Clonal Megakaryocyte Dysplasia with Normal Blood Values Is a Distinct Myeloproliferative Neoplasm

2021 ◽  
pp. 1-8
Author(s):  
Giovanni Barosi ◽  
Vittorio Rosti ◽  
Margherita Massa ◽  
Rita Campanelli ◽  
Laura Villani ◽  
...  
Keyword(s):  
Disease Progression ◽  
Somatic Mutations ◽  
Thrombotic Event ◽  
Myeloproliferative Neoplasm ◽  
Myeloproliferative Disorder ◽  
Normal Blood ◽  
Blast Transformation ◽  
Generation Sequencing ◽  
Death Data

<b><i>Introduction:</i></b> In 1991, we reported 18 persons with a clinical-pathologic entity and termed atypical myeloproliferative disorder because they did not meet the contemporary diagnostic criteria for a myeloproliferative neoplasm. We sought to gain further knowledge on this disease entity. <b><i>Methods:</i></b> This retrospective cohort study included consecutive subjects registered in the database of the Center for the Study of Myelofibrosis in Pavia, Italy, from 1998 to 2020 (June), and diagnosed with atypical myeloproliferative disorder according to our adjudicated criteria. We studied clinical, histological, cytogenetic, and molecular covariates and risks of thrombosis, disease progression, and death. Data were compared with those of concurrent subjects with prefibrotic myelofibrosis. <b><i>Results:</i></b> Fifteen new subjects with atypical myeloproliferative disorder were identified. Seven were male. Median age was 50 years (IQR, 41–54 years). Thirteen were diagnosed with a synchronous symptomatic or incidentally detected thrombotic event. The bone marrow showed megakaryocyte hyperplasia with dysplasia. <i>JAK2</i>V617F was present in 10 subjects and <i>CALR</i> mutation in one. No other somatic mutations were identified in next generation sequencing. After a median follow-up of 101 months (IQR, 40–160 months), no subject had disease progression or blast transformation. Incidence of post-diagnosis or recurrent thrombosis was 3.9 events (95% confidence interval, 3.5–4.0) and 5.0 events (4.6–5.6) per 100 person-years. Features of subjects with atypical myeloproliferative disorder differed markedly from those of 546 subjects with prefibrotic myelofibrosis. <b><i>Conclusion:</i></b> Our data indicate that these 15 persons have a distinct myeloproliferative neoplasm. We propose naming this new disorder clonal megakaryocyte dysplasia with normal blood values.

scholarly journals Targeted Next Generation Sequencing Identifies Novel Genetic Mutations in Patients with Waldenstrom's Macroglobulinemia/Lymphoplasmacytic Lymphoma or IgM-Monoclonal Gammopathies of Undetermined Significance

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2928-2928 ◽  
Author(s):  
Marzia Varettoni ◽  
Silvia Zibellini ◽  
Ettore Rizzo ◽  
Luca Malcovati ◽  
Virginia Valeria Ferretti ◽  
...  
Keyword(s):  
Sanger Sequencing ◽  
Somatic Mutations ◽  
Genetic Mutations ◽  
Wild Type ◽  
Targeted Next Generation Sequencing ◽  
Coefficient Of Concordance ◽  
Generation Sequencing ◽  
Myd88 L265p ◽  
Undetermined Significance

