Group Of Myeloproliferative Disorders Research Articles

S3593 Eosinophilic Gastritis in Idiopathic Hypereosinophilic Syndrome: A Case Report

Introduction: Idiopathic hypereosinophilic syndrome (IHES) is a group of myeloproliferative disorders causing multi-organ dysfunction with unknown etiology. We report a case of IHES in a patient presenting with gastric wall thickening, multiple organ damage including acute coronary syndrome, encephalopathy, and multiple cortical infarcts. Case Description/Methods: A 47-year-old male patient with past medical history significant for type 2 diabetes mellitus and hypertension presented with nausea, vomiting, abdominal pain, and food intolerance for 7 days. He also complained of intermittent, substernal chest pain for 1-2 days at presentation. His labs were significant for elevated troponin of serum creatinine of 2.85mg/dL and significant leukocytosis (32.80 10^3/cmm). Absolute eosinophilic count was elevated at 14.70 10^3/cmm. Echocardiogram showed hypokinetic mid inferior and inferolateral walls. CT chest/abdomen angiogram was done for concerns of dissection. It showed diffuse gastric wall thickening with upper abdominal retroperitoneal lymphadenopathy and extensive retroperitoneal fat stranding. He was started on antiplatelet agent and heparin drip. Ischemic workup was deferred as troponin plateaued and patient had new-onset altered mental status. MRI brain showed numerous punctate cortical and subcortical foci of restricted diffusion consistent with acute watershed distribution infarcts. In view of possible need for dual anti-platelet therapy and the high concern for gastric malignancy on CT that required tissue biopsy, gastroenterology was consulted for esophagogastroduodenoscopy (EGD). It did not show any gastric mass but diffuse gastritis. Biopsy showed mild chronic gastritis and a focal area showing increased eosinophilic infiltration with eosinophilic cryptitis (Figure). An extensive workup for eosinophilia including infectious etiology returned negative. No secondary causes of hypereosinophilia were identified. Patient was started on 1mg/kg of prednisone with normalization of eosinophils to 0 within 24 hours. Steroids were tapered and patient improved clinically with resolution of altered mental status, abdominal pain, and chest pain. Follow-up EGD has been scheduled to re-evaluate eosinophilic deposits. Discussion: The stomach biopsy showing eosinophilia was the key to diagnosis. Resolution of peripheral eosinophilia with steroids confirms the diagnosis in the absence of a secondary cause. A repeat EGD with biopsy is scheduled to look for histopathological resolution.Figure 1.: Gastric mucosa with increased eosinophilic infiltration within the lamina propria and focal glandular involvement with eosinophils.

Clustering of aberrations to specific chromosomes in human neoplasms.

This survey of chromosomal aberrations in human neoplasms comprises 1,871 cases distributed on 15 groups of malignant disease, viz. 4 groups of myeloproliferative disorders with 1,328 cases, 5 groups of lymphoproliferative disorders with 369 cases and 6 groups of solid tumors with 174 cases. The material is presented in 17 tables, in which the variation of each chromosome is listed separately for each geographic region. In the discussion part a number of special problems are looked into. The difference in variation between the individual chromosomes was highly signifcant statistically. Within each tumor, all chromosomes which exceeded the average variation with more than 1 standard deviation were considered selectively involved. In all neoplasms taken together, the chromosomes selectively involved clustered to 15 of the 24 human chromosome types. Other topics taken up for discussion were the following: possible differences in chromosome variation between geographic regions; the specificity of certain marker chromosomes; the hypothesis of 2 essentially different kinds of chromosome aberration in cancer. The phenomena of genic amplification and recurrent translocation often found in cancer require the assumption of unorthodox cytogenetic mechanisms. One main conclusion of the paper is that the aberrations of the selectively involved chromosomes influence cancer development because of the genes they carry.

Loss of heterozygosity identifies genetic changes in chronic myeloid disorders, including myeloproliferative disorders, myelodysplastic syndromes and chronic myelomonocytic leukemia

