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Biomedical subjects

Ayalew Tefferi

Publications and source records attributed to Ayalew Tefferi.

At least 145 records · Page 8Linked to original sources
PubMed2003

Involvement of reactive oxygen species in adaphostin-induced cytotoxicity in human leukemia cells.

Adaphostin (NSC 680410), an analog of the tyrphostin AG957, was previously shown to induce Bcr/abl down-regulation followed by loss of clonogenic survival in chronic myelogenous leukemia (CML) cell lines and clinical samples. Adaphostin demonstrated selectivity for CML myeloid progenitors in vitro and remained active in K562 cells selected for imatinib mesylate resistance. In the present study, the mechanism of action of adaphostin was investigated in greater detail in vitro. Initial studies demonstrated that adaphostin induced apoptosis in a variety of Bcr/abl- cells, including acute myelogenous leukemia (AML) blasts and cell lines as well as chronic lymphocytic leukemia (CLL) samples. Further study demonstrated that adaphostin caused intracellular peroxide production followed by DNA strand breaks and, in cells containing wild-type p53, a typical DNA damage response consisting of p53 phosphorylation and up-regulation. Importantly, the antioxidant N-acetylcysteine (NAC) blunted these events, whereas glutathione depletion with buthionine sulfoximine (BSO) augmented them. Collectively, these results not only outline a mechanism by which adaphostin can damage both myeloid and lymphoid leukemia cells, but also indicate that this novel agent might have a broader spectrum of activity than originally envisioned.

Acetylcysteine↗
PubMed2003

CHIC2 deletion, a surrogate for FIP1L1-PDGFRA fusion, occurs in systemic mastocytosis associated with eosinophilia and predicts response to imatinib mesylate therapy.

Imatinib mesylate is effective in the treatment of hematologic malignancies that are characterized by either abl- or PDGFR beta- activating mutations. The drug is also active in a subset of patients with eosinophilic disorders and systemic mast cell disease (SMCD). Recently, a novel tyrosine kinase that is generated from fusion of the Fip1-like 1 (FIP1L1) and PDGFR alpha (PDGFRA) genes has been identified as a therapeutic target for imatinib mesylate in hypereosinophilic syndrome (HES). We used fluorescence in situ hybridization (FISH) to detect deletion of the CHIC2 locus at 4q12 as a surrogate for the FIP1L1-PDGFRA fusion. CHIC2 deletion was observed in bone marrow cells for 3 of 5 patients with SMCD associated with eosinophilia. Deletion of this locus and expression of the FIP1L1-platelet-derived growth factor receptor alpha (PDGFRA) fusion was also documented in enriched eosinophils, neutrophils, or mononuclear cells by both FISH and reverse transcriptase-polymerase chain reaction (RT-PCR) for one patient. While all 3 patients with the FIP1L1-PDGFRA rearrangement achieved a sustained complete response with imatinib mesylate therapy, the other two, both carrying the c-kit Asp816 to Val (Asp816Val) mutation, did not. These observations suggest that the FIP1L1-PDGFRA rearrangement occurs in an early hematopoietic progenitor and suggests that the molecular pathogenesis for a subset of SMCD patients is similar to that of HES. Screening for the FIP1L1-PDGFRA rearrangement and Asp816Val mutation will advance rational therapy decisions in SMCD.

Adult↗
PubMed2003

A tyrosine kinase created by fusion of the PDGFRA and FIP1L1 genes as a therapeutic target of imatinib in idiopathic hypereosinophilic syndrome.

BACKGROUND: Idiopathic hypereosinophilic syndrome involves a prolonged state of eosinophilia associated with organ dysfunction. It is of unknown cause. Recent reports of responses to imatinib in patients with the syndrome suggested that an activated kinase such as ABL, platelet-derived growth factor receptor (PDGFR), or KIT, all of which are inhibited by imatinib, might be the cause. METHODS: We treated 11 patients with the hypereosinophilic syndrome with imatinib and identified the molecular basis for the response. RESULTS: Nine of the 11 patients treated with imatinib had responses lasting more than three months in which the eosinophil count returned to normal. One such patient had a complex chromosomal abnormality, leading to the identification of a fusion of the Fip1-like 1 (FIP1L1) gene to the PDGFRalpha (PDGFRA) gene generated by an interstitial deletion on chromosome 4q12. FIP1L1-PDGFRalpha is a constitutively activated tyrosine kinase that transforms hematopoietic cells and is inhibited by imatinib (50 percent inhibitory concentration, 3.2 nM). The FIP1L1-PDGFRA fusion gene was subsequently detected in 9 of 16 patients with the syndrome and in 5 of the 9 patients with responses to imatinib that lasted more than three months. Relapse in one patient correlated with the appearance of a T674I mutation in PDGFRA that confers resistance to imatinib. CONCLUSIONS: The hypereosinophilic syndrome may result from a novel fusion tyrosine kinase - FIP1L1-PDGFRalpha - that is a consequence of an interstitial chromosomal deletion. The acquisition of a T674I resistance mutation at the time of relapse demonstrates that FIP1L1-PDGFRalpha is the target of imatinib. Our data indicate that the deletion of genetic material may result in gain-of-function fusion proteins.

