Analysis of JAK2V617F and MPLW515L/K Mutation in 30 Patients with Early Stage Myeloproliferative Disease

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5230-5230
Author(s):  
Ri Zhang ◽  
Zhen Fan ◽  
Xuhui Zhang ◽  
Hairong Fei
Keyword(s):  
Polycythemia Vera ◽  
Mononuclear Cells ◽  
Early Stage ◽  
Statistical Significance ◽  
Myeloproliferative Disorders ◽  
Jak2v617f Mutation ◽  
High Rate ◽  
Myeloproliferative Disease ◽  
History Of ◽  
Almost All

Abstract The classic Bcr-Abl negative myeloproliferative disorders (MPDs) comprise polycythemia vera (PV), essential thrombocythemia (ET), and idiopathic myelofibrosis (IMF). They are considered clonal stem cell disorders. Recently two acquired somatic mutations JAK2V617F and MPLW515L/K have been identified to play an important role in pathogenisis of MPDs. JAK2V617F was detected in almost all PV and nearly 50% in ET and IMF, and the MPLW515L/K mutation occured in only 1% and 4% in ET and IMF respectively. However it is interesting that there are some patients with slightly increased blood cells did not meet the criteria of PV and ET clinically. These early prefibrotic stages of MPDs are overlooked by both the Polycythemia Vera Study Group (PVSG) and the 2001 WHO criteria for the diagnosis of PV, ET and IMF. In order to investigate the prevalence of JAK2V617F and MPLW515L/K mutation in patients with early MPDs without a secondary cause, genomic DNA from bone marrow or blood mononuclear cells of 30 patients with early MPDs was screened by allele specific polymerase chain reaction (AS-PCR) for JAK2V617F and MPLW515L/K mutations and the history of thrombosis was assessed retrospectively by using patient files. Results showed that 14 out of 30 patients (46.7%) were positive for the JAK2V617F mutation, and none of them had the MPLW515L/K. Of the 14 patients with JAK2V617F mutation, a history of thrombosis was comfirmed in 5 patients(35.7%), while none of 16 patients with WT JAK2 had the thrombosis history. The average age of patients with the JAK2V617F mutation exceeded the patients with wild type JAK2(P<0.05), whereas there is no statistical significance on sexual Athe counts of white cell and the occurance of complications (thrombosis) between the patients with and without the JAK2V617F mutation. All the patients have been followed up since onset and 22 patients have available results. Among them, 12 patients with the burden of JAK2V617F turned out to be MPDs, however only 1 out of 10 patients without this mutation also evolved to MPDs. Our results suggest that JAK2V617F mutation can occur in a certain percentage of these early stage of MPDs patients and has help to diagnose early MPDs. Because these patients might have a high rate of complications, proper treatment of the MPD including aspirin and/or cytoreductive therapy is recommended in latent MPDs patients associated with the JAK2V617F mutation.

Radiological manifestations of metastasis to the ovary

2012 ◽  
Vol 65 (7) ◽  
pp. 585-590 ◽  
Author(s):  
Fredric Willmott ◽  
Kader Abdel Allouni ◽  
Andrea Rockall
Keyword(s):  
Ovarian Cancer ◽  
Metastatic Disease ◽  
Early Stage ◽  
Primary Tumour ◽  
High Rate ◽  
Primary Cancer ◽  
Primary Ovarian Cancer ◽  
Radiological Features ◽  
History Of ◽  
Ovarian Lesion

MRI is an effective tool for detection of ovarian neoplastic lesions. However, there are no highly specific radiological features that differentiate primary from metastatic ovarian masses. Histological diagnosis preoperatively is not always possible as there is a risk of disseminating an otherwise early stage primary ovarian cancer. The preoperative diagnosis of an ovarian lesion is therefore heavily dependent on the radiological features. The radiologist must rely on a combination of knowing the natural history of any known primary cancer, together with the radiological features such as bilaterality, mucinous appearance, pseudomyxoma as well as the clinical progress of the primary tumour in order to evaluate and predict the likelihood of metastatic disease. Even if a non-ovarian primary cancer is known, an ovarian mass cannot always be assumed to be a secondary lesion. Some tumours, such as BRAC-positive breast cancer, are known to have a high rate of concomitant primary ovarian cancer. Conversely, other tumours, such as gastric and appendiceal cancer, are known to have a high rate of ovarian metastatic disease. However, histology remains the only true way to determine an ovarian metastasis from a primary lesion.