This study evaluates changes in genetic loci of chronic myeloid disorders using loss of heterozygosity (LOH) techniques. We present the combined results of three experiments. First, examination of a panel of genetic loci in groups of myeloproliferative disorders was evaluated. The second experiment involved microdissection of megakaryocytes from myeloproliferative disorders and comparison of their genetic changes to surrounding neoplastic marrow elements. Finally, we compared results of LOH studies of myeloproliferative disorders to those of myelodysplastic syndromes and chronic myelomonocytic leukemia. A total of 41 bone marrow biopsies were evaluated. Twenty-seven were myeloproliferative disorders (11 chronic idiopathic myelofibrosis, 11 essential thrombocythemia, 5 polycythemia vera). The remaining cases consisted of myelodysplastic syndromes (total=5; RAEB-1=2; RAEB-2=2; MDS, not otherwise specified=1) and chronic myelomonocytic leukemia (n=8). The abnormalities in myeloproliferative disorders were distributed as follows: D7S2554–4/14 (5/14); D8S263–4/15 (5/15); D9S157–5/15 (5/15); D9S161–7/17 (6/17); D13S319–5/14 (4/14); TP53–5/16 (5/16); D20S108–4/15 (4/15). In 75% cases diagnosed as essential thrombocythemia (6/8), both cases of polycythemia vera (2/2), and 29% cases of chronic idiopathic myelofibrosis (2/7), there were genetic differences between the megakaryocytes and the surrounding marrow. These results suggest that in some cases, megakaryocytes have different clonal abnormalities than surrounding hematopoietic tissue. The genetic profiles of myeloproliferative disorders had several differences from those of myelodysplastic syndromes. Although different from both, chronic myelomonocytic leukemia appeared more similar to myeloproliferative disorders using these techniques.

Functional and morphological cardiac changes in myeloproliferative disorders (clinical study)

Purpose: Cardiac involvement is not well defined in myeloproliferative disorders (MPD). The purpose of this study was to evaluate the cardiac involvement by transthoracic echocardiography in MPD. Materials and methods: The study groups were 36 patients (mean age: 58±15 years, 20 female and 16 male) with MPD and 30 age-matched healthy controls. MPD group included 15 essential thrombocythemia (ET), eight chronic phase chronic myelogenous leukemia (CML), seven idiopathic myelofibrosis (MF) and six polcythemia vera patients. Results: Valvular regurgitations were present in 14 patients (39%) and eight controls (27%), ( P>0.05). Mitral regurgitation (MR) was more prominent in CML compared to controls ( P=0.044). The rates of annular calcifications, valvular thickening, and vegetation like lesions were not different between MPD and control groups. Pulmonary hypertension (PHT) was present in six (17%) patients, but none of the controls ( P=0.021). The rates of PHT in CML and MF were significantly higher than controls ( P<0.05). The rate of PHT was not different in-between MPD patients with and without thromboembolic events, however, in MPD cases with thromboembolic events PHT was more common compared to controls ( P=0.037). Conclusion: This study showed that valvular lesions were not more prevalent in MPD. PHT was the most prominent cardiac pathology in MPD (especially in CML, MF and thromboembolic events subgroups) compared to controls. Further evaluation of the cardiac changes in MPD subgroups with extended studies including trans-oesophageal echocardiography and longer follow-up periods would be appropriate.

Flt-3 ligand does not induce the growth of peripheral blood granulocyte-macrophage colony-forming cells in myeloproliferative disorders.

Flt-3 ligand (FL) is a growth factor (GF) which might have clinical use as a mobilizer of stem and progenitor cells into peripheral blood (PB) in autologous transplantations of various malignant haematological diseases, unless FL stimulates the growth of malignant cells in these diseases. The present study evaluated the effects of FL on the proliferation of granulocytemacrophage (GM) progenitor cells collected from PB of 24 patients with chronic myeloproliferative disorders (MPDs) by using a methylcellulose assay in serum-free culture conditions. It was shown that FL as a single factor had no stimulatory effect on GM colony formation either in the whole MPD group or in the MPD subgroups, which comprised 9 patients with essential thrombocythaemia, 7 with polycythaemia vera and 8 with chronic myelogenous leukaemia. No increase in GM colony formation was observed, either, when FL was used in combination with other GFs, such as mast cell growth factor (MGF), granulocyte-colony stimulating factor (G-CSF), GM-CSF or interleukin-3 (IL-3). GM-CSF and IL-3 were the only single GFs which significantly increased GM colony formation in the whole MPD group. As a conclusion, FL does not seem to induce GM colony formation of MPDs alone or in combination with G-CSF in in vitro colony assays.

The effect of interleukin-4 with or without mast cell growth factor on peripheral blood granulocyte-macrophage colony-forming cells in healthy controls and in myeloproliferative disorders.

The effect of interleukin-4 (IL-4) on peripheral blood (PB) granulocyte-macrophage (GM) progenitors was investigated in the presence and absence of other hematopoietic growth factors, especially the mast cell growth factor (MGF), in eight healthy controls and in 26 patients with myeloproliferative disorders (MPDs) using a clonogenic cell culture assay. In the controls IL-4 was effective alone, stimulating myeloid colony growth in 50%, while MGF had no effect as a single factor. When either IL-4 or MGF was added to the combination of IL-3, GM-CSF, G-CSF, and IL-6, a statistically significant increase in the colony number was observed. The most potent colony formation took place when all these GFs were combined. In the combinations, the effect of IL-4 was additive, while MGF worked synergistically. In the MPDs, IL-4 had no effect at all on the GM progenitors in the whole group of MPDs or on the different subgroups.

