tbuckley/cabot-search huggingface dataset:
Systemic AL Amyloidosis: Current Approaches to Diagnosis and Management
Authors: Despina Fotiou, Meletios Athanasios Dimopoulos, Efstathios Kastritis
Journal: HemaSphere (2020)

AL amyloidosis is characterized by a low-level expansion of an indolent, small plasma cell clone that produces amyloidogenic light chains. Amyloid aggregates or preceding intermediaries cause direct cell damage through their proteotoxicity, and amyloid deposits distort tissue architecture, and, eventually, lead to organ impairment. It is a rare, underdiagnosed disease with a diverse clinical presentation depending on the organ tropism of the amyloid fibrils; cardiac and renal involvement is most common, but any organ can be affected, excluding the central nervous system. A high level of awareness and a systematic approach using newly emerging screening biomarkers is required to achieve early diagnosis. Management should be multidisciplinary as supportive management tailored to management of organ dysfunction is paramount to survival and minimization of treatment-associated toxicity. The initial therapeutic aim is to rapidly eliminate the clonal plasma cell that produces the circulating amyloid precursor and achieve a complete hematologic response, and if possible with undetectable minimal residual disease as assessed by next-generation methods (flow and sequencing), with minimal toxicity. Treatment is tailored to the initial risk assessment of the patients. Treatments are based on regimens adapted from the expanding options that are available for multiple myeloma patients and hematological response rates have improved. Organ response rates are strongly associated with deeper hematologic response but usually lag behind hematological response and are also dependent on the initial organ function reserve. Agents directed against the amyloid deposits have been explored to aid amyloid clearance and improve organ function, but data are still negative.
SAT0488 ETANERCEPT CONCENTRATION IN PATIENTS WITH JUVENILE IDIOPATHIC ARTHRITIS
Authors: J. Kärki, T. Levälampi, P. Vähäsalo, M. Backström, L. Kröger, M. Malin, A. Putto-Laurila, H. Pohjankoski, H. Kautiainen, T. S. Jokiranta, K. Aalto
Journal: Annals of the Rheumatic Diseases (2020)

Background: Etanercept (ETN) is the most used TNF blocker in children with JIA. There is still limited real-life data of etanercept concentrations in children, especially in association with dosing. Objectives: The aim of the study was to investigate association between ETN dosing and serum trough concentration in children with non-systemic JIA. Methods: We conducted a multicenter retrospective study of 180 Finnish JIA patients (Table 1) receiving ETN either as monotherapy or in combination with one or more DMARDs (Table 2). Prior biologicals were used by 17 % of the patients. Patients were divided into two groups, ETN started before or after one year of diagnosis (Figure 1). ETN concentration samples (collected 2014-2017) were analyzed using validated enzyme-linked immunosorbent assay (ELISA) in Sanquin Diagnostics, Amsterdam, the Netherlands. Results: Demographics at etanercept start and diagnoses are shown in Table 1. Duration of the treatment with ETN, ETN doses, concentrations and concomitant medications at the time of concentration measurement are shown in Table 2. Association between ETN dose and concentration is shown in Figure 1. Those who started medication early (&lt; 1 year from diagnosis) were younger than those who started later (Table 1) and association between ETN dose and concentration was more obvious (Figure 1). Conclusion: There was an association between etanercept dose used and serum trough concentration and it was more evident when medication was started early after diagnosis, when the patients were younger and BSA lower. References: [1]Kneepkens EL et al. Lower etanercept levels are associated with high disease activity in ankylosing spondylitis patients at 24 weeks of follow-up. Ann Rheum Dis 2015;74(10):1825-9. [2]Bader-Meunier B et al. Etanercept concentration and immunogenicity do not influence the response to Etanercept in patients with juvenile idiopathic arthritis. Semin Arthritis Rheum 2019;48(6):1014-1018. Disclosure of Interests: None declared
Recommendations for Pregnancy in Rare Inherited Anemias
Authors: Ali T Taher, Achille Iolascon, Charbel F Matar, Rayan Bou-Fakhredin, Lucia de Franceschi, Maria Domenica Cappellini, Wilma Barcellini, Roberta Russo, Immacolata Andolfo, Paul Tyan, Beatrice Gulbis, Yesim Aydinok, Nicholas P Anagnou, Gabriela Amstad Bencaiova, Hannah Tamary, Patricia Aguilar Martinez, Gianluca Forni, Raffaele Vindigni
Journal: HemaSphere (2020)

