A Worldwide Support Network For Chronic Myelogenous Leukemia
Posted by rob on July 31, 2009 under Uncategorized | 
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Nilotinib-induced bone marrow aplasia.
Eur J Haematol. 2009 Aug;83(2):161-2
Authors: Song MK, Choi YJ, Seol YM, Shin HJ, Chung JS, Cho GJ, Lee EY
PMID: 19459925 [PubMed - indexed for MEDLINE]
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Myofibroblast transformation in metastatic extramedullary chronic myeloid leukemia: a case report.
Ultrastruct Pathol. 2009;33(3):136-40
Authors: Ru YX, Eyden B, Li QH, Mao BY, Liu EB, Pang TX
Primary and metastatic carcinomas have a reactive stroma characterized by many myofibroblasts. These cells have also been documented in nonepithelial malignancies, such as sarcomas, malignant melanoma, and lymphoid tumors but in generally far fewer numbers. In non-Hodgkin’s lymphoma, Hodgkin’s disease, and leukemia, myofibroblasts are rather rarely documented. In particular, there appear to be no reports of myofibroblasts in either primary bone-marrow/peripheral blood leukemia or secondary deposits of leukemia. In this paper, a case of a relapsed chronic myeloid leukemia appearing in an inguinal lymph node is described, containing many myofibroblasts. The case is detailed and presented with a discussion on the role of myofibroblasts in the progression of nonepithelial cancers.
PMID: 19479654 [PubMed - indexed for MEDLINE]
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Chronic Myelogenous Leukemia with the e6a2 BCR-ABL and Lacking Imatinib Response: Presentation of Two Cases.
Acta Haematol. 2009 Jul 29;122(1):11-16
Authors: Vefring HK, Gruber FX, Wee L, Hovland R, Hjorth-Hansen H, Gedde Dahl T, Meyer P
The BCR-ABL fusion gene represents the hallmark of chronic myelogenous leukemia (CML) and is derived from a translocation between chromosome 9 and 22. The majority of CML patients have a breakpoint in the major BCR region of the BCR gene giving rise to e13a2 or e14a2 BCR-ABL transcripts. Occasionally, other BCR breakpoints occur. The current report describes two e6a2 CML patients with imatinib treatment failure and unusual disease progression. One patient was Philadelphia chromosome positive and one was Philadelphia chromosome negative with an atypical BCR-ABL rearrangement, ins (22;9).
PMID: 19641300 [PubMed - as supplied by publisher]
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In this study, we retrospectively analyzed the records of 24 patients who received allogeneic SCT from an HLA-matched sibling donor for acute and chronic myelogenous leukemia. Univariate analysis showed that two factors (the serum CsA level at the third week after SCT and the LDH level at the third week after SCT) were significantly associated with the incidence of aGVHD among several variables (age, sex, stem cell source, cell dose, C-reactive protein, absolute lymphocyte count, conditioning regimens, and time to engraftment). A higher serum level of CsA and lower serum LDH level at the third week after SCT were associated with a lower incidence of aGVHD (P=0.015, 0.030). In multivariate analysis, the serum CsA level (hazard ratio [HR], 0.12; 95% confidence interval [CI], 0.022-0.652, P=0…
Posted by rob on July 30, 2009 under Uncategorized | Comments are off for this article
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Successful treatment with intensive immunosuppressive therapy and mechanical ventilation for idiopathic pneumonia syndrome following allogeneic bone marrow transplantation.
Rinsho Ketsueki. 2009 Jul;50(7):563-7
Authors: Hino H, Kawatani E, Kuwahara N, Tominaga M, Matsuishi E, Masuda M, Mori D, Gondo H
A 45-year-old man with acute myelogenous leukemia (WHO classification, AML with multilineage dysplasia) received allogeneic bone marrow transplantation from an HLA-identical brother in first remission. He became febrile on day 7, and pulmonary failure and multi-organ failure developed subsequently, requiring mechanical ventilation. Chest X-ray and CT scan demonstrated diffuse interstitial shadows, suggesting the development of idiopathic pneumonia syndrome. Administration of methylprednisolone and tacrolimus was effective, but respiratory failure exacerbated along with a decrease in the dose of steroids. Lung biopsy revealed organizing pneumonia with CMV pneumonia. Methylprednisolone and mycophenolate mofetil were instituted, which led to an improvement of lung injury. Intensive immunosuppressive therapy with mechanical ventilation should be considered for the treatment of idiopathic pneumonia syndrome after allogeneic bone marrow transplantation.