Abstract Background. TheMYD88 (L265P) somatic mutation is present in more than 90% of patients (pts) with Waldenström's Macroglobulinemia (WM)/lymphoplasmacitic lymphoma (LPL). The second most common mutations are nonsense (NS) or frameshift (FS) mutations in the CXCR4 gene, detectable in approximately 25-30% of WM pts by Sanger sequencing. Limited data are available about other genetic mutations in WM/LPL and its precursor condition IgM-monoclonal gammopathy of undetermined significance (IgM-MGUS). Pts and methods. Using targeted next generation sequencing (NGS), we evaluated the prevalence of somatic mutations of 11 genes selected on the basis of evidences available from the literature (MYD88, CXCR4, ARID1A, KMT2D, TP53, NOTCH2, PRDM1, CD79b, TRAF3,TNFAIP3, MYDBBP1A) in 119 pts, classified as WM/LPL (n=63) or IgM-MGUS (n=56) according to International Consensus Criteria. Median age of pts (67 males, 52 females) was 65 years (range: 38-82). Samples were collected at diagnosis (n=101), after diagnosis but before any treatment (n=9) or at progression after therapy (n=9). Paired tumor and germline DNA extracted respectively from CD19-selected and CD19-depleted bone marrow (BM) mononuclear cells was available in all pts. Mean resequencing depth across gene panel was 1009x. Only mutations tagged as oncogenic or possibly oncogenic based on information derived from the literature and on in silico prediction effect were considered in the analysis. For MYD88 (L265P) and CXCR4 mutations, results obtained with NGS were compared with those obtained respectively with allele-specific PCR (AS-PCR) and Sanger sequencing. Results. Overall, we found 151 mutations in 88 pts (74%). The median number of mutations was significantly higher in WM/LPL as compared with IgM-MGUS and in pts previously treated as compared with untreated ones (median 2 versus 1, P < 0.001 for both comparisons). MYD88 mutations were found in 80/119 pts (67%), with a median allele burden of 34.2% (range: 2.5-93.3%). The prevalence of MYD88 mutations was significantly higher in WM/LPL as compared with IgM-MGUS (86% versus 46%, P <0.001). MYD88 mutations other than classical L265P (n=76) were found in 4 pts and were represented by V217F (n=2), S219C (n=1), M232T (n=1). Fifteen pts who were MYD88 (L265P) wild-type by NGS were found to be mutated by AS-PCR (K coefficient of concordance between NGS and AS-PCR: 70%, P < 0.001). CXCR4 mutations were found in 19/119 pts (16%), with a median allele burden of 34% (range: 4.2-84%). The prevalence of CXCR4 mutations was significantly higher in WM/LPL as compared with IgM-MGUS (24% versus 7%, P < 0.02). The K coefficient of concordance between NGS and Sanger was 83% (P < 0.001), with 2 pts mutated only by NGS and 2 pts mutated only by Sanger. Somatic mutations were also found in KMT2D (formerly known as MLL2) (16% of pts), TP53 (8%), NOTCH2 (7%), PRDM1 (4%), ARID1A (3%), CD79b (2%), and TRAF3 (1%). No mutations were found in MYBBP1A and TNFAI3. Overall, the prevalence of these mutations was significantly lower in pts wild-type either for MYD88 or CXCR4 as compared with those with MYD88 and/or CXCR4 mutations (15% versus 41%, P = 0.04). The prevalence of KMT2D mutations was significantly higher in WM/LPL as compared with MGUS (25% versus 5%), while for the other genes the distribution was not statistically different according to diagnosis. With a median follow-up of 20 months (range: 0-264), we did not find a statistically significant correlation between genetic mutations and pts' outcome in terms of overall survival or time to first treatment. Conclusions. In this cohort of pts with WM/LPL and IgM-MGUS studied with NGS we could demonstrate that: i) NGS identifies MYD88 mutations other than L265P in a small proportion of pts; ii) the prevalence of CXCR4 mutations by Sanger is confirmed by NGS, despite the higher sensitivity of the latter method; iii) the subgroup of pts wild type either for MYD88 or CXCR4 shows a low incidence of other genetic mutations; iv) 25% of pts with WM/LPL were found to carry KMT2D mutations, a prevalence similar to that reported in marginal zone lymphoma; v) genetic mutations are more common in WM/LPL than in IgM-MGUS in agreement with the hypothesis that multiple genetic hits are required for progression from a pre-benign condition to a neoplastic disease; vi) due to the indolent nature of these disorders, longer follow-up is probably needed to see the prognostic impact of these mutations, if any. Disclosures No relevant conflicts of interest to declare.

