tbuckley/cabot-search huggingface dataset:
PF282 THE EFFECT OF MODERN THERAPEUTICS IN ADULT ACUTE MYELOID LEUKEMIA (AML): POPULATION‐BASED ANALYSIS OF LONG‐TERM OUTCOMES FROM THE MANITOBA CANCER REGISTRY
Authors: L. Tapley, O. Bucher, K. Galloway, K. Paulson, M. Seftel
Journal: HemaSphere (2019)

Background: While the prognosis for adults with acute myeloid leukemia (AML) is historically poor, advances in supportive care and new therapeutics such as blood and marrow transplant (BMT) and hypomethylating agents may have improved overall outcomes. In the Canadian province of Manitoba, all patients with AML are managed at a single cancer centre with support from a community cancer program. Clinical and demographic data are collected in a provincial cancer registry. This registry captures all cases of AML, increasing the reliability of population‐based data as case ascertainment and follow‐up follow a uniform approach. Aims: We sought to describe the clinical characteristics, incidende and relative survival for patients with AML in the province of Manitoba, with attention to temporal trends and outcomes in rural patients, where access to care may be challenging. Methods: We collected data on consecutively diagnosed adult cases of AML that were reported to the Manitoba Cancer Registry (MCR) from 1990 ‐ 2014. Life tables from Statistics Canada were used as a reference for expected survival in the general population. Patient demographics were stratified by age, time period and residence at diagnosis. Two‐year age‐standardized relative survival estimates of patients in Manitoba with AML were estimated using the cohort method within various subcategories, including time period of diagnosis (in 5 year increments), sex and urban (Winnipeg) versus non‐Winnipeg location. Results: A total of 910 patients from the ages of 15 to 99 were diagnosed from 1990 ‐ 2014 with available survival data to 2016. Of the 910 patients, 517 were men and 393 were women and 511 (56%) were residents of Winnipeg at diagnosis. Two‐year crude relative survival estimates by time period and age group demonstrated improving relative survival for each age quintile category within each 5‐year time period, with the most notable increase over time in patients aged 15–44 and 45–54. Total two‐year age‐standardized relative survival for all patients was 20.37% (CI 95% 17.81–23.05%). Two‐year age‐standardized relative survival in males was 19.22% (CI 95% 15.95–22.73%) and 21.93% (CI 95% 17.88–26.25%) in females. Two‐year age‐standardized relative survival by residence at diagnosis was 20.32% (CI 95%. 16.92–23.94%) for urban (Winnipeg) residents, and 20.54% (CI 95% 16.74–24.62%) for those outside of Winnipeg. Summary/Conclusion: We demonstrate improved relative survival in adult AML over time, most notably in adults aged 15–54, where BMT has played an increasingly important therapeutic role. Advanced supportive care and hypomethylating agents may also have contributed to improved outcomes, especially in older patients. Similar relative survival for urban and rural patients supports the benefits of a centralized and coordinated leukemia centre with its closely linked community cancer program.
Correlation of BMI with tumor stage in early breast cancer patients (pts): Pooled analysis of the German SUCCESS A, B, and C trials.
