scholarly journals Spleen Stiffness By Magnetic Resonance Elastography or Ultrasound Elastography As a Surrogate Marker of Bone Marrow Fibrosis in Myelofibrosis Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4619-4619
Author(s):  
Laura Coutinho Vassalli ◽  
Alex Freire Sandes ◽  
Angela Hissae Motoyama Caiado ◽  
Giuseppe D`Ippolito ◽  
Alberto Lobo Machado ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Magnetic Resonance ◽  
Myeloproliferative Neoplasms ◽  
Prognostic Score ◽  
Liver Stiffness ◽  
Magnetic Resonance Elastography ◽  
Ultrasound Elastography ◽  
Prognostic Scores ◽  
Bone Marrow Fibrosis ◽  
Marrow Fibrosis

Abstract Introduction Primary myelofibrosis (PM) is a myeloproliferative neoplasm characterised by bone marrow fibrosis and extramedullary hematopoiesis. Both clinical findings and laboratory parameters are used for prognostic scores in Myelofibrosis patients. In addition, the degree of bone marrow fibrosis has an important prognostic value and has correlation with overall survival. Recently, bone marrow fibrosis was correlated with degree of splenic stiffness (SS) measured by imaging elastography techniques. 1,2 Despite these findings, there were patients with insignificant measures that could not be classified according to marrow fibrosis. In order to advance knowledge in this field, we studied splenic and hepatic stiffness (HS) in patients with myelofibrosis using elastography by two methods, ultrasonography (EUS) and magnetic resonance elastography (MRE), and its correlation with prognostic scores and bone marrow fibrosis. Study Design and Methods This is a prospective, cross-sectional, observational study in patients from the outpatient clinic for myeloproliferative neoplasms who had given informed consent according to procedures approved by institution´s ethical committee. Patients with PM, as well as post-essential thrombocythemia (ET) or post-polycythemia vera (PV) myelofibrosis, were included in this study. Myelofibrosis patients with diagnosis of other associated pathologies that may alter SS, as portal hypertension or cirrhosis, were excluded from the study. Patients were assessed for splenic stiffness measured by ultrasound conducted by two examiners, with more than 10 years of experience. EUS was performed in US Epiq 7 equipment - Philips - with ARFI elastometry methodology. The SS measurements was reported in m/s. In addition, they were also evaluated for splenic and liver stiffness by MRI technique. All exams were performed in 1.5 T MR equipment (Magneton Aera, Siemens Healthineers, Erlangen, Germany) and the MRI protocol included T2-weighted and gradient-echo MRE sequences using steady-state 60-Hz excitation and an external driver placed on the right side and, on the left side of the abdomen. The measures of SS were also obtained by two experienced examiners Results At this moment we present the results of 16 patients with myelofibrosis (PM: 8 cases; post-PV myelofibrosis: 2 cases; post-ET myelofibrosis: 6 cases). The median age was 69y (41-88y) and 62,5% of participants were male. The JAK2 V617F mutation was detected in 9 cases; three cases were CALR positive, and three cases were triple negative. The CBC showed: Hb: 10.9 g/dL (6.5-18.7); WBC (x10 9/L): 9.17 (1.8-44.5) and platelets (x10 9/L): 393 (10-957). Our preliminary results show that bone marrow fibrosis increased according to splenic stiffness by EUS and MRE (Figure 1a; table 1). Patients with osteosclerosis also presented a higher SS by MRE (Figure 1b). We could not find correlation of splenic stiffness with prognostic score DIPSS plus, although Int-2/High risk patients presented a trend to be associated with higher liver stiffness. Conclusion To the moment, our preliminary findings suggest a correlation between SS and degree of bone marrow fibrosis and osteosclerosis, though the correlation between both measures and prognostic scores is still to be determined. We expect to have a better definition for all correlations, as we progress through the assessment of the other patients in our service. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Alterations In Wnt Signalling In the Megakaryocytic Lineage Leads to Bone Marrow Failure and Myelofibrosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 628-628
Author(s):  
Simon D Calaminus ◽  
Gareth Inman ◽  
Cedric Ghaevert ◽  
Owen Sansom ◽  
Steve P Watson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Wnt Pathway ◽  
Bone Marrow Failure ◽  
Prognostic Score ◽  
Fold Increase ◽  
Wnt Signalling ◽  
Beta Catenin ◽  
Bone Marrow Fibrosis ◽  
Platelet Factor ◽  
Marrow Fibrosis