Adult↗
PubMed2003

The myelodysplastic syndrome(s): a perspective and review highlighting current controversies.

The myelodysplastic syndrome (MDS) includes a diverse group of clonal and potentially malignant bone marrow disorders characterized by ineffective and inadequate hematopoiesis. The presumed source of MDS is a genetically injured early marrow progenitor cell or pluripotential hematopoietic stem cell. The blood dyscrasias that fall under the broad diagnostic rubric of MDS appear to be quite heterogeneous, which has made it very difficult to construct a coherent, universally applicable MDS classification scheme. A recent re-classification proposal sponsored by the World Health Organization (WHO) has engendered considerable controversy. Although the precise incidence of MDS is uncertain, it has become clear that MDS is at least as common as acute myelogenous leukemia (AML). There is considerable overlap between these two conditions, and the former often segues into the latter; indeed, the distinction between AML and MDS can be murky, and some have argued that the current definitions are arbitrary. Despite the discovery of several tantalizing pathophysiological clues, the basic biology of MDS is incompletely understood. Treatment at present is generally frustrating and ineffective, and except for the small subset of patients who exhibit mild marrow dysfunction and low-risk cytogenetic lesions, the overall prognosis remains rather grim. In this narrative review, we highlight recent developments and controversies within the context of current knowledge about this mysterious and fascinating cluster of bone marrow failure states.

Combined Modality Therapy↗
PubMed2003

Clonal cytogenetic abnormalities in bone marrow specimens without clear morphologic evidence of dysplasia: a form fruste of myelodysplasia?

Cytogenetic abnormalities suggestive of a myeloid disorder are occasionally observed in the bone marrow (BM) cells of patients with morphologically and immunohistochemically unremarkable marrow aspirates and biopsies. Between 1994 and 2000, 55 such patients were seen at our institution (34 men; median age of 66 years). The indications for BM sampling included unexplained cytopenias (31 patients), staging or follow-up of a lymphoproliferative disorder or a plasma cell dyscrasia (18 patients), or another miscellaneous reason (6 patients). Specific cytogenetic abnormalities included a 20q deletion or monosomy 20 (10 patients), a chromosome 7 deletion (8 patients), +8 (5 patients), del(5q) or a 5q translocation (4 patients), and del(13q) (2 patients). Eleven patients had a complex karyotype. As of January 2002, 23 of the 55 patients were dead; median follow-up for living patients is 20 months. Of the 23 dead patients, 1 died of acute myelogenous leukemia (AML) and 6 of complications related to cytopenias. This study provides support for obtaining cytogenetic studies in patients with unexplained cytopenias if a morphologic explanation for the cytopenias is lacking. Continued follow-up of this heterogeneous cohort and further studies of similar patients will more clearly define the disease processes and prognosis for this constellation of laboratory findings.

Aged↗
PubMed2003

Bone marrow immunohistochemical studies of angiogenic cytokines and their receptors in myelofibrosis with myeloid metaplasia.

Bone marrow specimens from 11 patients with myelofibrosis with myeloid metaplasia (MMM) and seven normal controls were studied immunohistochemically to determine expression of transforming growth factor beta (TGF-beta), platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and corresponding receptors. Staining distribution and intensity for TGF-beta, PDGF, VEGF, TGF-beta type II receptor, a receptor for PDGF, and receptors for VEGF and bFGF were similar in patients and controls. Bone marrow from 10 MMM patients showed increased TGF-beta type I receptor (TGF-betaRI) expression in small vessel endothelial cells. Eight patient specimens had bFGF overexpression in megakaryocytes. Increased microvessel density and decreased concentration of bFGF-staining stromal cells accompanied these changes. Microvascular TGF-betaRI upregulation and bFGF overexpression by megakaryocytes may cause bone marrow microenvironmental changes in MMM patients.

