tbuckley/cabot-search huggingface dataset:
Alan Stevens: diagnostic histopathologist and author of prizewinning textbooks
Authors: Rebecca Wallersteiner
Journal: BMJ (2019)

Photo credit: James Lowe

Alan Stevens (called “Steve” by his friends and colleagues) was born in Chesterfield to Ivy (a milliner) and Herman (an accountant). He soon shone at Brampton Board Primary School before moving up to Chesterfield Grammar School. He developed ambitions to become a doctor, although he was apprehensive about the prospect of leaving his home and girlfriend (Chris).

His Chesterfield roots were worn with great pride throughout his life, with “conspicuous northernness” a trademark. He would never be going to use the bathroom, rather he would be “off to have a rubdown with an oily rag,” he never invited anyone to help themselves, rather he said “fill your boots.”

Supported by his family he gained a place at medical school and started studies at Guy’s Hospital, London, in 1960. Things did not go smoothly. The death of his father left him the man of the family. A bout of pneumonia followed, and he resolved to give up his medical training and return home. Encouraged by his mother and Chris, however, he decided to continue. Alan and Chris married in 1963. They settled in South Woodford, north east London, before Alan had fully qualified as a doctor, and their long and happy …
Vessels Encapsulating Tumor Clusters (VETC) Is a Powerful Predictor of Aggressive Hepatocellular Carcinoma
Authors: Salvatore Lorenzo Renne, Ha Young Woo, Sarah Allegra, Noemi Rudini, Hirohisa Yano, Matteo Donadon, Luca Viganò, Jun Akiba, Hye Sun Lee, Hyungjin Rhee, Young Nyun Park, Massimo Roncalli, Luca Di Tommaso
Journal: Hepatology (2019)

We investigated the clinical significance of a vascular growth pattern of hepatocellular carcinoma (HCC), the vessels that encapsulate tumor clusters (VETC), previously linked to HCC metastatic dissemination. VETC was assessed in a large multi‐institutional cohort of 541 resected HCCs from Italy, Korea and Japan, and matched against a full spectrum of clinical and pathological variables. The VETC phenotype (defined as ≥ 55% tumor area by CD34 immunostaining) was easily reproducible and reliably detectable in whole sections and small‐sized tissues of tissue microarray. VETC HCCs represented 18.9% of the whole series, the lowest proportion occurring in the cohort with smallest tumors (8.7%, Japanese series). VETC was significantly associated with several clinical and pathological features such as high alfa‐fetoprotein (AFP) level, tumor size greater than 5 cm, poor differentiation, macrotrabecular pattern, less compact pattern, less inflammatory infiltrates, and frequent microvascular invasion. VETC was associated with early recurrence (hazard ratio [HR]: 1.52 [1.06‐2.19], P = 0.023), disease‐free survival (HR: 1.66 [1.21‐2.27], P = 0.002), and overall survival (HR: 2.26 [1.37‐3.72], P = 0.001) at multivariable analysis. VETC affected the survival in HCC patients stratified for etiology (hepatitis C virus/hepatitis B virus), vascular invasion, and specific molecular phenotypes (β‐catenin/GS+). This distinct vascular pattern was enriched in the recently reported macrotrabecular massive HCC subtype, which was seen in 7.8% (42 of 541) of patients and associated with high AFP levels and poor differentiation. Conclusion: The VETC pattern was found to be easily detectable in a consistent fraction of HCC and a powerful pathological finding affecting survival. This study suggests that the heterogeneous pattern of angiogenesis is involved in HCC behavior.
A Phase I Trial of the VEGF Receptor Tyrosine Kinase Inhibitor Pazopanib in Combination with the MEK Inhibitor Trametinib in Advanced Solid Tumors and Differentiated Thyroid Cancers
Authors: Razelle Kurzrock, Douglas W. Ball, Marianna L. Zahurak, Barry D. Nelkin, Vivek Subbiah, Shabina Ahmed, Ashley O'Connor, Enusha Karunsena, Rose M. Parkinson, Justin A. Bishop, Yoonji Ha, Rajni Sharma, Christopher D. Gocke, Ralph Zinner, Michelle A. Rudek, Steven I. Sherman, Nilofer S. Azad
Journal: Clinical Cancer Research (2019)