A Survey on Clinical and Biological Characteristic and Therapy Management of an Italian Series of 455 Adult Patients with Systemic Mastocytosis on Behalf of Italian Registry of Mastocytosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3188-3188
Author(s):  
Lisa Pieri ◽  
Patrizia Bonadonna ◽  
Chiara Elena ◽  
Cristina Papayannidis ◽  
Federica Irene Grifoni ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Disease Progression ◽  
Myeloid Leukemia ◽  
Systemic Mastocytosis ◽  
Myeloproliferative Neoplasm ◽  
Large Series ◽  
Refractory Anemia

Abstract Systemic mastocytosis (SM) is a rare myeloproliferative neoplasm characterized by proliferation and hyperactivation of clonal mast cells. Clinical manifestations are heterogeneous and encompass cutaneous lesions, gastrointestinal alterations, osteoporosis, anaphylaxis and involvement of bone marrow and other organs due to neoplastic mast cells (MC) infiltration. As consequence, diagnosis may be difficult and patients (pts) are often evaluated by different specialists before the disease is recognized. To date, only few studies (Lim 2009, Escribano 2009, Cohen 2014) described relatively large series of pts with SM. We performed a multicentre retrospective study to evaluate clinical and biological features and therapeutic management in a large series of pts from 10 Italian centres experienced in management of SM and organized in multidisciplinary groups of specialists. We collected 455 pts diagnosed with SM according to WHO criteria. Additionally 26 pts with mastocytosis in the skin (MIS) evaluated with BM examination did not fulfil criteria for SM, leading to diagnosis of Cutaneous Mastocytosis (CM); however 2/26 pts with CM had both cKITD816V mutation and CD2/CD25 expression on MC in BM, additional 3 showed either cKITD816V or CD2/CD25. Moreover, we found 22 pts without MIS but with features of monoclonal mast cell activation syndrome. Of the 455 pts with WHO-SM (male 56%), 252 (55%) had MIS: median age at MIS diagnosis (dg) was 37 years (y) (range 0-79), while at SM dg it was 46.5 (range 18-82). Time from onset of MIS to dg of SM was 9 y (range 0-43). In 18/252 pts (7%) MIS occurred before age of 18 y (median 9, range 0-17) and persisted over childhood. Median age at dg of SM without MIS (203/455 pts, 45%) was older: 54 y, range 19-79 (p<0.0001). First manifestations of SM were MIS in 46.5% of pts, anaphylaxis in 47.8%, mediator related symptoms in 6.4%, osteoporosis/bone lesions in 5.2%, organomegaly in 3.4%, hematologic alterations in 0.4%. Anaphylaxis was observed in 76/252 (30.1%) pts with MIS, of which 23 had tryptase <20 mcg/L. BM multifocal infiltrates of MC were present in 61.6% of pts, while in 38.4% dg was performed only by using minor criteria. cKIT D816V mutation was detected in BM of 394/432 analysed pts (91.2%). Three D816V-negative pts had different cKIT mutations: M541L, D816H and K546K. In peripheral blood cKIT D816V was evaluated in 165 pts and found in 49.7%. CD2 and/or CD25 expressing MC were found in 99% of pts of the 426 evaluated. Mean tryptase value at dg was 75.9±263 mcg/L. SM subtypes were indolent SM (ISM) 402/455 (88.4%), of which 140 isolated bone marrow mastocytosis (BMM) (34.5% of ISM) and 34 smoldering SM (SSM) (8.4% of ISM), aggressive SM (ASM) 32/455 (7%), SM associated with hematological non mast cell disorders (SM-AHNMD) 20/455 (4.4%), mast cell leukemia (MCL) 1/455 (0.2%). In SM-AHNMD the associated hematologic disease was chronic myelomonocytic leukemia (6/20, 30%), non-Hodgkin lymphoma and refractory anemia with ring sideroblasts and thrombocytosis (3/20 each, 15%), essential thrombocythemia and not otherwise characterized myeloproliferative neoplasm (2/20 each, 10%), myelodysplastic syndrome, myelofibrosis, multiple myeloma and acute myeloid leukemia (AML) (1/20 each, 5%). Median follow up was 23 months (mo), range 2-289. At last follow up, 27/455 pts died (5.9%). 52% of pts had ASM, 18.5% SM-AHNMD, 14.7% SSM, 7.4% ISM and 3.7% each MCL and BMM. Causes of death were disease progression in 21/27 pts (77.8%), other solid neoplasms in 3/27 (11.1%), arterial thrombosis in 2/27 (9.5%), cerebral haemorrhage in 1/27 (3.7%). Disease progression consisted in evolution to AML in 6 pts with ASM, 1 pts with SSM and 1 pts with SM-AHNMD; median time to progression to AML was 30 mo (range 13-149); 2 pts developed other AHNMD: chronic myeloid leukemia and myelofibrosis. 178/455 pts (39%) were treated with anti MC mediators therapies. Of the 60/455 (13%) treated with cytostatic therapy 47% had ASM, 12% SM-AHNMD, 2% MCL, 35% ISM of which 38% were SSM. The ISM cohort was treated mainly due to severe osteoporosis with vertebral fractures not C-findings or disease evolution. First line therapy was interferon (28.3%), hydroxyurea (20%), midostaurine (18.3%), imatinib (13.3%), cladribin (8.3%), dasatinib (6.7%) and masitinib (5%). This is one of the largest series reporting pts with SM that may provide useful information for clinical management of pts with this probably underestimated “rare” disease. Disclosures Martinelli: Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau; Pfizer: Consultancy; ARIAD: Consultancy.