Abstract Abstract 628 Introduction: Wnt signalling is fundamental in controlling stem cell self-renewal, cell proliferation and development in multicellular organisms. Stabilization of beta catenin or loss of the scaffold protein adenomatis polyposis coli (APC) causes aberrant activation of wnt signalling and often leads to cancer. Mutations to wnt pathway members in haematopoietic stem cells leads to haematopoietic failure and rapid lethality. In this study, we demonstrate that aberrant wnt signalling in the megakaryocyte lineage underlies myelofibrosis. Methods: We created a series of mice with altered wnt pathway signalling in their megakaryocytic lineage using PF4-Cre (platelet factor 4 cre) as follows: Ctnnb1fx(ex3)/wt_ Expresses stabilized active beta catenin henceforth termed PF4bcat+; APCfx/fx_ Loss of APC stabilises beta catenin termed PF4APC-KO; Ctnnb1fx/fx b-catenin knockout termed PF4bcat-KO. Results: By day 40, PF4bcat+ and PF4APC-KO mice are severely underweight, anaemic (wt 6.8+0.2×106/ml v. PF4bcat+ 4.2+0.3×106/ml, PF4APC-KO 5.5+0.5×106/ml), and have a significant reduction in platelet number (wt 1033+37×106/ml v. PF4bcat+ 717+57×106/ml, PF4APC-KO 747+68×106/ml). Furthermore PF4bcat+ and PF4APC-KO mice develop bone marrow fibrosis and consistently die within 50 days of birth. Both populations of mice have splenic extramedullary haemopoiesis with hyperplasia of splenic megakaryocytes, leading to a dramatic increase in spleen to body size ratio. In addition, both PF4bcat+ and PF4APC-KO mice have increased peripheral blood levels of active TGFb, providing a likely molecular basis of the induction in bone marrow fibrosis. PF4APC-KO and PF4bcat+ mutant mice show a dramatic (>10-fold) increase in platelet b-catenin protein levels over wt samples. By comparison, human myelofibrosis patients (n=16) show a 2.7+0.6-fold increase in platelet b-catenin expression over controls. Moreover, overexpression of b-catenin within human patient samples is correlated with a worsening Primary Myelofibrosis prognostic score (Blood, 2009 vol 113 p. 2895), with those patients with a low score (n=7) having a 1.3+/−0.37-fold increase over control, intermediate score (n=4) 4.52+/−1.23-fold, and high score (n=1) 4.56-fold. In contrast PF4bcat-KO mice show no changes in whole blood counts, weight, or evidence of splenic extramedullary haematopoiesis, indicating that b-catenin removal does not adversely affect megakaryocyte development or function. Conclusions: Stabilisation of b-catenin within mouse megakaryocytes leads to a myelodysplastic disorder and myelofibrosis. This finding demonstrates a defined role for aberrant activation of the wnt signalling pathway and marks the wnt pathway and the megakaryocyte lineage as important potential drug targets for the treatment of myelodysplastic disorders. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The implication of identifying JAK2 V617F in myeloproliferative neoplasms and myelodysplastic syndromes with bone marrow fibrosis

2008 ◽  
Vol 1 (2) ◽  
pp. 111-117 ◽  
Author(s):  
Randall J. Olsen ◽  
Cherie H. Dunphy ◽  
Dennis P. O’Malley ◽  
Lawrence Rice ◽  
April A. Ewton ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Myelodysplastic Syndromes ◽  
Myeloproliferative Neoplasms ◽  
Jak2 V617f ◽  
Bone Marrow Fibrosis ◽  
Marrow Fibrosis

Bone Marrow Fibrosis in Chronic Idiopathic Myelofibrosis Is Associated with Megakaryocyte Expression of Osteoprotegerin.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4955-4955
Author(s):  
Piotr Centkowski ◽  
Joanna Sawczuk-Chabin ◽  
Monika Prochorec-Sobieszek ◽  
Joanna Dobrzanska ◽  
Ilona Seferynska ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Staining Technique ◽  
Serum Levels ◽  
Osteoclast Formation ◽  
Prognostic Scores ◽  
Neoplastic Disease ◽  
Idiopathic Myelofibrosis ◽  
Bone Marrow Fibrosis ◽  
Marrow Fibrosis ◽  
Chronic Idiopathic Myelofibrosis