Abstract Rare inherited anemias are a subset of anemias caused by a genetic defect along one of the several stages of erythropoiesis or in different cellular components that affect red blood cell integrity, and thus its lifespan. Due to their low prevalence, several complications on growth and development, and multi‐organ system damage are not yet well defined. Moreover, during the last decade there has been a lack of proper understanding of the impact of rare anemias on maternal and fetal outcomes. In addition, there are no clear‐cut guidelines outlining the pathophysiological trends and management options unique to this special population. Here, we present on behalf of the European Hematology Association, evidence‐ and consensus‐based guidelines, established by an international group of experts in different fields, including hematologists, gynecologists, general practitioners, medical geneticists, and experts in rare inherited anemias from various European countries for standardized and appropriate choice of therapeutic interventions for the management of pregnancy in rare inherited anemias, including Diamond‐Blackfan Anemia, Congenital Dyserythropoietic Anemias, Thalassemia, Sickle Cell Disease, Enzyme deficiency and Red cell membrane disorders.
SAT0189 Clinical utility of diagnostic tests for rheumatoid factor
Authors: TM Madland, E Ulvestad, A Kaneström, E Thomassen, HJ Haga
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> To investigate and compare the accuracy and usefulness of diagnostic tests for rheumatoid factor (RF). <h3>Methods</h3> In a cross-sectional study sera derived from patients admitted to the Department of Rheumatology were tested for presence of RF using both nephelometry and the Waaler test. Diagnostic sensitivity and predictive values of the tests were calculated and compared. The accuracy of tests was compared using receiver-operating characteristics (ROC) methodology. <h3>Results</h3> Good agreement was found between the tests (kappa = 0.7). At cut-off 19 IU/mL nephelometry showed highest sensitivity (82.4%) and specificity (95.9%) for rheumatoid arthritis (RA). In comparison, the Waaler test had a sensitivity of 60.3% and specificity of 95.9% at cut-off titer 128. The tests showed nearly equal performance characteristics when predicting primary Sjögren`s syndrome (SS). <h3>Conclusion</h3> Although both tests exhibit good performance characteristics, nephelometry has a higher accuracy when predicting RA. The common practice of using both tests for detection of RF is not recommended.
Targeted Manganese doped silica nano GSH-cleaner for treatment of Liver Cancer by destroying the intracellular redox homeostasis
Authors: Hongxia Tang, Chaoqun Li, Yue Zhang, Hongyue Zheng, Ying Cheng, Jingjing Zhu, Xiaojie Chen, Zhihong Zhu, Ji-Gang Piao, Fanzhu Li
Journal: Theranostics (2020)

Glutathione (GSH), the primary antioxidant in cells, could fight against oxidative stress. Tumor cells display a higher GSH level than normal cells for coping with the hyperoxidative state, which meets the requirements of enhanced metabolism and vicious proliferation. Therefore, the consumption of GSH will lead to cell redox imbalance and impede life activities. Herein, targeted sorafenib (SFB) loaded manganese doped silica nanoparticle (FaPEG-MnMSN@SFB) was constructed, which could destroy the intracellular redox homeostasis by consuming GSH.
Sensitization to sunflower pollen and lung functions in sunflower processing workers
Authors: S. Atis, B. Tutluoglu, K. Sahin, M. Yaman, A.R. Küçükusta, I. Oktay
Journal: Allergy (2002)

Background: This study aimed to investigate whether exposure to sunflower pollen ( Helianthus annuus ) increases both sensitization and respiratory symptoms, and whether or not it affects lung functions in sunflower processing workers. Methods: The largest sunflower processing factories in the Thrace region of Turkey participated in this study. Workers from the units directly exposed to sunflower seed enrolled as the study group ( n = 102) and workers who were not directly exposed to Helianthus annuus pollen ( n = 102) were the control group. Detailed questionnaires covering respiratory and allergic symptoms were completed, and skin prick tests and lung function tests were performed. Results: We found a very high rate (23.5%) of sensitization to Helianthus annuus in the study group compared to the controls ( P &lt; 0.001). Logistic regression analysis showed that the risk of sensitization to H. annuus was increased 4.7‐fold (odds ratio = 4.17, 95% confidence interval = 1.3–16.7) if subjects were exposed to sunflower pollen in the workplace. While asthmatic symptoms and allergic skin diseases were not different between the two groups, workers in the study group had a higher rate of allergic rhinitis and conjunctivitis ( P &lt; 0.05). We found that pulmonary function was significantly impaired in the study group ( P &lt; 0.01). Using a multivariate analysis model, inclusion in the study group was found to be a predictive factor for impairment of lung function ( P = 0.002). Conclusions: We conclude that sunflower pollen has high allergenic potential, especially when there is close contact, and exposure to sunflower pollen in the workplace can result in impairment in lung function.
Subtype and grade-dependent spatial heterogeneity of T-cell infiltration in pediatric glioma
Authors: M Hope Robinson, Juan Vasquez, Akhilesh Kaushal, Tobey J MacDonald, José E Velázquez Vega, Matthew Schniederjan, Kavita Dhodapkar
Journal: Journal for ImmunoTherapy of Cancer (2020)