Abstract Purpose: Differentiated thyroid cancer (DTC) responds to VEGF receptor inhibitors. VEGF signals through RAS/RAF/MEK signaling. We evaluated the safety and efficacy of the VEGF receptor inhibitor pazopanib and MEK inhibitor trametinib in advanced solid tumors and DTC. Patients and Methods: Patients with advanced solid tumors were enrolled in a phase I, multicenter trial with a DTC expansion cohort. Patients received pazopanib 400–800 mg and trametinib 1–2 mg daily. Efficacy in the expansion cohort was assessed with objective response (OR) at 6 months of treatment. Results: Twenty-six patients were enrolled in five dose levels. MTD was not reached; the recommended phase II dose was pazopanib 800 mg orally and trametinib 2 mg orally every day. There was one dose-limiting toxicity on dose level 1 with grade 3 fatigue and muscle weakness. Common grade 3 adverse events were elevated transaminases (19%), diarrhea (15%), hypertension (12%), and fatigue (8%). Thirteen patients were enrolled in the DTC cohort; OR was 33% (95% confidence interval, 9.9, 65.1%) and median progression-free survival was 10.7 months. The cohort was terminated after planned interim analysis suggested insufficiently increased activity against the historical control of pazopanib alone. Reduction in tumor diameter negatively correlated with p-ERK change in tumor (Spearman ρ = −0.71; P = 0.05). NRAS mutation was associated with response (Fisher exact P = 0.008). Conclusions: Pazopanib + trametinib was tolerable at full single-agent doses with clinical activity in DTC but did not achieve the prespecified response rate target.
Evaluating important change in cutaneous disease activity as an efficacy measure for clinical trials in dermatomyositis
Authors: S. Ahmed, S. Chakka, J. Concha, R. Krain, R. Feng, V.P. Werth
Journal: British Journal of Dermatology (2019)

