Posted by rob on September 24, 2010 under Uncategorized | 
Superior ophthalmic vein thrombosis in a patient with chronic myeloid leukemia receiving antifibrinolytic and thrombopoietin receptor agonist therapy.
J Ocul Pharmacol Ther. 2010 Jun;26(3):293-6
Authors: Shinder R, Oellers P, Esmaeli B, Schiffman JS
Isolated superior ophthalmic vein (SOV) thrombosis is a rare condition usually related to inflammation of the orbit or paranasal sinuses. Patients present with acute orbital signs, including proptosis, ophthalmoplegia, globe dystopia, and periorbital edema, and may have diminished vision secondary to optic neuropathy. SOV thrombosis is typically seen in the setting of septic cavernous sinus thrombosis, and antimicrobial therapy is the treatment of choice. We herein report what may be the first case of isolated SOV thrombosis related to hypercoagulability in a patient with cancer who was receiving antifibrinolytic and thrombopoietin receptor agonist medications.
PMID: 20565317 [PubMed - indexed for MEDLINE]
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Hematology. Imatinib–should we have more of a good thing?
Nat Rev Clin Oncol. 2010 Jun;7(6):303-4
Authors: Apperley JF
Imatinib 400 mg has been the first-line therapy for chronic myeloid leukemia (CML) since 2001 but may have been licensed at too low a dose. A recent study compared the standard dose with higher doses in patients with newly diagnosed CML and found no difference in response rates at 12 months. But, is the devil in the detail?
PMID: 20517337 [PubMed - indexed for MEDLINE]
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Chronic myeloid leukaemia at the University Hospital of the West Indies: a 17-year review.
West Indian Med J. 2008 Nov;57(5):493-6
Authors: Buchner-Daley LM, Brady-West DC
OBJECTIVE: To determine the presenting features and evolution of patients diagnosed with chronic myeloid leukaemia between 1983 and 1999 at the University Hospital of the West Indies. METHODS: Forty-one records were retrospectively analyzed for the patients’ demographics, reasons for referral, clinical features, laboratory investigations and the time to blast transformation and death. RESULTS: Seventy-one per cent were males and 29% were females. The male to female ratio was 2.4:1. The median age at presentation was 37 years (range 14-81 years). Seventy-eight per cent of the patients presented in the chronic phase. Weight loss and splenomegaly were the most frequent presenting features being seen in 54 and 83 per cent respectively. The median survival was 36 months. CONCLUSION: In this study, the clinical features and evolution were comparable to existing data. Improved accrual and routine Philadelphia chromosome testing would provide a more accurate reflection of the status of CML in our population.
PMID: 19565982 [PubMed - indexed for MEDLINE]
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Posted by rob on September 23, 2010 under Uncategorized |
Acquired Robertsonian translocation is not always suggestive of poor prognosis: a case of acquired Rob(13;14) in Philadelphia chromosome-negative cells of chronic myelogenous leukemia.
Leuk Lymphoma. 2010 Sep 21;
Authors: Mu Q, Cheng Y, Xu W, Wang Y, Chen Z, Jin J
PMID: 20858089 [PubMed - as supplied by publisher]
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Posted by rob on September 17, 2010 under Uncategorized |
The BCR/ABL-inhibitors imatinib, nilotinib and dasatinib differentially affect NK cell reactivity.
Int J Cancer. 2010 Nov 1;127(9):2119-28
Authors: Salih J, Hilpert J, Placke T, Grünebach F, Steinle A, Salih HR, Krusch M
In chronic myeloid leukemia (CML), BCR/ABL-mediated oncogenic signaling can be targeted with the BCR/ABL-inhibitors Imatinib, Nilotinib and Dasatinib. However, these agents may also affect anti-tumor immunity. Here, we analyzed the effects of the 3 BCR/ABL-inhibitors on natural killer (NK) cell reactivity. Exposure of CML cells (K562, Meg-01) to pharmacological concentrations of Imatinib, Nilotinib and Dasatinib diminished expression of ligands for the activating immunoreceptor NKG2D to a similar extent. This resulted in comparably reduced NK cell cytotoxicity and IFN-gamma production. When direct effects on NK cell responses to K562 and primary CML cells as well as activating cytokines were studied, Dasatinib was found to abrogate NK cytotoxicity and cytokine production. Nilotinib did not alter cytotoxicity but, at high levels, impaired NK cytokine production, while Imatinib had no direct influence on NK cell reactivity. Of note, Nilotinib, but not the other BCR/ABL-inhibitors increased cell death within the preferentially cytokine-secreting CD56(bright)CD16(-) NK cell subset, which may, at least in part, serve to explain the effect of Nilotinib on NK cytokine production. Analysis of NK cell signaling revealed that Dasatinib inhibited proximal signaling events leading to decreased phosphorylation of PI3K and ERK that are crucial for NK cell reactivity. Imatinib and Nilotinib, in contrast, showed no relevant effect on NK cell PI3K or ERK activity. In light of the potential role of NK cells in the immunesurveillance of residual leukemia and for future combinatory immunotherapeutic approaches, our data indicate that choice and dosing of the most suitable BCR/ABL-inhibitor for a given patient require careful consideration.