Brain tumors are the leading cause of cancer-related mortality in children and have distinct genomic and molecular features compared with adult glioma. However, the properties of immune cells in these tumors has been vastly understudied compared with their adult counterparts. We combined multiplex immunofluorescence immunohistochemistry coupled with machine learning and single-cell mass cytometry to evaluate T-cells infiltrating pediatric glial tumors. We show that low-grade tumors are characterized by greater T-cell density compared with high-grade glioma (HGG). However, even among low-grade tumors, T-cell infiltration can be highly variable and subtype-dependent, with greater T-cell density in pleomorphic xanthoastrocytoma and ganglioglioma. CD3+ T-cell infiltration correlates inversely with the expression of SOX2, an embryonal stem cell marker commonly expressed by glial tumors. T-cells within both HGG and low-grade glioma (LGG) exhibit phenotypic heterogeneity and tissue-resident memory T-cells consist of distinct subsets of CD103+ and TCF1+ cells that exhibit distinct spatial localization patterns. TCF1+ T-cells are located closer to the vessels while CD103+ resident T-cells reside within the tumor further away from the vasculature. Recurrent tumors are characterized by a decline in CD103+ tumor-infiltrating T-cells. BRAF V600E mutation is immunogenic in children with LGG and may serve as a target for immune therapy. These data provide several novel insights into the subtype-dependent and grade-dependent changes in immune architecture in pediatric gliomas and suggest that harnessing tumor-resident T-cells may be essential to improve immune control in glioma.
Engineered PLGA microparticles for long-term, pulsatile release of STING agonist for cancer immunotherapy
Authors: Xueguang Lu, Lei Miao, Wenting Gao, Ziqi Chen, Kevin J. McHugh, Yehui Sun, Zachary Tochka, Stephanie Tomasic, Kaitlyn Sadtler, Alain Hyacinthe, Yuxuan Huang, Tyler Graf, Quanyin Hu, Morteza Sarmadi, Robert Langer, Daniel G. Anderson, Ana Jaklenec
Journal: Science Translational Medicine (2020)

Activation of the stimulator of interferon gene (STING) pathway within the tumor microenvironment has been shown to generate a strong antitumor response. Although local administration of STING agonists has promise for cancer immunotherapy, the dosing regimen needed to achieve efficacy requires frequent intratumoral injections over months. Frequent dosing for cancer treatment is associated with poor patient adherence, with as high as 48% of patients failing to comply. Multiple intratumoral injections also disrupt the tumor microenvironment and vascular networks and therefore increase the risk of metastasis. Here, we developed microfabricated polylactic-co-glycolic acid (PLGA) particles that remain at the site of injection and release encapsulated STING agonist as a programmable sequence of pulses at predetermined time points that mimic multiple injections over days to weeks. A single intratumoral injection of STING agonist-loaded microparticles triggered potent local and systemic antitumor immune responses, inhibited tumor growth, and prolonged survival as effectively as multiple soluble doses, but with reduced metastasis in several mouse tumor models. STING agonist-loaded microparticles improved the response to immune checkpoint blockade therapy and substantially decreased the tumor recurrence rate from 100 to 25% in mouse models of melanoma when administered during surgical resection. In addition, we demonstrated the therapeutic efficacy of STING microparticles on an orthotopic pancreatic cancer model in mice that does not allow multiple intratumoral injections. These findings could directly benefit current STING agonist therapy by decreasing the number of injections, reducing risk of metastasis, and expanding its applicability to hard-to-reach cancers.
Analysis of Hepatitis B Virus Haplotype Diversity Detects Striking Sequence Conservation Across Genotypes and Chronic Disease Phase
Authors: Josef Wagner, Lilly Yuen, Margaret Littlejohn, Vitina Sozzi, Kathy Jackson, Vithika Suri, Susanna Tan, Becket Feierbach, Anuj Gaggar, Patrick Marcellin, Maria Buti Ferret, Harry L.A. Janssen, Ed Gane, Henry L.Y. Chan, Danni Colledge, Gillian Rosenberg, Julianne Bayliss, Benjamin P Howden, Stephen A. Locarnini, Darren Wong, Alexander T. Thompson, Peter A. Revill
Journal: Hepatology (2020)

