tbuckley/cabot-search huggingface dataset:
AB0309 THE FREQUENCY OF HEMATOLOGICAL MALIGNANCIES IN AUTOIMMUNE RHEUMATIC DISEASES
Authors: Fulya Cosan, Ipek Geyikoglu, Ozgun Melike Gedar, Osman Kara
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Autoimmune rheumatic diseases are associated with increased risk of hematological malignancies. The pathogenesis of autoimmunity can cause of malignancies or immunosuppressive agents may increase the risk of malignancies. <h3>Objectives</h3> We aimed in this study to determine the frequency, type and characteristic of hematological malignancies in rheumatology practice. <h3>Methods</h3> 1640 rheumatology outpatient patient with autoimmune rheumatic diseases (Rheumatoid arthritis (RA), SLE, Sjogren's syndrome (SjS), myositis, systemic Sclerosis, undifferentiated connective tissue diseases (UCTD)) are screened for hematological malignancies. 16 patients are found with hematological diseases. The characteristics of these patients are reported retrospective from their outpatient clinic case files. <h3>Results</h3> The frequency of hematological diseases was found%0.04 in study group. 4 patients had myeloproliferative diseases (1 polycythaemia vera (PV), 1 primary myelofibrosis (MyF), 2 patients with essential thrombocythemia (ET)). Patients with PV and MyF had severe rheumatoid arthritis and because of unresponsiveness of MTX, they used rituximab for severe disease activity. Patient with ET had only minimal arthralgia and are followed under HCQ therapy. As lymphoproliferative diseases 4 patients had chronic lymphoid leukemia (CLL). 3 of them had RA and 1 of them had (SjS). 2 patients had non-Hodgkin lymphoma and these patients are seen after autolog bone marrow transplantation because of arthralgia, bur not detected arthritis. 1 patient had Hodgkin disease in her history, and had both RA and SjS, and receiving MTX therapy. 2 patients had multiple myeloma (MM). One of them is new diagnosis arthritis plus elevated sedimentation rate. Second one was seen with arthralgia after MM treatment and autologous bone marrow transplantation. 3 patients had mycosis fungoides, 1 of them had UCTD and received hydroxychloroquine. The other patient had RA under MTX therapy and one patient received rituximab therapy for severe RA activity. <h3>Conclusion</h3> Hematological malignancies are rare diseases in rheumatology practice, although expected high rate because of using immunosuppressive treatment and autoimmunity. The increased frequency of lymphoproliferative disorders are expected and associated with autoimmunity, but we don't found a high rate for lymphoproliferative malignancies. Myeloproliferative malignancies possibly not associated with the pathogenesis of autoimmune rheumatic diseases. <h3>Disclosure of Interests:</h3> None declared
Pooled RCTs: Lowering LDL-C levels using statins reduces major vascular events in all age groups
Authors: Justin Lee, Anne Holbrook
Journal: Annals of Internal Medicine (2019)

Source Citation Cholesterol Treatment Trialists' Collaboration. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials. Lancet. 2019;393:407-15. 30712900
MotHER: A registry for women with breast cancer who received trastuzumab (T) with or without pertuzumab (P) during pregnancy or within 6 months prior to conception.
Authors: Vikki Brown, Ann Partridge, Laura Chu, Tania Szado, Caroline Trudeau, Elizabeth B Andrews
Journal: Journal of Clinical Oncology (2013)