scholarly journals Revisiting comorbidities in gout: a cluster analysis

2013 ◽  
Vol 74 (1) ◽  
pp. 142-147 ◽  
Author(s):  
Pascal Richette ◽  
Pierre Clerson ◽  
Laure Périssin ◽  
René-Marc Flipo ◽  
Thomas Bardin
Keyword(s):  
Cluster Analysis ◽  
Renal Failure ◽  
Large Cohort ◽  
High Rate ◽  
Cross Sectional ◽  
High Prevalence ◽  
History Of ◽  
Obesity Hypertension ◽  
Almost All

ObjectivesThe reciprocal links between comorbidities and gout are complex. We used cluster analysis to attempt to identify different phenotypes on the basis of comorbidities in a large cohort of patients with gout.MethodsThis was a cross-sectional multicentre study of 2763 gout patients conducted from November 2010 to May 2011. Cluster analysis was conducted separately for variables and for observations in patients, measuring proximity between variables and identifying homogeneous subgroups of patients. Variables used in both analyses were hypertension, obesity, diabetes, dyslipidaemia, heart failure, coronary heart disease, renal failure, liver disorders and cancer.ResultsComorbidities were common in this large cohort of patients with gout. Abdominal obesity, hypertension, metabolic syndrome and dyslipidaemia increased with gout duration, even after adjustment for age and sex. Five clusters (C1–C5) were found. Cluster C1 (n=332, 12%) consisted of patients with isolated gout and few comorbidities. In C2 (n=483, 17%), all patients were obese, with a high prevalence of hypertension. C3 (n=664, 24%) had the greatest proportion of patients with type 2 diabetes (75%). In C4 (n=782, 28%), almost all patients presented with dyslipidaemia (98%). Finally, C5 (n=502, 18%) consisted of almost all patients with a history of cardiovascular disease and renal failure, with a high rate of patients receiving diuretics.ConclusionsCluster analysis of comorbidities in gout allowed us to identify five different clinical phenotypes, which may reflect different pathophysiological processes in gout.

scholarly journals Increased circulating neutrophils with surface receptor activity for immunoglobulin G in polycythemia vera and myeloid metaplasia

Blood ◽  
1979 ◽  
Vol 53 (6) ◽  
pp. 1106-1113 ◽  
Author(s):  
HS Gilbert ◽  
R Goldberg ◽  
L Ward
Keyword(s):  
Polycythemia Vera ◽  
High Titer ◽  
Myeloproliferative Disorders ◽  
Normal Subjects ◽  
Receptor Activity ◽  
Myeloproliferative Disease ◽  
Myeloid Metaplasia ◽  
Activated State ◽  
Surface Receptor ◽  
Igg Receptors

Abstract Reports of heterogeneity of IgG receptor activity of normal circulating neutrophils prompted measurements in myeloproliferative disease to determine if dysplasia of the hematic stem cell resulted in an abnormality of this membrane property. IgG receptors were assayed by rosette formation in suspension with human Rh-positive erythrocytes sensitized with high-titer Rh antiserum. IgG receptors were detected on 19 +/- 1.6% (mean +/- SEM) of neutrophils from 45 normal subjects. A significant increase in IgG-receptor-bearing neutrophils was found in polycythemia vera (PV) and myeloid metaplasia (MyM), with values of 70 +/- 3.6% and 69.7 +/- 4.3%, respectively. Normal values were observed in polycythemic states not due to myeloproliferative disease and in chronic myelocytic leukemia. Rosette-forming neutrophils were increased to 52.3 +/- 3.7% in infection and inflammatory disease, but this value was significantly lower than those in PV and MyM. Increased IgG receptors in PV and MyM may be related to the activated state of the neutrophil and may result from an intrinsic cellular abnormality of the proliferating clone or from altered bone marrow release. Quantitation of neutrophil IgG receptors may be of value in the differential diagnosis of PV and MyM and may offer insights into the derangement of hematopoiesis that underlies these myeloproliferative disorders.

