A Worldwide Support Network For Chronic Myelogenous Leukemia
Posted by rob on October 31, 2010 under Uncategorized | 
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Chronic myelogenous leukemia — Comprehensive overview covers causes, treatments and coping with this blood cancer. (Source: MayoClinic.com Full Feed)
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Posted by rob on October 30, 2010 under Uncategorized | Comments are off for this article
The Durable Clearance of the T315I BCR-ABL Mutated Clone in Chronic Phase Chronic Myelogenous Leukemia Patients on Omacetaxine Allows Tyrosine Kinase Inhibitor Rechallenge.
Clin Lymphoma Myeloma Leuk. 2010 Oct 1;10(5):394-9
Authors: Nicolini FE, Chomel JC, Roy L, Legros L, Chabane K, Ducastelle S, Nicolas-Virelizier E, Michallet M, Tigaud I, Magaud JP, Turhan A, Guilhot F, Hayette S
Purpose: The onset of a BCR-ABLT315I mutation during the course of chronic myelogenous leukemia (CML) on tyrosine kinase inhibitors (TKIs) usually results in poor survival, and therapeutic options remain few in the absence of any allogeneic donor. Patients and Methods: We have investigated the affect of subcutaneous omacetaxine (OMA, or homo-harringtonine) cycles on unmutated and T315I-mutated BCR-ABL transcripts in a series of 8 TKI-resistant chronic-phase CML patients and we have addressed the question of whether the administration of OMA could resensitize patients to TKIs. Patients were regularly monitored for total disease burden and for BCR-ABLT315I transcripts using a new quantitative sensitive technique (sensitivity threshold, 0.05%), for up to 27 cycles of OMA. Results: Overall, patients demonstrated hematologic, cytogenetic, or molecular improvement. An initial rapid decline and a sustained disappearance of T315I-mutated transcripts were observed in 50% of patients, after a median of 10.5 cycles (range, 3-27 cycles) of OMA. As the unmutated leukemic burden reduction was modest, 2 patients were submitted to nilotinib after 9 months of sustained BCR-ABLT315I transcripts negativity on OMA and mutated transcripts remained undetectable after a median follow-up of 12 months on nilotinib challenge. Conclusion: We suggest that OMA (ie, a non-targeted therapy) might provide a better disease control allowing the disappearance of the mutated clone probably elicited by the clone deselection after TKI release, and/or a preferential activity of OMA on the T315I-mutated cells through unknown mechanisms. These observations suggest that OMA could allow a safe TKI rechallenge in patients with resistant chronic-phase CML.
PMID: 21030353 [PubMed - in process]
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Imatinib should continue to be the front?line therapy for patients who have newly diagnosed chronic myelogenous leukemia accompanied by close monitoring. Patients should switch to a second?generation tyrosine kinase inhibitor at the earliest sign of resistance or suboptimal response to imatinib. (Source: Cancer)
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Posted by rob on October 29, 2010 under Uncategorized | Comments are off for this article
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Isolation and killing of candidate chronic myeloid leukemia stem cells by antibody targeting of IL-1 receptor accessory protein.
Proc Natl Acad Sci U S A. 2010 Sep 14;107(37):16280-5
Authors: Järås M, Johnels P, Hansen N, Agerstam H, Tsapogas P, Rissler M, Lassen C, Olofsson T, Bjerrum OW, Richter J, Fioretos T
Chronic myeloid leukemia (CML) is genetically characterized by the Philadelphia (Ph) chromosome, formed through a reciprocal translocation between chromosomes 9 and 22 and giving rise to the constitutively active tyrosine kinase P210 BCR/ABL1. Therapeutic strategies aiming for a cure of CML will require full eradication of Ph chromosome-positive (Ph(+)) CML stem cells. Here we used gene-expression profiling to identify IL-1 receptor accessory protein (IL1RAP) as up-regulated in CML CD34(+) cells and also in cord blood CD34(+) cells as a consequence of retroviral BCR/ABL1 expression. To test whether IL1RAP expression distinguishes normal (Ph(-)) and leukemic (Ph(+)) cells within the CML CD34(+)CD38(-) cell compartment, we established a unique protocol for conducting FISH on small numbers of sorted cells. By using this method, we sorted cells directly into drops on slides to investigate their Ph-chromosome status. Interestingly, we found that the CML CD34(+)CD38(-)IL1RAP(+) cells were Ph(+), whereas CML CD34(+)CD38(-)IL1RAP(-) cells were almost exclusively Ph(-). By performing long-term culture-initiating cell assays on the two cell populations, we found that Ph(+) and Ph(-) candidate CML stem cells could be prospectively separated. In addition, by generating an anti-IL1RAP antibody, we provide proof of concept that IL1RAP can be used as a target on CML CD34(+)CD38(-) cells to induce antibody-dependent cell-mediated cytotoxicity. This study thus identifies IL1RAP as a unique cell surface biomarker distinguishing Ph(+) from Ph(-) candidate CML stem cells and opens up a previously unexplored avenue for therapy of CML.