TPS658 Background: T and P are monoclonal antibodies that target different HER2 epitopes. T is approved for treatment of early and metastatic HER2+ BC while P is approved in combination with T for previously untreated HER2+ MBC. Oligohydramnios has been reported in patients (pts) who received T during pregnancy, and also in P-treated pregnant monkeys. Although both antibodies are FDA Pregnancy Category D, indicating evidence of fetal harm, some physicians and pts accept this risk and continue treatment. The MotHER registry was established in 2008 as an FDA postmarketing commitment to evaluate the effects of T therapy on pregnancy outcome; P was included in the study following its approval in 2012. MotHER is the first prospective study of the effects of a targeted cancer therapy on pregnancy outcome. Methods: MotHER is a US registry study of women exposed to T±P during pregnancy or within 6 months prior to conception. Women enroll voluntarily and are followed until pregnancy outcome; infants are followed through the first year of life. Medical information is primarily collected from healthcare providers. Information on potential birth defects noted at birth or during the pediatric follow-up is classified by a birth defect evaluator/clinical geneticist. Enrollment must be initiated before pregnancy outcome. Pts with known prenatal testing results may enroll, but to reduce the potential for bias these pts will be analyzed as a subset. Primary outcomes: number and nature of pregnancy complications, including oligohydramnios, pregnancy outcomes, fetal/infant outcomes and fetal/infant functional deficits. Secondary outcomes: preterm births, elective/therapeutic abortions, miscarriages, fetal growth abnormalities and delivery complications. The study is descriptive and not for formal hypothesis testing; event proportions with CIs will be calculated. The registry will accrue in the US from 2009 to 2019 for T-treated pts and from 2012 to 2022 for P+T-treated pts. The number of potential pts is small therefore physicians are encouraged to refer any eligible pt to increase knowledge about the safety of T±P in pregnancy. herceptinpregnancyregistry.com. Clinical trial information: NCT00833963.
PF442 TREATMENT WITH 5‐AZACYTIDINE RESULTS IN EXPRESSION OF LONG TERMINAL REPEAT (LTR) ELEMENTS IN PERIPHERAL BLOOD MONONUCLEAR CELLS OF PATIENTS WITH MDS AND AML: FIRST PILOT STUDY
Authors: M. Daskalakis, M. Haubitz, D. Steiner, M. Helf, A. Goyal, D. Brocks, L. Pleyer, R. Greil, C. Plass, G.M. Baerlocher, E. Oppliger Leibundgut
Journal: HemaSphere (2019)

Background: Epigenetic drugs are used for the treatment of several hematologic malignancies, but their pharmacological mechanism remains poorly understood. By genome wide analysis of transcription start sites (TSS), methylation status and chromatin dynamics, we showed for DNA methyltransferase and histone deacetylase inhibitors (DNMTi and HDACi) global reactivation of long terminal repeat elements (LTRs) in vitro (cell line models) and in vivo (neuroblastoma mouse xenograft model). The LTR reactivation is resulting in numerous fusion transcripts that encode novel protein isoforms which have the potential to influence cell proliferation, seem to be an explanation for the priming effect of epigenetic therapy and might be used as a potential marker for epigenetic treatment response. Aims: To investigate the reactivation of LTRs in sequential peripheral blood samples of AML and MDS patients upon epigenetic drug treatment with 5‐Azacytidine (DNMT‐inhibitor) by qRT‐PCR and ddPCR and to correlate the expression results with treatment response. Methods: Sequential RNA samples from peripheral blood mononuclear cells (PBMCs) of three AML and four MDS patients treated with 5‐Azacytidine were analyzed. Consensus primers covering the transcript variants of LTR12C as well as particular primers for specific LTR elements were used. Expression of LTRs was analyzed by qRT‐PCR technique with SYBRGreen as well as ddPCR technique with EvaGreen. Expression results were associated with treatment response. Results: In AML and MDS patients, we could detect LTR expression in sequential samples from PBMCs over time with 5‐Azacytidine treatment. LTR12C expression values measured by qRT‐PCR were confirmed by ddPCR and allowed to assess specific LTR elements. Patients with response to 5‐Azacytidine showed increased LTR12C expression whereas patients without treatment response had no increase in LTR12C expression. In contrast to the results from our previous NSCLC cell line model, specific LTR elements were only partially expressed in sequential PBMC samples from AML patients treated with 5‐Azacytidine. Summary/Conclusion: In this first in‐vivo pilot study, we detected LTR expression in sequential PBMC samples of AML and MDS patients treated with 5‐Azacytidine. In this group of patients, treatment response correlated with LTR expression over several treatment cycles with 5‐Azacytidine. These are the first results in AML and MDS patients showing expression of LTRs upon epigenetic drug treatment. Larger patient cohorts are necessary to confirm these results by either PCR‐ or genome wide‐analysis of transcription start sites (TSS) (Cap analysis of gene expression (CAGE) sequencing) as well as to evaluate the association of LTR expression and treatment response.
Reply from Authors re: Ananya Choudhury, Peter J. Hoskin. Predictive Biomarkers for Muscle-invasive Bladder Cancer: The Search for the Holy Grail Continues. Eur Urol 2019;76:69–70
Authors: Kent W. Mouw, David T. Miyamoto, Jason A. Efstathiou
Journal: European Urology (2019)
PS1336 DISCREPANCE OF ALLELIC BURDEN CHANGES AND CLINICAL RESPONSE IN PATIENTS WITH HIGHER RISK MYELODYSPLASTIC SYNDROME TREATED WITH HYPOMETHYLATING AGENTS
Authors: J.H. Moon, H.J. Cho, D.W. Baek, J.‐S. Ahn, S.‐Y. Ahn, S.H. Choi, T. Kim, Z. Zhang, S.K. Sohn, D.D. H. Kim, H.‐J. Kim
Journal: HemaSphere (2019)