Authors: Carola Anna Melcher, Uta Ortmann, Christoph Scholz, Thomas Zwingers, Andreas Schneeweiss, Werner Lichtenegger, Ralf Lorenz, Carsten Hagenbeck, Helmut Forstbauer, Hans Ulrich Ulmer, Nikola S. Kasprowicz, Georg Heinrich, Bernadette Anna Sophia Jaeger, Tanja N. Fehm, Matthias W. Beckmann, Wolfgang Janni, Brigitte Kathrin Rack
Journal: Journal of Clinical Oncology (2012)

1602 Background: Independent from known prognostic factors, e.g., tumor size and nodal status, obesity is a risk factor for poor disease free, distant disease free, and overall survival in breast cancer. The aim of this analysis was to examine the correlation of the body mass index (BMI) with tumor characteristics in early breast cancer. Methods: We analyzed the data of 7,997 pts with early, node positive or high risk node negative primary breast cancer treated with adjuvant taxan-based chemotherapy within the German multicenter phase III SUCCESS A, B, or C trials. The pts’ tumor stage at primary diagnosis was classified according to the UICC tumor-node-metastasis (TNM) classification. Additionally, the tumor’s hormone-receptor status and HER2/neu status were determined. Before enrollment into the study each patient was grouped according to the WHO global database on BMI. Contingency table methods were used to analyze the correlation of BMI and tumor characteristics. Results: Among the 7,997 pts 100 (1.3%) pts were underweight, 3,556 (44.5%) pts were normal weight, 2,569 (32.1%) pts were overweight and 1,772 (22.2%) were obese. Of all pts 4,508 pts (56.4%) suffered from a pT2-4 tumor, 4830 (60.4%) showed lymph node involvement (pN1-3) and 7509 (93.9%) had G2-3 tumors. 5839 pts (73.0%) showed positivity for ER or PR and 935 (11.7%) for HER2/neu. Overweight and obese pts had significantly larger tumors compared to pts with normal BMI (p&lt;0.0001; p&lt;0.0001). Furthermore, overweight and obesity were associated with a significantly higher rate of lymph node involvement (p=0.0001; p=0.0003) respectively. In contrast neither grading, tumor histology, ER/PR-status nor HER2/neu-overexpression were correlated with BMI. Conclusions: These data are the first to show in a large number of pts that both obese and overweight women suffering from primary breast cancer have significantly larger tumors and more often positive axillary lymph nodes. As there are no differences in tumor biology, the advanced tumor stage might be due to more difficult and delayed detection of breast cancer and lymph node lesions in these women.
PB1994 HEMATOPOIETIC STEM CELL EXPANSION IN THE PRESENCE OF NICOTINE AMIDE AND IN THE MICROFLUIDIC DEVISE AND THE DBM SCAFFOLD
Authors: M. Asgari, M. asgari
Journal: HemaSphere (2019)

Background: The low number of umbilical cord blood cells is an important barrier to successful bone marrow transplantation. Therefore, the growth of these cells while maintaining their functional characteristics is of great importance Aims: Using microfluidic technology as well as culturing cells on 3D scaffolds like DBM has greatly contributed to the simulation of the mechanical and chemical micro‐environment of the bone marrow tissue. There are also specific compounds for proliferation without differentiation of cells, one of them is nicotinamide Methods: In this study, hematopoietic stem cells were cultured 7 days in two groups: 1. In DBM in the microfluidic device 2. In DBM in the static state (control), under the following Conditions: 1.negative control with feeder 2.cytokine+feeder 3.nicotinamide+feeder 4.nicotinamide+cytokine+feeder After 7 days, cell count, real‐time PCR, their purity using flow cytometry, Colony forming unit assay and apoptosis was evaluated. The status of the cells on the scaffold was observed using electron microscopy. Results: Our results indicated that more cells were counted in static culture than microfluidic culture (perfusion), while the ability of cell colonization in microfluidic culture was far higher. The purity of HSCs was higher in microfluidic culture, and fewer cells entered the apoptotic phase. Summary/Conclusion: Nicotinamide by preventing epigenetic changes resulting from laboratory cell culture, and the microfluidic device associated with DBM by simulating bone marrow niche is a very a suitable compound for the development of these cells.
Aurora Kinase A Inhibition: A Mega-Hit for Myelofibrosis Therapy?
Authors: Richard T. Piszczatowski, Ulrich Steidl
Journal: Clinical Cancer Research (2019)

The positive but limited efficacy of JAK inhibitors has sparked the need for alternative therapeutic targets in the treatment of myelofibrosis. The discovery of novel targets, like Aurora Kinase A, may provide new avenues of single-agent and combinatorial therapy for myelofibrosis and restoration of normal bone marrow function.See related article by Gangat et al., p. 4898.
