. A change in diagnosis as a result of testing occurred in 3.3% of cases. Additionally, 19.4% of all patients had variants requiring further evaluation for potential germline alteration. Use of somatic NGS panel testing resulted in a significant impact on clinical care, including diagnosis, prognosis, and treatment planning in 78.7% of pediatric patients tested in our institution. Somatic NGS tumor testing should be implemented as part of the routine diagnostic workup of newly diagnosed and relapsed pediatric cancer patients.
A phase II study of pembrolizumab in combination with palliative radiotherapy (RT) for hormone receptor-positive (HR+) metastatic breast cancer (MBC).
Authors: Romualdo Barroso-Sousa, Ian E. Krop, Lorenzo Trippa, Zhenying Tan-Wasielewski, Tianyu Li, Wafa Osmani, Chelsea Andrews, Deborah Dillon, Edward T. Richardson, Eric P. Winer, Elizabeth A. Mittendorf, Jonathan Daniel Schoenfeld, Sara M. Tolaney
Journal: Journal of Clinical Oncology (2019)

1047 Background: RT is frequently used for palliation in MBC. In animal models its use has been reported to induce distant (abscopal) tumor responses when combined with immune checkpoint inhibitors. Here, we report the safety and efficacy of palliative RT plus pembrolizumab in a phase II single-arm study in patients (pts) with HR+/HER2- MBC. Methods: Eligible pts had HR+/HER2- MBC, ECOG PS &lt;2, indication for palliative RT, and ≥1 measurable lesion outside of the RT field; there was no limit on prior lines of therapy. A total RT dose of 20 Gray was delivered over 5 daily fractions. Pembrolizumab was given at 200 mg IV 2-7 days before day 1 of RT, then every 3 weeks until disease progression. The primary endpoint was objective response rate (ORR) outside the field of radiation by RECIST v1.1. Using the Simons “optimal” method, if ≥ 1/8 pts responded during the first stage, 19 more would be enrolled. If ≥ 3/27 responded, the null hypothesis (ORR=3%) would be rejected in favor of a 20% ORR. Predefined secondary endpoints included progression free survival (PFS) and toxicity. Analyses associating PD-L1 expression, tumor-infiltrating lymphocytes (TIL), and neutrophil/lymphocyte ratio (NLR) with outcomes were exploratory. Results: Eight women were enrolled into the first stage of the trial; no objective responses were seen, and the study was closed to further accrual. The median age was 59y (37-68y), 6 (75%) had ECOG PS 1, all had bone and 5 (63%) had liver metastases. The median number of prior cytotoxic therapies for MBC was 2 (range 0 to 8). While one patient had a PR by RECIST criteria, this patient experienced concurrent clinical progression. Two pts had SD &lt; 16 weeks and 5 had PD as best response. The median PFS was 1.4 months (95% CI 0.4 – 2.1). All-cause adverse events occurred in 87.5% of pts (G3-4, 12.5%). TIL were available for 6 pts: 4 had ≤10%, and 2 &gt; 10%. Among 5 pts with PD-L1 status available, 2 were positive. Six pts had NLR &gt; 4. Conclusions: Pembrolizumab combined with RT was well-tolerated, and no unexpected adverse events were observed; however, clinical benefit of the combination was not demonstrated in this heavily pretreated HR+ population. Clinical trial information: NCT03051672.
Dynamic changes in peripheral blood-targeted miRNA expression profiles in patients with severe traumatic brain injury at high altitude
Authors: Si-qing Ma, Xue-xia Xu, Zong-zhao He, Xin-hui Li, Jun-ming Luo
Journal: Military Medical Research (2019)

The aim of this work is to detect and compare the peripheral blood miRNA expression profiles in patients with severe traumatic brain injury (sTBI) 2, 12, 24, 48, and 72 h after injury at high altitude and to predict the target genes of differential expressed miRNAs. Twenty sTBI patients from high-altitude areas were randomly selected according to the inclusion and exclusion criteria and were divided into five groups: the 2-h group, 12-h group, 24-h group, 48-h group, and 72-h group. Peripheral blood miRNA expression profiles were detected using real-time quantitative PCR (qRT-PCR). The expression levels of miR-18a, miR-203, miR-146a, miR-149, miR-23b, and miR-let-7b in peripheral blood showed significant differences between the 2-h group and the 12-h group. The expression levels of miR-203, miR-146a, miR-149, miR-23b, and miR-let-7f in peripheral blood were up-regulated in the 24-h group. In the 48-h group, the expression levels of miR-181d, miR-29a, and miR-18b were upregulated. In the 72-h group, the expression levels of miR-203, miR-146a, miR-149, miR-23b, and miR-let-7f changed. The main target genes of the differentiation expressed miRNAs were genes that regulate inflammatory responses, apoptosis, and DNA damage/repair. miRNAs may be involved in the pathogenesis of sTBI by dynamically regulating the target genes that regulate inflammatory responses, apoptosis, and DNA damage/repair pathways.
