Do FISH Lesions Have Any Role in the Pathogenesis and Outcome of Chromosomally Normal MDS?

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1472-1472
Author(s):  
Paolo Bernasconi ◽  
Irene Dambruoso ◽  
Marina Boni ◽  
Paola Maria Cavigliano ◽  
Ilaria Giardini ◽  
...  
Keyword(s):  
High Risk ◽  
Conflicts Of Interest ◽  
Low Risk ◽  
Dna Double Strand Breaks ◽  
Disease Evolution ◽  
Molecular Tests ◽  
Single Defect ◽  
Increased Risk ◽  
Rad52 Protein ◽  
Conventional Cytogenetics

Abstract Abstract 1472 Background: The chromosomal pattern is one of the most relevant parameters to make an accurate diagnosis and predict disease outcome of MDS patients. However, in about 40–50% of patients, mostly low-risk MDS, conventional cytogenetics (CC) does not reveal any defect and thus it is not informative. In this MDS subset FISH with specific probes may identify clonal defects and improve CC results. In addition, recent aCGH data suggest that these patients may present novel lesions affecting unsuspected chromosomal regions harbouring genes with a crucial role in MDS pathogenesis. Objectives: Based on these findings the principal goal of the present study was to establish whether FISH with probes specific for chromosomal regions most commonly involved in MDS along with additional probes exploring chromosomal areas which alteration has been revealed by recent aCGH studies was truly able to unmask clonal cryptic defects in chromosomally normal MDS. Additional aims were to establish whether these defects consisted in either gains/losses or balanced rearrangements, to identify the potential affected genes and to evaluate any possible influence on OS and progression free interval (PFI). Methods: The ninety-eight consecutive chromosomally normal MDS patients analysed in the present study came to our observation in the period January 2005-December 2010. They were thirty-seven females and sixty-one males, median age 64 years (range 22–77). Eighteen patients were classified as RARS, 27 as RA, one as CRMDS, 15 as RCMD, 16 as RAEB-1 and 21 as RAEB-2. Considering IPSS score, 38 patients were considered low-risk, 36 intermediate-1 risk and 18 intermediate-2 risk and 6 as high-risk. Median follow-up was 33 months (range 1–84). At the time of the study four patient have died. FISH probes were chosen based on the frequency of their involvement in MDS and their Mb position determined using UCSC genome browser on Human Mar. 2003 assembly. They were obtained from BACPAC Resources Center at C.H.O.R.I. (Oakland, USA), labelled and applied as previously described. The probes applied were the followings: RP11-912D8 (19q13.2); RP11-196P12 (17q11.2); RP11-269C4 (14q12); RP11-351O1 (10q21.3); RP11-144G6 (10q11.2); RP11-122A11 (7q34); RP11-951K18 (5q13.1); RP11-101K5 (4p14); RP11-544H14 (2q33). i-FISH cut-off values were fixed at 10%. Results: An abnormal FISH pattern was revealed in 30 patients (33.7%). A single defect was revealed in 31 patients (31.6%) and more than two defects in 8 (26.7). Twenty-two patients (22.4%) presented a single defect, whereas 9 (9.1%) more than two defects. Band 19q13.2, 14q12, 4p14, 5q13.1, 7q34, 17q11.2, 7q22, 10q11.2, 10q21.3 and 2p33 deletions had an incidence of 54.8%, 25.8%, 16.1%, 12.9%, 12.9%, 12.9%, 9.6%, 6.4% and 3.2%. The RP11-196P12 covers the RDM-1 gene which encodes for a motif found in the RAD52 protein involved in DNA double strand breaks and homologous recombination and the RP11-144G6 covers the ANXA8L1 gene over-expressed in AML. Thus, these two genes are now analysed with additional molecular tests in order to check whether they may be affected by mutations. An abnormal FISH pattern was observed in 4/18 (22.2%) RARS, in 5/27 (18.5%) RA, in 4/15 (26.6%) RCMD, in 6/16 (37.5%) RAEB-1 and in 12/21 (57.1%) RAEB-2. Considering IPSS, an abnormal FISH pattern was revealed in 7/38 (18.4%) low-risk, in 12/36 (33.3%) intermediate-1 risk, in 9/18 (50%) intermediate-2 risk and in 3/6 (50%) high-risk patients. Disease evolution occurred in a total of 21 patients (2 RARS, 5RA, 6 RAEB-1 and 7 RAEB-2), 11 (one RARS, 2 RA, 5 RAEB-1 and 2 RAEB-2) presented an abnormal FISH pattern. At least two chromosomal deletions were observed in 7/11 patients. Conclusions: i) FISH reveals novel not expected karyotype defects, mostly deletions, in about 32% of chromosomally normal MDS; ii) some deletions pinpoint genes involved in DNA repair; iii) an abnormal FISH pattern correlates with advanced and int-2, high-risk MDS; iii) the presence of more than two lesions seems to associate with an increased risk of disease progression. Disclosures: No relevant conflicts of interest to declare.