Patients may experience improved quality of life (QoL) without complete clearance of skin disease. The Cutaneous Dermatomyositis Disease Area and Severity Index Activity (CDASI‐A) score correlates with the Symptoms and Emotions subscales of Skindex‐29, a measure of QoL, down to CDASI‐A scores of 7 points (for Symptoms) and 10 points (for Emotions). Our goal was to define an important change in disease activity, as measured by the CDASI‐A, that results in a meaningful change in QoL in patients with dermatomyositis. In 103 patients, we assessed the percentage change and actual change in CDASI‐A scores needed to achieve a meaningful improvement in QoL, using linear regression models. We found that meaningful improvement correlates with 7·86 points (P < 0·001) in Symptoms, and 10·29 points (P < 0·001) in Emotions, after correlating Skindex‐29 to an established definition of meaningful change in the Dermatology Life Quality Index (DLQI). For patients with initial CDASI‐A scores > 14 points, a 40% change in CDASI‐A between the first two visits suggests a meaningful change in Skindex‐29. In patients with moderate initial CDASI‐A (15–26 points), the changes in CDASI‐A resulting in meaningful changes in Symptoms and Emotions were 6 points (P < 0·001) and 7 points (P < 0·001), respectively. For initial CDASI‐A scores in the severe range (27–35 points), an improvement in CDASI‐A by 11 points (P = 0·030) and 9 points (P = 0·021) leads to a meaningful change in Symptoms and Emotions, respectively. In patients with an initial CDASI‐A score > 14 points, a 40% change in the CDASI‐A score can be used to indicate a meaningful change in QoL in future dermatomyositis trials. What's already known about this topic? The Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) is a validated disease assessment tool used to capture the extent of cutaneous activity and damage. The Skindex‐29 and Dermatology Life Quality Index are standardized and validated measures of quality of life (QoL) for clinical trials and correlate with CDASI Activity (CDASI‐A) scores. What does this study add? We identified what change in Skindex‐29 scores over two consecutive visits would indicate an important change (a minimal clinically important difference) in QoL. We determined which change in CDASI‐A scores over two consecutive visits would lead to a meaningful change in QoL. For patients with an initial CDASI‐A score > 14 points, a 40% change in the CDASI‐A score over two visits is associated with a meaningful change in QoL. What are the clinical implications of this work? Clinical trials can consider using a 40% change in the CDASI‐A score as an end point when assessing the clinical efficacy of drugs.
AB0844 THE ENIGMA OF FRAGILITY FRACTURE WITH NORMAL BONE MASS; EXPERIENCE OF A LIAISON SERVICE FRACTURE UNIT
Authors: Antonio Naranjo, Soledad Ojeda, Aida Saavedra, Cristina Sepúlveda, Amparo Molina, Tatiana Marrero, María Pino Afonso, Margarita Ramirez, Nieves Martín, Alicia Olivares, Carlos Rodriguez-Lozano
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The enigma of fragility fracture with normal bone mass; Experience of a Liaison Service Fracture Unit <h3>Objectives</h3> To describe the characteristics of patients with fragility fracture and normal DXA treated in an FLS unit. <h3>Methods</h3> Prospective 6-year observational study of a FLS fracture unit. Demographic variables, FRAX items, DXA and TBS were collected. The characteristics of patients with normal and abnormal DXA are described. The statistical analysis was performed by means of a descriptive, comparing the normal DXA/osteopenia/osteoporosis groups by means of contingency tables, Fisher's exact test, Student's t test or ANOVA, as appropriate, as well as regression analysis. <h3>Results</h3> 1,631 patients were included, 205 with normal DXA (12.5%), 747 with osteopenia (45.8%) and 680 with osteoporosis (41.6%). Patients with normal DXA were characterized by a higher percentage of males, a younger age and a higher BMI. Hip fracture was less frequent in patients with normal DXA, while the frequency of other fractures was higher. The frequency of previous fracture, history of hip fracture of the parents and secondary osteoporosis was lower in patients with normal DXA. The TBS