AB0379 GENDER DIFFERENCES IN RHEUMATOID ARTHRITIS: EFFECT OF ANTI-TUMOR NECROSIS FACTOR THERAPY
Authors: Chiara Gioia, Francesca Spinelli, Roberta Priori, Cristina Iannuccelli, Bruno Lucchino, Annarita Vestri, Guido Valesini, Manuela DI Franco
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Rheumatoid arthritis (RA) is more prevalent in women than men (F:M=4:1), due to hormonal, genetic and environment factors. Women present higher disease activity markers as Disease Activity Score-28 (DAS28) and Health Assessment Questionnaire (HAQ), at the onset and after c-DMARDs therapy, without correlation with radiographic damage. <h3>Objectives</h3> The purpose of this study was to assess gender differences in RA patients after anti- tumor necrosis factor (TNF) α treatment. <h3>Methods</h3> Ninety-six patients were enrolled at the beginning of anti-TNF α therapy (etanercept and adalimumab). All patients satisfied 1987 and 2010 ACR criteria for RA. They underwent to clinical and clinimetric evaluation at baseline (T0) and after three (T3) and six (T6) months of therapy with: tender and swollen joints, Visual Analogic Scale (VAS) pain, VAS patient and physician, DAS28, Clinical/Simplified clinical disease activity index (CDAI/SDAI) and HAQ. The evaluation of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Rheumatoid Factor (RF) and anti-citrullinated protein antibody (ACPA) was performed in all patients. <h3>Results</h3> Among these patients, 70 were women and 26 men; 81 patients (58 female, 23 male) started etanercept and 15 adalimumab (12 female, 3 male). They presented a mean age of 56.4 ± 14.5 years (women 55.2 ± 15.4, men 60 ± 11.2) and mean disease duration of 11 ± 6.8 years (woman 11.51 ± 6.3, men 9.6 ± 8.1). Both women and men had a DAS28 reduction after 3 and 6 months therapy (p&lt;0.05) but DAS28 in women was higher than men at T0, T3 and T6 (p&lt;0.05). Women presented higher number of tender joints in all evaluations, and more swollen joints than men at T0 and T6 (p&lt;0.05). Women felt more active disease at T6 (VAS patient) (p&lt;0.05). CDAI was higher in woman after 3 and 6 months (p&lt;0.05). There were no differences about physician evaluation, inflammation markers, RF and ACPA titles. <h3>Conclusion</h3> In this study, both women and men had a good response to anti-TNF treatment but women presented worse clinical response. Female gender resulted the only variable associated with DAS28 reduction differences. We could hypothesize that beyond to biological factors, also social contest, daily life and work activity could explain a worse impact of disease on women. <h3>References</h3> [1] Neovius M, Ann Rheum Dis 2011; [2] O.L. Quintero, et al., Journal of Autoimmunity 2012. [3] M Ahlm áen, Ann Rheum Dis 2010. [4] Jawaheer, et al, The Journal of Rheumatology 2010. [5] Jawaheer, et al, The Journal of Rheumatology 2012. [6] Arnett FC, Arthritis Rheum 1988. [7] Aletaha D, Arthritis Rheum 2010. <h3>Disclosure of Interests</h3> None declared
Inherited DNA repair and cell cycle gene defects in chronic lymphocytic leukemia.