Do Unexpected and Cryptic FISH Lesions Of Chromosomally Normal MDS Patients Have Any Prognostic Relevance?

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1549-1549
Author(s):  
Paolo Bernasconi ◽  
Irene Dambruoso ◽  
Marina Boni ◽  
Paola Maria Cavigliano ◽  
Ilaria Giardini ◽  
...  
Keyword(s):  
High Risk ◽  
Disease Progression ◽  
Low Risk ◽  
Disease Stage ◽  
Intermediate Risk ◽  
Disease Evolution ◽  
Prognostic Relevance ◽  
Increased Risk ◽  
Very High ◽  
Disease Specific

Abstract Conventional cytogenetic (CC) still remains a mandatory step in the routine diagnostic work-up of every MDS patient (pt), is one of the major determinant of disease outcome and guides potential treatment decisions. However, CC is not informative in about 50% of chromosomally normal (CN) pts and provides limited information in those with very rare defects even if the revised IPSS cytogenetic categories have tried to overcome this drawback. More sensitive techniques (aCGH, SNP-a and NGS), still used in the research setting only, suggest that CN pts may instead contain novel unexpected chromosomal lesions which prognosis is still undefined. Thus, the principal goal of our study was to establish whether FISH with disease specific probes (i.e. for chromosomal regions most commonly affected in MDS) along with non-disease specific probes (i.e. for regions which alteration in MDS has been demonstrated by aCGH only) may effectively unmask clonal cryptic defects. Other aims were to establish the nature of these defects, to identify the potentially targeted genes and to estimate their possible prognostic relevance. The one-hundred twenty-seven consecutive CN MDS pts of the present study came to our observation in the period January 2003-December 2012. They were forty-nine females and seventy-eight males, median age 66 years (range 24-88). Twenty-one pts were diagnosed as RARS, 29 as RA, one as CRMDS, one as U-MDS, 25 as RCMD, 26 as RAEB-1 and 24 as RAEB-2. On CC 122 pts presented a normal karyotype and five no mitotic figures. Considering the revised IPSS score, 62 pts were considered very low-risk, 32 low-risk, 23 intermediate risk, 8 high-risk and 2 very high-risk. Median follow-up was 22 months (range 1-90). At the time of the study nine pts have died. FISH probes were chosen based on the frequency of their involvement in MDS and their Mb position determined using UCSC genome browser on Human Mar. 2003 assembly. They were obtained from BACPAC Resources Center at C.H.O.R.I. (Oakland, USA), labelled and applied as previously described. These probes were: RP11-912D8 (19q13.2); RP11-196P12 (17q11.2); RP11-269C4 (14q12); RP11-351O1 (10q21.3); RP11-144G6 (10q11.2); RP11-122A11 (7q34); RP11-951K18 (5q13.1); RP11-101K5 (4p14); RP11-544H14 (2q33). i-FISH cut-off values were fixed at 10%. Thirty-one pts (24.4%) presented at least a single defect, always represented by deletions or gains of chromosomal material. Among them 8 pts (25.8%) presented at least two defects. Bands most commonly targeted by deletions/amplifications were 19q13.2 (61.3%), 14q12 (32.2%), 17q11.2 (16.1%), 5q13.1 (12.9%), 7q34 (12.9%), 4p14 (9.6%). Deletions of bands 10q11.2, 10q21.3 and 2p33 were more rare. As the RMD-1 gene, involved in DNA double strand breaks and homologous recombination, maps at band 19q13.2, the most commonly deleted chromosomal area, additional molecular tests are being developed to analyse this gene. An abnormal FISH pattern was observed in 2/21 (9.5%) RARS, in 7/29 (24.1%) RA, in 5/25 (20.0%) RCMD, in 8/26 (30.6%) RAEB-1 and in 9/24 (37.5%) RAEB-2. Considering IPSS, an abnormal FISH pattern was revealed in 7/62 (11.3%) very low-risk, in 8/32 (25%) low-risk, in 10/23 (43.4%) intermediate risk, in 5/8 (62.5%) high-risk and in 1/2 very high-risk patients. Disease evolution occurred in a total of 34 pts (3 RARS, 7 RA, 5 CRMD, 11 RAEB-1 and 8 RAEB-2), 16 (one RARS, 3 RA, 2 CRMD, 6 RAEB-1 and 4 RAEB-2) with an abnormal FISH pattern. All the 8 patients with at least two chromosomal deletions experienced disease progression. In conclusion, i) FISH reveals novel unexpected karyotype defects, most commonly deletions pinpointing genes involved in DNA repair, in about 24.4% of CN MDS; ii) band 19q13.2 deletion is the most common defect, frequently associated with disease evolution; ii) an abnormal FISH pattern is correlated with an advanced disease stage and an intermediate/high revised IPSS score; iii) >two lesions are associated with an increased risk of disease progression. Disclosures: No relevant conflicts of interest to declare.