125I-Fibrinogen Binding to Platelets in Myeloproliferative Disease

Recent reports have suggested a variation in the density and affinity of fibrinogen binding sites in platelets from patients with myeloproliferative disorders (MPD) which may reflect platelet functional abnormalities in these subjects. We have investigated the binding of 125I-fibrinogen (125I-Fb) to gel-filtered platelets from a large relatively homogeneous group of patients with MPD compared to normal age matched controls. Twenty-two of the patients investigated had polycythaemia vera and four essential thrombocythaemia. The maximal density and affinity (Kd) of 125I-Fb binding was assessed by saturation analysis in gel-filtered platelets (GFP) stimulated with either 10 microM ADP or 150 mU thrombin. In addition the functional significance of the binding sites was studied by evaluating the response of GFP from the two experimental groups by assessing the effects of increasing concentrations of added fibrinogen on the response to 10 microM ADP using standard light transmission aggregometry. In both groups the density of fibrinogen binding sites expressed in response to thrombin stimulation was significantly higher (approximately 2-3 fold) than that found in response to ADP. However, fewer binding sites were detected in the MPD group as compared with the control group in response to both ADP and thrombin. The Kd for 125I-Fb was similar for both agonists in normal controls and was significantly lower than that found in the MPD subjects. Although the 125I-Fb binding study results indicate a significant reduction in both the number and affinity of fibrinogen binding sites in patients with myeloproliferative disorders, the clinical and functional significance of these findings remain uncertain.

Altered high density lipoprotein metabolism in patients with myeloproliferative disorders and hypocholesterolemia

Patients with the myeloproliferative disorders (MPD), myeloid metaplasia and polycythemia vera, have significantly reduced concentrations of plasma low density (LDL) and high density (HDL) lipoprotein cholesterol (C). We have previously demonstrated that increased catabolism of LDL was associated with the low LDL-C levels. In the present study we have determined the rates of synthesis and removal of apolipoprotein A-1 (apoA-1) in five subjects with MPD who had markedly reduced HDL-C concentrations (18.2 ± 4.1 mg/dL). Their results were compared to those obtained in six subjects with hypertriglyceridemia (HTG) with similar levels of HDL-C (19.7 ± 3.9 mg/dL) and five subjects with normal (N) HDL-C concentrations (49.6 ± 7.4 mg/dL). The results demonstrated that the fractional catabolic rate (FCR) for apoA-1 was significantly increased in the MPD group v N (0.38 ± 0.15 v 0.21 ± 0.03 day −1, P < 0.05) while the synthetic rates for apoA-1 were similar in the two groups. The FCR for apoA-1 in the HTG group (0.36 ± 0.07 day −1) was nearly identical to that in the MPD group, in spite of the large differences in their plasma triglyceride concentrations (406.2 ± 217.9 v 117.0 ± 29.8 mg/dL, P < 0.05). Compositional studies indicated that the HTG group had very cholesterol depleted HDL while the HDL particles in the MPD group appeared to have a normal cholesterol content. These studies indicate that subjects with MPD have striking increases in HDL catabolism that can account fully for their markedly reduced levels of HDL cholesterol. The pathophysiologic mechanisms that are the basis of this alteration remain to be determined.

An ultrastructural morphometric analysis of platelet giant and fusion granules

Our purpose in this study was to establish ultrastructural morphometric criteria that can be used to define pathologic giant and fusion platelet granules and to determine whether patients with neoplastic myeloproliferative disorders (MPD) can be distinguished from other patients. We have morphometrically analyzed 2,391 giant and fusion granule profiles from 46 patients with neoplastic MPD, 127 other diseased control subjects, and 30 normal subjects using a computerized image analyzer. The largest granule profile observed in normal subjects had an area of 0.51 mu 2 and a perimeter of 3.21 mu. The most irregularly shaped of the large granule profiles photographed from normal subjects had a form factor (FF) value of 0.31. FF values indicate the degree of deviation of a given granule contour from a circle and is expressed by the formula 4 pi A/P2. A pathologic granule profile was then defined as a granule that exceeded any of these limits. Fifty-seven percent of the patients with neoplastic MPD were determined to have abnormal platelet granule profiles using the aforementioned morphometric criteria. It was determined, however, that morphometrically defined giant- and fusion-type granule profiles were nonspecific and were also found in 20% of the other diseased patients with no clinical evidence of an underlying neoplastic MPD. Morphometry has allowed us to define the upper limits of normal for the area and perimeter of individual platelet granules. Morphometrically defined giant fusion granules were determined to be more prevalent in the neoplastic MPD group, but because of their nonspecificity, may only have diagnostic significance for the individual patient in specific clinical settings. The pathogenesis of platelet fusion granules is discussed.