Authors: Nicholas S. Moore, Saud H. Aldubayan, Amaro Taylor-Weiner, Stephan Stilgenbauer, Gad Getz, Catherine J. Wu, Eliezer Mendel Van Allen, Jennifer R. Brown
Journal: Journal of Clinical Oncology (2019)

1508 Background: Chronic lymphocytic leukemia (CLL) is among the most heritable cancers, with 60% of disease risk genetically determined. However, most of the genetic heritability of CLL remains unexplained. Previously, we identified ATM as the first CLL risk gene. Here, we leverage a deep-learning-based germline variant calling algorithm to explore germline mutational enrichment in DNA repair and cell cycle genes in CLL. Methods: A two-stage case-control analysis was conducted using gene-based mutational enrichment analysis of 50 established cancer predisposition DNA repair and cell cycle genes. In the discovery phase, a total of 285 Spanish patients and 5,608 ancestry-matched controls were evaluated. In the validation stage, an independent cohort of 514 European patients and 27,173 ancestry-matched controls were analyzed. An FDR correction was applied to both datasets and genes with a q-value &lt; 0.2 in both cohorts were considered significant. Results: Our joint analysis of 799 CLL patients from 2 genetically distinct cohorts and 32,781 ancestry-matched cancer-free controls identified ATM and CHEK2 as significantly enriched in both CLL datasets. First, our analysis recaptured the previously reported finding of ATM variant enrichment in CLL patients. Carriers of pathogenic ATM mutations in our cohorts (n = 9 patients, discovery: 1.05%, validation: 1.17%) were 2.8–3.7 times more likely to develop CLL compared to cancer-free individuals (discovery: OR = 2.8, 95%CI = 0.7–9.0, q-value = 0.181; validation: OR = 3.7, 95%CI = 1.6–8.3, q-value = 0.0454). In addition, our analysis identified 21 CLL patients carrying pathogenic CHEK2 alterations (discovery: 1.40%, validation: 3.31%), making CLL patients 4.4-8.0 times more likely to carry such alterations compared to controls (discovery: OR = 8.0, 95%CI = 2.3–27.0, q-value = 0.026; validation: OR = 4.4, 95%CI = 2.5–7.3, q-value &lt; 0.001). Conclusions: Our analysis of genetically distinct CLL cohorts, using a high-sensitivity variant calling algorithm, supports CHEK2 as a potentially novel CLL predisposition gene that may explain a portion of the missing monogenic heritability of CLL. In addition, this study highlights the DNA repair and cell cycle regulation pathways as potential drivers of CLL susceptibility.
Case 52-1985
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, David A. Chad, Edward P. Richardson
Journal: New England Journal of Medicine (1985)

Presentation of Case First admission. A 64-year-old man was admitted to the hospital because of weakness of the legs.He was well until 10 days before admission, when numbness developed in the right lateral thigh, with lumbar pain. Two days later weakness appeared in the right leg. His symptoms worsened, and five days before admission he entered another hospital. During the next two days he lost the ability to move the right leg and could not control his bladder or retain an enema; an indwelling catheter was inserted. Two days before entry weakness was noted in the left leg. On . . .
SP0130 STANDARDISATION OF NORMAL VERSUS ABNORMAL AND PATHOLOGICAL CAPILLAROSCOPIC IMAGES
Authors: V. Smith
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> Medical doctors frequently get patients with Raynaud"s phenomenon (RP), a frequent symptom in the general population, referred. The importance of distinguishing normal capillaroscopic findings from (pathognomonic) abnormal (pathological) findings (scleroderma pattern), lies in the fact that this distinction allows the differentiation between a primary RP (not connected to any connective tissue disease [CTD]) from a secondary RP due to systemic sclerosis (SSc) and diseases of the scleroderma spectrum. What is normal in primary RP? A normal capillaroscopic pattern, by qualitative assessment, is characterized by a homogeneous distribution of hairpin shaped capillaries as a "comb-like structure", with a density of &gt;7capillaries per mm, with a normal dimension and absence of large hemorrhages Yet, there exists a wide intra- and inter- individual variety in a normal population which will be discussed in this session. What is pathognomonic abnormal in patients with RP due to SSc? Patients with the RP who have an underlying clinically recognizable (= with skin involvement) SSc show a very characteristic combination of capillary abnormalities in the nailfold, which can easily be assessed through qualitative assessment (= pattern recognition). Maricq et al. described last