scholarly journals The Philadelphia Chromosome in an Unusual Case of Myeloproliferative Disease

Blood ◽  
1965 ◽  
Vol 26 (4) ◽  
pp. 471-478 ◽  
Author(s):  
CLARK W. HEATH ◽  
WILLIAM C. MOLONEY
Keyword(s):  
Ankylosing Spondylitis ◽  
Direct Relationship ◽  
Unusual Case ◽  
Philadelphia Chromosome ◽  
Myeloproliferative Disorders ◽  
Clinical Findings ◽  
Myeloproliferative Disease ◽  
Diagnostic Significance ◽  
History Of

Abstract In an unusual case of myeloproliferative disease, the Ph1 chromosome was found in association with persistently elevated levels of LAP activity. Clinical findings in this case included marked thrombocytosis, basophilocytosis, absence of splenomegaly and a preceding history of untreated ankylosing spondylitis. Cytogenetic findings were compatible with the existence of the Ph1 chromosome in erythroid and megakaryocytic as well as granulocytic marrow precursors. This case illustrates the difficulties currently encountered in the clinical differentiation of myeloproliferative disorders and in interpreting the diagnostic significance of the Ph1 chromosome. The co-existence in this case of the Ph1 chromosome and elevated LAP does not support the concept of a direct relationship between Group G chromosomes and LAP activity.

Relationship between JAK2 V617F Mutation Status, Granulocyte CD177 mRNA Expression and CD177 Soluble Protein Level in Patients with Polycythemia Vera.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2578-2578
Author(s):  
Daniela Pietra ◽  
Alessandra Balduini ◽  
Carmela Marseglia ◽  
Matteo G. Della Porta ◽  
Luca Malcovati ◽  
...  
Keyword(s):  
Mrna Expression ◽  
Polycythemia Vera ◽  
Protein Level ◽  
Mononuclear Cells ◽  
Jak2 V617f ◽  
Myeloproliferative Disorders ◽  
Jak2 V617f Mutation ◽  
Serum Samples ◽  
Close Relationship ◽  
V617f Mutation

Abstract A unique gain-of-function mutation of the Janus kinase 2 (JAK2) gene has been recently described in patients with polycythemia vera (PV), essential thrombocythemia and chronic idiopathic myelofibrosis [N Engl J Med. 2005 Apr 28;352(17):1779–90]. Although the currently available data clearly demonstrate that the JAK2 V617F mutation participates in the pathogenesis of myeloproliferative disorders, the mutation’s precise place in the hierarchical order of pathogenetic events remains to be established. We have recently reported that altered gene expression in myeloproliferative disorders correlates with activation of signaling by the V617F mutation of JAK2 (Blood. 2005 Aug 4; Epub ahead of print). Granulocyte CD177 (PRV1) mRNA overexpression has been initially reported as a potential marker of PV but later shown by us to rather be a marker of neutrophil activation [Br J Haematol. 2004 Sep;126(5):650–6]. In this study, we analyzed the relationship between JAK2 V617F mutation status, granulocyte CD177 mRNA expression and CD177 soluble protein level in 72 patients with PV. We also investigated the ontogeny of CD177 expression by hematopoietic cells with the aim of defining the stage of mRNA expression during myeloid, erythroid and megakaryocytic cell differentiation. Finally we studied the effect of soluble CD177 protein on hematopoietic cell proliferation and differentiation. Granulocyte CD177 mRNA expression and percentage of JAK2 V617F alleles were evaluated by quantitative Real Time PCR (qRT-PCR), while serum CD177 protein level was measured by a flow cytometry-based competitive antibody-binding assay. Liquid cultures were performed by culturing peripheral blood mononuclear cells obtained from healthy individuals and PV patients in the presence of high CD177-expressing, low CD177-expressing or CD177-depleted sera. After 12 days of culture, cells were collected, counted and evaluated for colony growth, and for flow cytometry analysis of myeloid, erythroid, megakaryocytic and CD34-positive cell subpopulations. qRT-PCR studies showed a close relationship between CD177 mRNA level and percentage of JAK2 V617F alleles (r=0.412, P<0.001). CD177 mRNA expression was almost undetectable in cell populations other than granulocytes. Studies of CFU-GM growth and differentiation indicated that CD177 mRNA expression is a late event restricted to the neutrophil stage of differentiation. Analysis of serum samples showed variable values for mean fluorescence intensity (MFI), indicating variable levels of the soluble CD177 protein in the patients studied. A very close relationship was found between granulocyte CD177 mRNA expression and soluble CD177 protein level (r=0.56, P=0.02). Incubation of mononuclear cells with serum samples showing high levels of soluble CD177 protein resulted in increased numbers of CD34-positive cells (P<0.02) and of erythroid progenitors (P<0.03). This effect was not detectable when low CD177-expressing or CD177-depleted sera were employed. These observations clearly indicate that the JAK2 V617F mutation is associated with enhanced granulocyte CD177 mRNA expression, and that this latter results in high levels of soluble CD177 protein. These elevated levels might contribute to the increased red cell production that characterizes polycythemia vera.