and FRAX values were higher in the cases of normal DXA compared to osteopenia and osteoporosis. In the multiple regression analysis, excluding TBS, remained significant associated with abnormal DXA age (OR 1.04; 1.03-1.06), sex (OR 2.48; 1.71-3.58), BMI (OR 0.91; 0.89-0.94),) and parent hip fracture (OR 1.99; 1.11-3.58). Including TBS &lt;1,230 as a dichotomous variable (N = 451 cases) remained significant age (OR 1.03; 1.00-1.06), sex (OR 3.58; 1.81-7.10) and TBS (OR 5.23; 1.55-17.68). <h3>Conclusion</h3> Patients with fragility fracture and normal DXA are younger, with more frequent males and with BMI and higher TBS values. <h3>Acknowledgement</h3> Fabiola Santana y Carmen Alonso <h3>Disclosure of Interests</h3> Antonio Naranjo Grant/research support from: Amgen, Consultant for: UCB, Speakers bureau: Amgen, UCB, Soledad Ojeda Grant/research support from: AMGEN, Speakers bureau: AMGEN, Aida Saavedra: None declared, Cristina Sepúlveda: None declared, Amparo Molina Speakers bureau: AMGEN, Tatiana Marrero: None declared, María Pino Afonso: None declared, Margarita Ramirez: None declared, Nieves Martín: None declared, Alicia Olivares: None declared, Carlos Rodriguez-Lozano: None declared
THU0619 THE VALUE OF MORPHOLOGICAL AND BIOCHEMICAL MAGNETIC RESONANCE IMAGING (MRI) OF RADIOCARPAL CARTILAGE FOR THE DIFFERENTIATION OF RHEUMATOID ARTHRITIS AND OSTEOARTHRITIS
Authors: Philipp Sewerin, Lino Sawicki, Christoph Schleich, Daniel Abrar, Matthias Schneider, Stefan Vordenbäumen, Benedikt Ostendorf
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Using high-field MRI to differ morphologically between OA and RA. <h3>Objectives:</h3> To evaluate the value of morphological and biochemical, contrast-agent free high-field (3 Tesla) MRI of the radiocarpal cartilage to differ between osteoarthritis (OA) and rheumatoid arthritis (RA). <h3>Methods:</h3> The group consisted of 47 subjects, who were examined during the period from October 2016 to December 2017. The clinical dominant hand of 11 patients suffering from early rheumatoid arthritis (RA) (German ArthroMark cohort, Ø 52.8years; min: 32; max 74), seropositive (ACPA and/or RF), disease duration &lt; 6 months (range 2 –23 weeks)), 10 with osteoarthritis (OA) (Ø 48.55 ± 15.23 years, min: 34 years, max: 68 years, disease duration Ø 6 years ± 8.29) and 26 healthy volunteers (Ø 46.55 ± 17.55 years, min: 20 years, max: 79 years) were examined with a 3T MRI scanner, prospectively. Morphological and biochemical assessment of radiocarpal cartilage was performed using DESS, TrueFISP and T2* images. <h3>Results:</h3> Morphological sequences demonstrated significantly higher cartilage damage in RA and OA compared to healthy controls (DESS: p = 0.01, p = 0.0004; TrueFISP: p = 0.02, p = 0.0001), while there was no significant difference between RA and OA patients. With biochemical MRI using T2* imaging, patients with OA showed higher cartilage integrity compared to patients with RA (p = 0.01). <h3>Conclusion:</h3> Morphological and biochemical MRI of radiocarpal cartilage could be helpful to differentiate between RA and OA patients. Both, RA and OA, are associated with cartilage damage measured by morphological MRI of the hand. Hence, OA was associated with more loss of cartilage integrity compared to RA using biochemical MRI, whereby only early RA patients were analyzed in this first evaluation. Non-contrast-agent morphological and biochemical MRI could be a non-invasive tool to investigate cartilage integrity in RA and OA patients and could help to differ disease pattern in the future. <h3>Acknowledgement:</h3> We would like to thank Erika Rädisch for the assistance in receiving the MRI scans. <h3>Disclosure of Interests:</h3> Philipp Sewerin: None declared, Lino Sawicki: None declared, Christoph Schleich: None declared, Daniel Abrar: None declared, Matthias Schneider Grant/research support from: GlaxoSmithKline and UCB Pharma for performing the LuLa-study., Speakers bureau: Chugai, Stefan Vordenbäumen: None declared, Benedikt Ostendorf: None declared
PB1843 EFFECT OF ADHERENCE TO PHYSICAL THERPY REGIMEN ON JOINTS OUTCOMES FOR HEMOPHILIAC CHILDREN AT ZAGAZIG UNIVERSITY HOSPITALS
Authors: M. Hesham, A. El‐Dakhakhny, M. Hanfy, A. Abo‐Elsoaud
Journal: HemaSphere (2019)