PMID: 19638724 [PubMed - in process]
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Preferred co-localization of chromosome 8 and 21 in myeloid bone marrow cells detected by three dimensional molecular cytogenetics.
Int J Mol Med. 2009 Sep;24(3):335-41
Authors: Manvelyan M, Kempf P, Weise A, Mrasek K, Heller A, Lier A, Höffken K, Fricke HJ, Sayer HG, Liehr T, Mkrtchyan H
The impact of chromosome architecture in the formation of chromosome aberrations is a recent finding of interphase directed molecular cytogenetic studies. Also positive correlation of translocation frequencies and spatial proximity of chromosomes was described. Thus, disease specific chromosomal translocations could be due to tissue specific genomic organization. However, no three-dimensional interphase fluorescence in situ hybridization (FISH) studies for the nuclear architecture of bone marrow (BM) cells have previously been done. In this study, BM of three secondary acute myelogenous leukemia (AML) cases with trisomy 8 and otherwise normal karyotype were evaluated. Bone marrow cells of one AML and one ALL (acute lymphoblastic leukemia) case, peripheral blood lymphocytes and human sperm, all of them with normal karyotype, served as controls. Multicolor banding (MCB) probes for chromosomes 8 and 21 were applied in suspension-FISH (S-FISH). Interestingly, in myeloid bone marrow cells chromosomes 8 (di- and trisomic) and 21 tended to co-localize with their homologue chromosome(s), rather than to be separated. Thus, the co-localization of chromosomes 8 and 21 might promote a translocation providing a selective advantage of t(8;21) cells in AML-M2. In summary, the concept that tissue specific spatial proximity of chromosomes leads to enhanced translocation frequencies was further supported.
PMID: 19639225 [PubMed - in process]
Posted by rob on July 29, 2009 under Uncategorized | Comments are off for this article
Conclusion
Most patients with increases in QPCR remain in CGCR. Patients who lose a MMR or never achieve a MMR, and have more than 1 log increase of QPCR, should be monitored more closely, and may be evaluated for mutations of BCR-ABL kinase domain and considered for investigational therapeutic interventions. (Source: Journal of Clinical Oncology)
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Conclusion
Gene expression profiling of CML at diagnosis for PTGS1 may be useful in predicting imatinib response and in selecting alternate therapy. (Source: Journal of Clinical Oncology)
Posted by rob on July 28, 2009 under Uncategorized | Comments are off for this article
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Tyrosine kinase inhibitor-induced platelet dysfunction in patients with chronic myeloid leukemia.
Blood. 2009 Jul 9;114(2):261-3
Authors: Quintás-Cardama A, Han X, Kantarjian H, Cortes J
Dasatinib is associated with increased risk of bleeding among patients with chronic myeloid leukemia, even in the absence of thrombocytopenia, suggesting the presence of a hemostatic defect. We tested platelet aggregation in 91 patients with chronic myeloid leukemia in chronic phase either off-therapy (n = 4) or receiving dasatinib (n = 27), bosutinib (n = 32), imatinib (n = 19), or nilotinib (n = 9). All but 3 patients simultaneously receiving imatinib and warfarin had normal coagulation studies. All 4 patients off therapy had normal platelet aggregation. Impaired platelet aggregation on stimulation with arachidonic acid, epinephrine, or both was observed in 70%, 85%, and 59% of patients on dasatinib, respectively. Eighty-five percent of patients on bosutinib, 100% on nilotinib, and 33% on imatinib had normal platelet aggregation. Dasatinib 400 nM induced rapid and marked prolongation of closure time to collagen/epinephrine in normal whole blood on the PFA-100 system. In conclusion, dasatinib and, to some extent, imatinib produce abnormalities in platelet aggregometry testing.