scholarly journals Incidence and Prognosis of Clonal Hematopoiesis in patients with Chronic Idiopathic Neutropenia

Blood ◽  
2021 ◽  
Author(s):  
Grigorios Tsaknakis ◽  
Anna Galli ◽  
Stavros Papadakis ◽  
Peggy Mary Kanellou ◽  
Chiara Elena ◽  
...  
Keyword(s):  
Relative Risk ◽  
Somatic Mutations ◽  
Variant Allele Frequency ◽  
Total Group ◽  
Clonal Hematopoiesis ◽  
Diagnosis And Prognosis ◽  
Chronic Idiopathic Neutropenia ◽  
Generation Sequencing ◽  
Undetermined Significance

The incidence and prognosis of clonal hematopoiesis in patients with isolated neutropenia among patients with idiopathic cytopenia of undetermined significance (ICUS), known as ICUS-N or chronic idiopathic neutropenia (CIN) patients, is poorly defined. In the present study we sought to investigate the frequency and clinical significance of mutations of genes implicated in myeloid malignancies using next generation sequencing, in CIN patients (n=185) with a long follow-up. We found that 21/185 patients (11.35%) carried totally 25 somatic mutations in 6 genes with median variant allele frequency (VAF) 12.75%. The most frequently mutated genes were DNMT3A and TET2 involving more than 80% of patients followed by IDH1/2, SRSF2 and ZRSR2. The frequency of transformation to a myeloid malignancy was low in the total group of patients (5/185 patients; 2.70%). However, from the transformed patients four belonged to the clonal (4/21; 19.05%) and one to the non-clonal (1/164; 0.61%) group, indicating that the presence of mutation(s) confers a relative risk for transformation 31.24 (P = 0.0017). The VAF of the mutant clones in the transformed patients was higher than 10% in all cases and the genes most frequently associated with malignant transformation were the SRSF2 and IDH1. No significant differences were identified between clonal and non-clonal groups in the severity of neutropenia. Patients with clonal disease were older compared to non-clonal patients. These data contribute to the better understanding of the heterogeneous entities underlying ICUS and highlight the importance of the mutation analysis for the diagnosis and prognosis of patients with unexplained neutropenias.

scholarly journals Comprehensive Molecular Profiling of Idiopathic Erythrocytosis By Genetic Ancestry

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 945-945
Author(s):  
Caitlin O'Neill ◽  
Zarko Manojlovic ◽  
Ah-Reum Jeong ◽  
Yili Xu ◽  
Yuxin Jin ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Copy Number ◽  
Somatic Mutations ◽  
Chromatin Assembly ◽  
Whole Exome ◽  
Mutation Burden ◽  
History Of ◽  
Generation Sequencing ◽  
Idiopathic Erythrocytosis