Targeting Tumors with IL-10 Prevents Dendritic Cell-Mediated CD8+ T Cell Apoptosis
Authors: Jian Qiao, Zhida Liu, Chunbo Dong, Yan Luan, Anli Zhang, Casey Moore, Kai Fu, Jianjian Peng, Yang Wang, Zhenhua Ren, Chuanhui Han, Ting Xu, Yang-Xin Fu
Journal: Cancer Cell (2019)

Increasing evidence demonstrates that interleukin-10 (IL-10), known as an immunosuppressive cytokine, induces antitumor effects depending on CD8+ T cells. However, it remains elusive how immunosuppressive effects of IL-10 contribute to CD8+ T cell-mediated antitumor immunity. We generated Cetuximab-based IL-10 fusion protein (CmAb-(IL10)2) to prolong its half-life and allow tumor-targeted delivery of IL-10. Our results demonstrated potent antitumor effects of CmAb-(IL10)2 with reduced toxicity. Moreover, we revealed a mechanism of CmAb-(IL10)2 preventing dendritic cell (DC)-mediated CD8+ tumor-infiltrating lymphocyte apoptosis through regulating IFN-γ production. When combined with immune checkpoint blockade, CmAb-(IL10)2 significantly improves antitumor effects in mice with advanced tumors. Our findings reveal a DC-regulating role of IL-10 to potentiate CD8+ T cell-mediated antitumor immunity and provide a potential strategy to improve cancer immunotherapy.
Value of Speckle Tracking–Based Deformation Analysis in Screening Relatives of Patients With Asymptomatic Dilated Cardiomyopathy
Authors: Job A.J. Verdonschot, Jort J. Merken, Hans-Peter Brunner-La Rocca, Mark R. Hazebroek, Casper G.M.J. Eurlings, Eline Thijssen, Ping Wang, Jerremy Weerts, Vanessa van Empel, Georg Schummers, Marcus Schreckenberg, Arthur van den Wijngaard, Joost Lumens, Han G. Brunner, Stephane R.B. Heymans, Ingrid P.C. Krapels, Christian Knackstedt
Journal: JACC. Cardiovascular imaging (2019)
PS1477 PLATELET DISFUNCTION IN NOONAN AND 22Q11.2 DELETION SYNDROMES IN CHILDHOOD
Authors: A. RUIZ, I. ISOLA, S. GASSIOT, A. CATALÀ, M. DÍAZ‐RICART, A.F. MARTÍNEZ‐MONSENY, M. SERRANO, R. BERRUECO
Journal: HemaSphere (2019)

Background: An underlying thrombocytopathy seems to be the responsible for hemorrhagic symptoms in patients diagnosed with 22q11.2 deletion syndrome (22q11DS) and Noonan syndromes (NS). Whereas in 22q11DS it is explained by a defect in the membrane glycoprotein complex Ib‐V‐IX, the cause of thrombocytopathy in NS remains unclear. Aims: To study the incidence of thrombocytopathy in pediatric patients diagnosed with 22q11DS or NS assessing the utility of ISTH‐BAT questionnaire and laboratory techniques in this regard. Methods: Prospective study between March and December 2018 in children (2 to 18 year‐old) diagnosed with 22q11DS or NS. Hemorrhagic symptoms, total cell blood count, platelet indices, closure time and platelet aggregation were evaluated in all patients. Membrane glycoprotein expression was only performed in 22q11DS patients. Results: Among NS patients (n = 22), near 80% had an aggregation defect with adenosine diphosphate (ADP) and epinephrine without thrombocytopenia. A significant correlation ( p &lt; 0.05) between closure times and aggregation with arachidonic acid, epinephrine and ADP was found. This correlation was more evident in those patients with hemorrhagic symptoms. Five out 29 (17%) patients diagnosed with 22q11DS had thrombocytopenia. Impairment in ristocetin‐induced platelet aggregation was found. This defect was correlated with prolonged closure times. Moreover, a significant correlation between thrombocytopenia, closure times and hemorrhagic symptoms was demonstrated. Summary/Conclusion: This study shows in a cohort of patients with NS and 22q11DS a significant impairment of platelet aggregation which correlates with hemorrhagic symptoms and closure times. Thus, closures times might be useful as screening test to evaluate the bleeding risk in this group of patients.