Overuse of DVT Prophylaxis in Medical Inpatients

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5563-5563 ◽  
Author(s):  
Jing Deng ◽  
Lisa Thomas ◽  
Huijing Li ◽  
Elvin Varughesekutty ◽  
Qi Shi ◽  
...  
Keyword(s):  
Risk Assessment ◽  
High Risk ◽  
Conflicts Of Interest ◽  
Medical Center ◽  
Low Risk ◽  
Risk Of Bleeding ◽  
Dvt Prophylaxis ◽  
Increased Risk ◽  
Medical Inpatients ◽  
Nonsurgical Patients

Abstract Introduction: Unfractionated heparin (UFH), or low-molecular-weight heparin (LMWH), is commonly used with mechanical prophylaxis as an anticoagulant to reduce the risk for venous thromboembolism (VTE). However, overuse of these prophylaxes can increase the risk of bleeding, heparin-induced thrombocytopenia (HIT) and associated medical cost. PURPOSE: The aim of this study is to determine the incidence of DVT prophylaxis among hospitalized nonsurgical patients in a community medical center. To evaluate the use of the prophylaxes as described above, the investigators collected data on medical inpatients and addressed how to avoid overuse. Method: A retrospective inpatient chart review of 100 general internal medicine patients analyzed data using Padua Prediction Score as the risk estimate for deep venous thrombosis (DVT). High risk for VTE was defined by a cumulative score >=4 and low risk was a score <4. Only patients at increased risk for DVT but not at high risk for bleeding qualified for heparin treatment. Results: A total of 100 patients were surveyed. 54/100 (54%) patients had low risk of DVT with score < 4, and of those 29/54 (53.7%) patients received DVT prophylaxis with SCDs and/or heparin, and 17/54 (31.5%) patients were treated with heparin. All 46 patients with score >= 4 were treated with DVT prophylaxis of which 10 patients were only treated with heparin and 36 patients were given both mechanical and chemical prophylaxis. Collectively, 53.7% of the patients received treatment with DVT prophylaxis (p < 0.001, Chi-Square test). Discussion: In hospital settings, physicians want to avoid DVT or PE so they tend to consider patients as being at moderate risk for DVT without using any method of DVT risk assessment. This leads to unnecessary overuse of DVT prophylaxis on patients and may increase the risk of bleeding and injury. Conclusion: Our data suggests that there DVT prophylaxis including UFH and LMWH was over prescribed among patients with who had marginal risk for DVT in hospitalized nonsurgical patients in a community medical center. Clinical implications: To avoid the overuse of DVT prophylaxis, physicians need to follow guidelines. Education and inclusion of the guidelines in EHRs of information on VTE risk assessment for hospitalized medical patients upon admission may reduce unneeded DVT prophylaxis and the risk of bleeding and costs associated with additional care needs. Disclosures No relevant conflicts of interest to declare.

FISH Reveals Abnormalities of Unsuspected Regions in Chromosomally Normal De Novo Myelodysplastic Syndromes (MDS).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2599-2599
Author(s):  
Paolo Bernasconi ◽  
Irene Dambruoso ◽  
Marina Boni ◽  
Paola Maria Cavigliano ◽  
Ilaria Giardini ◽  
...  
Keyword(s):  
De Novo ◽  
Chromosomal Abnormalities ◽  
Conflicts Of Interest ◽  
Prognostic Significance ◽  
Normal Karyotype ◽  
Low Risk ◽  
Fish Analysis ◽  
Disease Evolution ◽  
Therapeutic Decisions ◽  
Conventional Cytogenetics

