tbuckley/cabot-search huggingface dataset:
Curriculum for endoscopic submucosal dissection training in Europe: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement
Authors: Pedro Pimentel-Nunes, Mathieu Pioche, Eduardo Albéniz, Frieder Berr, Pierre Deprez, A. Ebigbo, Pieter Dewint, Amyn Haji, Alba Panarese, Bas L. A. M. Weusten, Evelien Dekker, James E. East, David S. Sanders, Gavin Johnson, Marianna Arvanitakis, Thierry Ponchon, Mário Dinis-Ribeiro, Raf Bisschops
Journal: Endoscopy (2019)

Main Recommendation There is a need for well-organized comprehensive strategies to achieve good training in ESD. In this context, the European Society of Gastrointestinal Endoscopy (ESGE) have developed a European core curriculum for ESD practice across Europe with the aim of high quality ESD training. Advanced endoscopy diagnostic practice is advised before initiating ESD training. Proficiency in endoscopic mucosal resection (EMR) and adverse event management is recommended before starting ESD training ESGE discourages the starting of initial ESD training in humans. Practice on animal and/or ex vivo models is useful to gain the basic ESD skills. ESGE recommends performing at least 20 ESD procedures in these models before human practice, with the goal of at least eight en bloc complete resections in the last 10 training cases, with no perforation. ESGE recommends observation of experts performing ESD in tertiary referral centers. Performance of ESD in humans should start on carefully selected lesions, ideally small ( &lt; 30 mm), located in the antrum or in the rectum for the first 20 procedures. Beginning human practice in the colon is not recommended. ESGE recommends that at least the first 10 human ESD procedures should be done under the supervision of an ESD-proficient endoscopist. Endoscopists performing ESD should be able to correctly estimate the probability of performing a curative resection based on the characteristics of the lesion and should know the benefit/risk relationship of ESD when compared with other therapeutic alternatives. Endoscopists performing ESD should know how to interpret the histopathology findings of the ESD specimen, namely the criteria for low risk resection (“curative”), local risk resection, and high risk resection (“non-curative”), as well as their implications. ESD should be performed only in a setting where early and delayed complications can be managed adequately, namely with the possibility of admitting patients to a ward, and access to appropriate emergency surgical teams for the organ being treated with ESD.
Gene Correction of LGMD2A Patient-Specific iPSCs for the Development of Targeted Autologous Cell Therapy
Authors: Sridhar Selvaraj, Neha R. Dhoke, James Kiley, Alba Judith Mateos-Aierdi, Sudheer Tungtur, Ricardo Mondragon-Gonzalez, Grace Killeen, Vanessa K.P. Oliveira, Adolfo López de Munain, Rita C.R. Perlingeiro
Journal: Molecular Therapy (2019)

Limb girdle muscular dystrophy type 2A (LGMD2A), caused by mutations in the Calpain 3 (CAPN3) gene, is an incurable autosomal recessive disorder that results in muscle wasting and loss of ambulation. To test the feasibility of an autologous induced pluripotent stem cell (iPSC)-based therapy for LGMD2A, here we applied CRISPR-Cas9-mediated genome editing to iPSCs from three LGMD2A patients to enable correction of mutations in the CAPN3 gene. Using a gene knockin approach, we genome edited iPSCs carrying three different CAPN3 mutations, and we demonstrated the rescue of CAPN3 protein in myotube derivatives in vitro. Transplantation of gene-corrected LGMD2A myogenic progenitors in a novel mouse model combining immunodeficiency and a lack of CAPN3 resulted in muscle engraftment and rescue of the CAPN3 mRNA. Thus, we provide here proof of concept for the integration of genome editing and iPSC technologies to develop a novel autologous cell therapy for LGMD2A. Limb girdle muscular dystrophy type 2A (LGMD2A), caused by mutations in the Calpain 3 (CAPN3) gene, is an incurable autosomal recessive disorder that results in muscle wasting and loss of ambulation. To test the feasibility of an autologous induced pluripotent stem cell (iPSC)-based therapy for LGMD2A, here we applied CRISPR-Cas9-mediated genome editing to iPSCs from three LGMD2A patients to enable correction of mutations in the CAPN3 gene. Using a gene knockin approach, we genome edited iPSCs carrying three different CAPN3 mutations, and we demonstrated the rescue of CAPN3 protein in myotube derivatives in vitro. Transplantation of gene-corrected LGMD2A myogenic progenitors in a novel mouse model combining immunodeficiency and a lack of CAPN3 resulted in muscle engraftment and rescue of the CAPN3 mRNA. Thus, we provide here proof of concept for the integration of genome editing and iPSC technologies to develop a novel autologous cell therapy for LGMD2A.
Circulating dipeptidyl peptidase 3 is a myocardial depressant factor: dipeptidyl peptidase 3 inhibition rapidly and sustainably improves haemodynamics
Authors: Benjamin Deniau, Linda Rehfeld, Karine Santos, Anke Dienelt, Feriel Azibani, Malha Sadoune, Paul R. Kounde, Jane L. Samuel, Heli Tolpannen, Johan Lassus, Veli‐Pekka Harjola, Nicolas Vodovar, Andreas Bergmann, Oliver Hartmann, Alexandre Mebazaa, Alice Blet
Journal: European Journal of Heart Failure (2019)
Endothelial senescence-associated secretory phenotype (SASP) is regulated by Makorin-1 ubiquitin E3 ligase
Authors: Sivareddy Kotla, Nhat-Tu Le, Hang Thi Vu, Kyung Ae Ko, Young Jin Gi, Tamlyn N. Thomas, Carolyn Giancursio, Aldos J. Lusis, John P. Cooke, Keigi Fujiwara, Jun-ichi Abe
Journal: Metabolism (2019)
Utility of the baseline cardiac imaging in the treatment decision for young patients with acute leukemia.
Authors: Ali El Sayed, Patrick Michael Dillon, John Densmore, James Patrie, Hanna Kelly Sanoff
Journal: Journal of Clinical Oncology (2013)