Background: Hypomethylating agents (HMAs) such as azacitidine (AZA) and decitabine (DEC) are used to treat higher risk myelodysplastic syndrome (HR‐MDS). However, underlying genetics and allelic burden change after HMAs needs to be clarified. Aims: This study investigated the effects of alleleic burden changes on the clinical outcomes after treatment with HMAs. Methods: This study included bone marrow samples from 64 patients (34 AZA and 30 DEC) taken at diagnosis and follow‐up after median 4 cycles. Targeted deep sequencing on a custom myeloid gene panel of 84 genes (Agilent SureSelect) was performed on trios of T‐cell, pre‐HMA, and post‐HMA samples on 64 HR‐MDS patients. Results: At diagnosis, we detected 135 mutations from 54 patients. Most frequently mutated genes were TP53 (n = 9), DNMT3A (n = 7), ASXL1 (n = 7), DDX41 (n = 7) and U2AF1 (n = 6). HMAs were administered median 4 cycles (range 1–14). At follow‐up, allelic burdens were decreased from median 13.7% (range 1.5–87.7) to 1.7% (range 0.0–49.4%), where from median 9.9% to 0.8% in AZA group ( p &lt; 0.001) and from median 17.8% to 6.7% in DEC group (p = 0.005). CR/mCR rate were higher in patients with allelic burden reduction &lt;2% (n = 26/43, 60%) than those without (24%, n = 5/21), but not significantly different (p = 0.765). With median follow‐up duration of 19.3 months (range 0.2–99.6 months), 2‐year overall survival (OS) rates were 54.6 ± 8.1% and 44.8 ± 11.3% in patients with and without allelic burden reduction, respectively (p = 0.907). The presence of TP53 mutations did not affect the achievement of CR/mCR (p = 0.379). However, the presence of TP53 mutations were associated with inferior OS rates: 2‐year OS rates of 56.5 ± 7.2% and 22.2 ± 13.9% (p = 0.001). In the multivariate analysis, IPSS high (HR 5.34) and the presence of TP53 mutations (HR 3.42) affected adversely on OS, while the achievement of CR/mCR (HR 0.23) and the performance of allogeneic transplantation (HR 0.33) were favorable factors for OS. Summary/Conclusion: This study showed that allelic burden is decreased after treatment with both azacitidine and decitabine in HR‐MDS patients. However, the allelic burden reduction is independent to the achievement of CR and OS. The presence of TP53 mutation remained independent prognostic factor in HR‐MDS patients treated with HMAs, even with decreased allelic burden.
SP0175 POST-TRANSLATIONAL MODIFICATIONS OF ANTIBODIES: WHERE THERE”S SMOKE THERE”S FIRE
Authors: Rene Toes
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> Rheumatoid arthritis (RA) is a prototype autoimmune disease, with the hallmark signs of synovial inflammation and the presence of autoantibodies. One of the most prominent examples of such autoantibodies are anti-citrullinated protein antibodies (ACPA), which are directed against a wide-array of citrullinated proteins. The immune response to citrullinated antigens is a dynamic response that expands before the onset of disease and generates antibodies that are extensively glycosylated in the variable domain. This feature of ACPAs is remarkable and might be involved in the breach of tolerance to citrullinated proteins as well as function as an additional biomarker to predict disease onset in subjects at risk. Next to ACPA, it has become clear that the autoantibody response in RA extends towards several other modified proteins, such as proteins modified by carbamylation or acetylation. Carbamylation leads to the formation of homocitrulline. Structurally, homocitrulline greatly resembles citrulline but is one methylene group longer. In contrast, acetylation is mediated by intracellular acetyltransferases and is structurally less related to citrulline or homo-citrulline. Although the presence of autoantibodies against these post-translationally modified proteins (Anti-Modified Protein Antibodies; AMPA) hallmark RA, at present, there is no conceptual framework explaining the concordant presence of different AMPA-responses in RA. In the context of this presentation, the latest insights into the development of humoral response against citrullinated-, carbamylated and acetylated proteins in relation to their role as biomarkers to predict the development of RA will be discussed. <h3>Disclosure of Interests:</h3> Rene Toes Grant/research support from: Sanofi
Nasal gene expression changes with inhaled corticosteroid treatment in asthma
Authors: Ilse M. Boudewijn, Andy Lan, Alen Faiz, Claire A. Cox, Sharon Brouwer, Siebrig Schokker, Sebastiaan J. Vroegop, Martijn C. Nawijn, Prescott G. Woodruff, Stephanie A. Christenson, Paul Hagedoorn, Henderik W. Frijlink, David F. Choy, Uilke Brouwer, Marissa Wisman, Dirkje S. Postma, James Fingleton, Richard Beasley, Maarten van den Berge, Victor Guryev
Journal: Allergy (2019)