Background: The maintenance of healthy joints and muscles is crucial to the quality of life of patients with hemophilia. Clotting factor replacement may stop or even prevent bleeds but it does not restore joint or muscle function. Only regular movement and exercise and adherence to them can do that. Physiotherapy aims to bring relief from pain, restore muscle power and control, restore range of joint movement and prevent further injury to a target joint. Enhancing adherence, joint function and decreasing pain by using physiotherapy is the major hope for all hemophiliac patients, especially in developing countries with limited access to treatment. Aims: to Identify the effect of adherence to physical therapy regimen on joint outcomes for children with hemophilia. Methods: A quasi–experimental study was conducted on a sample of “35” children were suffering from hemophilia “A” or “B” at the Pediatric Hematology outpatient clinic at Zagazig University Hospitals. The knee joint was selected to perform the physiotherapy regimen Tools was composed of three parts Part I: a structured interview sheet. Part II assessment of adherence using (attendance at clinic appointments, SIRAS a and Patient Self‐Report Scale of their Home‐Based Rehbiltation adherence). Part III was the assessment of the musculoskeletal status and joint evaluation using (Gibert score, FISH © and the musculoskeletal data sheet). Results: ‐ There was a significant statistical relation and improvement in the mean score of functional ability of the studied group throughout the intermediate and post‐test phases than the pre‐test phase. ‐ There was a significant statistical improvement in the studied sample adherence and knee joint outcomes throughout the study phases. Summary/Conclusion: the adherence to physiotherapy have a profound effect on improving joint outcomes. So,we recommend encouraging the awareness of hemophiliac patients about physiotherapy and its beneficial role in decreasing the musculoskeletal complications.
Changes in rapid HIV treatment initiation after national “treat all” policy adoption in 6 sub-Saharan African countries: Regression discontinuity analysis
Authors: Olga Tymejczyk, Ellen Brazier, Constantin T. Yiannoutsos, Michael Vinikoor, Monique van Lettow, Fred Nalugoda, Mark Urassa, Jean d’Amour Sinayobye, Peter F. Rebeiro, Kara Wools-Kaloustian, Mary-Ann Davies, Elizabeth Zaniewski, Nanina Anderegg, Grace Liu, Nathan Ford, Denis Nash
Journal: PLoS Medicine (2019)