Introduction: Idiopathic erythrocytosis (IE) is characterized by a persistently elevated hemoglobin, equivocal erythropoietin (EPO) levels, absence of janus kinase 2 (JAK2) mutations suggestive of polycythemia vera (PV) and no secondary cause. One study used a targeted 21 gene next-generation sequencing panel and identified novel variants in known erythrocytosis-related genes as well as novel genes associated with the oxygen-sensing pathway. However, expanded sequencing of blood and matched tissue samples in a large ethnically diverse group of IE patients has not been performed. Methods: All patients signed informed consent to participate in an observational study approved by the Institutional Review Board; they provide blood and buccal mucosa samples at study entry and at 24-month follow-up. Patients were enrolled if JAK2 testing and a complete work up for secondary causes was negative. They were required to have hemoglobin levels greater than 16 g/dL on two occasions or greater than 15 g/dL if undergoing phlebotomy. Our initial sequencing of 20 IE patients was performed utilizing high resolution whole-exome sequencing of circulating blood samples (disease) at a mean coverage of 390x and matched normal (buccal) samples at mean coverage of 300x. To stratify samples by genetic ancestry, we performed a population stratification principle component analysis (PCA) and STRUCTURE using Ancestry Informative Markers derived from 1K Genome Phase1_v3 Exome database. The primary in-silico analysis was performed on the baseline samples from treatment-naïve patients. The whole-exome data was generated in accordance to GATK's best practices with same filters applied as described by Exome Aggregation Consortium. The additional downstream in-silico paired analysis was performed using MutSig2.0 (Mutation Significance) algorithm to determine significant mutations and GISTIC (The Genomic Identification of Significant Targets in Cancer) to identify the significant copy number events, IPA (Ingenuity Pathway Analysis) to determine pathways along with other computational . Results: Median age at baseline was 52 years (range 35-71). Six patients (30%) were female and 14 (70%) were male. Median values and ranges for laboratory parameters at baseline were as follows: WBC 6.6 x 109/L (5-9.7), Hgb 17 g/dL (15.5-19.8), Plt 218 x 109/L (86-374), and EPO level 9.8 IU/L (2-14.3). Three patients had a personal history of malignancy, including 2 with lymphoma. Two patients had a family history of myeloid malignancy (chronic myeloid leukemia and PV). Our ancestry analysis of initial 20 patients with IE identified 6 patients with high European percent ancestry (EUR), 1 patient with high Asian percent ancestry (EAS) and 13 patients with high percent Ad Mixed ancestry (AMR). In our cohort, 60% (12/20) of patients had been also diagnosed with a liver disorder (11 with fatty liver, 1 with cirrhosis) that was not significantly different across populations. We identified, on average, 42 non-silent somatic mutations (not present in the buccal samples) in whole blood across our cohort with no statistical difference (p=0.671) in mutation burden between ancestry groups or between patients with and without liver disease. Age, gender, and ethnicity were not associated with mutation burden. Utilizing MutSig algorithm, we identified a novel candidate gene, CHAF1A, with high mutation prevalence of 30% in patients with IE. Further analysis of mutation landscape identified somatic nonsilent mutations in 25 known oncogenes which were present in at least 10% of patients. Our mutation signatures in IE identified a significant association with failure of double stranded DNA repair. Only one patient had a mutation in TET2. Further analysis of copy number indicated copy number loss in genes such as SETD3 and GSH associated with chromatin assembly which may suggest alterations in chromatin assembly and changes in the epigenome. Our analysis also identified a high number of 9p and 13q gains in patients with IE. Conclusion: In this study, we utilized high-resolution next generation sequencing in association with comprehensive clinical annotation to determine potential molecular drivers of IE in a multi-ethnic population. We identified somatic mutations in a subset of patients which may represent clonal hematopoiesis. Long term follow up of outcomes in this cohort may clarify the significance of these mutations in the pathogenesis of IE. Disclosures No relevant conflicts of interest to declare.