PMID: 20805474 [PubMed - indexed for MEDLINE]
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GTPase regulator associated with the focal adhesion kinase (GRAF) transcript was down-regulated in patients with myeloid malignancies.
J Exp Clin Cancer Res. 2010;29:111
Authors: Qian Z, Qian J, Lin J, Yao DM, Chen Q, Ji RB, Li Y, Xiao GF, Li JY
BACKGROUND: GTPase regulator associated with the focal adhesion kinase (GRAF), a putative tumor suppressor gene, is found inactivated in hematopoietic malignancies by either genetic or epigenetic abnormalities. However, the expression level of GRAF gene has not yet been studied in leukemia. The aim of this study was to investigate the expression level of GRAF gene in those patients with myeloid malignancies including acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and chronic myeloid leukemia (CML). METHODS: The expression levels of GRAF transcript were determined in 94 patients using real-time quantitative PCR (RQ-PCR). Clinical and laboratory data of these patients were collected and analyzed. RESULTS: The significantly decreased level of GRAF transcript was observed in three myeloid malignancies compared to controls. Within AML, there was no difference in the level of GRAF transcript among different FAB subtypes (P > 0.05). Difference was not observed in the amount of GRAF mRNA between CML at chronic phase and controls. As CML progressed, GRAF transcript significantly decreased. In MDS, three cases with 5q deletion had lower GRAF transcript than four without 5q deletion (median 0.76 vs 2.99) (P > 0.05). CONCLUSION: our results demonstrate that the GRAF transcript is decreased in myeloid malignancies.
PMID: 20704716 [PubMed - indexed for MEDLINE]
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S-trityl-L-cysteine derivative induces caspase-independent cell death in K562 human chronic myeloid leukemia cell line.
Cancer Lett. 2010 Dec 1;298(1):99-106
Authors: Shimizu M, Ishii H, Ogo N, Unno Y, Matsuno K, Sawada J, Akiyama Y, Asai A
Effect of CF(3)-STLC, a potent kinesin spindle protein (KSP) inhibitor, on K562 human CML cell line was investigated. Treatment with CF(3)-STLC induced mitotic arrest of the cell cycle with the appearance of characteristic monoastral spindles, subsequent apoptotic cell death and cleavage of PARP-1, caspase-3, and 4E-BP1. The wide ranging caspase inhibitor z-VAD fmk prevented the cleavage of caspase-3 and 4E-BP1, but failed to attenuate PARP-1 cleavage or cell death triggered by CF(3)-STLC. These results suggest that CF(3)-STLC can induce apoptotic cell death in a caspase-independent manner, and may work effectively as an anti-cancer agent for hematological malignancies.
PMID: 20619960 [PubMed - indexed for MEDLINE]
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Methylation status of DDIT3 gene in chronic myeloid leukemia.
J Exp Clin Cancer Res. 2010;29:54
Authors: Wang YL, Qian J, Lin J, Yao DM, Qian Z, Zhu ZH, Li JY
BACKGROUND: DNA-damage-inducible transcript 3 (DDIT3), a candidate tumor suppressor gene (TSG), has been found involved in the regulation of cellular growth and differentiation. The epigenetic changes of TSGs are recently recognized as an abnormal mechanism contributing to the development of chronic myeloid leukemia (CML). The aim of this study was to investigate the methylation status of DDIT3 gene in CML patients. METHODS: The methylation status of DDIT3 promoter was detected in the bone marrow mononuclear cells from 53 patients with CML using methylation-specific PCR (MSP). The expression levels of DDIT3 and bcr/abl transcript were determined by real-time quantitative PCR (RQ-PCR). Clinical data of these patients were collected and analyzed. RESULTS: The aberrant methylation of DDIT3 gene promoter was found in 35 of 53 (66%) CML cases. Correlation was not found between DDIT3 promoter hypermethylation and the age, sex, hemoglobin concentration, platelet counts, chromosomal abnormalities, bcr/abl transcript, and staging of CML patients (P > 0.05), but found between DDIT3 promoter hypermethylation and WBC counts of CML cases (R = 0.781, P < 0.001). The level of DDIT3 transcript in CML patients was significantly lower than that in controls (median 3.28 vs 19.69, P < 0.001), however, there was no difference in the level of DDIT3 transcript between methylation-positive CML cases (0.05-65.32, median 2.13) and methylation- negative CML cases (0.12-126.04, median 3.92) (P > 0.05). CONCLUSION: Our results demonstrate that aberrant methylation of DDIT3 occurs in CML frequently.