We conducted haplotype analysis of complete hepatitis B virus (HBV) genomes following deep sequencing from 368 patients across multiple phases of chronic hepatitis B (CHB) infection from four major genotypes (A-D), analyzing 4,110 haplotypes to identify viral variants associated with treatment outcome and disease progression.Between 18.2% and 41.8% of nucleotides and between 5.9% and 34.3% of amino acids were 100% conserved in all genotypes and phases examined, depending on the region analyzed. Hepatitis B e antigen (HBeAg) loss by week 192 was associated with different haplotype populations at baseline. Haplotype populations differed across the HBV genome and CHB history, this being most pronounced in the precore/core gene. Mean number of haplotypes (frequency) per patient was higher in immune-active, HBeAg-positive chronic hepatitis phase 2 (11.8) and HBeAg-negative chronic hepatitis phase 4 (16.2) compared to subjects in the "immune-tolerant," HBeAg-positive chronic infection phase 1 (4.3, P< 0.0001). Haplotype frequency was lowest in genotype B (6.2, P< 0.0001) compared to the other genotypes (A = 11.8, C = 11.8, D = 13.6). Haplotype genetic diversity increased over the course of CHB history, being lowest in phase 1, increasing in phase 2, and highest in phase 4 in all genotypes except genotype C. HBeAg loss by week 192 of tenofovir therapy was associated with different haplotype populations at baseline.Despite a degree of HBV haplotype diversity and heterogeneity across the phases of CHB natural history, highly conserved sequences in key genes and regulatory regions were identified in multiple HBV genotypes that should be further investigated as targets for antiviral therapies and predictors of treatment response.
The Effect of Advances in Lung-Cancer Treatment on Population Mortality
Authors: Nadia Howlader, Gonçalo Forjaz, Meghan J. Mooradian, Rafael Meza, Chung Yin Kong, Kathleen A. Cronin, Angela B. Mariotto, Douglas R. Lowy, Eric J. Feuer
Journal: New England Journal of Medicine (2020)

Lung cancer is made up of distinct subtypes, including non-small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). Although overall mortality from lung cancer has been declining in the United States, little is known about mortality trends according to cancer subtype at the population level because death certificates do not record subtype information.Using data from Surveillance, Epidemiology, and End Results (SEER) areas, we assessed lung-cancer mortality and linked deaths from lung cancer to incident cases in SEER cancer registries. This allowed us to evaluate population-level mortality trends attributed to specific subtypes (incidence-based mortality). We also evaluated lung-cancer incidence and survival according to cancer subtype, sex, and calendar year. Joinpoint software was used to assess changes in incidence and trends in incidence-based mortality.Mortality from NSCLC decreased even faster than the incidence of this subtype, and this decrease was associated with a substantial improvement in survival over time that corresponded to the timing of approval of targeted therapy. Among men, incidence-based mortality from NSCLC decreased 6.3% annually from 2013 through 2016, whereas the incidence decreased 3.1% annually from 2008 through 2016. Corresponding lung cancer-specific survival improved from 26% among men with NSCLC that was diagnosed in 2001 to 35% among those in whom it was diagnosed in 2014. This improvement in survival was found across all races and ethnic groups. Similar patterns were found among women with NSCLC. In contrast, mortality from SCLC declined almost entirely as a result of declining incidence, with no improvement in survival. This result correlates with limited treatment advances for SCLC in the time frame we examined.Population-level mortality from NSCLC in the United States fell sharply from 2013 to 2016, and survival after diagnosis improved substantially. Our analysis suggests that a reduction in incidence along with treatment advances - particularly approvals for and use of targeted therapies - is likely to explain the reduction in mortality observed during this period.
2019 EULAR points to consider for the assessment of competences in rheumatology specialty training
Authors: Francisca Sivera, Alessia Alunno, Aurélie Najm, Tadej Avcin, Xenofon Baraliakos, Johannes W Bijlsma, Sara Badreh, Gerd Burmester, Nada Cikes, Jose AP Da Silva, Nemanja Damjanov, Maxime Dougados, Jean Dudler, Christopher J Edwards, Annamaria Iagnocco, Frédéric Lioté, Elena Nikiphorou, Marloes van Onna, Simon R Stones, Dimitrios Vassilopoulos, Catherine Haines, Sofia Ramiro
Journal: Annals of the Rheumatic Diseases (2020)