Adult↗
PubMed2003

Flt-3 and c-kit mutation studies in a spectrum of chronic myeloid disorders including systemic mast cell disease.

We screened 115 patients with chronic myeloid disorders (CMD) for known flt-3 and c-kit mutations in both the juxtamembrane (JM) and the activation loop (AL) domains. None of the patients displayed flt-3 (JM or AL) or c-kit JM mutations. However, the c-kit AL (D816V) mutation was detected in 5 of 16 patients with systemic mast cell disease (SMCD) but in none of the remaining 99 patients with other CMD. In SMCD, the presence of D816V mutation was significantly associated with advanced age, an aggressive clinical course, increased bone marrow mast cell content, and chronic myelomonocytic leukemia.

Adult↗
PubMed2003

Splenic histopathological patterns in chronic myelomonocytic leukemia with clinical correlations: reinforcement of the heterogeneity of the syndrome.

The syndrome of chronic myelomonocytic leukemia (CMML) includes a heterogeneous group of patients who exhibit both myelodysplastic and myeloproliferative clinicopathological features. Troublesome splenomegaly is uncommon in myelodysplastic syndrome (MDS), but when organomegaly occurs, this complication is more likely to be associated with myelodysplastic-myeloproliferative overlap syndromes such as CMML rather than "dysplasia-only" MDS types such as refractory anemia. We report a single-institution experience with splenectomy in CMML patients, including a detailed review of splenic histopathology. Twelve patients with CMML underwent splenectomy at the Mayo Clinic, primarily because of refractory thrombocytopenia and/or mechanical complications related to splenomegaly. Three of the 12 patients (25%) died as a direct result of surgery, and significant postoperative morbidity was seen in another 4 patients (33%). Thrombocytopenia improved in 4 of the 11 patients (36%) with low platelet counts before surgery. Three of the four responders had an abundance of CD68 (PGM1)-positive foamy histiocytes in the marginal zone surrounding the splenic white pulp-a pattern which can be seen in immune thrombocytopenia-and two of these three patients had thrombocytopenia out of proportion to the degree of anemia pre-operatively, suggestive of peripheral destruction of platelets. More consistent splenic pathological findings in the 12 patients included trilineage extramedullary hematopoiesis in splenic red pulp and expansion of splenic cords by a myelomonocytic infiltrate. This study underscores both the uniformity and diversity of splenic findings in CMML, highlights the potential dangers and benefits of splenectomy in this group, and suggests peripheral destruction of platelets as a mechanism contributing to thrombocytopenia in a subset of CMML patients.

Adult↗
PubMed2003

Eosinophils are derived from the neoplastic clone in patients with systemic mastocytosis and eosinophilia.

Twenty to thirty-three percent of systemic mast cell disease (SMCD) patients have some degree of peripheral blood and/or bone marrow eosinophilia. While the clonality of SMCD was established by identification of the pathogenic c-kit Asp816 to Val (D816V) mutation in sorted cells of different hematopoietic lineages, this mutation has not previously been demonstrated in eosinophils from SMCD patients. In the current study, we demonstrate the D816V mutation in purified eosinophils from two patients with aggressive, eosinophilia-associated SMCD, thus proving that the eosinophils are clonal and not reactive in nature. The clinical implications of this finding are discussed.

Aged↗
PubMed2003

Thrombocythaemia and pregnancy.

The diagnosis of essential thrombocythaemia (ET) is considered when all causes of reactive (secondary) thrombocytosis have been excluded in a patient with a persistent thrombocytosis. Among the chronic myeloproliferative disorders, ET has the highest proportion of young as well as female patients affected. As such, the optimal management of ET during pregnancy becomes an important issue. Although ET is not a contraindication to childbearing, the risks to both the fetus and mother are increased, and would-be-parents should be counselled regarding these. Obstetric complications occurring at higher than expected rates include spontaneous abortion in the first-trimester. Maternal complications, both haemorrhagic and thrombotic, are reported relatively infrequently. It is generally difficult to make specific management recommendations because of the relative rarity of the association between ET and pregnancy, which has precluded adequately powered controlled trials. In this communication, we review our own experience as well as that of other investigators on the subject matter and provide management guidelines that are based on best available information.

Disease Management↗
PubMed2003

Chronic basophilic leukemia: a distinct clinico-pathologic entity?