PB1791 THE ROLE OF SURGERY IN BONE LYMPHOMA: WHAT IMPACT IT HAS ON SURVIVAL?
Authors: M. Salamoon, M. balti, M. kenj
Journal: HemaSphere (2019)

Background: bone lymphoma is an extra-nodal lymphoma which runs either an aggressive or indolent course depending on affected site and pathologic subtype. Since it is a rare tumor, little data was reported about the role of surgery, benefit and timing. However, there is no consensus about the role of surgery since it represent a systemic disease. Aims: : this study is a retrospective one demonstrating the role of surgery in a series of patients diagnosed with bone lymphoma at different localizations treated with surgery at diagnosis or later during the course of treatment with an overall survival at 5 years as a primary end point. Methods: this is a multicenter retrospective study where we have reviewed 112 cases with bone lymphoma with only 59 patients fitting the criteria (surgery) between 2005 and 2012. Affected sites distributed as follows: 19 in the vertebral column, 8 in the pelvis, 6 in humorous, 2 in the mandible and the remaining 24 in the femur and femoral neck. 32 patients (54%) are operated at the very beginning as an emergency procedure in order to correct disability, pain control and to get a sample to reach the diagnosis as well. Pathology was diffuse large B-cell lymphoma in 54 patients vs indolent lymphoma in the remaining 5 patients. Most patients are treated with R-CHOP and R-CHOP like regimen. Results: Response rate was slow and partial on those who were not operated at diagnosis, however, local control was improved after surgery performed at the end of chemotherapy. All patients were treated by radiotherapy as well. 53 patients were reported alive after 5 years of follow up with an overall survival rate of (89.8%). Local control was better in those with femoral localization (p. value 0.02). factors affecting survival were high international prognostic index (IPI) score, high LDH score, bone biopsy positive disease, older age of patient and patient with high weight, however, p. values did not statistically significant. Summary/Conclusion: primary bone lymphoma is a rare disease which can be treated by different approaches such as surgery, chemotherapy and radiotherapy. Few data was published on this type of lymphoma which is diagnosed without the knowledge of hematologists making treatment guidelines hard to be established. However, in our retrospective study, we have demonstrated the important role of surgery in restoring limb function which has in turn a positive impact on both social and psychological status of patients making them more ready to continue chemotherapy with a good performance status. Therefore, we highly recommend surgery at the time of diagnosis.