century, with the widefield technique (magnification X12–14) the scleroderma pattern. This pathognomonic combination contains the following: a striking widening of all three segments of the capillary loop (arterial, venous and intermediate), loss of capillaries and disorganization of the nailfold capillary bed. Many branched "bushy" capillaries may also be observed. In 2000, Cutolo et al. qualitatively assessed the nailfolds of an SSc cohort with patients fulfilling the American College of Rheumatology (ACR) criteria for SSc with the nailfold videocapillaroscopic (NVC) technique (magnification X200). According to the different proportions of the hallmark parameters of the scleroderma pattern (giants, capillary loss, hemorrhages and abnormal shapes: (neo)angiogenesis, Cutolo et al. defined three patterns "early", "active" and "late". The central role of capillaroscopy in distinction between a primary and secondary RP due to SSc is reflected by the fact that capillaroscopy is one of the new ACR/EULAR criteria for classifying a patient as having SSc. In this lecture the standard "FAST TRACK" recognition system of the EULAR Study Group on Microcirculation in Rheumatic Diseases to discern scleroderma patterns from non-scleroderma patterns will be taught to the attendees. <h3>Suggested further reading:</h3> [1] Smith V, et al. Rheumatology (Oxford). 2016;55(5):883-90. [2] Cutolo M, et al. Rheumatology (Oxford). 2018;57(4):757-759. [3] Cutolo M, et al. Autoimmun Rev. 2018;17(4):344-352. <h3>Disclosure of Interests:</h3> None declared
Donor metabolic characteristics drive effects of faecal microbiota transplantation on recipient insulin sensitivity, energy expenditure and intestinal transit time
Authors: Pieter de Groot, Torsten Scheithauer, Guido J Bakker, Andrei Prodan, Evgeni Levin, Muhammad Tanweer Khan, Hilde Herrema, Mariette Ackermans, Mireille J M Serlie, Maurits de Brauw, Johannes H M Levels, Amber Sales, Victor E Gerdes, Marcus Ståhlman, Alinda W M Schimmel, Geesje Dallinga-Thie, Jacques JGHM Bergman, Frits Holleman, Joost B L Hoekstra, Albert Groen, Fredrik Bäckhed, Max Nieuwdorp
Journal: Gut (2019)

Bariatric surgery improves glucose metabolism. Recent data suggest that faecal microbiota transplantation (FMT) using faeces from postbariatric surgery diet-induced obese mice in germ-free mice improves glucose metabolism and intestinal homeostasis. We here investigated whether allogenic FMT using faeces from post-Roux-en-Y gastric bypass donors (RYGB-D) compared with using faeces from metabolic syndrome donors (METS-D) has short-term effects on glucose metabolism, intestinal transit time and adipose tissue inflammation in treatment-naïve, obese, insulin-resistant male subjects.Subjects with metabolic syndrome (n=22) received allogenic FMT either from RYGB-D or METS-D. Hepatic and peripheral insulin sensitivity as well as lipolysis were measured at baseline and 2 weeks after FMT by hyperinsulinaemic euglycaemic stable isotope (2H2-glucose and 2H5-glycerol) clamp. Secondary outcome parameters were changes in resting energy expenditure, intestinal transit time, faecal short-chain fatty acids (SCFA) and bile acids, and inflammatory markers in subcutaneous adipose tissue related to intestinal microbiota composition. Faecal SCFA, bile acids, glycaemic control and inflammatory parameters were also evaluated at 8 weeks.We observed a significant decrease in insulin sensitivity 2 weeks after allogenic METS-D FMT (median rate of glucose disappearance: from 40.6 to 34.0 µmol/kg/min; p<0.01). Moreover, a trend (p=0.052) towards faster intestinal transit time following RYGB-D FMT was seen. Finally, we observed changes in faecal bile acids (increased lithocholic, deoxycholic and (iso)lithocholic acid after METS-D FMT), inflammatory markers (decreased adipose tissue chemokine ligand 2 (CCL2) gene expression and plasma CCL2 after RYGB-D FMT) and changes in several intestinal microbiota taxa.Allogenic FMT using METS-D decreases insulin sensitivity in metabolic syndrome recipients when compared with using post-RYGB-D. Further research is needed to delineate the role of donor characteristics in FMT efficacy in human insulin-resistant subjects.NTR4327.
Abstract 14115: Changes in Body Fat Distribution Predict Arterial Health
Authors: Frank E Corrigan, Heval M Kelli, Devinder S Dhindsa, Robert E Heinl, Ibhar Al Mheid, Muhammad Hammadah, Salim S Hayek, Salman Sher, Danny J Eapen, Greg S Martin, Arshed A Quyyumi
Journal: Circulation (2016)

Introduction: Truncal obesity is associated with insulin resistance, dyslipidemia, hypertension and ultimately to cardiovascular risk. Arterial stiffness and endothelial dysfunction are markers of ...