OBJECTIVE: We sought to better define a group of rare and poorly understood myeloproliferative disorders that are characterized by prominent chronic basophilia in the absence of the Philadelphia chromosome (Ph) or its molecular equivalent. METHODS: We screened our institution's electronic database from 1975 onwards, and identified four such cases. Clinical data and bone marrow pathology were carefully reviewed for these patients. RESULTS: Two patients had prominent manifestations of basophil mediator-release and another presented with pituitary dysfunction. Bone marrow examination uniformly revealed trilineage hyperplasia with basophilia and eosinophilia, dysplastic megakaryocytic hyperplasia, and the absence of megakaryocyte clustering. An abnormal pattern of atypical mast cells was noted in two cases. While disease palliation was effectively achieved with hydroxyurea for one patient, transformation to acute myeloid leukemia was eventually observed in this case. Another patient has achieved long-term disease-free survival after undergoing allogeneic stem cell transplantation. CONCLUSIONS: Our observations reveal a striking pathologic similarity among all four cases, and suggest this disease, which may be aggressive with the potential to transform into acute leukemia, to possibly represent a distinct clinico-pathologic entity (chronic basophilic leukemia).

Adult↗
PubMed2003

Clinical features in T-cell vs. natural killer-cell variants of large granular lymphocyte leukemia.

OBJECTIVE: Standard clinical and laboratory evaluations and novel laboratory techniques were used to identify patients with T-cell large granular lymphocyte leukemia (LGLL) and those with natural killer-cell variants of LGLL for comprehensive clinical evaluation. METHODS: We used bone marrow histologic analysis, immunophenotypic markers of clonality, and T-cell-receptor gene rearrangement studies to identify patients. RESULTS: The study identified 44 patients with T-cell LGLL and 14 with natural killer-cell LGLL. The two disorders were similar in sex and age distribution of patients; peripheral blood lymphocyte, neutrophil, and platelet counts; and incidence of rheumatoid arthritis. Among the two groups, patients with the T-cell LGLL presented with significantly lower hemoglobin concentrations (P < 0.04) and a higher frequency of palpable splenomegaly (P < 0.01). CONCLUSION: Overall disease progression and response to immunosuppressive therapy are similar between T-cell and natural killer-cell variants of LGLL.

Adolescent↗
PubMed2003

Differential expression of CD2 on neoplastic mast cells in patients with systemic mast cell disease with and without an associated clonal haematological disorder.

Recently, aberrant coexpression of CD2 and CD25 has been reported to reliably distinguish neoplastic mast cells from normal or so-called reactive mast cells. Such expression is included in the consensus diagnostic criteria for systemic mast cell disease (SMCD). In our study of patients with SMCD, we found CD2 expression to be more prevalent on mast cells from patients without an associated haematological disorder (P = 0.04). Furthermore, no correlation was found between mast cell CD2 expression and other clinicopathological features in these patients.

Antigens, Neoplasm↗
PubMed2003

Demonstration of aberrant T-cell and natural killer-cell antigen expression in all cases of granular lymphocytic leukaemia.

The diagnosis of granular lymphocytic leukaemia (GLL) requires the presence of an immunophenotypically distinct T-cell (T-GLL) or natural killer-cell (NK-GLL) population. Flow cytometric immunophenotyping was performed on 21 T-GLL patients, 11 NK-GLL patients and 20 normal control subjects using antibodies to T and NK cell-associated antigens in order to accurately identify the distinguishing features of T-GLL and NK-GLL. The NK antigens evaluated included: CD16, CD57, CD94, CD161, and the killing inhibitory receptors (KIRs) CD158a, CD158b and CD158e (p70). Abnormal T-antigen expression was present in all T-GLL patients. CD57 was frequently expressed in T-GLL, however, one-third of patients showed partial CD57 expression similar to that seen in T cells from normal control subjects. Ten T-GLL were KIR positive; all expressed a single KIR isoform. All NK-GLL showed a distinctive, abnormal immunophenotype. Four NK-GLL expressed a single KIR isoform; the remaining seven patients lacked all tested KIRs, which is also a distinct, abnormal finding. Immunoperoxidase staining of bone marrow biopsy specimens from NK-GLL patients with antibodies to CD8, TIA-1 and granzyme B revealed the disease-specific distinctive staining patterns previously found in T-GLL. These studies delineate the unique immunophenotypic features diagnostic of T-GLL and provide strong evidence that NK-GLL, like T-GLL, represents a clonal lymphoproliferative disorder.

Adolescent↗
PubMed2003

Factors that influence platelet recovery after transfusion: resolving donor quality from ABO compatibility.