Abstract A feature that distinguishes chronic idiopathic myelofibrosis (CIM) from other chronic myeloproliferative disorders is the progression to bone marrow fibrosis and osteosclerosis. Because osteoclast formation can be inhibited by osteoprotegerin (OPG), we investigated its megakaryocytes’ expression and serum concentration in patients (pts) with CIM (n=20, median age 64 years, range 46–81) and in 20 controls showing no evidence of neoplastic disease (median age 62 years, range 46–82). The study group comprised 10 pts with prefibrotic cellular CIM and 10 with severe fibrosis. Assessment of OPG concentration in serum was performed using Osteoprotegerin ELISA Kit (Biomedica, Austria). EnVision (DAKO) kit with monoclonal anti-human osteoprotegerin/TNFRSF11B antibody - MAB8051 (R&D Systems, USA) was used to evaluate OPG expression in megakaryocytes. Gomori silver staining technique was applied for semi-quantitative assessment of bone marrow fibrosis according to increased amount of reticulin fibers. OPG serum levels in pts with CIM were significantly higher than in controls (105.78 vs 85.14 pg/ml, p=0.02), and showed positive correlation with age in both groups (r=0.61, p=0.0037 and r=0.55, p=0.012, respectively). Serum levels of OPG in pts with CIM patients were not associated with erythrocyte, leukocyte, platelet numbers and with the Visani, Lille or Cervantes prognostic scores. There was no correlation between serum levels of OPG and its expression in megakaryocytes in pts and controls. In megakaryocytes derived from patients with CIM as well as from controls, OPG expression was detected, but in those derived from CIM hematopoiesis (at any stage of the disease) were significantly higher. OPG expression in megakaryocytes derived from prefibrotic CIM was significantly lower than from advanced stages of the disease (p=0.007). We conclude that OPG appears to be involved in bone marrow fibrosis in CIM through overexpression by megakariocyte.

scholarly journals Nonfamilial,MPLS505N-Mutated Essential Thrombocythaemia

2013 ◽  
Vol 2013 ◽  
pp. 1-4 ◽  
Author(s):  
Ruth Morrell ◽  
Stephen E. Langabeer ◽  
Liam Smyth ◽  
Meegahage Perera ◽  
Gerard Crotty
Keyword(s):  
Bone Marrow ◽  
Clinical Features ◽  
Clinical Course ◽  
Myeloproliferative Neoplasms ◽  
Significant Proportion ◽  
Essential Thrombocythaemia ◽  
Bone Marrow Fibrosis ◽  
Thrombotic Risk ◽  
Exon 10 ◽  
Marrow Fibrosis

Mutations ofMPLare present in a significant proportion of patients with the myeloproliferative neoplasms (MPN), primary myelofibrosis (PMF), and essential thrombocythaemia (ET). The most frequent of these mutations, W515L and W515K, occur in exon 10 ofMPL, which encodes the receptor for thrombopoietin. Another exon 10 mutation,MPLS505N, has been shown to be a founder mutation in several pedigrees with familial thrombocythaemia where it is associated with a high thrombotic risk, splenomegaly and progression to bone marrow fibrosis. Rare cases of sporadic, nonfamilial,MPLS505N MPN have been documented, but the presenting laboratory and clinical features have not been described in detail. The diagnosis and clinical course of a case ofMPLS505N-positive MPN are presented with diagnostic features and treatment response resembling typical ET but with evidence of increasing bone marrow fibrosis. Further MPN cases possessing this genotype require reporting in order to ascertain whether any particular morphological or clinical features, if present, determine clinical course and aid the refinement of therapeutic options.

scholarly journals Spleen Stiffness Measurement By Transient Elastography As a Predictor of Bone Marrow Fibrosis in Primary Myelofibrosis Patients

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1825-1825
Author(s):  
Alessandra Iurlo ◽  
Daniele Cattaneo ◽  
Mariangela Giunta ◽  
Umberto Gianelli ◽  
Giovanni Casazza ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Portal Hypertension ◽  
Liver Disease ◽  
Transient Elastography ◽  
Liver Stiffness ◽  
Primary Myelofibrosis ◽  
Bone Marrow Fibrosis ◽  
Predicted Probability ◽  
Spleen Stiffness ◽  
Marrow Fibrosis