Abstract Abstract 2599 Poster Board II-575 In de novo MDS the chromosomal pattern is a mandatory step for an accurate diagnosis, predicts overall survival (OS) and the risk of MDS/AML evolution, guides therapeutic decisions. However, conventional cytogenetics (CC) studies show a normal un-informative chromosomal pattern in about half of MDS patients, especially in low-risk disease. FISH with probes pinpointing the chromosomal regions most frequently affected in MDS can increase the incidence of abnormal karyotypes up to 60%, but the percentage of normal karyotypes remains high and makes the search of novel cytogenetic/molecular markers a urgent need. A fundamental contribution to overcome CC and FISH shortcomings, has been recently provided by array CGH (aCGH) studies which have revealed that, independently of the cytogenetic pattern, MDS patients may harbour novel abnormalities involving unsuspected chromosomal regions. Based on this assumption, we decided to investigate whether FISH with probes already employed in aCGH studies can truly unmask cryptic lesions in chromosomally normal MDS patients, whether these defects are either chromosomal gains/losses or balanced rearrangements and whether these chromosomal abnormalities influence OS and disease evolution. FISH analyses were carried out in thirty-five patients examined between January 2005 and June 2008. There were thirteen females and twenty-two males, whose median age was 66 years (range 24–78). According to WHO classification, 6 patients were classified as RA, 13 as RAEB-1 and 16 as RAEB-2. According to IPSS score, 7 patients were considered low-risk, 14 intermediate-1 risk and 14 intermediate-2 risk. Median follow-up was nine months (range 1–46). At the time of the analyses no patients has died; 6 have progressed to RAEB-2 and 3 to AML. Probes for FISH analysis were chosen following two criteria: the frequency of their involvement in chromosomal abnormalities identified by aCGH studies and their Mb position on Human Mar. 2003 assembly according to the UCSC genome browser. All probes, obtained from BACPAC Resources Center at C.H.O.R.I. (Oakland, USA), were labelled and applied as previously reported. The following probes were applied: RP11-912d8 (19q13.2); RP11-196p12 (17q11.2); RP11-269c4 (14q12); RP11-351o1 (10q21.3); RP11-144g6 (10q11.2); RP11-122a11 (7q34); RP11-951k18 (5q13.1); RP11-100m20 (4p14); RP11-544h14 (2q33). The cut-off values for interphase FISH (i-FISH) were obtained from the analysis of 300 nuclei from ten normal samples and were fixed at 10%. An abnormal FISH pattern was revealed in eighteen patients (51.4%). It was observed in 3/6 RA patients, in 7/13 RAEB-1 and in 8/16 RAEB-2 and in 2/7 IPSS low-risk, in 7/14 intermediate-1 risk and in 9/14 intermediate-2 risk MDS patients. Seven presented a 19q13.2 deletion, three a 14q12 deletion, four an amplification of band 4p14, two a defect of band 10q21.3, two a potential amplification and one a deletion of band 10q11.2, two a deletion of band 5q13.1 and one a deletion of band 17q11.2. Cryptic defects were also revealed in six of the nine patients who experienced disease evolution on FISH analyses. This event occurred in 2/3 RA, in 2/7 RAEB-1 and in 2/8 RAEB-2 patients with an abnormal FISH pattern. Despite these data, the prognostic significance of an abnormal FISH pattern needs to be assessed on additional patients. In conclusion, our data show that i) FISH can truly reveal novel lesions involving unsuspected chromosomal regions in 51% of MDS patients with a normal karyotype; ii) most of these lesions consist of chromosomal gains/losses; iii) an abnormal FISH pattern seems to correlate with disease progression, but this correlation needs to be tested on additional patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Multidimensional dynamic healthcare personnel (HCP)-centric model from a low-income and middle-income country to support and protect COVID-19 warriors: a large prospective cohort study

BMJ Open ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. e043837
Author(s):  
Usha Dutta ◽  
Anurag Sachan ◽  
Madhumita Premkumar ◽  
Tulika Gupta ◽  
Swapnajeet Sahoo ◽  
...  
Keyword(s):  
High Risk ◽  
Low Income ◽  
Tertiary Care ◽  
Low Risk ◽  
Transmission Risk ◽  
Healthcare Personnel ◽  
Risk Zone ◽  
Increased Risk ◽  
Medium Risk ◽  
Risk Zones

ObjectivesHealthcare personnel (HCP) are at an increased risk of acquiring COVID-19 infection especially in resource-restricted healthcare settings, and return to homes unfit for self-isolation, making them apprehensive about COVID-19 duty and transmission risk to their families. We aimed at implementing a novel multidimensional HCP-centric evidence-based, dynamic policy with the objectives to reduce risk of HCP infection, ensure welfare and safety of the HCP and to improve willingness to accept and return to duty.SettingOur tertiary care university hospital, with 12 600 HCP, was divided into high-risk, medium-risk and low-risk zones. In the high-risk and medium-risk zones, we organised training, logistic support, postduty HCP welfare and collected feedback, and sent them home after they tested negative for COVID-19. We supervised use of appropriate personal protective equipment (PPE) and kept communication paperless.ParticipantsWe recruited willing low-risk HCP, aged <50 years, with no comorbidities to work in COVID-19 zones. Social distancing, hand hygiene and universal masking were advocated in the low-risk zone.ResultsBetween 31 March and 20 July 2020, we clinically screened 5553 outpatients, of whom 3012 (54.2%) were COVID-19 suspects managed in the medium-risk zone. Among them, 346 (11.4%) tested COVID-19 positive (57.2% male) and were managed in the high-risk zone with 19 (5.4%) deaths. One (0.08%) of the 1224 HCP in high-risk zone, 6 (0.62%) of 960 HCP in medium-risk zone and 23 (0.18%) of the 12 600 HCP in the low-risk zone tested positive at the end of shift. All the 30 COVID-19-positive HCP have since recovered. This HCP-centric policy resulted in low transmission rates (<1%), ensured satisfaction with training (92%), PPE (90.8%), medical and psychosocial support (79%) and improved acceptance of COVID-19 duty with 54.7% volunteering for re-deployment.ConclusionA multidimensional HCP-centric policy was effective in ensuring safety, satisfaction and welfare of HCP in a resource-poor setting and resulted in a willing workforce to fight the pandemic.

scholarly journals Polygenic risk scores predict diabetic complications and their response to therapy

