Posted by rob on January 9, 2012 under Uncategorized | 
During the week I graduated from high school, my mother was diagnosed with chronic myelogenous leukemia (CML). Today, patients with CML are treated with imatinib and do remarkably well, but at the time, there was no effective treatment available and my mother passed away three years later. Watching her battle with cancer spurred my interest in medical research. I currently study pancreatic cancer.
read more (Source: Stand Up 2 Cancer)
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Imatinib mesylate treatment markedly reduces the burden of leukemia cells in chronic myelogenous leukemia (CML) patients. However, patients remain at risk for relapse on discontinuing treatment. We have previously shown that residual BCR-ABL+ progenitors can be detected in CML patients within the first 2 years of imatinib treatment. However, reduced rates of relapse and continued decline of BCR-ABL levels with prolonged treatment, together with the ability of selected patients to maintain remission after discontinuing treatment, led us to investigate whether prolonged imatinib exposure resulted in reduction or elimination of BCR-ABL+ stem cells. We evaluated BCR-ABL expression in CD34+CD38+ (38+) committed progenitors and CD34+CD38– (38–) stem/primitive progenitor cells in samp…
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Authors: Serpa M, Sanabani SS, Dorlhiac-Llacer PE, Nardinelli L, de Barros Ferreira P, Borges Martins TF, Seguro F, Bendit I
Abstract
Despite the beneficial effects of imatinib mesylate, some patients may either not respond or respond suboptimally. Here, we report two chronic myelogenous leukemia patients; one had a suboptimal response according to European LeukemiaNet criteria (a major molecular response was not achieved after 18 months of standard-dose imatinib therapy) and the other had failure with a standard dose of imatinib. At the time of the suboptimal response in patient 1 and the failure in patient 2, we were able to detect the F359I mutation in the BCR-ABL tyrosine kinase domain using DNA sequencing in both patients. Therefore, it was decided to change the therapeutic re…
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AbstractDisease overview: Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by stem cell?derived clonal myeloproliferation, abnormal cytokine expression, bone marrow fibrosis, anemia, splenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, cachexia, leukemic progression, and shortened survival.Diagnosis: Diagnosis is based on bone marrow morphology. The presence of fibrosis, JAK2/MPL mutation or +9/13q? cytogenetic abnormality is supportive but not essential for diagnosis. Prefibrotic PMF mimics essential thrombocythemia in its presentation and the distinction is prognostically relevant. Differential diagnosis of myelofibrosis should include chronic myelogenous leukemia, myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute my…
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Conclusions Aberrant MAPK-activation triggered by ABL-inhibitors and positively regulated by BCR-ABL kinase mutation T315I might be an
experimental explanation for the clinical observation that patients carrying high-resistance mutations show a highly aggressive
course of their disease when tyrosine kinase inhibitor treatment is not discontinued in time.
Content Type Journal ArticleCategory Original PaperPages 1-10DOI 10.1007/s00432-011-1086-xAuthors
Nicolai Härtel, III. Medizinische Universitätsklinik, Universitätsmedizin Mannheim der Universität Heidelberg, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, GermanyThomas Klag, Klinik f. Innere Medizin II, Abt. f. Hämatologie/Onkologie, Universitätsklinikum Jena, Erlanger Allee 101, 07740 Jena, GermanyBenjamin Hanfstei…
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Abstract:? Porokeratosis is a rare disorder of epidermal keratinization that is regarded as a precancerous. Recipients of hematopoietic stem cell transplantation (HSCT) have a greater risk of skin cancer; chronic graft versus host disease (GVHD) is an additional risk factor. A 16?year?old boy who had received HSCT for acute myelogenous leukemia was referred to us for sclerodermoid chronic cutaneous GVHD. Two years later, he developed disseminated porokeratosis with a few atypical lesions. Despite cryotherapy, numerous lesions of porokeratosis recurred rapidly. Acitretin resulted in good clinical response and reduced the rate of onset of new lesions. (Source: Pediatric Dermatology)
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Damien Reynaud, Eric Pietras, Keegan Barry-Holson, Alain Mir, Mikhail Binnewies, Marion Jeanne, Olga Sala-Torra, Jerald P. Radich, Emmanuelle Passegué. Using a mouse model recapitulating the main features of human chronic myelogenous leukemia (CML), we uncover the hierarchy of leukemic stem and progenitor cells contributing to disease pathogenesi…. (Source: Cancer Cell)