e18005 Background: Anthracyclines, the backbone of acute leukemia induction regimens, are associated with risk of cardiotoxicity. Routine cardiac imaging is routinely performed before induction treatment with anthracycline based regimens (ABR).There is no standard guideline on the optimal method of LVEF assessment, nor consensus for the treatment implication of a borderline LVEF finding. The NCCN recommends cardiac imaging for patients with prior heart disease, prior anthracycline use, or clinical symptoms of cardiac dysfunction. We examine the role of routine pre-induction cardiac imaging in young adults diagnosed with acute leukemia. Methods: A database search at the University of Virginia identified patients newly diagnosed with ALL and AML (including APML), between the ages of 18 and 49 from 2000 to 2011. Baseline demographics, pre-treatment cardiac imaging, and the induction chemotherapy regimen chosen were abstracted. Results: A total of 71 patients with ALL or AML were identified. Thirty-three patients (46.5%) were female, and the average age was 36.1 (SD=9.9 years, range 18 to 49 ). Median baseline LVEF was 62.5 (range 54-74). Out of 71 patients, 25 had a borderline LVEF between 50% and 60%.The lowest baseline EF was 54%. Among 25 patients with borderline LVEF, all received ABR for induction. Conclusions: In patients under age 50 with newly diagnosed acute leukemias, pre-treatment cardiac imaging did not alter standard induction therapy with ABR. This suggests that induction therapy should not be delayed to await baseline LVEF assessment. A potential cost saving may be achieved in this population. Routine cardiac imaging may be more helpful in older adults or patients with prior cardiac history or anticipated need for consolidation with an ABR (ie APML).
Communicating Oncologic Prognosis with Empathy (COPE) Pilot Study.
Authors: Boone W. Goodgame, Farya Phillips, Wenhui Vivian Zhang, Barbara L. Jones
Journal: Journal of Clinical Oncology (2019)

11613 Background: Multiple studies show that patients with advanced cancer often believe the goal of treatment is cure. Our interprofessional team designed the Communicating Oncologic Prognosis with Empathy (COPE) guide to enhance communication for patients, families, and the healthcare team. This unique, single-page tool allows treating physicians to estimate prognosis for patients, including likelihood of living 6 mo, 1y, 2y, and 5y, with or without treatment. Methods: Patients with incurable cancer were enrolled at one oncology clinic. Using a pre/post-test design, participants completed the validated prognosis and treatment perception survey (PTPQ) then met with their oncologist. The COPE guide was used for the discussion and the patient received a copy of the completed COPE. The COPE guide was placed in the patient chart and the healthcare team (social work, spiritual care etc.) used it to provide patient support and explore the patient’s response to the information. Post-test was completed 4-8 weeks later. Qualitative exit interviews were used to assess patient reported impact on communication with medical team, caregivers and family, and quality of life. Results: 43 patients were enrolled and 25 completed all study measures. All patients had advanced cancer with 96% of patients (24) extremely unlikely to be cured ( &lt; 1% chance). Oncologist’s treatment goals were better quality of life and longer life. All participants completing the study found the communication guide helpful, scoring 9-10 out of 10. 95% of patients enrolled wanted to hear details about their prognosis. Pre-intervention, 28% (7) of patients reported their primary goal of treatment as cure (n = 7; 28%) or to extend life as long as possible (n = 7; 28%). Pre-intervention, patient’s perceptions of their oncologist’s goals of treatment were cure (n = 11; 44%) or extend life (n = 8; 32%). At post-test, 8% of participants (2) inaccurately reported goal of treatment as cure (p &lt; 0.05). Conclusions: These findings highlight major gaps in patients’ understanding of their prognosis. COPE is a promising mechanism to enhance patient-centered communication about prognosis and treatment for patients with incurable cancer.
GPs earned £94 800 on average last year, but expenses continue to rise
Authors: Gareth Iacobucci
Journal: BMJ (2019)