An Ultrastructural Morphometric Analysis of Platelet Giant and Fusion Granules

Our purpose in this study was to establish ultrastructural morphometric criteria that can be used to define pathologic giant and fusion platelet granules and to determine whether patients with neoplastic myeloproliferative disorders (MPD) can be distinguished from other patients. We have morphometrically analyzed 2,391 giant and fusion granule profiles from 46 patients with neoplastic MPD, 127 other diseased control subjects, and 30 normal subjects using a computerized image analyzer. The largest granule profile observed in normal subjects had an area of 0.51 mu 2 and a perimeter of 3.21 mu. The most irregularly shaped of the large granule profiles photographed from normal subjects had a form factor (FF) value of 0.31. FF values indicate the degree of deviation of a given granule contour from a circle and is expressed by the formula 4 pi A/P2. A pathologic granule profile was then defined as a granule that exceeded any of these limits. Fifty-seven percent of the patients with neoplastic MPD were determined to have abnormal platelet granule profiles using the aforementioned morphometric criteria. It was determined, however, that morphometrically defined giant- and fusion-type granule profiles were nonspecific and were also found in 20% of the other diseased patients with no clinical evidence of an underlying neoplastic MPD. Morphometry has allowed us to define the upper limits of normal for the area and perimeter of individual platelet granules. Morphometrically defined giant fusion granules were determined to be more prevalent in the neoplastic MPD group, but because of their nonspecificity, may only have diagnostic significance for the individual patient in specific clinical settings. The pathogenesis of platelet fusion granules is discussed.

Cobalamin (vitamin B12) and B12 binding proteins in hypereosinophilic syndromes and secondary eosinophilia

Serum cobalamin (vitamin B12) and unsaturated B12 binding capacity (UBBC) have been measured in 24 cases of hypereosinophilia: 16 were cases of hypereosinophilic syndrome (HES) and 8 of secondary eosinophilia. The two groups were similar with respect to absolute eosinophil counts. Serum cobalamin and UBBC were found to be markedly increased in most cases of HES and normal in secondary eosinophilia. This elevation of UBBC was mainly related to the increase of R binders (transcobalamins I and III). The elevated serum cobalamin and R binders in HES were due neither to a higher intracellular content of R binders nor to an increased release of these binders from eosinophils of HES. Pure fractions of eosinophils obtained from HES and secondary eosinophilia did not exhibit any difference in vitamin B12 binders. On the other hand, neutrophil-rich fractions from the same patients showed a higher content of intracellular B12 binding proteins than pure eosinophil fractions, irrespective of the cause of eosinophilia. These findings suggest that the increased serum vitamin B12 and UBBC could reflect an expanded pool of both eosinophils and neutrophils in HES and, thus, provide an additional argument for the inclusion of this syndrome in the group of myeloproliferative disorders.

Cobalamin (Vitamin B12) and B12 Binding Proteins in Hypereosinophilic Syndromes and Secondary Eosinophilia

AbstractSerum cobalamin (vitamin B12) and unsaturated B12 binding capacity (UBBC) have been measured in 24 cases of hypereosinophilia: 16 were cases of hypereosinophilic syndrome (HES) and 8 of secondary eosinophilia. The two groups were similar with respect to absolute eosinophil counts. Serum cobalamin and UBBC were found to be markedly increased in most cases of HES and normal in secondary eosinophilia. This elevation of UBBC was mainly related to the increase of R binders (transcobalamins I and III). The elevated serum cobalamin and R binders in HES were due neither to a higher intracellular content of R binders nor to an increased release of these binders from eosinophils of HES. Pure fractions of eosinophils obtained from HES and secondary eosinophilia did not exhibit any difference in vitamin B12 binders. On the other hand, neutrophil-rich fractions from the same patients showed a higher content of intracellular B12 binding proteins than pure eosinophil fractions, irrespective of the cause of eosinophilia. These findings suggest that the increased serum vitamin B12 and UBBC could reflect an expanded pool of both eosinophils and neutrophils in HES and, thus, provide an additional argument for the inclusion of this syndrome in the group of myeloproliferative disorders.