MvdB reports grants paid to the University from Astra Zeneca, TEVA, GSK, and Chiesi. IMB reports consultancy fees paid to the University from GSK. MCN reports grants paid to the University from GSK. PGW reports a grant from Medimmune and consultancy fees from Astra Zeneca, Regeneron, Sanofi, Genentech, Novartis, and Glemmark. SAC reports a grant from Medimmune, fees from Astra Zeneca and nonfinancial support from Genentech. PH is involved in development and design of the Twincer high-dose dry powder inhaler, and his employer receives royalties from the sales of the Novolizer and Genuair. HWF has a patent WO2003/000325 with royalties paid to Astra-Zeneca and his employer receives royalties from the sales of Genuair products. DFC is an employee of Genentech and has submitted patents for methods for the diagnosis and treatment of respiratory disease patients. DSP reports grants paid to the University from Astra Zeneca, Chiesi, Genentech, GSK, and Roche and reports consultancy fees paid to the University by Astra Zeneca, Chiesi, and GSK. JF reports grants from Health Research Council of New Zealand, AstraZeneca, GSK, Fisher & Paykel, and Genentech; fees from AstraZeneca and Boehringer-Ingelheim and nonfinancial support from Novartis and Boehringer-Ingelheim. RB reports grants from Health Research Council of New Zealand, Astra Zeneca, GSK, and Genentech and fees from Astra Zeneca. AL, AF, CAC, SB, SS, SJV, UB, MW, and VG have nothing to disclose. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
PB1678 CONCORDANCE OF MINIMAL RESIDUAL DISEASE MEASURED BY PCR AND FLOW CYTOMETRY IN PH-POSITIVE B-ALL ADULTS IN RUSSIAN STUDY
Authors: Y. Davydova, E. Parovichnikova, O. Gavrilina, I. Galtseva, N. Kapranov, A. Abdullaev, A. Sudarikov, G. Baskhaeva, K. Zarubina, A. Sokolov, V. Troitskaya, V. Savchenko
Journal: HemaSphere (2019)