PMID: 19414863 [PubMed - indexed for MEDLINE]
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Imatinib: a designer drug, another cutaneous complication.
Clin Exp Dermatol. 2009 Jul;34(5):603-4
Authors: Dickens E, Lewis F, Bienz N
A 55-year-old man with a history of mild psoriasis was started on imatinib for chronic myeloid leukaemia. He developed new nail dystrophy after treatment with an exacerbation of his psoriasis. Although not a contraindication for this drug, it should be remembered that psoriasis may worsen with imatinib.
PMID: 19486036 [PubMed - indexed for MEDLINE]
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JAK2 inhibitors: not the next imatinib but researchers see other possibilities.
J Natl Cancer Inst. 2009 Jul 15;101(14):980-2
Authors: Garber K
PMID: 19584324 [PubMed - indexed for MEDLINE]
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Outpacing cancer.
Nat Med. 2009 Jul;15(7):718-22
Authors: Dorans K
PMID: 19584848 [PubMed - indexed for MEDLINE]
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Molecular inversion probes reveal patterns of 9p21 deletion and copy number aberrations in childhood leukemia.
Cancer Genet Cytogenet. 2009 Aug;193(1):9-18
Authors: Schiffman JD, Wang Y, McPherson LA, Welch K, Zhang N, Davis R, Lacayo NJ, Dahl GV, Faham M, Ford JM, Ji HP
Childhood leukemia, which accounts for >30% of newly diagnosed childhood malignancies, is one of the leading causes of death for children with cancer. Genome-wide studies using microarray chips to identify copy number changes in human cancer are becoming more common. In this pilot study, 45 pediatric leukemia samples were analyzed for gene copy aberrations using novel molecular inversion probe (MIP) technology. Acute leukemia subtypes included precursor B-cell acute lymphoblastic leukemia (ALL) (n=23), precursor T-cell ALL (n=6), and acute myeloid leukemia (n=14). The MIP analysis identified 69 regions of recurring copy number changes, of which 41 have not been identified with other DNA microarray platforms. Copy number gains and losses were validated in 98% of clinical karyotypes and 100% of fluorescence in situ hybridization studies available. We report unique patterns of copy number loss in samples with 9p21.3 (CDKN2A) deletion in the precursor B-cell ALL patients, compared with the precursor T-cell ALL patients. MIPs represent an attractive technology for identifying novel copy number aberrations, validating previously reported copy number changes, and translating molecular findings into clinically relevant targets for further investigation.
PMID: 19602459 [PubMed - indexed for MEDLINE]
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Gender and ethnic differences in chronic myelogenous leukemia prognosis and treatment response: a single-institution retrospective study.
J Hematol Oncol. 2009 Jul 24;2(1):30
Authors: Lee JP, Birnstein E, Masiello D, Yang D, Yang AS
ABSTRACT: BACKGROUND: In the last decade the importance of ethnicity, socio-economic and gender differences in relation to disease incidence, diagnosis, and prognosis has been realized. Differences in these areas have become a major health policy focus in the United States. Our study was undertaken to examine the demographic and clinical features of chronic myelogenous leukemia (CML) patients presenting initially at the LAC+USC Medical Center, which serves an ethnically diverse population. RESULTS: Patients were evenly split by gender, overwhelmingly Hispanic (60.9%), and quite young (median age 39, range 17-65) compared with previously reported CML patient populations. Previous CML studies identified significant anemia (Hgb <12 g/dl), significant thrombocytosis (platelets >450 x 10;9/l), and significant leukocytosis (WBC >50 x 10;9/l) as significant adverse pretreatment prognostic factors. Using these indicators, in addition to the validated Hasford and Sokal scores, patients were stratified and analyzed via gender and ethnicity. A significantly greater proportion of women presented with significant anemia (p=0.019, Fisher’s exact test) and significant thrombocytosis (p=0.041, Fisher’s exact test) compared to men, although no differences were found in risk stratification or treatment response. MCV values for women were significantly (p=0.02, 2-sample t-test) lower than those for men, suggesting iron deficiency anemia. Focusing on ethnicity, Hispanics as a whole had significantly lower Hasford risk stratification (p=0.046, Fisher’s exact test), and significantly greater likelihood (p=0.016, Fisher’s exact test) of achieving 3-month complete haematological remission (CHR) compared with non-Hispanics at LAC+USC Medical Center, though differences in treatment outcome were no longer significant with analysis limited to patients treated with first-line imatinib. CONCLUSIONS: Female CML patients at LAC+USC Medical Center present with more significant adverse pre-treatment prognostic factors compared to men, but achieve comparable outcomes. Hispanic patients present with lower risk profile CML and achieve better treatment responses compared to non-Hispanic patients as a whole; these ethnic differences are no longer significant when statistical analysis is limited to patients given imatinib as first-line therapy. Our patients achieve response rates inferior to those of large-scale national studies. This constellation of findings has not been reported in previous studies, and is likely reflective of a unique patient population.