Erythropoiesis in Polycythemia Vera Is Hyper-Proliferative and Has Accelerated Differentiation during In Vitro Erythroid Expansion and Is Associated with Higher Expressions of cMYB and EPOR at Early Erythroid Progenitors

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1549-1549
Author(s):  
Hana Bruchova ◽  
Donghoon Yoon ◽  
Archana Agarwal ◽  
Eva Otahalova ◽  
Hyojin Kim ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Mononuclear Cells ◽  
Early Stage ◽  
Severe Disease ◽  
Erythroid Differentiation ◽  
Erythroid Progenitors ◽  
Peripheral Blood Mononuclear ◽  
Healthy Donors ◽  
Differentiation Stage

Abstract Erythroid differentiation is a dynamic process leading to the production of mature red blood cells. Even small variations in this process may result in severe disease phenotype. To study this process, we used a three-phase erythroid expansion system to expand homogeneous erythroid progenitors (EPs) from peripheral blood mononuclear cells (PB-MNCs) (Bruchova H. et al, 2007, Exp. Hematology, in press). We then characterized the expanded EPs from polycythemia vera (PV) patients and healthy donors at various points of maturation comparing cell proliferation and differentiation stage. EPs from PV patients outgrew controls up to day 14 (∼12 fold for PV and ∼4 fold for control compared to day 1). Differentiation was analyzed using both FACS analysis (with CD71/CD235a staining) and morphological evaluation (Wright-Giemsa staining), and demonstrated a more rapid differentiation of PV EPs when compared to controls up to day 14. We then evaluated apoptosis/cell cycle analysis by propidium iodide staining. Although PV EPs contained larger S phase population (45%) than controls (34%) at day 11, the apoptosis proportion of PV EPs was increased ∼2 fold to control from day 14. To understand the molecular mechanism of these differences between PV and controls, we analyzed the gene expression of several known regulators in erythropoiesis - BCL2, EPOR, cMYB, p27. Two transcripts (EPOR and cMYB) showed unique profiles on PV EPs. The EPOR transcript increased earlier in PV; i.e. from day 7 until day 21 and reached a plateau at day 11, compared to day 9 until day 19 and plateau at day 14 in controls. In addition, PV EPs contained higher levels of EPOR transcripts than control on most of timepoints. Interestingly, cMYB, which is known to augment early progenitor proliferation, was highly expressed from day 7 in PV, through day 11. Control EPs also expressed cMYB from day 9 through day 11; however, cMYB levels from any stages of control EPs were markedly lower than PV EPs at day 7. In this study, we demonstrate that PV erythropoiesis has unique features of hyperproliferation and an accelerated differentiation. These features are associated with earlier and higher expressions of cMYB and EPOR at the early stage of erythropoiesis.