Next-Generation Sequencing of Matched Normal Blood Identifies Clonal Hematopoiesis in a Significant Subset of Solid Tumor Patients without Hematologic Malignancies

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2447-2447
Author(s):  
Catherine C. Coombs ◽  
Ahmet Zehir ◽  
Sean Devlin ◽  
Sumit Middha ◽  
Donavan Cheng ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Hematologic Malignancies ◽  
Normal Blood ◽  
Genomic Profiling ◽  
Hematologic Disease ◽  
Tumor Patients ◽  
Advisory Committees ◽  
Clonal Hematopoiesis ◽  
Generation Sequencing

Abstract Background: Recent genomic studies have identified somatic mutations in leukemia genes in asymptomatic individuals without known hematologic disease. These mutations lead to clonal expansion of hematopoietic cells, in the absence of clinically overt hematologic transformation. This entity is thought to be analogous to other precursor conditions such as monoclonal gammopathy of undetermined significance (MGUS) and monoclonal B-cell lymphocytosis (MBL); consistent with this notion, a subset of patients with clonal hematopoiesis can subsequently develop myeloid malignancies, including myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). However, the incidence of clonal hematopoiesis in patients with solid tumors has not been extensively studied. Moreover, most genomic profiling platforms used to identify somatic mutations in epithelial tumors use blood as the matched normal control, which may lead to the identification of clonal hematopoiesis in a subset of cancer patients. We therefore sought to assess for clonal hematopoiesis in patients with solid tumors seen at Memorial Sloan Kettering Cancer Center (MSKCC) who were profiled using paired tumor/blood sequencing which is primarily designed to identify tumor-specific mutations. Methods: The study population included patients at MSKCC who were consented on protocol NCT01775072, “Tumor genomic profiling in patients evaluated for targeted cancer therapy.” All patients had tumor and blood genomic profiling sequenced using the MSK-IMPACT hybridization capture-based next-generation sequencing assay, which encompasses all protein-coding exons of 410 cancer-associated genes. For assessment of the incidence and distribution of blood mutations, 3,964 patients consented were evaluated. Patients with known active hematologic malignancies at time of sequencing were excluded from analyses. For comparisons regarding clinical correlations, 2,146 patients were included for whom detailed chart review has been performed. We investigated for the presence of “hotspot” mutations, collected from COSMIC database (v71), in matched blood DNA. Mutations were scored as present in the normal blood if they were detected in more than 8 reads with a variant allele frequency (VAF) greater than 2% which was at least twice the VAF seen in tumor. For cases where at least one mutation exceeded these thresholds, we reduced the VAF threshold in blood to 1% to detect secondary events. Mutations where VAF in the normal blood and the tumor sample were both greater than 30% were excluded as likely germline events. Results: Clonal hematopoiesis was identified in 108/3,964 solid tumor patients who had paired tumor/blood sequencing (2.7% of all patients); 7 patients had 2 unique mutations. DNMT3A mutations were most frequent, occurring in 34% of patients with clonal hematopoiesis (Figure 1). 107/115 mutations (93%) were in known leukemia-associated genes. We collected and analyzed detailed clinical parameters for 2,146 patients, including 42 patients (2.0%) with clonal hematopoiesis. The mean age at the time of testing was 62.1 years in patients with clonal hematopoiesis and 57.2 years in patients without evidence of clonal hematopoiesis (p = 0.015). When comparing baseline blood parameters, there were no statistically significant differences between the two groups. 62% of patients with clonal hematopoiesis had previous radiation therapy compared to 45% of patients without clonal mutations in their blood (p = 0.046). There was no statistically significant difference in the proportion of patients who had received previous chemotherapy (71% of patients in each group). On prospective follow up of patients with clonal hematopoiesis, no patients have progressed to develop overt MDS or AML, though median follow up was limited (median 11.7 months, range 5.5-16.7 months). Conclusions: Clonal hematopoiesis in solid tumor patients without known hematologic disease is common and is associated with increasing age and prior radiation therapy. In our cohort, no patients with clonal hematopoiesis progressed to overt MDS or AML though follow up is limited. Ongoing prospective observation of these patients is imperative to determine the clinical impact of these mutations after ongoing exposure to cytotoxic therapy. Further data including updated clinical and genomic correlates will be presented. Reference: Cheng DT et al. J Mol Diagn 2015 May; 17(3): 251-64. Figure 1. Figure 1. Disclosures Hyman: Chugai Pharma: Consultancy; Biotherapeutics: Consultancy; Atara: Consultancy, Honoraria. Levine:Loxo Oncology: Membership on an entity's Board of Directors or advisory committees; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees; Foundation Medicine: Consultancy.