The average earnings of GPs in the UK was £94 800 in 2017-18, an increase of 2.5% from the previous year, latest figures1 from NHS Digital show.

GP partners earned an average of £109 100 before tax—an increase of 3.5% from 2016 to 17, while salaried GPs earned an average of £58 400, a 2.9% rise. Both increases were statistically significant.

But GP partners’ expenses continued to rise last year, from £203 200 in 2016-17 to £217 500 in 2017-18 (a 7% increase). This followed an 8.7% …
Caspase-8 modulates physiological and pathological angiogenesis during retina development
Authors: Nathalie Tisch, Aida Freire-Valls, Rosario Yerbes, Isidora Paredes, Silvia La Porta, Xiaohong Wang, Rosa Martín-Pérez, Laura Castro, Wendy Wei-Lynn Wong, Leigh Coultas, Boris Strilic, Hermann-Josef Gröne, Thomas Hielscher, Carolin Mogler, Ralf H. Adams, Peter Heiduschka, Lena Claesson-Welsh, Massimiliano Mazzone, Abelardo López-Rivas, Thomas Schmidt, Hellmut G. Augustin, Carmen Ruiz de Almodovar
Journal: Journal of Clinical Investigation (2019)

During developmental angiogenesis, blood vessels grow and remodel to ultimately build a hierarchical vascular network. Whether, how, cell death signaling molecules contribute to blood vessel formation is still not well understood. Caspase-8 (Casp-8), a key protease in the extrinsic cell death–signaling pathway, regulates cell death via both apoptosis and necroptosis. Here, we show that expression of Casp-8 in endothelial cells (ECs) is required for proper postnatal retina angiogenesis. EC-specific Casp-8–KO pups (Casp-8ECKO) showed reduced retina angiogenesis, as the loss of Casp-8 reduced EC proliferation, sprouting, and migration independently of its cell death function. Instead, the loss of Casp-8 caused hyperactivation of p38 MAPK downstream of receptor-interacting serine/threonine protein kinase 3 (RIPK3) and destabilization of vascular endothelial cadherin (VE-cadherin) at EC junctions. In a mouse model of oxygen-induced retinopathy (OIR) resembling retinopathy of prematurity (ROP), loss of Casp-8 in ECs was beneficial, as pathological neovascularization was reduced in Casp-8ECKO pups. Taking these data together, we show that Casp-8 acts in a cell death–independent manner in ECs to regulate the formation of the retina vasculature and that Casp-8 in ECs is mechanistically involved in the pathophysiology of ROP.
Pavord S and Hunt B, The Obstetric Hematology Manual, 2 <sup>nd</sup> Edn, Cambridge University Press, Cambridge, 2018.
Authors: Barbara J. Bain
Journal: American Journal of Hematology (2019)

With hematology becoming increasingly complex and specialized, there is an increasing role for books such as this, that deal with one part of the specialty in depth and are cross-disciplinary in their approach. There are 50 authors, drawn from hematology, blood transfusion, obstetrics, anesthesia, and radiology. The book is scholarly and authoritative but at the same time practical. It will be welcomed by hematologists and obstetricians alike. Themes covered include the management during pregnancy of hematinic deficiency anemias, and sickle cell disease, thalassemia, and other inherited red cell disorders. Thrombosis and hemostasis are dealt with in great detail – the physiological changes in coagulation during pregnancy, inherited coagulation defects, thrombophilia, management of thromboembolism, prosthetic heart valves, anticoagulant therapy and obstetric hemorrhage. There are chapters on the important themes of pre-eclampsia and thrombotic microangiopathies and on the, fortunately uncommon, occurrences of hematological neoplasms during pregnancy. The late effects of chemoradiotherapy and how they may be prevented or ameliorated are discussed. The fetus is specifically dealt with in chapters on red cell and platelet alloimmunisation, and on prenatal diagnosis and management of congenital bleeding disorders. A particularly useful feature is the use of illustrative case reports at the conclusion of each chapter, including occasional examples of “What can go wrong?” Despite being published by Cambridge University Press, part of the University of Cambridge, the book is published in American English, which should appeal to American readers. Could anything be improved? In the thalassemia chapter, I would have liked a clear discussion of the use of iron-chelating therapy during the first trimester of pregnancy and during breast-feeding. Proof reading was not always rigorous; in one chapter headings of tables are attached to the wrong tables; in another, two “color” figures are in black, white and gray. However, these are minor imperfections. This comprehensive book will be of considerable value to those working in this field and is strongly recommended.
Therapy discontinuation processes in a gynecologic oncology population.
Authors: Catherine H. Watson, Allison Puechl, Tracy Truong, Stephanie Lim, Laura Jean Havrilesky, Brittany Anne Davidson
Journal: Journal of Clinical Oncology (2019)