Aerobic Glycolysis Predicts Outcome in Early Chronic Lymphocytic Leukemia.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2482-2482
Author(s):  
Jeffrey R Gardner ◽  
Sean Devlin ◽  
Kristina Knapp ◽  
Francesco Bauli ◽  
Nicole Lamanna ◽  
...  
Keyword(s):  
Natural History ◽  
Cancer Biology ◽  
Mononuclear Cells ◽  
Early Stage ◽  
Aerobic Glycolysis ◽  
Lymphocytic Leukemia ◽  
Cell Populations ◽  
History Of ◽  
Discrete Populations ◽  
Two Populations

Abstract Abstract 2482 Despite the advent of prognostic factors such as cytogenetics and IGH mutational status, the natural history of chronic lymphocytic leukemia (CLL) remains heterogenous and difficult to predict in individual patients. We used the carbocyanine dye, JC-1, to investigate mitochondrial membrane potential in patients with untreated, predominantly early stage CLL. We found that JC-1 staining separated CD5+/CD19+ CLL cells into two discrete populations, Low Red (R)/Green (G) and High R/G, which mainly differed with regard to JC-1 green fluorescence (530 nm) in all patients (Fig. 1). In evaluating CLL patients, we found substantial variation in the proportion of cells in the two populations, with a range of 1.1% to 96.7% (median=79.9%) in the High R/G population. CD19+ B-cells from normal individuals typically had few cells with high JC-1 red fluorescence and had a JC-1 staining pattern that was distinct from CLL patients. Electron microscopy revealed disorganized mitochondrial christae, particularly in patients with elevated High R/G cell populations, compared with mononuclear cells from normal donors. Consistent with the morphologic disorganization, we found that the two populations of CLL cells had differential survival in culture with pyruvate and glucose as primary energy sources; cells in the High R/G population had inferior survival (p=0.016), while cells in the Low R/G population had equal survival in pyruvate compared with glucose (Fig. 2). This result indicates that the CLL clonal cell population can be subdivided into cells able to use oxidative phosphorylation and those dependent on aerobic glycolysis fro metabolic energy needs. Interestingly, patient samples with High R/G cell populations >90% had better cell survival in glucose-containing medium than samples derived from patients with < 75% High R/G cells (p=0.0085). We found that the mononuclear cells from patients with CLL expressed the M2 isoform of pyruvate kinase, which has been linked to the regulated utilization of aerobic glycolysis. We assessed the outcome of 100 patients with untreated CLL with more than 1 month of follow up (median 36 months) after measuring the proportion of cells in the mononuclear fraction of the peripheral blood with in the High R/G population. The clinical characteristics of the patients at the time of JC-1 staining are characteristic of patients with early stage, untreated CLL. The population was divided into approximate quartiles based on the percentage of mononuclear cells in the High R/G population, and progression-free survival (PFS) was estimated within each quartile. Patients with 50% or fewer cells in the High R/G gate appeared to have an indolent natural history; an estimated 88% (95% CI: 73%, 99%) of the patients had no evidence of significant clinical progression at two years. In contrast, patients with more than 90% of cells in the gate with High R/G cells had rapid progression with an estimated PFS of 50% (95% CI: 31%–82%) at two years (Fig. 3). Patients with 50–90% cells in the High R/G gate had an intermediate disease course. There was strong evidence of a difference in survival distributions across the four JC-1 categories (log-rank p-value < 0.001). The percentage of cells in the High R/G gate provided prognostic information that was independent of good risk or poor risk cytogenetic changes. In summary, we found that the clonal, neoplastic cells in patients with CLL comprise discrete populations separated on their metabolic dependence on aerobic glycolysis and aerobic glycolysis. We also show that the percentage of cells utilizing glycolysis has a significant adverse impact on the natural history of patients with CLL. Aerobic glycolysis, the so-called Warburg effect, is a common and incompletely understood aspect of cancer biology. These data tie the acquisition of aerobic glycolysis to more aggressive cancer biology, identify an important new prognostic measure for CLL and could lead to the development of therapies that target metabolic differences in cancer cells. Disclosures: No relevant conflicts of interest to declare.