Germline mutations in the transcription factor IKZF5 cause thrombocytopenia
Authors: Claire Lentaigne, Daniel Greene, Suthesh Sivapalaratnam, Remi Favier, Denis Seyres, Chantal Thys, Luigi Grassi, Sarah Mangles, Keith Sibson, Matthew Stubbs, Frances Burden, Jean-Claude Bordet, Corinne Armari-Alla, Wendy Erber, Samantha Farrow, Nicholas Gleadall, Keith Gomez, Karyn Megy, Sofia Papadia, Christopher J. Penkett, Matthew C. Sims, Luca Stefanucci, Jonathan C. Stephens, Randy J. Read, Kathleen E. Stirrups, Willem H. Ouwehand, Michael A. Laffan, Mattia Frontini, Kathleen Freson, Ernest Turro
Journal: Blood (2019)
Automatic assessment of glioma burden: a deep learning algorithm for fully automated volumetric and bidimensional measurement
Authors: Ken Chang, Andrew L Beers, Harrison X Bai, James M Brown, K Ina Ly, Xuejun Li, Joeky T Senders, Vasileios K Kavouridis, Alessandro Boaro, Chang Su, Wenya Linda Bi, Otto Rapalino, Weihua Liao, Qin Shen, Hao Zhou, Bo Xiao, Yinyan Wang, Paul J Zhang, Marco C Pinho, Patrick Y Wen, Tracy T Batchelor, Jerrold L Boxerman, Omar Arnaout, Bruce R Rosen, Elizabeth R Gerstner, Li Yang, Raymond Y Huang, Jayashree Kalpathy-Cramer
Journal: Neuro-Oncology (2019)

Longitudinal measurement of glioma burden with MRI is the basis for treatment response assessment. In this study, we developed a deep learning algorithm that automatically segments abnormal fluid attenuated inversion recovery (FLAIR) hyperintensity and contrast-enhancing tumor, quantitating tumor volumes as well as the product of maximum bidimensional diameters according to the Response Assessment in Neuro-Oncology (RANO) criteria (AutoRANO). Two cohorts of patients were used for this study. One consisted of 843 preoperative MRIs from 843 patients with low- or high-grade gliomas from 4 institutions and the second consisted of 713 longitudinal postoperative MRI visits from 54 patients with newly diagnosed glioblastomas (each with 2 pretreatment "baseline" MRIs) from 1 institution. The automatically generated FLAIR hyperintensity volume, contrast-enhancing tumor volume, and AutoRANO were highly repeatable for the double-baseline visits, with an intraclass correlation coefficient (ICC) of 0.986, 0.991, and 0.977, respectively, on the cohort of postoperative GBM patients. Furthermore, there was high agreement between manually and automatically measured tumor volumes, with ICC values of 0.915, 0.924, and 0.965 for preoperative FLAIR hyperintensity, postoperative FLAIR hyperintensity, and postoperative contrast-enhancing tumor volumes, respectively. Lastly, the ICCs for comparing manually and automatically derived longitudinal changes in tumor burden were 0.917, 0.966, and 0.850 for FLAIR hyperintensity volume, contrast-enhancing tumor volume, and RANO measures, respectively. Our automated algorithm demonstrates potential utility for evaluating tumor burden in complex posttreatment settings, although further validation in multicenter clinical trials will be needed prior to widespread implementation.
TGF-β signaling underlies hematopoietic dysfunction and bone marrow failure in Shwachman-Diamond syndrome
Authors: Cailin E. Joyce, Assieh Saadatpour, Melisa Ruiz-Gutierrez, Ozge Vargel Bolukbasi, Lan Jiang, Dolly D. Thomas, Sarah Young, Inga Hofmann, Colin A. Sieff, Kasiani C. Myers, Jennifer Whangbo, Towia A. Libermann, Chad Nusbaum, Guo-Cheng Yuan, Akiko Shimamura, Carl D. Novina
Journal: Journal of Clinical Investigation (2019)

Shwachman-Diamond Syndrome (SDS) is a rare and clinically-heterogeneous bone marrow (BM) failure syndrome caused by mutations in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. Although SDS was described over 50 years ago, the molecular pathogenesis is poorly understood due, in part, to the rarity and heterogeneity of the affected hematopoietic progenitors. To address this, we used single cell RNA sequencing to profile scant hematopoietic stem and progenitor cells from SDS patients. We generated a single cell map of early lineage commitment and found that SDS hematopoiesis was left-shifted with selective loss of granulocyte-monocyte progenitors. Transcriptional targets of transforming growth factor-beta (TGFβ) were dysregulated in SDS hematopoietic stem cells and multipotent progenitors, but not in lineage-committed progenitors. TGFβ inhibitors (AVID200 and SD208) increased hematopoietic colony formation of SDS patient BM. Finally, TGFβ3 and other TGFβ pathway members were elevated in SDS patient blood plasma. These data establish the TGFβ pathway as a novel candidate biomarker and therapeutic target in SDS and translate insights from single cell biology into a potential therapy.