2019 ◽  
Author(s):  
J. Tremblay ◽  
M. Haloui ◽  
F. Harvey ◽  
R. Tahir ◽  
F.-C. Marois-Blanchet ◽  
...  
Keyword(s):  
High Risk ◽  
Prediction Model ◽  
Risk Group ◽  
Intensive Therapy ◽  
Cardiovascular Death ◽  
Response To Therapy ◽  
Low Risk ◽  
Number Needed To Treat ◽  
Genome Wide Association Studies ◽  
Increased Risk

AbstractType 2 diabetes increases the risk of cardiovascular and renal complications, but early risk prediction can lead to timely intervention and better outcomes. Through summary statistics of meta-analyses of published genome-wide association studies performed in over 1.2 million of individuals, we combined 9 PRS gathering genomic variants associated to cardiovascular and renal diseases and their key risk factors into one logistic regression model, to predict micro- and macrovascular endpoints of diabetes. Its clinical utility in predicting complications of diabetes was tested in 4098 participants with diabetes of the ADVANCE trial followed during a period of 10 years and replicated it in three independent non-trial cohorts. The prediction model adjusted for ethnicity, sex, age at onset and diabetes duration, identified the top 30% of ADVANCE participants at 3.1-fold increased risk of major micro- and macrovascular events (p=6.3×10−21 and p=9.6×10−31, respectively) and at 4.4-fold (p=6.8×10−33) increased risk of cardiovascular death compared to the remainder of T2D subjects. While in ADVANCE overall, combined intensive therapy of blood pressure and glycaemia decreased cardiovascular mortality by 24%, the prediction model identified a high-risk group in whom this therapy decreased mortality by 47%, and a low risk group in whom the therapy had no discernable effect. Patients with high PRS had the greatest absolute risk reduction with a number needed to treat of 12 to prevent one cardiovascular death over 5 years. This novel polygenic prediction model identified people with diabetes at low and high risk of complications and improved targeting those at greater benefit from intensive therapy while avoiding unnecessary intensification in low-risk subjects.

scholarly journals Mutational Characteristics and Changing Pattern from Idiopathic Cytopenia of Undetermined Significance to High-Risk Myelodysplastic Syndrome Stratified By IPSS-R

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3009-3009
Author(s):  
Eun-Ji Choi ◽  
Young-Uk Cho ◽  
Seongsoo Jang ◽  
Chan-jeoung Park ◽  
Han-Seung Park ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Myelodysplastic Syndrome ◽  
Rna Splicing ◽  
Conflicts Of Interest ◽  
Low Risk ◽  
International Prognostic Scoring System ◽  
Intermediate Risk ◽  
Sequencing Data ◽  
Undetermined Significance

Background: Unexplained cytopenia comprises a spectrum of hematological diseases from idiopathic cytopenia of undetermined significance (ICUS) to myelodysplastic syndrome (MDS). Revised International Prognostic Scoring System (IPSS-R) is the standard tool to assess risk in MDS. Here, we investigated the occurrence, characteristics, and changing pattern of mutations in patients with ICUS and MDS stratified by IPSS-R score. Methods: A total of 211 patients were enrolled: 73 with ICUS and 138 with MDS. We analyzed the sequencing data of a targeted gene panel assay covering 141 genes using the MiSeqDx platform (Illumina). The lower limit of variant allele frequency (VAF) was set to 2.0% of mutant allele reads. Bone marrow components were assessed for the revised diagnosis according to the 2016 WHO classification. Lower-risk (LR) MDS was defined as those cases with very low- or low-risk MDS according to the IPSS-R. Higher-risk (HR) MDS was defined as those cases with high- or very high-risk MDS according to the IPSS-R. Results: Patients with ICUS were classified as very low-risk (39.7%), low-risk (54.8%), and intermediate-risk (5.5%) according to the IPSS-R. Patients with MDS were classified as LR (35.5%), intermediate-risk (30.4%), and HR (34.1%). In the ICUS, 28 (38.4%) patients carried at least one mutation in the recurrently mutated genes in MDS (MDS mutation). The most commonly mutated genes were DNMT3A (11.0%), followed by TET2 (9.6%), BCOR (4.1%), and U2AF1, SRSF2, IDH1 and ETV6 (2.7% for each). IPSS-R classification was not associated with mutational VAF and the number of mutations in ICUS. In the 49 LR MDS, 28 (57.1%) patients carried at least one MDS mutation. The most commonly mutated genes were SF3B1 (20.4%), followed by TET2 (12.2%), U2AF1 (10.2%), DNMT3A (10.2%), ASXL1 (10.2%), and BCOR (6.1%). Higher VAF and number of mutations were observed in LR MDS compared to ICUS patients. In the 42 intermediate-risk MDS, 27 (64.3%) patients carried at least one MDS mutation. The most commonly mutated genes were ASXL1 (23.8%), followed by TET2 (21.4%), RUNX1 (16.7%), U2AF1 (14.3%), DNMT3A (14.3%), SF3B1 (9.5%), and SRSF2, BCOR, STAG2 and CBL (7.1% for each). In the 47 HR MDS, 36 (76.6%) patients carried at least one MDS mutation. The most commonly mutated genes were TET2 (25.5%), followed by DNMT3A (14.9%), TP53 (14.9%), RUNX1 (12.8%), U2AF1 (10.6%), ASXL1 (10.6%), and SRSF2 and KRAS (6.4% for each). As the disease progressed, VAF and number of the MDS mutations gradually increased, and mutations involving RNA splicing, histone modification, transcription factor or p53 pathway had a trend for increasing frequency. Specifically, ASXL1, TP53, and RUNX1 mutations were the most striking features in patients with advanced stage of the disease. Cohesin mutations were not detected in ICUS, whereas these mutations were detected at a relatively high frequency in HR MDS. Our data were summarized in Table 1. Conclusions: We demonstrate that on disease progression, MDS mutations are increased in number as well as are expanded in size. Furthermore, a subset of mutations tends to be enriched for intermediate- to HR MDS. The results of this study can aid both diagnostic and prognostic stratification in patients with unexpected cytopenia. In particular, characterization of MDS mutations can be useful in refining bone marrow diagnosis in challenging situations such as distinguishing LR MDS from ICUS. Disclosures No relevant conflicts of interest to declare.