Successful Treatment of HU-Refractory Polycythemia Vera with Atorvastatin and Low Dose Hydroxyurea. Results from a Pilot Study in Bolivia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5621-5621
Author(s):  
Ricardo Amaru ◽  
Ariel Amaru ◽  
Hortensia Miguez ◽  
Gina Torres ◽  
Josue Mamani ◽  
...  
Keyword(s):  
Pilot Study ◽  
High Risk ◽  
Polycythemia Vera ◽  
Mononuclear Cells ◽  
Jak2v617f Mutation ◽  
World Health ◽  
La Paz ◽  
Healthy Donors

Abstract Background Polycythemia Vera (PV) is a clonal myeloproliferative neoplasm, characterized by the JAK2V617F mutation. The main goal of current therapies for PV is to prevent thrombotic events and delay transformation to Myelofibrosis (MF) or Acute Myeloid Leukemia (AML).Treatment for PV to keep an hematocrit (Hct) level <45 %, has been associated with a reduction in cardiovascular deaths and thrombotic events (Marchioli, R et al. NEJM 2013). Currently, low-risk PV patients (<60 years and no previous thrombotic events) are treated with aspirin and phlebotomy while high-risk patients require additional cytoreductive therapy, usually with Hydroxyurea (HU). Resistance to HU is associated with an increased risk of transformation and reduced survival. This is why for HU-refractory patients, second line treatments with interferon alpha, anagrelide or even ruxolitinib are recommended. In Latin America, because of high cost and drugs availability, this last group reflects difficulties to be treated. Because statins have been reported to modulate the erythroid clonogenic activity of normal BM erythroid colonies we performed a pilot study to investigate in vitro and in vivo the biologic and clinical activity of atorvastatin in PV patients Patients and Methods Ten high risk PV patients with a median age of 64.3 years (range 58-73) entered into this study. The diagnosis of PV was done according to the 2008 World Health Organization diagnostic criteria and patients were stratified according to an algorithm proposal provided by Griesshammer et al. (Ann Hematol, 2015). The definition of HU resistance (Barosi, G et al.: BJH 2009) was applicable to five patients (median age 63.9 years) failing to achieve a satisfactory hematologic response upon treatment with more than 2 g of HU, 100 mg of Aspirin and phlebotomies. The assessment of the JAK2V617F mutation was performed as previously described (Guerini et al.: Leukemia 2009). Colony assay, proliferation and apoptosis tests were performed with or without Simvastatin (3.5 uM), as previously described (Amaru, A, Experimental Hematology 2012), on cell lines (UKE1 and K562) and bone marrow mononuclear cells obtained from PV patients and healthy donors. Patients with HU refractory PV (n=5) and high risk PV with hypercholesterolemia (n=5) were eligible to receive Atorvastatin (20 mg/day) added on the top of the ongoing treatment with phlebotomies, Aspirin (100 mg/day) and cytoreductive HU therapy (500 mg/day). All treated patients were high altitude residents (> 3.600 m.a.s.l.) of La Paz (Bolivia) where the normal Hct level of healthy subjects is 48-57% for men and 44-54% for women. This pilot study was approved by the Review Board of the Hospital and the University of San Andres, La Paz. Results In a preliminary set of in vitro proliferation cell assays, simvastatin (3.5 uM), added for 5 days, induced a 33% inhibition of cell proliferation of UKE-1 (JAK2V617F mutated) as compared to 5 % of K562 (BCR/ABL positive). A comparable result was obtained in a 7-day clonogenic cell assay where the colony inhibition was 50 % for UKE-1 and 10 % for K562. On the basis of these results similar experiments were also performed using BM mononuclear cells derived from PV patients and healthy donors. In these experiments performed with the addition of simvastatin, it induced a 41% of inhibition in BFU-E colonies of PV patients and a 25% of inhibition in healthy donors. Furthermore, BFU-E colonies inhibited by simvastatin presented a decrease in hemoglobinization and the size of colonies. HU refractory PV patients and High-risk PV patients with hypercholesterolemia treated with the addition of Atorvastatin, Aspirin, cytoreductive HU and phlebotomies; after a follow-up of 2.6 years (1-7 years), induced a decrease of WBC from 16.500 to 9.270/ul, Hct 61.1 to 52.3% and PLT 457.900,000 to 324.7000/ul. The number of required phlebotomies is reduced in comparison to the required at starting treatment. None of the patients presented thrombotic or cardiopulmonary event. One patient died within two years of starting treatment, due to complications of diabetes mellitus. Conclusions In vitro and in vivo, statins showed some evidence of inhibitory activity of the hematopoiesis of PV patients. These preliminary results might indicate the opportunity to further investigate the potential clinical value of these molecules in the treatment of PV. Disclosures Off Label Use: Atorvastatin was used for its antiproliferative activity on myeloid progenitor cells shown by in vitro experiments.