PMID: 20143399 [PubMed - indexed for MEDLINE]
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Posted by rob on September 16, 2010 under Uncategorized |
Acute myelogenous leukemia in a patient with severe factor IX deficiency.
Pediatr Blood Cancer. 2010 Sep 14;
Authors: Clark C, Gidvani VK
We present a case of acute myelogenous leukemia in a patient with severe hemophilia and our approach to the prevention of bleeding complications during chemotherapy. In the few reports of acute leukemia occurring in patients with hemophilia, management of bleeding has mostly consisted of replacement of factor and platelets on demand. By prophylactically treating our patient with Factor IX at 50% correction three times per week and maintaining his platelet count above 30â??Ã?â??10(3)/mm(3), bleeding complications were avoided. However, due to the rarity of this combination, it is difficult to draw a best practice recommendation. Pediatr Blood Cancer. © 2010 Wiley-Liss, Inc.
PMID: 20842752 [PubMed - as supplied by publisher]
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Expression of myelopoiesis-associated microRNA in bone marrow cells of atypical chronic myeloid leukaemia and chronic myelomonocytic leukaemia.
Ann Hematol. 2010 Sep 15;
Authors: Hussein K, Büsche G, Muth M, Göhring G, Kreipe H, Bock O
The microRNA/miR deregulation in BCR-ABL-negative myelodysplastic-myeloproliferative neoplasms (MDS/MPN) is not known. Myelopoiesis-associated miR-10a, miR-17-5p, miR-155, miR-223 and miR-424 were analysed by real-time polymerase chain reaction (PCR) in bone marrow cells of atypical chronic myeloid leukaemia (aCML, nâ??=â??7) and chronic myelomonocytic leukaemia (CMML, nâ??=â??8) and were compared to BCR-ABL-positive chronic myelogenous leukaemia (CML, nâ??=â??10) and non-neoplastic haematopoiesis (nâ??=â??10). Down-regulation of miR-10a was found in CMML but also in CML (each pâ??<â??0.05, versus controls). Overexpression of miR-424 was detected in aCML (pâ??<â??0.05, versus CML and controls). Despite different compositions of bone marrow cells, expression of myelopoiesis-associated microRNA shows mainly similar patterns in aCML and its main differential diagnosis CMML and does not allow discrimination of these two MDS/MPN entities. Therefore, the link of deregulated microRNA expression to disease-related phenotype and the underlying molecular mechanism are still unknown.
PMID: 20842500 [PubMed - as supplied by publisher]
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Chloroma/Granulocytic Sarcoma: Abdominal & Pelvic Presentation of Acute Myelogenous Leukemia.
J Cancer. 2010;1:98-100
Authors: Tsikitis VL, Corning C, Henderson J, Rose J
There is limited literature documenting granulocytic sarcoma of the colon. We report a case of a 28 year-old female with a colonic granulocystic sarcoma of the colon as a complication of AML, as it is an important consideration with surgical management of typhilitis.
PMID: 20842230 [PubMed - as supplied by publisher]
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Clonal chromosomal abnormalities in CD34+/CD38- hematopoietic cells from cytogenetically normal chronic myeloid leukemia patients with a complete cytogenetic response to tyrosine kinase inhibitors.
Leukemia. 2010 Aug;24(8):1525-8
Authors: Bumm T, Deininger J, Newell AH, Lawce H, Olson S, Mauro M, Druker B, Deininger M
PMID: 20535153 [PubMed - indexed for MEDLINE]
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BCR and BCR-ABL regulation during myeloid differentiation in healthy donors and in chronic phase/blast crisis CML patients.