scholarly journals Cervicovaginal Levels of Lactoferrin, Secretory Leukocyte Protease Inhibitor, and RANTES and the Effects of Coexisting Vaginoses in Human Immunodeficiency Virus (HIV)-Seronegative Women with a High Risk of Heterosexual Acquisition of HIV Infection

2007 ◽  
Vol 14 (9) ◽  
pp. 1102-1107 ◽  
Author(s):  
Richard M. Novak ◽  
Betty A. Donoval ◽  
Parrie J. Graham ◽  
Lucy A. Boksa ◽  
Gregory Spear ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
High Risk ◽  
Hiv Infection ◽  
Protease Inhibitor ◽  
Genital Tract ◽  
Secretory Leukocyte Protease Inhibitor ◽  
Low Risk ◽  
High Risk Women ◽  
Increased Risk ◽  
Immunodeficiency Virus

ABSTRACT Innate immune factors in mucosal secretions may influence human immunodeficiency virus type 1 (HIV-1) transmission. This study examined the levels of three such factors, genital tract lactoferrin [Lf], secretory leukocyte protease inhibitor [SLPI], and RANTES, in women at risk for acquiring HIV infection, as well as cofactors that may be associated with their presence. Women at high risk for HIV infection meeting established criteria (n = 62) and low-risk controls (n = 33) underwent cervicovaginal lavage (CVL), and the CVL fluid samples were assayed for Lf and SLPI. Subsets of 26 and 10 samples, respectively, were assayed for RANTES. Coexisting sexually transmitted infections and vaginoses were also assessed, and detailed behavioral information was collected. Lf levels were higher in high-risk (mean, 204 ng/ml) versus low-risk (mean, 160 ng/ml, P = 0.007) women, but SLPI levels did not differ, and RANTES levels were higher in only the highest-risk subset. Lf was positively associated only with the presence of leukocytes in the CVL fluid (P < 0.0001). SLPI levels were lower in women with bacterial vaginosis [BV] than in those without BV (P = 0.04). Treatment of BV reduced RANTES levels (P = 0.05). The influence, if any, of these three cofactors on HIV transmission in women cannot be determined from this study. The higher Lf concentrations observed in high-risk women were strongly associated with the presence of leukocytes, suggesting a leukocyte source and consistent with greater genital tract inflammation in the high-risk group. Reduced SLPI levels during BV infection are consistent with an increased risk of HIV infection, which has been associated with BV. However, the increased RANTES levels in a higher-risk subset of high-risk women were reduced after BV treatment.

Risk results from screening for a high cardiovascular disease risk by means of traditional risk factor measurement or coronary artery calcium scoring in the ROBINSCA trial

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
C Van Der Aalst ◽  
S.J.A.M Denissen ◽  
M Vonder ◽  
J.-W.C Gratema ◽  
H.J Adriaansen ◽  
...  
Keyword(s):  
Cardiovascular Disease ◽  
Coronary Artery ◽  
High Risk ◽  
Risk Score ◽  
Coronary Artery Calcium ◽  
Preventive Treatment ◽  
Low Risk ◽  
Funding Source ◽  
Cvd Risk ◽  
Increased Risk