PMID: 19630970 [PubMed - as supplied by publisher]
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Authors: Vefring HK, Gruber FX, Wee L, Hovland R, Hjorth-Hansen H, Gedde Dahl T, Meyer P
The BCR-ABL fusion gene represents the hallmark of chronic myelogenous leukemia (CML) and is derived from a translocation between chromosome 9 and 22. The majority of CML patients have a breakpoint in the major BCR region of the BCR gene giving rise to e13a2 or e14a2 BCR-ABL transcripts. Occasionally, other BCR breakpoints occur. The current report describes two e6a2 CML patients with imatinib treatment failure and unusual disease progression. One patient was Philadelphia chromosome positive and one was Philadelphia chromosome negative with an atypical BCR-ABL rearrangement, ins (22;9).
PMID: 19641300 [PubMed - as supplied by publisher] (Source: Acta Haematologica)
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Conclusion: These data quantify the deteriorating impact of CML disease progression and the impact of nonresponse to treatment. The study results add to evidence from other disease areas that systematic differences exist in preference values between countries. (Source: Value in Health)
Posted by rob on July 27, 2009 under Uncategorized | Comments are off for this article
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Longstanding remission of adult onset Still’s disease under imatinib therapy in a patient with chronic myelogenous leukemia.
J Rheumatol. 2009 Jun;36(6):1349-51
Authors: Nagasaki Y, Miyamoto T, Henzan H, Nagafuji K, Harada M, Akashi K
PMID: 19509096 [PubMed - in process]
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CUDC-305, a novel synthetic HSP90 inhibitor with unique pharmacologic properties for cancer therapy.
Clin Cancer Res. 2009 Jun 15;15(12):4046-57
Authors: Bao R, Lai CJ, Qu H, Wang D, Yin L, Zifcak B, Atoyan R, Wang J, Samson M, Forrester J, DellaRocca S, Xu GX, Tao X, Zhai HX, Cai X, Qian C
PURPOSE: We designed and synthesized CUDC-305, an HSP90 inhibitor of the novel imidazopyridine class. Here, we report its unique pharmacologic properties and antitumor activities in a variety of tumor types. EXPERIMENTAL DESIGN: The potency of the compound was analyzed by fluorescence polarization competition binding assay. Its antiproliferative activities were assessed in 40 human cancer cell lines. Its pharmacologic properties and antitumor activities were evaluated in a variety of tumor xenograft models. RESULTS: CUDC-305 shows high affinity for HSP90alpha/beta (IC(50), approximately 100 nmol/L) and HSP90 complex derived from cancer cells (IC(50), 48.8 nmol/L). It displays potent antiproliferative activity against a broad range of cancer cell lines (mean IC(50), 220 nmol/L). CUDC-305 exhibits high oral bioavailability (96.0%) and selective retention in tumor (half-life, 20.4 hours) compared with normal tissues. Furthermore, CUDC-305 can cross blood-brain barrier and reach therapeutic levels in brain tissue. CUDC-305 exhibits dose-dependent antitumor activity in an s.c. xenograft model of U87MG glioblastoma and significantly prolongs animal survival in U87MG orthotopic model. CUDC-305 also displays potent antitumor activity in animal models of erlotinib-resistant non-small cell lung cancer and induces tumor regression in animal models of MDA-MB-468 breast cancer and MV4-11 acute myelogenous leukemia. Correlating with its efficacy in these various tumor models, CUDC-305 robustly inhibits multiple signaling pathways, including PI3K/AKT and RAF/MEK/ERK, and induces apoptosis. In combination studies, CUDC-305 enhances the antitumor activity of standard-of-care agents in breast and colorectal tumor models. CONCLUSION: CUDC-305 is a promising drug candidate for the treatment of a variety of cancers, including brain malignancies.