Leukemia. 2010 Aug;24(8):1445-9
Authors: Marega M, Piazza RG, Pirola A, Redaelli S, Mogavero A, Iacobucci I, Meneghetti I, Parma M, Pogliani EM, Gambacorti-Passerini C
Chronic myeloid leukemia (CML) is caused by the BCR-ABL hybrid gene. The molecular mechanisms leading from chronic phase (CP) to blast crisis (BC) are not understood. However, both the presence and the levels of BCR-ABL seem to be important for CML progression. BCR-ABL is under the transcriptional control of BCR promoter. Here we focused on the gene expression control of BCR and BCR-ABL upon myeloid differentiation in healthy donors (HDs), CP and BC patients. As previously reported, BCR-ABL is downregulated during myeloid maturation in CP patients. A similar pattern was detected for BCR (but not for ABL) in CP-CML and in HD, thus suggesting that the two genes may be under a similar transcriptional control. In BC this mechanism is similarly impaired for both BCR-ABL and BCR. These data indicate the presence of an ‘in trans’ deregulated transcription of both BCR and BCR-ABL promoters, associated with CML progression.
PMID: 20520635 [PubMed - indexed for MEDLINE]
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Posted by rob on September 15, 2010 under Uncategorized |
Chronic myelogenous leukemia maintains specific CD8(+) T cells through IL-7 signaling.
Eur J Immunol. 2010 Jul 30;
Authors: Mumprecht S, Schürch C, Scherrer S, Claus C, Ochsenbein AF
Chronic myelogenous leukemia (CML) is a malignant myeloproliferative disease of hematopoietic stem cells. The disease progresses after several years from an initial chronic phase to a blast phase. Leukemia-specific T cells are regularly detected in CML patients and may be involved in the immunological control of the disease. Here, we analyzed the role of leukemia-specific CD8(+) T cells in CML disease control and the mechanism that maintains CD8(+) T-cell immunosurveillance in a retroviral-induced murine CML model. To study antigen-specific immune responses, the glycoprotein of the lymphocytic choriomeningitis virus was used as model leukemia antigen. Leukemia-specific CTL activity was detectable in vivo in CML mice and depletion of CD8(+) T cells rapidly led to disease progression. CML-specific CTL were characterized by the expression of the IL-7 receptor α-chain. In addition, leukemia cells produced IL-7 that was crucial for the maintenance of leukemia-specific CTL and for disease control. Therefore, CML cells maintain the specific CD8(+) T-cell-mediated immune control by IL-7 secretion. This results in prolonged control of disease and probably contributes to the characteristic chronic phase of the disease.
PMID: 20836157 [PubMed - as supplied by publisher]
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Inhibitor screening of protein kinases using MALDI-TOF MS combined with separation and enrichment of phosphopeptides by TiO(2) nanoparticle deposited capillary column.
Analyst. 2010 Sep 13;
Authors: Lü S, Luo Q, Li X, Wu J, Liu J, Xiong S, Feng YQ, Wang F
A MALDI-TOF mass spectrometric method for rapid screening of protein tyrosine kinase (PTK) inhibitors has been developed. To circumvent the ion suppression of phosphorylated substrate peptides caused by the presence of high abundant non-phosphorylated peptides in the enzymatic reaction mixtures, a separation and enrichment process of the phosphorylated peptides from complex mixtures was carried out by using an in-house fabricated TiO(2) nanoparticle-coated capillary column prior to the MS analysis. With a synthetic phosphopeptide (DAIpYAAPFAKKK), of which the sequence is similar to that of the substrate (EAIYAAPFAKKK) of the Abelson tyrosine kinase (Abl), as the internal standard, the signal ratio of the phosphorylated substrate to the standard detected by MALDI-TOF MS is linearly correlated with the molar ratio of the two phosphopeptides over the range of 0.3 to 3 with r(2) = 0.99. We validated the MS method by determining the IC(50) value of imatinib, an Abl inhibitor for clinical treatment of chronic myelogenous leukaemia (CML). The obtained IC(50) value (234 nM) is consistent with that determined by ELISA (291 nM). Then, six analogues of imatinib synthesized in our laboratory were screened using the method, giving rise to inhibitory potential results which are in good agreement with the docking analysis data. The developed method is sensitive, operationally simple, does not require isotope-labelling and is cost/time effective, providing an alterative method for rapid screening of PTK inhibitors as therapeutic agents for tumours.
PMID: 20835477 [PubMed - as supplied by publisher]
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Simultaneous occurrence of chronic lymphocytic and chronic myeloid leukemia.