Background: Measurement of minimal residual disease (MRD) in B-cell acute lymphoblastic leukemia (B-ALL) is integrated in treatment protocols due to it prognostic significance. In Ph+ B-ALL BCR-ABL1 transcripts are the preferential molecular targets for MRD assessment. However it is known that BCR-ABL1 may persist not only in leukemic cells but in myeloid and other cells. In this case MRD determined by other methods may clarify the real status of the disease. Aims: To compare results of MRD study in Ph+ B-ALL patients performed by reverse transcription PCR (RT-PCR, BCR-ABL1) and multicolor flow cytometry (MFC). Methods: The main principle of Ph + RALL-2012 is non-intensive treatment but non-interruptive with simultaneous administration of tyrosine kinase inhibitors. Study of MRD included 12 patients (m = 5, f = 7, median age = 39). MRD was determined after 36, 70, 133 and 190 days of protocol. BCR-ABL1 transcripts were evaluated by RT-PCR with sensitivity of at least 0.01%. MRD by MFC was analyzed by 6-color flow cytometry with minimal sensitivity of 0.01%. Results: On +36 day MRD analysis was performed for 8 patients. All MFC-studies were positive and MRD varied from 0.0014% to 17.5% (median = 0.22%). 7 patients had detectable BCR-ABL1 transcript (0.84% to 72.34%) and 1 patient with MFC-MRD 0.0014% was RT-PCR negative. On +70 day MRD was determined in 10 pts. Only 1 pts was MRD- negative by both methods. In 9 pts PCR-MRD was found (0.007-29.63%), but only in 5 of them MFC-MRD was positive too (0.005- 5.88%). On +133 day MRD was measured in 10 patients. Two pts were PCR and MFC -negative and 8 pts had BCR-ABL1 varied from 0.008 to 0.44% but 6 of them were MFC-negative. On +190 day MRD was detected in 8 pts. MRD by PCR was found in 7 of them and MFC-MRD was positive in 2 samples. Results of two methods mismatched in 5 patients. The parallel study of MRD by MFC and RT-PCR was performed in 37 samples. The concordance of the results was in 20 cases (16 double-positive and 4 double-negative, 54%), and 16 (43%) cases were PCR+MFC− and 1(2.7%) case was PCR-MFC+. The R2 was 0.99, and the proportion of tumor cells determined by RT-PCR was 4 times greater than in MFC data (fig. 1).Summary/Conclusion: On 36 day, the greatest concordance of MRD results was observed, probably due to low clearance of tumor cells. However, on 70 and 133 days, negative results were often observed by MFC while BCR-ABL1 transcripts persisted. This could happen due to persistence of BCL-ABL1 transcript in non-leukemic cells or due to higher sensitivity of RT-PCR. This conclusion may improve the predictive ability of the MRD tests in the prospective studies.
Environmental Justice: Young Hearts Suffer in Poorer Countries
Authors: Carol Potera
Journal: Environmental Health Perspectives (2004)

Cardiovascular disease (CVD) is a well-known killer of older people in affluent countries. In developing countries, however, the disease is striking a younger age group. In India, South Africa, Brazil, and the Russian republic of Tatarstan, people aged 35–65 die from CVD significantly more often than counterparts in the United States, according to a report released recently by Columbia University’s Earth Institute.

CVD is on the rise in developing nations for the same reasons that made it a killer in the west: a rise in cigarette smoking, a higher-fat diet, and lack of physical exercise. The CVD death rate in developing areas is reminiscent of that experienced in the United States in the 1950s and 1960s before effective public health measures, like warnings about the dangers of smoking and treatment for hypertension, became common. But such measures “have not yet occurred in developing countries, and treatment is often unavailable,” says epidemiologist Stephen Leeder of the University of Sydney in Australia, who coordinated the project while a visiting fellow at Columbia University.

Leeder’s team combined available death rate and workforce data from five representative middle- and low-income regions to estimate the economic impact of CVD on society. Their report, released in April 2004, reveals a silent epidemic affecting both women and men of working age.

In Tatarstan, CVD deaths among men aged 35–64 have soared 70% in just 20 years. Among women aged 15–34, four times more die from CVD than from pregnancy-related problems—a surprise, given that CVD is rarely considered a woman’s disease in developing nations. China’s CVD death rate currently mirrors that of the United States but is expected to be twice the U.S. rate by 2030, when half of the 9 million projected Chinese CVD deaths will be among people aged 35–64. In Brazilians aged 35–44, the male death rate from CVD is 30% higher and the female death rate 75% higher than for the same age group in the United States. In South Africa, CVD ranks third as cause of death in women and sixth for men.

The report’s title, A Race Against Time, refers to a 20-year window of opportunity to tackle the problem. “Younger people can be educated about lifestyle changes and treated with drugs,” says Leeder. If action is not taken now, the health costs in 20 years as these people reach end-stage disease “will be stupendous,” he warns.

As world health organizations struggle to finance treatments for infectious diseases such as malaria and AIDS, the report reminds us that “we need to pay attention to chronic diseases like heart disease,” says Daniel Fox, president of the Milbank Memorial Fund, which works with decision makers to bring the best available evidence to bear on health care and public health policy. The report is “analytically tight,” says Fox, and suggests that the economic and social impact of heart disease in the next generation may dwarf that of communicable diseases.