Abstract Introduction: transient elastography (TE) is a standardized, non-invasive tool which predicts severity of chronic liver disease (CLD). Owing to the known relationships between liver fibrosis, portal hypertension and splenomegaly, the measurement of spleen stiffness (SS) has been evaluated as an alternative and/or complementary method to liver stiffness (LS) in order to evaluate liver disease severity. In particular, a significant correlation between SS and portal hypertension has been established with hemodynamic measurements, demonstrating that SS accurately predicts the risk of both esophageal varices and clinical decompensation in patients with viral cirrhosis. Recently, we conducted a study in CLD patients with the aim to assess the diagnostic accuracy of combined LS and SS in the prediction of liver fibrosis and portal hypertension; it also included 64 healthy volunteers and 48 patients with a previous diagnosis of hematological malignancies as control population. Among the few hematological patients enrolled in that study, a significant correlation between SS and bone marrow fibrosis grade (p<0.01) was found and it was more pronounced in the 23 primary myelofibrosis (PMF) patients than in those with other hematological neoplasms. Methods: to validate further these preliminary observations, we enrolled 108 patients with a clinical and histological diagnosis of PMF based on WHO 2008 criteria. All patients concurrently underwent liver and spleen TE, in conjunction with a bone marrow biopsy, ultrasound evaluation of spleen size and chemistries. Once we found normal LS values granted for the absence of liver disease potentially interfering with SS assessments, according to the updated WHO classification, we considered only two main bone marrow fibrosis categories defined as follows: pre-fibrotic/early fibrotic (MF-0/1) and advanced fibrotic stage (MF-2/3). Results: transient elastography of the liver and spleen was successfully performed in 88 PMF patients (81.5%), whereas 20 (18.5%) had indeterminate spleen-TE results; however, this rate of spleen-TE failure is similar to that reported by previous studies in CLD patients (15 to 20% of all cases). The median liver-TE and spleen-TE values were 7.1 kPa (range 3.5-19.6) and 40.1 kPa (range 11.8–75.0), respectively. In a univariate analysis both spleen (p<.0001) and liver stiffness (p=.0074) correlated with the severity of bone marrow fibrosis, whereas age, gender and the PMF prognostic scoring systems IPSS, DIPSS and DIPSS-plus did not. Furthermore, bone marrow fibrosis did not correlate with the presence of JAK2 V617F or CALR mutations, whereas it did with Hb (p=0.0001), LDH (p<.0001) and peripheral blood CD34-positive cells count (p=0.0003). At multivariate analysis, only SS, LDH and CD34-positive cells count maintained a significant correlation with bone marrow fibrosis, with a discriminative ability assessed by the c statistic of 0.904 (95% CI, 0.841-0.967). According to these results, we were able to propose an equation for the estimation of the probability of being MF-2/3, arranged as follows: probability MF-2/3= exp[-4.83+0.0380*SS+0.0039*LDH+0.0148*CD34]/[1+exp(-4.83+0.0380*SS+0.0039*LDH+0.0148*CD34)]. The model entails two decisional threshold values that predict the probability of diagnosing PMF severity: the best cut-off for the diagnosis of MF-0/1 was 0.15 (negative predictive value=0.97) and the best cut-off for the diagnosis of MF-2/3 was 0.73 (positive predictive value=0.94), with an accuracy of 97% for the former and 94% for the latter. Figure 1 describes the two decisional thresholds and the distribution of our patients in the MF-0/1 and MF-2/3 categories. Conclusions: to our knowledge, this study represents the first attempt to evaluate the entity of SS in PMF patients as a measure of disease severity. Furthermore, our results allow us to suggest the use of SS as a surrogate marker of bone marrow fibrosis, particularly following the fibrogenetic progression of the disease, especially when it is considered together with such routine chemistries as LDH and CD34-positive cells count, a finding that may limit the need for an invasive and more expensive procedure like bone marrow biopsy in the management of PMF patients. Figure 1 Patients’ distribution in the two main bone marrow fibrosis categories according to the predicted probability cut-off values Figure 1. Patients’ distribution in the two main bone marrow fibrosis categories according to the predicted probability cut-off values Disclosures No relevant conflicts of interest to declare.

scholarly journals CXCL8/CXCR2 signaling mediates bone marrow fibrosis and represents a therapeutic target in myelofibrosis

2021 ◽  
Author(s):  
Andrew Dunbar ◽  
Dongjoo Kim ◽  
Min Lu ◽  
Mirko Farina ◽  
Julie L. Yang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Human Cancer ◽  
Myeloproliferative Neoplasms ◽  
Critical Role ◽  
Transfer Model ◽  
Inflammatory Signaling ◽  
Bone Marrow Fibrosis ◽  
Hematopoietic Stem ◽  
Disease Evolution ◽  
Marrow Fibrosis

Pro-inflammatory signaling is a hallmark feature of human cancer, including in myeloproliferative neoplasms (MPNs), most notably myelofibrosis (MF). Dysregulated inflammatory signaling contributes to fibrotic progression in MF; however, the individual cytokine mediators elicited by malignant MPN cells to promote collagen-producing fibrosis and disease evolution remain yet to be fully elucidated. Previously we identified a critical role for combined constitutive JAK/STAT and aberrant NF-kB pro-inflammatory signaling in myelofibrosis development. Using single-cell transcriptional and cytokine-secretion studies of primary MF patient cells and two separate murine models of myelofibrosis, we extend this previous work and delineate the role of CXCL8/CXCR2 signaling in MF pathogenesis and bone marrow fibrosis progression. MF patient hematopoietic stem/progenitor cells are enriched in a CXCL8/CXCR2 gene signature and display dose- dependent proliferation and fitness in response to exogenous CXCL8 ligand in vitro. Genetic deletion of Cxcr2 in the hMPLW515L adoptive transfer model abrogates fibrosis and extends overall survival, and pharmacologic inhibition of the CXCR1/2 pathway improves hematologic parameters, attenuates bone marrow fibrosis, and synergizes with JAK inhibitor therapy. Our mechanistic insights provide a rationale for therapeutic targeting of the CXCL8/CXCR2 pathway in MF patients at risk for continued fibrotic progression.

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