Coll Antropol. 2010 Jun;34(2):653-5
Authors: KatoviÄ? SK, Vasilj A, MariceviÄ? I, Carzavec D, JuriÄ? SC
The coexistence of chronic lymphocytic (CLL) and chronic myeloid leukemia (CML) in the same patient has only been reported occasionally. Most of these cases represent the patients who developed CLL during the course of CML. Reviewing the literature, only a few cases of simultaneous occurrence of CLL and CML were found. Here we represent a previously healthy 50-year old man in whom the diagnosis of CLL and CML was established by FNAB of the bone marrow. The diagnosis was then confirmed by histopathology, immunophenotypization of the peripheral blood and by a cytogenetic study of the bone marrow. Four years after the diagnosis the patient is well, with leucocytosis of 40 x 10(9)/L, and lymphocytosis of 93%.
PMID: 20698147 [PubMed - indexed for MEDLINE]
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Membranoproliferative glomerulonephritis secondary to chronic myeloid leukemia.
Saudi J Kidney Dis Transpl. 2010 Jul;21(4):738-41
Authors: Subramanian M, Kilara N, Manjunath R, Mysorekar V
The nephrotic syndrome (NS) is a well documented complication of hematological malignancies. However, chronic myeloid leukemia (CML) is rarely complicated by the NS, and it occurs usually after allogenic stem cell transplantation or interferon alpha therapy for CML. The NS as a complication of untreated CML is also rare. We report a 31-year-old patient who presented with features of The NS. He was diagnosed to have CML one year ago and was on irregular treatment with imatinib mesylate. The renal biopsy and immunofluorescence revealed membrano-proliferative glomerulonephritis type I. The patient was retreated with imatinib mesylate and the NS resolved gradually over three months. This maybe the third case in literature of membrano-proliferative glomerulonephritis associated with CML.
PMID: 20587884 [PubMed - indexed for MEDLINE]
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Renal lymphangiectasia associated with chronic myeloid leukemia.
Saudi J Kidney Dis Transpl. 2010 Jul;21(4):724-7
Authors: Rastogi R, Rastogi UC, Sarikwal A, Rastogi V
Renal lymphangiectasia is a rare disorder characterized by dilatation of peripelvic, renal and perirenal lymphatic ducts. The exact etiology is not known. Congenital forms and ac-quired forms have been described. The latter has been attributed to obstruction of draining retro-peritoneal lymphatic ducts caused by either infection, inflammation or any other cause. We des-cribe the rare association of renal lymphangiectasia with chronic myeloid leukemia, which is probably not yet reported in the medical literature.
PMID: 20587880 [PubMed - indexed for MEDLINE]
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Graft-versus-leukemia effects of Wilms’ tumor 1 protein-specific cytotoxic T lymphocytes in patients with chronic myeloid leukemia after allogeneic hematopoietic stem cell transplantation.
Chin Med J (Engl). 2010 Apr 5;123(7):912-6
Authors: Wang ZD, Li D, Huang XJ
BACKGROUND: The role of Wilms’ tumor 1 protein (WT1)-specific cytotoxic T cells (CTL) in eradicating chronic myeloid leukemia (CML) cells is to be established. The aim of this study was to determine whether WT1 contributed to the graft-versus-leukemia effects (GVLE) for CML following allogeneic hematopoietic stem cell transplantation (HSCT). METHODS: High-resolution human leukocyte antigen (HLA) class I genotyping was performed by sequence-specific polymerase chain reaction (PCR). Fifteen HLA-A*2402 patients with CML who underwent allogeneic HSCT were enrolled in this study. We monitored the frequency of WT1-specific CTL by pentamer assay and the molecular minimal residual disease by real-time quantitative PCR. RESULTS: A CD8(+) T-cell response to WT1 was observed in 14 of 15 patients after HSCT. The median frequencies of WT1-CTL were 0.54%, 0.62%, 0.81% and 1.28% (%CD8) on days 30, 60, 90 and 180, respectively. The median frequency of WT1-CTL (1.38%) in patients with molecular remission (MoR) was significantly higher than that in those without MoR (0.38%) on day 30, while no significant differences between them were detected on days 60, 90 and 180. The increase of WT1-CTL was associated with a decrease in bcr-abl expression and MoR; and the decrease of WT1-CTL was associated with an increase in bcr-abl expression, suggesting a WT1-driven GVL effect. WT1-CTL had a predominant effector-memory phenotype (CD45RO(+)CD27(-)CD57(+)). CONCLUSIONS: The emergence of WT1-CTL with an effector-memory phenotype is associated with GVLE in CML patients after HSCT. This will pave the way for the WT1 vaccines to enhance GVLE after HSCT in CML.