Abstract Aims Screening for a high cardiovascular disease (CVD) risk followed by preventive treatment can potentially reduce coronary heart disease (CHD)-related morbidity and mortality. ROBINSCA (Risk Or Benefit IN Screening for CArdiovascular disease) is a population-based randomized controlled screening trial that investigates the effectiveness of CVD screening in asymptomatic participants using the Systematic COronary Risk Evaluation (SCORE) model or Coronary Artery Calcium (CAC) scoring. This study describes the distributions in risk and treatment in the ROBINSCA trial. Methods and results Individuals at expected elevated CVD risk were randomized (1:1:1) into the control arm (n=14,519; usual care); screening arm A (n=14,478; SCORE, 10-year fatal and non-fatal risk); or screening arm B (n=14,450; CAC scoring). Preventive treatment was largely advised according to current Dutch guidelines. Risk and treatment differences between the screening arms were analysed. 12,185 participants (84.2%) in arm A and 12,950 (89.6%) in arm B were screened. 48.7% were women, and median age was 62 (InterQuartile Range 10) years. SCORE screening identified 45.1% at low risk (SCORE&lt;10%), 26.5% at intermediate risk (SCORE 10–20%), and 28.4% at high risk (SCORE≥20%). According to CAC screening, 76.0% were at low risk (Agatston&lt;100), 15.1% at high risk (Agatston 100–399), and 8.9% at very high risk (Agatston≥400). CAC scoring significantly reduced the number of individuals indicated for preventive treatment compared to SCORE (relative reduction women: 37.2%; men: 28.8%). Conclusion We showed that compared to risk stratification based on SCORE, CAC scoring classified significantly fewer men and women at increased risk, and less preventive treatment was indicated. ROBINSCA flowchart Funding Acknowledgement Type of funding source: Public grant(s) – EU funding. Main funding source(s): Advanced Research Grant

Low-Density Lipoprotein Subfractionation: What Is the Role of the Lab When Reporting Discrepant Results?

2020 ◽  
Vol 154 (Supplement_1) ◽  
pp. S8-S9
Author(s):  
Nicholas E Larkey ◽  
Leslie J Donato ◽  
Allan S Jaffe ◽  
Jeffrey W Meeusen
Keyword(s):  
Coronary Artery ◽  
High Risk ◽  
Clinical Decision Making ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Low Risk ◽  
Lipid Lowering ◽  
Low Density ◽  
Small Dense Ldl ◽  
Increased Risk

Abstract Plasma concentrations of low-density-lipoprotein cholesterol (LDL-C) are directly associated with risk for coronary artery disease (CAD). Multisociety guidelines define LDL-C&gt;160mg/dL as a risk factor for CAD and LDL-C&gt;190mg/dL as an indication for lipid lowering medication, regardless of other clinical factors. Subfractionation of LDL according to size (LDL-s) enables differentiation between two LDL phenotypes: large-buoyant LDL and small-dense LDL. The small-dense LDL phenotype reportedly conveys increased risk for CAD. Major societies do not recommend LDL subfractions be used for clinical decision making and most payers do not cover LDL subfraction testing. Despite these restrictions, LDL subfraction is routinely requested by clinicians. Nuclear magnetic resonance (NMR) spectroscopy measures LDL-C and LDL-s. Following inquiries regarding interpretation of conflicting LDL-C and LDL-s results, we investigated associations between LDL-C and LDL-s measured by NMR in order to determine how often they provide contradicting or additive information. Verification of NMR LDL-C accuracy was confirmed by ß-quantification in a subset of patient samples (n=250). The average bias was -4.5mg/dL and the correlation coefficient was 0.92. High-risk was defined as LDL-C&gt;160mg/dL or LDL-s&lt;20.5 nm (small-dense LDL); and low-risk was defined as LDL-C&lt;70mg/dL or LDL-s&gt;20.5nm (large-buoyant LDL). In 26,710 clinical NMR analyses, the median LDL-C was 94.0mg/dL (range:5-436mg/dL) with median LDL-s of 20.8 nm (range:19.4–23.0nm). LDL-s moderately correlated with LDL-C (Ï#129;=0.51;p&lt;0.01). Small-dense-LDL was identified in only 18% (407/2,191) of patients with elevated LDL-C (&gt;160mg/dL) and was more common (73.2% of 6,093) in patients with low LDL-C (&lt;70mg/dL;p&lt;0.001). Associations with CAD were investigated among patients without cholesterol-lowering medication treatment referred for angiography (n=356). CAD (defined as stenosis &gt;50% in one or more coronary artery) was diagnosed in 14% (1/7) of subjects with low LDL-C (&lt;70mg/dL) compared to 59% (47/80) of subjects with elevated LDL-C (p=0.01). When stratifying by LDL-s, CAD was diagnosed in 50% (57/115) of subjects with small-dense LDL compared to 43% (104/241) of subjects with large-buoyant LDL (p=0.2). Small-dense LDL was identified in only 33% (26/80) of cases with elevated LDL-C. Limiting to subjects with elevated LDL-C, CAD was diagnosed in 50% (13/26) of subjects with concordant (high-risk) small-dense LDL compared to 61% (33/54) of subjects with discordant (low-risk) large-buoyant LDL (LDL-s&gt;20.5nm) (p=0.3). Our data confirm that LDL-s subfraction measured by NMR is reported discordantly in most cases when LDL-C is unequivocally high or low. Furthermore, CAD diagnosis was significantly associated with LDL-C, but not with LDL-s. Our data also show that in discrepant samples, elevated LDL-C correlates better with disease state compared to LDL-s. Therefore, LDL-s should not be used to justify treatment decisions in patients with elevated LDL-C. Laboratories should consider carefully whether or not to report LDL-s when it is known that misleading and discordant values will be reported in a majority of cases.