Thrombotic Complications Are Associated with Phlebotomy Therapy in Patients with Chuvash Polycythemia

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 936-936 ◽  
Author(s):  
Adelina Sergueeva ◽  
Galina Miasnikova ◽  
Ekaterina Lisina ◽  
Mehdi Nouraie ◽  
Sergei A. Nekhai ◽  
...  
Keyword(s):  
Mononuclear Cells ◽  
Conflicts Of Interest ◽  
Negative Regulator ◽  
High Rate ◽  
Systolic Pulmonary Artery Pressure ◽  
Risk Of Death ◽  
Increased Risk ◽  
History Of ◽  
Baseline Characteristics

Abstract Background: In Chuvash polycythemia (CP) (Problemi Gematologii I Perelivaniya Krovi 1974, 10:30), impaired degradation of hypoxia inducible factor (HIF)-1α and HIF-2α from a homozygous germline VHLR200W mutation leads to augmented hypoxic responses during normoxia (Nat Genet 2002, 32:614). In addition to elevated hematocrit, CP is marked by leg varices, benign vertebral hemangiomas, decreased systemic blood pressure, increased systolic pulmonary artery pressure, and by the defining phenotypes of thrombosis and early mortality (Blood 2004, 103:3924; Haematologica 2012, 97:193). There is no effective therapy. While phlebotomy has been recommended for idiopathic polycythemia by the British Committee for Standards in Haematology (Br J Haematol 2005, 130:174) and is administered to some CP patients, its benefits are unknown. Phlebotomy-induced iron deficiency inhibits PHD2 enzyme, the principal negative regulator of HIFs, which further augments hypoxic responses. This affects the transcription of many genes (BCMD 2014, 52:35). Hypoxia-regulated IRAK1 is augmented in inflammation and may promote thrombosis (Circ Res. 2013, 112:103). Methods: 165 patients with CP were enrolled in a registry between 2001 and 2009 after providing written informed consent. Survival analysis was used to examine the predictors of new thrombosis and death during the follow-up period. mRNA from peripheral blood mononuclear cells (PBMCs) was profiled by Affymetrix Human Exon 1.0 ST Array in 42 of the subjects. Results: The median age at enrollment was 35 years and 90 participants were females, 25 had a history of one thrombosis, 5 of two thromboses and 3 of three thromboses. In the year prior to study entry, 72 had received phlebotomy therapy (Table 1). In July 2015 the median follow-up was 9.0 years (range 1-14.5). During this follow-up period, 30 (18.2%) participants had one new thrombosis, 6 (3.6%) had two new thromboses and 17 (10.3%) died. The median age of death was 55 years (range 16-76) and deaths were related to thrombotic cerebrovascular accident (n = 4), myocardial infarction (n = 4), mesenteric or portal vein thrombosis (n = 3), other major thromboembolic events (n = 2) and trauma or unknown cause (n = 2). Baseline characteristics of older age, prior thrombosis, pentoxifylline treatment, smoking and splenomegaly were independently associated with greater thrombosis risk during follow-up (P < 0.003). After adjustment for these variables, the estimated probability of new thrombosis at 10 years was 26% in those receiving phlebotomies compared to 12% in those not phlebotomized (log rank P = 0.014) (Figure 1). There was also a trend for increased risk of death with phlebotomy: estimated probability 8.7% versus 3.7% (P = 0.15). Examination of gene transcripts affecting thrombosis by logistic regression identified 12 protective and 16 risk genes at 5% false discovery rate. Upregulation of two mRNAs was of singular significance: 1) IL1RAP, a proximal signaling adaptor of IRAK1 (Immunity 1997, 7: 837) and 2) THBS1, encoding thrombospondin1 (Blood 2015, 125: 399). Both genes have known roles in thrombosis promotion and we previously reported that THBS1 is upregulated in CP (BCMD 2014, 52:35). Further analysis revealed a further upregulation of THBS1 in patients with baseline history of phlebotomy (β=0.41, P=0.046). Conclusion: These findings underscore a high rate of thrombosis and death in patients with CP and reveal a potential role of increased IRAK1/IL1RAP signaling in these complications. They raise the possibility that phlebotomy therapy has a detrimental rather than beneficial effect, possibly contributed to by increased THBS1 expression. Table 1. Baseline characteristics by phlebotomy in the year prior to enrollment. Results in median (interquartile range) or n (%); four without phlebotomy data. No phlebotomy N=89 Received phlebotomy N=72 Age (years) 32 (18-48) 37 (26-49) 0.08 Female gender, n (%) 52 (58%) 34 (47%) 0.16 Smoking, n (%) 18 (20%) 24 (33%) 0.060 History of thrombosis, n (%) 20 (23%) 12 (17%) 0.4 Splenomegaly, n (%) 2 (2.3%) 2 (2.8%) 0.8 ASA treatment, n (%) 27 (30%) 36 (50%) 0.011 Pentoxifylline, n (%) 7 (7.9%) 17 (23.6%) 0.005 BMI (kg/m2) 20.4 (18.3-22.9) 21.6 (19.9-24.6) 0.010 Systolic BP (mm Hg) 109 (100-123) 118 (105-124) 0.6 Diastolic BP (mm Hg) 76 (68-84) 78 (71-83) 0.8 Hemoglobin (g/dL) 18.1 (16.4-21.0) 17.9 (16.0-19.8) 0.5 WBC (per uL) 5.7 (4.6-7.0) 5.5 (4.6-6.7) 0.9 Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Clinical outcomes of postoperative intraperitoneal chemotherapy for patients with early-stage high-grade serous ovarian cancer (HGSC) treated at British Columbia cancer agency.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e17105-e17105
Author(s):  
Joohyun Lee ◽  
Anna Tinker
Keyword(s):  
Ovarian Cancer ◽  
British Columbia ◽  
Overall Survival ◽  
Clinical Outcomes ◽  
Early Stage ◽  
Statistical Significance ◽  
Progression Free Survival ◽  
Stage I ◽  
High Rate ◽  
Free Survival

