Evidence Of Clonal Proliferation Research Articles

Flow cytometry for systemic mastocytosis

Mastocytosis is a heterogeneous group of disorders characterised by abnormal proliferation of mast cells. In most cases of adult mastocytosis it is possible to demonstrate evidence of clonal proliferation. As is the case with other clonal disorders of haematopoietic lineage, flow cytometry has become a major diagnostic modality. Flow cytometry is particularly useful in the diagnosis of systemic mastocytosis, where the mast cells may still occur at a very low frequency in the bone marrow, despite neoplastic growth. Numerous studies have compared immunophenotype of mast cells in mastocytosis and those in normal and diseased controls. Some aberrantly expressed antigens on mast cells are of such high specificity for systemic mastocytosis that their expression on mast cells has become a minor World Health Organisation (WHO) criterion for diagnosis (CD2, CD25). This presentation will discuss the phenotype of normal mast cell and compare with abnormal immunophenotype – both in the context of the WHO diagnostic criteria as well as other diagnostically useful antigens that are not part of the criteria.

Renal smooth muscle hamartoma

A large (4 cm in diameter) smooth muscle tumor was found in the medial aspect of the right kidney in a 54-year-old Caucasian woman with acute hypertension. Clonality assay (HUMARA) showed no evidence of clonal proliferation, and array comparative genomic hybridization (aCGH) analysis failed to identify any copy number genomic change. These findings are consistent with smooth muscle hamartoma, a rare benign renal tumor-like lesion.

Hypereosinophilic syndromes (HESs) variable clinical presentations and responses to treatment

17529 Background: Hypereosinophilic syndromes (HESs) refers to a heterogenous group of disorders characterised by marked blood eosinophilia (>1500/cu mm) and tissue eosinophilia (lasting for more than 6 months), in the absence of other eitiologies for eosinophilia, resulting in end organ damage. Eosinophilias may be reactive or due to a chronic myeloproliferative disorder (with evidence of clonal proliferation).Clonal eosinophilias are very often associated with the fusion gene FIP1L1-PDGFR alpha which causes the generation of a constitutively active Tyrosine Kinase. Treatment modalities for HES includes corticosteroids, chemotherapeutic agents, alpha- interferon, tyrosine kinase inhibitors (eg Imatinib mesylate) and the monoclonal anti-interleukin 5. Patients carrying FIP1L1-PDGFRalpha respond very well to Imatinib. Aim:Retrospective review of the variable response of 7 patients with HES (over a period of 6 months), to current treatment modalities. Methods: The 7 patients (6 Male, 1 Female; age range 37–80 yrs; mean age 56 yr) presented with eosinophilia in the range 2600–73,000 /cu mm.They were followed up for >6 months. A response to treatment was defined as Eosinophil count<1500 /cumm or Eosinophil count < 5% of the total leucocyte count .Four of the 7 patients received Imatinib as initial treatment. Two patient initially had steroids followed by Imatinib and 1 patient (aged 80 yr) was treated with Hydroxyurea initially. Results: Four of the 6 patients receiving Imatinib responded to it. Of the 2 patients not responding to Imatinib,1 responded partially to Hydroxyurea and the other did not respond to monotherapy with steroid or alpha-interferon (but eventually responded to a combination of the two). The patient who had initial treatment with Hydroxyurea responded well. Of the 7 patients 1 was positive for the FIP1L1-PDGFRalpha fusion gene,1 result was equivocal, 3 were negative and 2 were not tested (not available at the time). Of the 2 that were negative,1 responded to Imatinib. Conclusions: Response of HES patients to the various treatment modalities, is variable and often unpredictable.The FIP1L1-PDGFR alpha fusion gene is not often present;however other Tyrosine Kinases may be dysregulated and hence a trial of Imatinib is worth considering in most cases. No significant financial relationships to disclose.

Hypereosinophilic Syndromes (HES)-Variable Presentation and Response to Current Treatment Options: Absence of the FIP1L1-PDGFRa Fusion Gene Does Not Exclude Imatinib as a Treatment Option.