11611 Background: The decision to discontinue anti-cancer therapies in oncology patients is a complex one and may occur in several unique ways. We sought to understand the processes of therapy discontinuation in a gynecologic oncology population and to discern possible changes in the distribution of these processes after implementation of a palliative care (PC) quality improvement project. Methods: Women with incurable gynecologic malignancies seen in the outpatient setting at an academic center were identified with the recommendation for ‘goals of care’ discussion within 3 visits following identification. Processes of discontinuing chemotherapy for this population were assessed and categorized into 1 of 4 categories: definitive outpatient decision, definitive inpatient decision, interruption by hospitalization, treatment holiday, and “no decision.” Retrospective chart review identified a similar cohort of women prior to the implementation of our PC intervention. Univariate analyses were conducted to determine associations between characteristics and binary outcome of definitive outpatient decision versus all other decision processes. Results: 90/102 (88%) pre-intervention subjects and 83/157 (53%) post-intervention subjects had died at time of analysis. Of the total deceased cohort, 59/173 (34%) made a definitive decision to stop therapy in the outpatient setting. After implementation of the PC initiative, there was a trend towards fewer women identified as having made “no decision” (18.1% vs 30%). Those who made a definitive outpatient decision were less likely to die within 30 days of hospitalization than those who did not (OR 0.16 [95% CI 0.07,0.390], p &lt; 0.0001). Conclusions: Discontinuation of therapy is a nuanced concept in gynecologic oncology patients that can be stratified into several processes. While our data demonstrates a possible increase in active decision-making with the PC initiative, a majority of patients near the end of life still did not make definitive therapy cessation decisions. This reveals an urgent need for the development of initiatives to enhance patient engagement and shared decision making for women near the end of life.
Cord Blood Units Containing Lower CD34+ Cells (0.5 - 1.0 x 105 /kg) Could be Alternative Donor Candidates for Single-Unit Cord Blood Transplantation for Adults: A Retrospective Study of 421 Patients in a Single Institute
Authors: Shinsuke Takagi, Mitsuhiro Yuasa, Naoyuki Uchida, Michiho Ebihara, Takashi Mitsuki, Kosei Kageyama, Daisuke Kaji, Yuki Taya, Aya Nishida, Kazuya Ishiwata, Hisashi Yamamoto, Go Yamamoto, Yuki Asano-Mori, Yukako Koike, Shigeyoshi Makino, Akiko Yoneyama, Atsushi Wake, Shuichi Taniguchi
Journal: Blood (2018)
Predicting severe toxicity of targeted therapies in elderly patients with cancer (PreToxE): A multicenter, prospective, and retrospective study.
Authors: Coriolan Lebreton, Coralie Cantarel, Emilie Toulza, Romain Desgrippes, Laurence Bozec Lemoal, Esma Saada, Agnes Ducoulombier, Magalie Pascale Tardy, Elena Paillaud, Caroline Lalet, Simone Mathoulin-Pélissier, Antoine Italiano
Journal: Journal of Clinical Oncology (2019)