PMID: 20497687 [PubMed - indexed for MEDLINE]
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Allogeneic hematopoietic stem cell transplantation for adult acute lymphoblastic leukemia.
Cancer Treat Res. 2009;144:441-54
Authors: Weisdorf D, Forman S
PMID: 19779879 [PubMed - indexed for MEDLINE]
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Posted by rob on September 12, 2010 under Uncategorized |
Changes in cell adhesivity and cytoskeleton-related proteins during imatinib-induced apoptosis of leukemic JURL-MK1 cells.
J Cell Biochem. 2010 Sep 9;
Authors: Kuželová K, Pluskalová M, Grebenová D, Pavlásková K, Halada P, Hrkal Z
The fusion protein Bcr-Abl, which is the molecular cause of chronic myelogenous leukemia (CML) interacts in multiple points with signaling pathways regulating the cellular adhesivity and cytoskeleton architecture and dynamics. We explored the effects of imatinib mesylate, an inhibitor of Bcr-Abl protein used in front-line CML therapy, on the adhesivity of JURL-MK1 cells to fibronectin and searched for underlying changes in the cell proteome. As imatinib induces apoptosis of JURL-MK1 cells, we used three different caspase inhibitors to discriminate between direct consequences of Bcr-Abl inhibition and secondary changes related to the apoptosis. Imatinib treatment caused a transient increase in JURL-MK1 cell adhesivity to fibronectin, possibly due to the switch off of Bcr-Abl activity. Subsequently, we observed a number of changes including a decrease in cell adhesivity, F-actin decomposition, reduction of integrin β1, CD44 and paxillin expression levels and a marked increase in cofilin phophorylation at Ser3. These events were generally related to the proceeding apoptosis but they differed in their sensitivity to the individual caspase inhibitors. © 2010 Wiley-Liss, Inc.
PMID: 20830748 [PubMed - as supplied by publisher]
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Granulocytic Sarcoma Mimicking HSV Encephalitis.
Neurologist. 2010 Sep;16(5):319-21
Authors: Shah RS, Shin RK, Castellani RJ
INTRODUCTION:: Granulocytic sarcomas, or chloromas, are extramedullary collections of immature granulocytes. Central nervous system involvement is rare and of those cases described, most are complications of acute myelogenous leukemia. CASE REPORT:: A 40-year-old man with chronic myelogenous leukemia presented with seizure and encephalopathy. Magnetic resonance imaging of the brain revealed temporal T2 hyperintensities with gyriform cortical enhancement. Cerebrospinal fluid showed mild pleocytosis and elevated protein. Electroencephalography demonstrated periodic lateralized epileptiform discharges. Acyclovir was initiated for herpes simplex encephalitis, however, follow-up MRI showed extension of the lesion. MR spectroscopy suggested tumor, confirmed by brain biopsy. Postradiation MRI showed a significant decrease in lesion size. CONCLUSION:: Granulocytic sarcoma can present as intraparenchymal cerebral lesions in patients with chronic myelogenous leukemia and may mimic herpes simplex encephalitis.
PMID: 20827123 [PubMed - in process]
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Role of symmetric and asymmetric division of stem cells in developing drug resistance.
Proc Natl Acad Sci U S A. 2010 Sep 8;
Authors: Tomasetti C, Levy D
Often, resistance to drugs is an obstacle to a successful treatment of cancer. In spite of the importance of the problem, the actual mechanisms that control the evolution of drug resistance are not fully understood. Many attempts to study drug resistance have been made in the mathematical modeling literature. Clearly, in order to understand drug resistance, it is imperative to have a good model of the underlying dynamics of cancer cells. One of the main ingredients that has been recently introduced into the rapidly growing pool of mathematical cancer models is stem cells. Surprisingly, this all-so-important subset of cells has not been fully integrated into existing mathematical models of drug resistance. In this work we incorporate the various possible ways in which a stem cell may divide into the study of drug resistance. We derive a previously undescribed estimate of the probability of developing drug resistance by the time a tumor is detected and calculate the expected number of resistant cancer stem cells at the time of tumor detection. To demonstrate the significance of this approach, we combine our previously undescribed mathematical estimates with clinical data that are taken from a recent six-year follow-up of patients receiving imatinib for the first-line treatment of chronic myelogenous leukemia. Based on our analysis we conclude that leukemia stem cells must tend to renew symmetrically as opposed to their healthy counterparts that predominantly divide asymmetrically.
PMID: 20826440 [PubMed - as supplied by publisher]
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