Background: Hypereosinophilic syndromes (HES) refers to a heterogenous group of disorders characterised by marked blood eosinophilia (>1500/cu mm) and tissue eosinophilia (lasting for more than 6 months), in the absence of other eitiologies for eosinophilia, resulting in end organ damage. Eosinophilias may be a reactive condition or a chronic myeloproliferative disorder( with evidence of clonal proliferation). Reactive eosinophilias are due to release of cytokines(IL-3, IL-5, GM-CSF etc) and the common causes are parasitic (helminthic) infections, allergic diseases, vasculitides drug reactions and malignancies. Clonal eosinophilias are those in which the eosinophilia is a part of a clonal haematological malignancy, which is very often associated with the fusion gene FIP1L1-PDGFR alpha which causes the generation of a constitutively active Tyrosine Kinase. Several visceral complications like cardiomyopathies, nervous system involvement (eg paraparesis, cerebral infarction, eosinophilic meningitis etc) are often fatal illnesses. Treatment modalities for HES includes corticosteroids, chemotherapeutic agents(hydroxyurea, cyclophosphamide, vincristine) and alpha-interferon. Newer treatment modalities including tyrosine kinase inhibitors(eg Imatinib mesylate) and monoclonal anti-IL5 antibodies are now available. Patients carrying this fusion gene respond well to the Tyrosine Kinase Inhibitor, Imatinib. Some patients with HES, that are negative for this fusion gene, may also respond to Imatinib, suggesting that in such cases other Tyrosine Kinases may be dysregulated.Aim: Retrospective review of the variable response of 7 patients with HES (over a period of 6 months), to current treatment modalities.Methods: The 7 patients (6 Male, 1 Female; age range 37–80 yrs; mean age 56 yr) presented with eosinophilia in the range 2600–73,000/cumm. A response to treatment was defined as Eosinophil count<1500/cumm or Eosinophil count < 5% of the total leucocyte count in the peripheral blood. Four of the 7 patients received Imatinib as initial treatment. Two patient initially had steroids(Prednisolone/Methyl Prednisolone) followed by Imatinib and 1 patient (aged 80 yr) was treated with Hydroxyurea initially.Results: Four of the six patients receiving Imatinib responded to it. Of the 2 patients not responding to Imatinib,1 responded partially to Hydroxyurea and the other did not respond to monotherapy with steroid or alpha-interferon(but eventually responded to a combination of steroids and alpha-interferon). The patient who had initial treatment with Hydroxyurea responded well. Of the 7 patients 1 was positive for the FIP1L1-PDGFRa fusion gene. One was equivocal, 3 were negative and 2 were not tested. Of the 2 that were negative 1 responded to Imatinib(see table).Summary: Thus response of HES patients to the various treatment modalities is variable and often unpredictable. A trial of Imatinib is worth considering in all cases including the ones that are negative for the fusion gene, as they often respond.

Imatinib Mesylate Can Induce Molecular Complete Remission in Idiopathic Hypereosinophilic Syndrome (HES). A Phase II Multicentric Italian Clinical Trial.