11550 Background: It is crucial that targeted therapies are also studied in senior patients to establish predictive factors of severe toxicity. Methods: The PRETOXE study includes 3 multicentric independent cohorts of patients ≥70 years old with advanced solid tumor (2 retrospectives and one prospective) and treated with a tyrosine/threonine kinase inhibitor (TKI) as per drug label. Data on clinical and biological characteristics of the patient, disease and treatment were centrally collected at the beginning of the treatment. Primary endpoint is severe toxicity defined as treatment-related death, persistant or significant disability/incapacity, hospitalization or discontinuation of treatment for more than three weeks. Predictive factors of severe toxicity were first identified in a training retrospective cohort by multivariate analysis. Two independent cohorts ( retrospective and prospective) will be used for external validation. Results: 371 patients entered the study (training retrospective cohort n = 171, 46.1 %; validation retrospective cohort: n = 160, 43.1%, validation prospective cohort: n = 40, 10.8%). Median age was 74.0 (range 70.0-88.0) in the training retrospective cohort. 73 patients (42.7%) were male. The most frequent solid tumors were lung 64 (37.4%), breast 50 (29.2%), sarcomas 27 (15.8%), colon 10 (5.8%) and kidney 8 (4.7%). The five most frequent prescribed TKIs were everolimus 51 (29.8%), erlotinib 43 (25.1%), pazopanib 18 (10.5%), gefitinib 17 (9.9%) and regorafenib 14 (8.2%). The prescribed dose was lower than that recommended in the drug label in 32.1% of cases. 46 (26.9%) patients had a severe toxicity as per protocol definition in retrospective cohort: hospitalization 5 (10.9%), discontinuation of treatment more than 3 weeks 4 (8.7%), definitive discontinuation of treatment 38 (82.6%), persistent or significant disability/incapacity 14 (30.4%). On multivariate analysis, female gender, ≥3 concomitant medications and anti-angiogenic activity of TKI were independent predictive factors of severe toxicity. External validation on the other two independent cohorts (retrospective and prospective) will be presented at the meeting. Conclusions: One in four cancer patient ≥ 70 years old and treated with a TKI has severe toxicity impacting treatment outcome. The role of geriatric intervention to prevent such toxicities should be considered particularly in female patients, patients with ≥3 concomitant medications or when the TKI targets the VEGF receptors family. Clinical trial information: NCT02751827.
P166 Impact of disease activity, duration and muscle involvement on changes of body composition in myositis patients
Authors: S Oreska, M Spiritovic, P Cesak, O Marecek, H Storkanova, H Smucrova, B Hermankova, K Kubinova, M Klein, L Vernerova, O Ruzickova, K Pavelka, L Senolt, H Mann, J Vencovsky, M Tomcik
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Career situation of first and presenting author</h3> Student for a master or a PhD. <h3>Introduction</h3> Skeletal muscle, pulmonary and articular involvement in idiopathic inflammatory myopathies (IIM) limit the mobility/self-sufficiency of patients, and can have a negative impact on body composition. <h3>Objectives</h3> To assess body composition and physical activity of IIM patients and healthy controls (HC). <h3>Methods</h3> 54 patients with IIM (45 females; mean age 57.7; disease duration 5.8 years; PM, 22/DM, 25/IMNM, 7) and 54 age-/sex-matched HC (45 females, mean age 57.7) without rheumatic/tumor diseases were included. PM/DM patients fulfilled Bohan/Peter criteria for PM/DM. We assessed anthropometric parameters and body composition (by densitometry: iDXA Lunar, and by bioelectric impedance: BIA2000-M), and physical activity (by Human Activity Profile questionnaire, HAP). Routine biochemistry analysis was performed after 8 hours of fasting. Disease activity was evaluated by MITAX and MYOACT activity score, muscle involvement by manual muscle test (MMT-8) and functional index 2 (FI2). <h3>Results</h3> Compared to HC, patients with IIM had significantly increased body fat% (BF%) but significantly decreased lean body mass (LBM), bone mineral density (BMD) and increased extracellular mass/body cell mass (ECM/BCM) ratio, which reflects worse muscle predispositions for physical activity and deteriorated nutritional status. Disease duration negatively correlated with BMD and LBM (assessed by BIA). Disease activity assessed by MITAX and MYOACT positively correlated with LBM (assessed by both BIA and DXA), as well as with basal metabolic rate (BMR), and fat free mass (FFM). CRP was positively associated with BF% (iDXA and BIA). Higher BF% (iDXA) was associated with worse physical endurance (FI2) and worse ability to perform physical activity (HAP). MMT-8 score negatively correlated with ECM/BCM ratio. <h3>Conclusions</h3> We found significant negative changes in body composition of our IIM patients compared to healthy age-/sex-matched individuals, associated with their disease activity and duration, inflammatory status, skeletal muscle involvement, and physical activity. These data could reflect their impaired nutritional status and predispositions for physical exercise, aerobic fitness and performance. <h3>References</h3> None. <h3>Acknowledgements</h3> Supported by AZV NV18–01-00161A, MHCR 023728 and GAUK 312218 <h3>Disclosure of Interest</h3> None declared.