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A 56-year-old woman with diabetic retinopathy and chronic myelogenous leukemia had phacoemulsification cataract removal and hydrophilic acrylic intraocular lens (IOL) (Akreos MI-60) implantation in both eyes. One month after surgery, significant IOL opacity and severe cystoid macular edema were observed in both eyes. After bilateral intravitreal injection of bevacizumab (Avastin) to control macular edema, central clearing of the IOL opacity was observed in both eyes. Two months after the injection, the IOL opacity had almost disappeared from both eyes. To our knowledge, this is the first case of early postoperative bilateral IOL opacity in a hydrophilic acrylic IOL cleared after anti-vascular endothelial growth factor (VEGF) intravitreal injection. The role of anti-VEGF therapy in clearing…
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Conclusion
The use of second-generation TKIs as initial therapy in CML induces high rates of CCyR at early time points. The ELN definitions of response proposed for imatinib therapy are not applicable in this setting. We propose that achievement of CCyR and partial cytogenetic response at 3 months should be considered optimal and suboptimal responses, respectively. The achievement of MMR offered no advantage over CCyR in defining long-term outcome in patients with newly diagnosed CML treated with second-generation TKIs. (Source: Journal of Clinical Oncology)
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We describe the case of a 37-year-old woman who had CML and pain in the extremities. She was diagnosed with lymphoid blast crisis of CML on the basis of the following findings: presence of promyelocytes, myelocytes, and metamyelocytes in peripheral blood smear; detection of major and minor BCR/ABL transcripts by polymerase chain reaction analysis; proliferation of lymphoblastic cells with abnormal B-cell phenotype; and aberrant expression of myeloid antigens in the bone marrow. The patient underwent one course of idarubicin and cytosine arabinose therapy combined with imatinib followed by daunorubicin/cyclophosphamide plus vincristine and prednisone/L: -asparaginase (DNR/COP/L: -ASP) therapy, high-dose cytosine arabinose, and CHOP therapy (cyclophosphamide, doxorubicin, vincristine, and pr…
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Although Philadelphia chromosome (Ph) is most commonly associated with chronic myelogenous leukemia (CML) and precursor B acute lymphoblastic leukemia, in rare instances patients with acute myeloid leukemia (AML) have been reported to be carrying this chromosomal anomaly, with occurrences found to be fewer than 1% of all newly diagnosed AML . Selective BCR-ABL1 tyrosine kinase inhibitors (TKIs) induce a high molecular response rate in patients with CML. TKIs have also been reported to be effective in patients with Ph positive (Ph+) de novo AML, especially in patients undergoing post-remission therapy . While Ph chromosome can also appear in the course of AML, late-appearing Ph+ AML is extremely rare and the efficacy of TKIs in such patients remains unclear. (Source: Leukemia Research)
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In this study, we sought to enhance cellular immunity by co-expression of BCR/ABL and murine IL-12 gene on the tumor cell surface as a glycosyl-phosphatidylinositol (GPI)-form. The successfully constructed plasmid pBudCE4.1-BCR/ABL-GPI-mIL12 resulted in high levels of splenocyte proliferative responses, significant levels of IL-2 and IFN-?, and strong cytotoxic T lymphocyte (CTL) responses in vitro. In a murine transplant model, the vaccinated mice showed decreased infiltration of leukemia cells and reduced expression of BCR/ABL transcripts and protein in bone marrow cells. Results of the present study indicated that this novel immunization strategy is useful in enhancing immune protection in mice, which would provide new insights into the development of effective vaccines for treating CM…
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Authors: Ok CY, Singh RR, Vega F
Abstract
The hedgehog (HH) signaling pathway is a highly regulated signaling pathway that is important not only for embryonic development, tissue patterning, and organogenesis but also for tissue repair and the maintenance of stem cells in adult tissues. In the adult hematopoietic system, HH signaling regulates intrathymic T-cell development, and it is one of the survival signals provided by follicular dendritic cells to prevent apoptosis in germinal center B cells. HH signaling is required for primitive hematopoiesis; however, conflicting data have been reported regarding the role of the HH pathway in adult hematopoiesis. Inappropriate activation of the HH signaling pathway occurs in several human cancers, including hematopoietic neoplasms. Emergin…