Idiopathic hyper-eosinophilic syndrome (HES) is a rare haematological disorder characterized by persistent peripheral blood greater than 1,500 cells/μL lasting for more than 6 months, in the absence of other apparent aetiologies for eosinophilia with signs and symptoms of organ involvement. HES may be a reactive condition or a chronic myeloproliferative disorder with evidence of clonal proliferation, in which latter case it is usually referred to as chronic eosinophilic leukemia (CEL). Patients with HES generally have a poor prognosis, but the course of the disease may be variable. Severe visceral complications, including cardiopathies, are common and are often fatal illness. Treatment of HES includes corticosteroids, chemotherapeutic agents (such as cyclophosphamide, vincristine, and hydroxyurea), and, more recently, interferon-alpha (IFN-alpha).Recently, Cools et al. reported the involvement of PDGFRA, fused with FIP1L1, in a number of HES patients responsive to imatinib therapy. We treated with imatinib mesylate (100 to 400 mg daily) 59 patients affected by Hyper-Eosinophilic Syndrome (HES) enrolled in a multicentric Italian phase 2 clinical trial. All the patients were studied by molecular analysis for expression of FIP1L1-PDGFRA, TEL-PDGFRB, FGFR1-BCR and BCR-ABL chimerical transcripts. 32 patients (45%) were positive for the FIP1L1-PDGFRA rearrangement. Rapid, haematological complete responses (HCR) were recorded after one month of therapy in all FIP1L1-PDGFRA positive. In 36 patients resulted negative for FIP1L1-PDGFRA rearrangement we observed 8 (22%) hematological improvement (HI) and one HCR (HI+HCR 25%). Furthermore, a molecular complete remission (defined as the disappearance of FIP1L1-PDGFRA at qualitative RT-PCR evaluation) was recorded in 13 (68%) patients of the 19 valuable after three months of therapy, and all but one (94%) patients resulted negative for the presence of the rearrangement after six months of therapy. No significant toxicity was seen during the treatment. The median follow up was 4 months (range: 2–39). This is the largest series of HES patients treated with Imatinib with strong evidence of hematological and molecular effectiveness and absence of long term significant toxicity.This phase II study supports the use of Imatinib as first line therapy in FIP1L1-PDGFRA rearrangements positive HES patients. Acknowledgments: COFIN 2003, by FIRB 2001, by the University of Bologna (60%), by the Italian Association for Cancer Research (A.I.R.C.), by the Italian National Research Council (C.N.R), by Fondazione Del Monte of Bologna and Ravenna (Italy), A.I.L. grants, European LeukemiaNet grants.

Is PLC a Clonal T-Cell Lymphoproliferative Disorder?

The nature of pityriasis lichenoides chronica (PLC) and its relationship to pityriasis lichenoides et varioliformis acuta (PLEVA) and mycosis fungoides (MF) remain enigmatic. Recently, evidence of clonal proliferation has been reported in cases of PLEVA, strengthening the evidence that …

Cytogenetic evidence of clonal proliferation of leukemic progenitor cells from patients with acute promyelocytic leukemia (APL)

We have studied in-vitro growth of leukemic progenitor cells (L-CFU) in ten patients with acute promyelocytic leukemia (APL). All patients showed consistently an extraordinarily high incidence of cluster formation under the stimulation of human placental conditioned medium (HPCM) and/or phytohemagglutinin-stimulated leukocyte conditioned medium (PHA-LCM). Cytogenetic analyses of clusters or colonies disclosed the presence of a 15;17 translocation. These findings may represent the close relationship between specific chromosomal aberration, t(15;17), and the growth pattern of L-CFU of APL in vitro.

The effects of sexual and asexual reproduction on geographic variation in the sea anemone Actinia tenebrosa

Allelic and genotypic frequencies were determined for samples from 35 widely distributed Australasian colonies of Actinia tenebrosa and 2 South African colonies of A. equina. These data provided no evidence of gene flow between Australisian and South African Actinia colonies and indicated that there may be some restriction of gene flow between widely separated Australasian colonies.Both species are viviparous, and brooded A. tenebrosa are known to be produced asexually. The present data indicate that, within both species, almost all genotypic diversity is generated by sexual reproduction with recombination. Sexually produced juveniles appear to be widely dispersed and panmixis may occur over thousands of kilometres. However, successful sexual recruitment must be episodic or rare. Colonies on stable shores displayed relatively low levels of genotypic diversity, as compared with expectations for sexually reproducing populations, indicating strong local effects of asexual recruitment. Clonal genotypes may be spread over hundreds of metres of shore, but are typically restricted to discrete colonies. Asexual recruitment is highly localised and asexual dispersal appears to be limited by lengths of shore (≤500 m) which are unsuitable for colonization. Colonies on unstable shores are significantly more diverse genotypically and show little evidence of clonal proliferation.