e17105 Background: Intraperitoneal (IP) chemotherapy has been shown to prolong overall survival in optimally debulked stage III ovarian cancer in randomized trials. In British Columbia, we extrapolated this benefit of IP chemotherapy to early stage HGSC patients for the last 10 years, as these patients are optimally debulked at surgery but still have a high rate of recurrence. We conducted a retrospective study of clinical outcomes associated with IP/IV chemotherapy compared to IV chemotherapy for optimally debulked stage I HGSC cases. Methods: This was a retrospective cohort study of women with stages IA-IC HGSC who had primary surgery between 2007-2015, and received either IV or IP/IV chemotherapy post-operatively. We compared progression-free survival (PFS) and overall survival (OS) outcomes between these 2 groups. Kaplan-Meier method evaluated chemotherapy delivery route with progression free survival (PFS) and overall survival (OS), using the statistical program R. Results: We identified 99 patients; 80 (81%) received IV chemotherapy and 19 (19%) received IP/IV chemotherapy. Among IP/IV cohort, 2/19 (11%) discontinued IP therapy during treatment due to abdominal pain at IP port site or hypersensitivity reaction to IV paclitaxel. 5-year PFS was 88.4% (74.5-100%) and 69.7% (58.7-82.7%) among the IP/IV and IV cohorts, respectively (p = 0.549). There was a trend for higher 5-year OS for the IP/IV group; however, this did not reach statistical significance (100% vs. 71.4%; p = 0.182). Conclusions: In our study, IP/IV chemotherapy for stage I HGSC patients was associated with a trend for higher 5-year PFS and OS compared to IV chemotherapy. This observation warrants further prospective investigation.

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