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Authors: Woessner DW, Lim CS, Deininger MW
Abstract
ABSTRACT: Targeted small-molecule drugs have revolutionized treatment of chronic myeloid leukemia (CML) during the last decade. These agents interrupt a constitutively active BCR-ABL, the causative agent for CML, by interfering with adenosine 5′ triphosphate-dependent ABL tyrosine kinase. Although the efficacy of tyrosine kinase inhibitors (TKIs) has resulted in overall survival of greater than 90%, TKIs are not curative. Moreover, no currently approved TKIs are effective against the T315I BCR-ABL variant. However, a new generation of TKIs with activity against T315I is on the horizon. We will highlight the clinical utility of historical CML therapeutics, those used today (first- and second-generation TKIs), and discuss treatment …
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Authors: Santos FP, Kantarjian H, Quintás-Cardama A, Cortes J
Abstract
ABSTRACT: The clinical outcome for patients with chronic myelogenous leukemia (CML) has changed dramatically in the past 15 years. This has been due to the development of tyrosine kinase inhibitors (TKIs), compounds that inhibit the activity of the oncogenic BCR-ABL1 protein. Imatinib was the first TKI developed for CML, and it led to high rates of complete cytogenetic responses and improved survival for patients with this disease. However, approximately 35% of patients in chronic phase treated with imatinib will develop resistance or intolerance to this drug. The recognition of the problem of imatinib failure led to the design of second-generation TKI (dasatinib, nilotinib, and bosutinib). These drugs are high…
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Authors: Palmeira A, Helena Vasconcelos M, Paiva A, Fernandes MX, Pinto M, Sousa E
Abstract
For many pathologies, there is a crescent effort to design multiple ligands that interact with a wide variety of targets. 1-Aminated thioxanthone derivatives were synthesized and assayed for their in vitro dual activity as antitumor agents and P-glycoprotein (P-gp) inhibitors. The approach was based on molecular hybridization of a thioxanthone scaffold, present in known antitumor drugs, and an amine, described as an important pharmacophoric feature for P-gp inhibition. A rational approach using homology modeling and docking was used, to select the molecules to be synthesized by conventional or microwave-assisted Ullmann C-N cross-coupling reaction. The obtained aminated thioxanthones were hi…
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Before the days of transplantation and tyrosine kinase inhibitor therapy, all cases of chronic myelogenous leukemia would inevitably proceed from chronic phase through accelerated and blast crisis, implying that there is a program of progression set in motion by unopposed BCR-ABL activity. Since then, much work has identified a plethora of genetic changes associated with progression, the common themes being changes in self-renewal, differentiation, and deregulation of apoptotic pathway. Some of the genes and pathways uncovered offer some progress for research on novel therapy for blast crisis. (Source: Hematology/Oncology Clinics of North America)
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Authors: Xiao X, Zhang Y, Zhang GS, Zheng WL, Xiao L, Liu SF
Abstract
No abstract available.
PMID: 22025110 [PubMed - as supplied by publisher] (Source: Acta Haematologica)
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In this study, we investigated the molecular mechanisms for BMME-mediated drug resistance and BM lodgment in chronic myelogenous leukemia (CML). Gene-expression profile as well as signal pathway and protein analyses revealed that galectin-3 (Gal-3), a member of the ?-gal–binding galectin family of proteins, was specifically induced by coculture with HS-5 cells, a BM stroma cell-derived cell line, in all five CML cell lines examined. It was also found that primary CML cells expressed high levels of Gal-3 in BM. Enforced expression of Gal-3 activated Akt and Erk, induced accumulation of Mcl-1, and promoted in vitro cell proliferation, multidrug resistance to tyrosine kinase inhibitors for Bcr-Abl and genotoxic agents as a result of impaired apoptosis induction, and chemotactic cell migrat…
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Conclusion: For patients with TKI resistance, mutation and ACA screening may play a role in identifying patients with poorer prognosis.
PMID: 22005133 [PubMed - as supplied by publisher] (Source: Acta Haematologica)
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