BACKGROUND: A system was established to examine the extent to which the apheresis donor determines platelet recovery after transfusion, to measure the impact of ABO identity, and to predict outcome by evaluating the donor. STUDY DESIGN AND METHODS: The percentage of platelet recovery was measured after prophylactic transfusion of apheresis units divided from single donors to paired recipients with uncomplicated thrombocytopenia secondary to leukemia chemotherapy. Platelet microaggregation induced by citrate was measured at the time of apheresis. RESULTS: Platelet recoveries in paired recipients correlated strongly when both transfusions were ABO- identical. When one recipient was ABO-identical and the other was ABO-nonidentical, nonidentical transfusions yielded one-third the recovery of ABO-identical transfusions. In ABO-identical transfusions, platelet recovery in donors having microaggregates in the before-apheresis ACD sample was one-third that in donors without microaggregates. This difference was observed at 1 and 24 hours. Expression of P-selectin in the apheresis units at the time of transfusion correlated well with ACD microaggregates in the before-apheresis sample. CONCLUSION: When transfusions of platelets are ABO-identical, donor quality dominates recovery in circulation. Donor quality is predicted by a rapid and simple assay of citrate-induced microaggregation performed at the time of apheresis. When donor quality is factored out, ABO identity prevails.

ABO Blood-Group System↗
PubMed2003

Treatment approaches in myelofibrosis with myeloid metaplasia: the old and the new.

Myelofibrosis with myeloid metaplasia (MMM) is currently classified as a chronic myeloproliferative disorder (CMPD) and is characterized by prominent bone marrow stromal reaction including collagen fibrosis, osteosclerosis, and angiogenesis. Among the CMPD, MMM carries the worst prognosis with an overall median survival of 5 years; the clinical course is marred by profound constitutional symptoms, progressive anemia, and symptomatic splenomegaly. Causes of death include leukemic transformation, which occurs in approximately 10% of patients in the first decade of the disease. At present, allogeneic hematopoietic stem cell transplantation (HSCT) is the only treatment modality that has the potential to either cure the disease or prolong survival. Both drug therapy and autologous HSCT are currently palliative. Conventional treatment agents in MMM include androgen preparations, corticosteroids, erythropoietin (EPO), and hydroxyurea. In addition, both splenectomy and radiation therapy have defined therapeutic roles. Thalidomide is the most effective investigational agent at the present time. Optimal therapy for an individual patient requires a sound understanding of disease risk factors, as well as a full appreciation of the risk to benefit ratio for a specific treatment modality.

Angiogenesis Inhibitors↗
PubMed2003

Intensive care unit support and Acute Physiology and Chronic Health Evaluation III performance in hematopoietic stem cell transplant recipients.

OBJECTIVE: Hematopoietic stem cell transplant (HSCT) recipients admitted to the intensive care unit (ICU) have high mortality. The prognostic importance of peripheral blood stem cell source in critically ill HSCT recipients and the performance of Acute Physiology and Chronic Health Evaluation (APACHE) III have not been well studied. In a previous study, the hospital mortality rate of HSCT recipients admitted to our ICU was 77%. The objectives of this study were to describe the clinical course of HSCT recipients admitted to the ICU and to determine the performance of APACHE III in predicting their mortality. DESIGN: Retrospective cohort study. SETTING: Academic medical center. PATIENTS: HSCT recipients admitted to the ICU. MEASUREMENTS: Demographics, transplant type, stem cell source, APACHE II and III predicted mortality, development of sepsis and organ failure, use of mechanical ventilation, duration of hospital stay, and mortality. RESULTS: Ninety-four percent of the 112 HSCT recipients were white and 64% male. The mean APACHE II and III scores were 25 and 44, respectively. The APACHE II and III hospital predicted mortality rates were 44% and 42%, respectively. Mechanical ventilation was provided to 63%. Organ failure developed in 94% and sepsis in 62%. The ICU, hospital, and 30-day mortality rates were 33%, 46%, and 52%, respectively. Allogeneic transplant and higher APACHE III scores, but not bone marrow stem cell source, were associated with increased mortality. Invasive mechanical ventilation, vasoactive medication use, sepsis, and organ failure during patients' ICU course were also associated with increased mortality. The area under the receiver operating characteristic curve for APACHE III hospital mortality prediction was 0.704 (95% confidence interval, 0.610-0.786). For APACHE III hospital mortality prediction, the value of the Hosmer-Lemeshow statistic showed good model fit. CONCLUSIONS: Current mortality figures of HSCT recipients admitted to the ICU are better than previously reported. The APACHE III prognostic model has moderate discrimination and good calibration in predicting hospital mortality in these patients.

APACHE↗