Striving for harmonisation of specialty training and excellence of care in rheumatology, the European League Against Rheumatism (EULAR) established a task force to develop points to consider (PtCs) for the assessment of competences during rheumatology specialty training.A systematic literature review on the performance of methods for the assessment of competences in rheumatology specialty training was conducted. This was followed by focus groups in five selected countries to gather information on assessment practices and priorities. Combining the collected evidence with expert opinion, the PtCs were formulated by the multidisciplinary task force, including rheumatologists, medical educationalists, and people with rheumatic and musculoskeletal diseases. The level of agreement (LoA) for each PtC was anonymously voted online.Four overarching principles and 10 PtCs were formulated. The overarching principles highlighted the importance of assessments being closely linked to the rheumatology training programme and protecting sufficient time and resources to ensure effective implementation. In the PtCs, two were related to overall assessment strategy (PtCs 1 and 5); three focused on formative assessment and portfolio (PtCs 2-4); three focused on the assessment of knowledge, skills or professionalism (PtCs 6-8); one focused on trainees at risk of failure (PtC 9); and one focused on training the trainers (PtC 10). The LoA (0-10) ranged from 8.75 to 9.9.These EULAR PtCs provide European guidance on assessment methods throughout rheumatology training programmes. These can be used to benchmark current practices and to develop future strategies, thereby fostering continuous improvement in rheumatology learning and, ultimately, in patient care.
Safety and efficacy of CAR-T cell targeting BCMA in patients with multiple myeloma coinfected with chronic hepatitis B virus
Authors: Lu Han, Jian Zhou, Keshu Zhou, Xinghu Zhu, Lingdi Zhao, Baijun Fang, Qingsong Yin, Xudong Wei, Hu Zhou, Linlin Li, Bengling Xu, Jishuai Zhang, Yongping Song, Quanli Gao
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Reactivation of hepatitis B virus (HBV) infection is a well-recognized complication in patients with chronic or resolved HBV infection undergoing anticancer therapy. There is a risk of HBV reactivation after infusion of chimeric antigen receptor (CAR) T cells for patients with refractory/relapsed (R/R) multiple myeloma (MM). Methods We administered B cell maturation antigen (BCMA) CAR-T cell by infusion to nine patients with R/R MM with chronic or resolved HBV infection. Patient serum was analyzed to determine the expression of five components of HBV and the copy number of HBV DNA. HBV reactivation was defined if a patient re-exhibited hepatitis B surface antigen (HBsAg) or HBV DNA regrowth after CAR-T therapy. Results In one patient who was HBsAg-positive, no HBV reactivation was observed during the follow-up period of 9.8 months after administration of anti-HBV drugs before and after CAR-T therapy. Among eight patients with MM who had resolved HBV infection, two patients administered prophylactic anti-HBV drugs did not exhibit HBV reactivation. Of the six patients who did not use prophylactic antiviral drugs, five did not exhibit HBV reactivation, while one showed recurrence of HBsAg without detection of HBV DNA or damage to liver function. The best objective response rate was 100%, and the progression-free survival (PFS) at 12 months was of 88.89% (median PFS was not observed). Conclusions These findings showed that BCMA CAR-T cell therapy could be used in patients with R/R MM with chronic or resolved HBV infection and that antiviral drugs should be administered in these patients during CAR-T cell therapy.
Roger Williams: global leader in liver disease
Authors: John Illman
Journal: BMJ (2020)

Photo: Chris Young/PA

In 2013 Roger Williams, who helped to develop the UK’s first liver transplant programme, said, “I still do my 12 hours a day.” He was then well into his 80s. His wish to keep going until he “keeled over backwards” was granted. The covid-19 lockdown gave him an unexpected chance to complete, some three months ahead of deadline, the 7th Lancet Commission report into liver disease in the UK.

The author of more than 2750 publications, 340 in the past 10 years, Williams was one of the most highly cited and influential hepatologists, according to the Institute of Scientific Information. He spent more than 50 years at the forefront of research and, uniquely, led three liver institutes.

Williams told the Lancet in 2013, “I’ve always wanted to be in medicine doing the best, as it were, and not having to refer to someone else to do something special. I’m never happier than when I’m working on and trying out new advances.”

His rise to prominence began in 1959 when he moved to the Royal Free Hospital, London, under Sheila Sherlock, the doyenne of liver disease—and a great talent spotter (read obituary: www.bmj.com/content/324/7330/174.1). Starting in the …