scholarly journals New risk model is able to identify patients with a low risk of progression in systemic sclerosis

RMD Open ◽  
2021 ◽  
Vol 7 (2) ◽  
pp. e001524
Author(s):  
Nina Marijn van Leeuwen ◽  
Marc Maurits ◽  
Sophie Liem ◽  
Jacopo Ciaffi ◽  
Nina Ajmone Marsan ◽  
...  
Keyword(s):  
Machine Learning ◽  
Systemic Sclerosis ◽  
High Risk ◽  
Disease Progression ◽  
Risk Model ◽  
Immunosuppressive Drugs ◽  
Low Risk ◽  
Expert Assessment ◽  
Risk Of Progression

ObjectivesTo develop a prediction model to guide annual assessment of systemic sclerosis (SSc) patients tailored in accordance to disease activity.MethodsA machine learning approach was used to develop a model that can identify patients without disease progression. SSc patients included in the prospective Leiden SSc cohort and fulfilling the ACR/EULAR 2013 criteria were included. Disease progression was defined as progression in ≥1 organ system, and/or start of immunosuppression or death. Using elastic-net-regularisation, and including 90 independent clinical variables (100% complete), we trained the model on 75% and validated it on 25% of the patients, optimising on negative predictive value (NPV) to minimise the likelihood of missing progression. Probability cutoffs were identified for low and high risk for disease progression by expert assessment.ResultsOf the 492 SSc patients (follow-up range: 2–10 years), disease progression during follow-up was observed in 52% (median time 4.9 years). Performance of the model in the test set showed an AUC-ROC of 0.66. Probability score cutoffs were defined: low risk for disease progression (<0.197, NPV:1.0; 29% of patients), intermediate risk (0.197–0.223, NPV:0.82; 27%) and high risk (>0.223, NPV:0.78; 44%). The relevant variables for the model were: previous use of cyclophosphamide or corticosteroids, start with immunosuppressive drugs, previous gastrointestinal progression, previous cardiovascular event, pulmonary arterial hypertension, modified Rodnan Skin Score, creatine kinase and diffusing capacity for carbon monoxide.ConclusionOur machine-learning-assisted model for progression enabled us to classify 29% of SSc patients as ‘low risk’. In this group, annual assessment programmes could be less extensive than indicated by international guidelines.

scholarly journals A longitudinal analysis of the progression from normal blood pressure to stage 2 hypertension: A 12-year Korean cohort

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Eun Sun Yu ◽  
Kwan Hong ◽  
Byung Chul Chun
Keyword(s):  
Blood Pressure ◽  
Health Insurance ◽  
American Heart Association ◽  
American Heart ◽  
Heart Association ◽  
Normal Blood ◽  
Normal Blood Pressure ◽  
The Mean ◽  
Stage 1

Abstract Background The study aimed to estimate the incidence of and period of progression to stage 2 hypertension from normal blood pressure. Methods We selected a total of 21,172 normotensive individuals between 2003 and 2004 from the National Health Insurance Service-Health Screening and followed them up until 2015. The criteria for blood pressure were based on the American College of Cardiology/American Heart Association 2017 guideline (normal BP: SBP < 120 and DBP < 80 mmHg, elevated BP: SBP 120–129 and DBP < 80 mmHg, stage 1 hypertension: SBP 130–139 or DBP 80–89 mmHg, stage 2 hypertension: SBP ≥140 or DBP ≥ 90 mmHg). We classified the participants into four courses (Course A: normal BP → elevated BP → stage 1 hypertension→ stage 2 hypertension, Course B: normal BP → elevated BP → stage 2 hypertension, Course C: normal BP → stage 1 hypertension → stage 2 hypertension, Course D: normal BP → stage 2 hypertension) according to their progression from normal blood pressure to stage 2 hypertension. Results During the median 12.23 years of follow-up period, 52.8% (n= 11,168) and 23.6% (n=5004) of the participants had stage 1 and stage 2 hypertension, respectively. In particular, over 60 years old had a 2.8-fold higher incidence of stage 2 hypertension than 40–49 years old. After the follow-up period, 77.5% (n=3879) of participants with stage 2 hypertension were found to be course C (n= 2378) and D (n=1501). After the follow-up period, 77.5% (n=3879) of participants with stage 2 hypertension were found to be course C (n= 2378) and D (n=1501). The mean years of progression from normal blood pressure to stage 2 hypertension were 8.7±2.6 years (course A), 6.1±2.9 years (course B), 7.5±2.8 years (course C) and 3.2±2.0 years, respectively. Conclusions This study found that the incidence of hypertension is associated with the progression at each stage. We suggest that the strategies necessary to prevent progression to stage 2 hypertension need to be set differently for each target course.