PMID: 20492726 [PubMed - indexed for MEDLINE]
Posted by rob on October 28, 2010 under Uncategorized | Comments are off for this article
Second-generation tyrosine kinase inhibitors in chronic myelogenous leukemia: before or after imatinib?
Cancer. 2010 Oct 26;
Authors: Tefferi A
PMID: 20979064 [PubMed - as supplied by publisher]
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Postremission gemtuzumab ozogamicin for elderly patients with acute myelogenous leukemia with favorable characteristics and comorbid conditions.
Int J Hematol. 2010 Oct 28;
Authors: Ichikawa M, Hangaishi A, Nannya Y, Kurokawa M
PMID: 20978876 [PubMed - as supplied by publisher]
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JAK2 Translocations in hematological malignancies: Review of the literature.
J Assoc Genet Technol. 2010;36(3):107-9
Authors: Ho K, Valdez F, Garcia R, Tirado CA
JAK2 is a cytoplasmic tyrosine kinase whose gene is located on chromosome 9p24. It is involved in the regulation of different cytokines and growth factors and plays an important role in the diagnosis and treatment of myeloproliferative neoplasms (Smith et al., 2008). Translocations involving the JAK2 locus are uncommon with just a few cases described in the literature, and they usually lead to a fusion protein with JAK2 (Patnaik et al., 2010). Chromosome 9p24 abnormalities have been described in myeloid and lymphoid neoplasms including chronic myelogenous leukemia (CML), acute megakaryoblastic leukemia, CD10+ B-cell acute lymphoblastic leukemia, T-cell ALL and chronic myeloproliferative disorders (CMD) (Smith et al., 2008; Lacronique et al., 1997). Although the breakpoints of each translocation are known, characterization of the partner gene has not been done in many of the cases reported due to insufficient sample or other factors. In the present study we review all translocations involving JAK2 that have been reported in the literature.
PMID: 20978341 [PubMed - in process]
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Participation of CYP2C8 and CYP3A4 in the N-demethylation of imatinib in human hepatic microsomes.
Br J Pharmacol. 2010 Nov;161(5):1059-69
Authors: Nebot N, Crettol S, D’Esposito F, Tattam B, Hibbs DE, Murray M
BACKGROUND AND PURPOSE Imatinib is a clinically important inhibitor of tyrosine kinases that are dysregulated in chronic myelogenous leukaemia and gastrointestinal stromal tumours. Inter-individual variation in imatinib pharmacokinetics is extensive, and influences drug safety and efficacy. Hepatic cytochrome P450 (CYP) 3A4 has been implicated in imatinib N-demethylation, but the clearance of imatinib decreases during prolonged therapy. CYP3A phenotype correlates with imatinib clearance at the commencement of therapy, but not at steady state. The present study evaluated the possibility that multiple CYPs may contribute to imatinib oxidation in liver. EXPERIMENTAL APPROACH Imatinib biotransformation in human liver microsomes (n= 20) and by cDNA-expressed CYPs was determined by LC-MS. Relationships between imatinib N-demethylation and other drug metabolizing CYPs were assessed. KEY RESULTS N-desmethylimatinib formation was correlated with microsomal oxidation of the CYP3A4 substrates testosterone (?= 0.60; P < 0.01) and midazolam (?= 0.46; P < 0.05), and the CYP2C8 substrate paclitaxel (?= 0.58; P < 0.01). cDNA-derived CYPs 2C8, 3A4, 3A5 and 3A7 supported imatinib N-demethylation, but 10 other CYPs were inactive; in kinetic studies, CYP2C8 was a high-affinity enzyme with a catalytic efficiency ?15-fold greater than those of CYPs 3A4 and 3A5. The CYP3A inhibitors ketoconazole and troleandomycin, and the CYP2C8 inhibitors quercetin and paclitaxel decreased imatinib oxidation. From molecular modelling, the imatinib structure could be superimposed on a pharmacophore for CYP2C8 substrates. CONCLUSIONS AND IMPLICATIONS CYP2C8 and CYPs 3A contribute to imatinib N-demethylation in human liver. The involvement of CYP2C8 may account in part for the wide inter-patient variation in imatinib pharmacokinetics observed in clinical practice.
PMID: 20977456 [PubMed - in process]
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The antimicrobial peptide human cationic antimicrobial protein-18/cathelicidin LL-37 as a putative growth factor for malignant melanoma.