Comparing Toxicities and Survival Outcomes with Total Therapy 4 (TT4) for 70-Gene (R70)-Defined Low-Risk Multiple Myeloma (MM) to Results Obtained with Total Therapy 3 Protocols TT3A and TT3B

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 368-368 ◽  
Author(s):  
Elias J. Anaissie ◽  
Frits van Rhee ◽  
Antje Hoering ◽  
Sarah Waheed ◽  
Yazan Alsayed ◽  
...  
Keyword(s):  
High Risk ◽  
Conflicts Of Interest ◽  
Low Risk ◽  
Phase Iii ◽  
Survival Outcomes ◽  
Phase Iii Trial ◽  
Baseline Characteristics ◽  
Total Therapy ◽  
Timing Of Onset

Abstract Abstract 368 Background: TT3, incorporating bortezomib and thalidomide with induction prior to and consolidation after melphalan 200mg/m2-based transplants and 3 year maintenance with VTD (year 1) and TD (years 2+3) in TT3A and with VRD for 3 years in TT3B resulted in a high CR rate of ∼60% and, in the 85% of patients with GEP-defined low-risk MM, 5-yr OS/EFS of 80%/78%; 5-year CR duration estimate was 88%. Patients and Methods: Phase III trial TT4 for low-risk MM randomized patients between standard (S) and light (L) arms. TT4-L applied 1 instead of 2 cycles of induction therapy with M-VTD-PACE prior to and 1 instead of 2 cycles of consolidation with dose-reduced VTD-PACE after tandem transplantation. M-VTD-PACE comprised melphalan, bortezomib, thalidomide, dexamethasone and 4-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide. TT4-S applied standard single dose melphalan 200mg/m2, while TT4-L used a 4-day fractionated schedule of melphalan 50mg/2 on days 1–4. VRD maintenance for 3 years was identical in both arms. Here we report, for both TT4 arms combined, on grade >2 mucosal toxicities, applying CTCAE version 3.0, and on efficacy (CR, EFS, OS) in relationship to TT3 in low-risk MM. At the time of analysis, median follow-up on TT4 is 10.7 months and on TT3A/B 62.3/33.4 months. To facilitate comparisons between trials with different follow-up times, TT3 data were backdated to follow-up time comparable to TT4 as of this reporting time. Results: Baseline characteristics were similar in TT3 (n=364) and TT4 (n=165) in terms of B2M both >=3.5mg/L and >5.5mg/L, and elevated levels of CRP, creatinine, and LDH. Presence of cytogenetic abnormalities (CA) overall and in terms of CA13/hypodiploidy was similar in both. Fewer TT4 patients had ISS-1 (31% v 43%, P=0.010) and more had hemoglobin <10g/dL (35% v 26%, P=0.029). While neither trial had GEP-defined high-risk in the 70-gene model (R70), the more recently validated R80 distribution showed 7% high-risk in TT4 v 3% in TT3 (P=0.031). DelTP53 was more prevalent in TT4 than TT3 (39% v 10%, P<0.001), and MY favorable subgroup designation pertained to 3% in TT4 v 12% in TT3 (P=0.002). Toxicities are reported per protocol phase. During induction (TT4, n=160; TT3, n=364), grade >2 mucosal toxicities included colitis in 0%/1% (P=0.32), esophagitis/dysphagia in 0%/1% (P=0.33), GI mucositis, NOS in 1%/1% (P=0.99) and stomatitis/pharyngitis in 0%/1% (P=0.99). With transplant-1, (TT4, n=139; TT3, n=344), grade >2 mucosal toxicities included colitis in 3%/1% (P=0.24), esophagitis/dysphagia in 1%/5% (P=0.03), gastritis in 1%/0% (P=0.29), GI mucositis, NOS in 1%/2% (P=0.73) and stomatitis/pharyngitis in 0%/5% (P=0.008); with transplant-2 (TT4, n=105; TT3, n=294), grade >2 mucosal toxicities included colitis in 4%/3% (P=0.77), esophagitis/dysphagia in 0%/2% (P=0.20), GI mucositis, NOS in 2%/3% (P=0.99) and stomatitis/pharyngitis in 0%/1% (P=0.58). With consolidation (TT4, n=85; TT3, n=280), grade >2 mucosal toxicities included colitis in 0%/3% (P=0.36) and GI mucositis, NOS in 0%/1% (P=0.99). Timing of onset and final levels of CR differed substantially between TT4 and TT3 in favor of TT4 (P=0.006); no differences were observed in OS (P=0.36), EFS (P=0.66), and CR duration (P=0.12). Conclusion: TT4 (both arms combined) provided, despite higher proportions of patients with unfavorable characteristics than in TT3, superior CR rate and comparable survival outcomes to TT3's low-risk population. GI toxicities were reduced in TT4 v TT3. Results of TT4 arms will be presented. Disclosures: No relevant conflicts of interest to declare.

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