scholarly journals A case of hypereosinophilic syndrome with STAT5b N642H mutation

2021 ◽  
Vol 2021 (1) ◽  
Author(s):  
Feihong Ding ◽  
Chaoping Wu ◽  
Yun Li ◽  
Sudipto Mukherjee ◽  
Subha Ghosh ◽  
...  
Keyword(s):  
Complete Blood Count ◽  
Hypereosinophilic Syndrome ◽  
Organ Damage ◽  
Myeloid Neoplasm ◽  
Acute Eosinophilic Pneumonia ◽  
Myeloid Neoplasms ◽  
Somatic Signal ◽  
Generation Sequencing

ABSTRACT Hypereosinophilia is defined as persistent eosinophilia (&gt;1.5 × 109/L). Hypereosinophilic syndrome (HES) is a term used to describe a group of disorders characterized by sustained hypereosinophilia associated with end-organ damage. Based on underlying molecular mechanism of eosinophilia, there are different subtypes of HES. Diagnosis of HES subtype can be challenging, especially in the absence of overt lymphoid/myeloid neoplasms or discernable secondary causes. Long-term outpatient follow-up with periodic complete blood count and repeated bone marrow biopsy may be needed to monitor disease activity. Somatic signal transducer and activation transcription 5b (STAT5b) N642H mutation was recently found to be associated with myeloid neoplasms with eosinophilia. We report a case of HES who presented with pulmonary embolism and acute eosinophilic pneumonia, found to have recurrent STAT5b N642H mutation by next-generation sequencing, suggesting possible underlying myeloid neoplasm.

scholarly journals Chronic kidney disease progression among patients with type 2 diabetes identified in US administrative claims: a population cohort study

2020 ◽  
Author(s):  
Csaba P Kovesdy ◽  
Danielle Isaman ◽  
Natalia Petruski-Ivleva ◽  
Linda Fried ◽  
Michael Blankenburg ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Chronic Kidney Disease ◽  
Cohort Study ◽  
Kidney Disease ◽  
Disease Progression ◽  
Administrative Claims ◽  
Short Period ◽  
Ckd Stage

Abstract Background Chronic kidney disease (CKD), one of the most common complications of type 2 diabetes (T2D), is associated with poor health outcomes and high healthcare expenditures. As the CKD population increases, a better understanding of the prevalence and progression of CKD is critical. However, few contemporary studies have explored the progression of CKD relative to its onset in T2D patients using established markers derived from real-world care settings. Methods This retrospective, population-based cohort study assessed CKD progression among adults with T2D and with newly recognized CKD identified from US administrative claims data between 1 January 2008 and 30 September 2018. Included were patients with T2D and laboratory evidence of CKD as indicated by the established estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (UACR) criteria. Disease progression was described as transitions across the eGFR- and UACR-based stages. Results A total of 65 731 and 23 035 patients with T2D contributed to the analysis of eGFR- and UACR-based CKD stage progression, respectively. CKD worsening was observed in approximately 10–17% of patients over a median follow-up of 2 years. Approximately one-third of patients experienced an increase in eGFR values or a decrease in UACR values during follow-up. Conclusions A relatively high proportion of patients were observed with disease progression over a short period of time, highlighting the need for better identification of patients at risk of rapidly progressive CKD. Future studies are needed to determine the clinical characteristics of these patients to inform earlier diagnostic and therapeutic interventions aimed at slowing disease progression.

Sign in / Sign up

Export Citation Format

Share Document