Most countries have formally adopted the World Health Organization's 2015 recommendation of universal HIV treatment ("treat all"). However, there are few rigorous assessments of the real-world impact of treat all policies on antiretroviral treatment (ART) uptake across different contexts.
Integrated time course omics analysis distinguishes immediate therapeutic response from acquired resistance
Authors: Genevieve Stein-O’Brien, Luciane T. Kagohara, Sijia Li, Manjusha Thakar, Ruchira Ranaweera, Hiroyuki Ozawa, Haixia Cheng, Michael Considine, Sandra Schmitz, Alexander V. Favorov, Ludmila V. Danilova, Joseph A. Califano, Evgeny Izumchenko, Daria A. Gaykalova, Christine H. Chung, Elana J. Fertig
Journal: Genome Medicine (2018)

Targeted therapies specifically act by blocking the activity of proteins that are encoded by genes critical for tumorigenesis. However, most cancers acquire resistance and long-term disease remission is rarely observed. Understanding the time course of molecular changes responsible for the development of acquired resistance could enable optimization of patients' treatment options. Clinically, acquired therapeutic resistance can only be studied at a single time point in resistant tumors. To determine the dynamics of these molecular changes, we obtained high throughput omics data (RNA-sequencing and DNA methylation) weekly during the development of cetuximab resistance in a head and neck cancer in vitro model. The CoGAPS unsupervised algorithm was used to determine the dynamics of the molecular changes associated with resistance during the time course of resistance development. CoGAPS was used to quantify the evolving transcriptional and epigenetic changes. Applying a PatternMarker statistic to the results from CoGAPS enabled novel heatmap-based visualization of the dynamics in these time course omics data. We demonstrate that transcriptional changes result from immediate therapeutic response or resistance, whereas epigenetic alterations only occur with resistance. Integrated analysis demonstrates delayed onset of changes in DNA methylation relative to transcription, suggesting that resistance is stabilized epigenetically. Genes with epigenetic alterations associated with resistance that have concordant expression changes are hypothesized to stabilize the resistant phenotype. These genes include FGFR1, which was associated with EGFR inhibitors resistance previously. Thus, integrated omics analysis distinguishes the timing of molecular drivers of resistance. This understanding of the time course progression of molecular changes in acquired resistance is important for the development of alternative treatment strategies that would introduce appropriate selection of new drugs to treat cancer before the resistant phenotype develops.
SP0011 HOW THE GUT INFLUENCES THE IMMUNE SYSTEM
Authors: Mario Zaiss
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> A disturbed gut microbiota composition has been associated with autoimmune diseases. Recent findings support the hypothesis that the onset of RA might be linked with the gut microbiota. Moreover, we could recently show that high fiber diets change the microbiota, increase SCFA levels and attenuate inflammatory arthritis and bone destruction <sup>(1)</sup>. However, direct mechanistic links between the gut microbiota and onset of autoimmune diseases remain largely unknown. <h3>Objectives:</h3> Herein, we intended to identify if the intestinal barrier integrity could serve as a key checkpoint translating autoimmunity to inflammation. <h3>Results:</h3> Restoration of the intestinal barrier in the pre-phase of arthritis using different approaches inhibited the development of arthritis. <h3>Conclusion:</h3> In summary, our data identify a new preventive approach for the onset of autoimmune disease by specifically targeting impaired intestinal barrier function. <h3>Reference:</h3> [1]Lucas S, Omata Y, Hofmann J, Böttcher M, Iljazovic A, Sarter K, Albrecht O, Schulz O, Krishnacoumar B, Krönke G, Herrmann M, Mougiakakos D, Strowig T, Schett G and Zaiss M M. (2018). Short-chain fatty acids regulate systemic bone mass and protect from pathological bone loss. Nat Commun 9: 55. <h3>Disclosure of Interests:</h3> None declared
Assessment of Antibiotic Treatment of Cellulitis and Erysipelas
Authors: Richard Brindle, O. Martin Williams, Edward Barton, Peter Featherstone
Journal: JAMA Dermatology (2019)

The optimum antibiotic treatment for cellulitis and erysipelas lacks consensus. The available trial data do not demonstrate the superiority of any agent, and data are limited on the most appropriate route of administration or duration of therapy.To assess the efficacy and safety of antibiotic therapy for non-surgically acquired cellulitis.The following databases were searched to June 28, 2016: Cochrane Central Register of Controlled Trials (2016, issue 5), Medline (from 1946), Embase (from 1974), and Latin American and Caribbean Health Sciences Information System (LILACS) (from 1982). In addition, 5 trials databases and the reference lists of included studies were searched. Further searches of PubMed and Google Scholar were undertaken from June 28, 2016, to December 31, 2018.Randomized clinical trials comparing different antibiotics, routes of administration, and treatment durations were included.For data collection and analysis, the standard methodological procedures of the Cochrane Collaboration were used. For dichotomous outcomes, the risk ratio and its 95% CI were calculated. A summary of findings table was created for the primary end points, adopting the GRADE approach to assess the quality of the evidence.The primary outcome was the proportion of patients cured, improved, recovered, or symptom-free or symptom-reduced at the end of treatment, as reported by the trial. The secondary outcome was any adverse event.A total of 43 studies with a total of 5999 evaluable participants, whose age ranged from 1 month to 96 years, were included. Cellulitis was the primary diagnosis in only 15 studies (35%), and in other studies the median (interquartile range) proportion of patients with cellulitis was 29.7% (22.9%-50.3%). Overall, no evidence was found to support the superiority of any 1 antibiotic over another, and antibiotics with activity against methicillin-resistant Staphylococcus aureus did not add an advantage. Use of intravenous antibiotics over oral antibiotics and treatment duration of longer than 5 days were not supported by evidence.In this systematic review and meta-analysis, only low-quality evidence was found for the most appropriate agent, route of administration, and duration of treatment for patients with cellulitis; future trials need to use a standardized set of outcomes, including severity scoring, dosing, and duration of therapy.