SP0154 REASONS FOR QUALITATIVE RESEARCH FOR HPR
Authors: Romualdo Ramos
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> Qualitative research plays a pivotal role in clinical practice by providing insights from the patient"s perspective. This becomes all the more relevant, as we move into the era of patient-centered care. In this presentation, we shed light on the different approaches to qualitative data collection and analysis, as well as systematic literature reviews of qualitative research. We will also elaborate on how qualitative research methods are used to better understand which outcomes are relevant to patients, self-management of symptoms, non-adherence to medication and non-pharmacological methods, the doctor-patient relationship, and to evaluate policy and interventions within the realm of RMDs. Finally, in an open panel, we will discuss how qualitative and quantitative methods triangulate, contributing to mixed methods approaches. <h3>Disclosure of Interests:</h3> None declared
Targeting protein tyrosine phosphatase PTP-PEST (PTPN12) for therapeutic intervention in acute myocardial infarction
Authors: Chiu-Fen Yang, Yi-Yun Chen, Jai Prakash Singh, Shu-Fang Hsu, Yu-Wen Liu, Chun-Yi Yang, Chia-Wei Chang, Szu-Ni Chen, Rou-Ho Shih, Shang-Te Danny Hsu, Yuh-Shan Jou, Ching-Feng Cheng, Tzu-Ching Meng
Journal: Cardiovascular Research (2019)

The myocardial ischaemia/reperfusion (I/R) injury is almost inevitable since reperfusion is the only established treatment for acute myocardial infarction (AMI). To date there is no effective strategy available for reducing the I/R injury. Our aim was to elucidate the mechanisms underlying myocardial I/R injury and to develop a new strategy for attenuating the damage it causes.Using a mouse model established by ligation of left anterior descending artery, we found an increase in activity of protein tyrosine phosphatases (PTPs) in myocardium during I/R. Treating the I/R-mice with a pan-PTP inhibitor phenyl vinyl sulfone attenuated I/R damage, suggesting PTP activation to be harmful in I/R. Through analysing RNAseq data, we showed PTPs being abundantly expressed in mouse myocardium. By exposing primary cardiomyocytes ablated with specific endogenous PTPs by RNAi to hypoxia/reoxygenation (H/R), we found a role that PTP-PEST (PTPN12) plays to promote cell death under H/R stress. Auranofin, a drug being used in clinical practice for treating rheumatoid arthritis, may target PTP-PEST thus suppressing its activity. We elucidated the molecular basis for Auranofin-induced inactivation of PTP-PEST by structural studies, and then examined its effect on myocardial I/R injury. In the mice receiving Auranofin before reperfusion, myocardial PTP activity was suppressed, leading to restored phosphorylation of PTP-PEST substrates, including ErbB-2 that maintains the survival signalling of the heart. In line with the inhibition of PTP-PEST activity, the Auranofin-treated I/R-mice had smaller infarct size and better cardiac function.PTP-PEST contributes to part of the damages resulting from myocardial I/R. The drug Auranofin, potentially acting through the PTP-PEST-ErbB-2 signalling axis, reduces myocardial I/R injury. Based on this finding, Auranofin could be used in the development of new treatments that manage I/R injury in patients with AMI.
The landscape of selection in 551 esophageal adenocarcinomas defines genomic biomarkers for the clinic
Authors: Alexander M. Frankell, SriGanesh Jammula, Xiaodun Li, Gianmarco Contino, Sarah Killcoyne, Sujath Abbas, Juliane Perner, Lawrence Bower, Ginny Devonshire, Emma Ococks, Nicola Grehan, James Mok, Maria O’Donovan, Shona MacRae, Matthew D. Eldridge, Simon Tavaré, Rebecca C. Fitzgerald
Journal: Nature Genetics (2019)