PMID: 19509149 [PubMed - in process]
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Epigenetic modifiers: basic understanding and clinical development.
Clin Cancer Res. 2009 Jun 15;15(12):3918-26
Authors: Piekarz RL, Bates SE
More than 60 years after the first description of differentiation in cell culture and 40 years after the synthesis of 5-azacytidine, epigenetic therapies have been added to the anticancer armamentarium. DNA methyltransferase (DNMT) inhibitors such as 5-aza-2′-deoxycytidine or 5-azacytidine have been approved in myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML), whereas the histone deacetylase inhibitors (HDIs) including vorinostat, romidepsin, panobinostat, belinostat, and entinostat have been shown to be active in cutaneous and peripheral T-cell lymphoma. Although the range of malignancies in which monotherapy with DNMT inhibitors or HDIs are effective has been limited to date, the possibility remains that a broader spectrum of activity will be identified as combination studies are completed. Meanwhile, basic science has provided a steadily increasing understanding of the complexity of the epigenome, including the histone code and triggers for aberrant methylation, and their contribution to oncogenesis. As our basic understanding of the epigenetics of cancer increases, the number of potential therapeutic targets will also increase, offering more hope in the quest to treat cancer by normalizing the epigenome. This issue of CCR Focus is dedicated to understanding the clinical and translational aspects of epigenetics research.
PMID: 19509169 [PubMed - in process]
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Human schwannomas express activated platelet-derived growth factor receptors and c-kit and are growth inhibited by Gleevec (Imatinib Mesylate).
Cancer Res. 2009 Jun 15;69(12):5099-107
Authors: Mukherjee J, Kamnasaran D, Balasubramaniam A, Radovanovic I, Zadeh G, Kiehl TR, Guha A
Schwannomas, although benign, can be fatal or give rise to significant morbidity due to an unpredictable growth rate. They can reoccur after surgery or radiation, current treatments each with significant inherent risks. These risks are further amplified in neurofibromatosis type 2 (NF2), a germ line predisposition syndrome characterized by multiple schwannomas, underlying the need for biological targeted therapies. Gleevec (STI571, imatinib mesylate), in addition to the bcr-abl oncogene in chronic myelogenous leukemia, inhibits c-kit and platelet-derived growth factor receptor (PDGFR) signaling, thereby expanding its use to several malignant and benign human diseases. In the present study, we show that human sporadic and NF2-associated schwannomas have increased expression along with activation of PDGFR-alpha, PDGFR-beta, and c-kit receptors, compared with normal or traumatic nerve. Using the human NF2-null HEI-193 schwannoma cell line, Gleevec inhibited schwannoma viability, proliferation, and anchorage-independent growth, as well as induced apoptosis in a dose-dependent manner (IC(50) 5-10 micromol/L). These antitumorigenic effects were correlated to inhibition of PDGFR-alpha, PDGFR-beta, and c-kit activation/phosphorylation and major downstream signaling pathways. Lack of robust xenograft or transgenic models of schwannomas prevents extension of these studies in vivo. However, the established long track record and tolerable toxicity of Gleevec already in clinical use and our preclinical data lead us to propose that Gleevec should be evaluated in human schwannomas with shown progressive growth.
PMID: 19509233 [PubMed - indexed for MEDLINE]