Br J Dermatol. 2010 Nov;163(5):959-67
Authors: Kim JE, Kim HJ, Choi JM, Lee KH, Kim TY, Cho BK, Jung JY, Chung KY, Cho D, Park HJ
Background? Recent evidence suggests cathelicidin LL-37 to be a growth factor for various human cancers such as lung cancer, ovarian cancer and breast cancer. However, the effect of LL-37 against malignant skin cancer has not been reported. Objectives? To investigate whether the human cathelicidin LL-37 is involved in the carcinogenesis of various skin tumours. Methods? Human cationic antimicrobial protein-18 (hCAP-18)/LL-37 production in several cell lines including HaCaT, a chronic myelogenous leukaemia (CML) cell line and various melanoma cell lines was examined using reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay. Immunohistochemical analysis of melanoma, nonmelanoma skin cancer and precancerous and benign skin lesions was performed. After adding LL-37 to a melanoma cell line, tumour cell proliferation, migration and invasion were investigated. Results? Human malignant melanoma cell lines overexpressed hCAP-18/LL-37 mRNA and peptide compared with HaCaT and CML cell lines. Immunohistochemistry showed that the peptide was strongly expressed in malignant melanoma and moderately expressed in squamous cell carcinoma, whereas basal cell carcinoma, precancerous lesions and seborrhoeic keratosis showed no or weak expression. LL-37 also stimulated melanoma cell proliferation, migration and invasion in vitro. Conclusions? Cathelicidin LL-37 was primarily expressed in human malignant skin cancer. LL-37 promoted melanoma cell proliferation, migration and invasion in vitro. We report that an increase in the level of LL-37 is associated with malignant skin tumours such as malignant melanoma. These results highlight the importance of LL-37 in the malignant tendency of skin tumours.
PMID: 20977442 [PubMed - in process]
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Properties of CD34+ CML stem/progenitor cells that correlate with different clinical responses to imatinib mesylate.
Blood. 2010 Sep 23;116(12):2112-21
Authors: Jiang X, Forrest D, Nicolini F, Turhan A, Guilhot J, Yip C, Holyoake T, Jorgensen H, Lambie K, Saw KM, Pang E, Vukovic R, Lehn P, Ringrose A, Yu M, Brinkman RR, Smith C, Eaves A, Eaves C
Imatinib mesylate (IM) induces clinical remissions in chronic-phase chronic myeloid leukemia (CML) patients but IM resistance remains a problem. We recently identified several features of CML CD34(+) stem/progenitor cells expected to confer resistance to BCR-ABL-targeted therapeutics. From a study of 25 initially chronic-phase patients, we now demonstrate that some, but not all, of these parameters correlate with subsequent clinical response to IM therapy. CD34(+) cells from the 14 IM nonresponders demonstrated greater resistance to IM than the 11 IM responders in colony-forming cell assays in vitro (P < .001) and direct sequencing of cloned transcripts from CD34(+) cells further revealed a higher incidence of BCR-ABL kinase domain mutations in the IM nonresponders (10%-40% vs 0%-20% in IM responders, P < .003). In contrast, CD34(+) cells from IM nonresponders and IM responders were not distinguished by differences in BCR-ABL or transporter gene expression. Interestingly, one BCR-ABL mutation (V304D), predicted to destabilize the interaction between p210(BCR-ABL) and IM, was detectable in 14 of 20 patients. T315I mutant CD34(+) cells found before IM treatment in 2 of 20 patients examined were preferentially amplified after IM treatment. Thus, 2 properties of pretreatment CML stem/progenitor cells correlate with subsequent response to IM therapy. Prospective assessment of these properties may allow improved patient management.
PMID: 20574046 [PubMed - indexed for MEDLINE]
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Activity of the multitargeted kinase inhibitor, AT9283, in imatinib-resistant BCR-ABL-positive leukemic cells.
Blood. 2010 Sep 23;116(12):2089-95
Authors: Tanaka R, Squires MS, Kimura S, Yokota A, Nagao R, Yamauchi T, Takeuchi M, Yao H, Reule M, Smyth T, Lyons JF, Thompson NT, Ashihara E, Ottmann OG, Maekawa T
Despite promising clinical results from imatinib mesylate and second-generation ABL tyrosine kinase inhibitors (TKIs) for most BCR-ABL(+) leukemia, BCR-ABL harboring the mutation of threonine 315 to isoleucine (BCR-ABL/T315I) is not targeted by any of these agents. We describe the in vitro and in vivo effects of AT9283 (1-cyclopropyl-3[5-morpholin-4yl methyl-1H-benzomidazol-2-yl]-urea), a potent inhibitor of several protein kinases, including Aurora A, Aurora B, Janus kinase 2 (JAK2), JAK3, and ABL on diverse imatinib-resistant BCR-ABL(+) cells. AT9283 showed potent antiproliferative activity on cells transformed by wild-type BCR-ABL and BCR-ABL/T315I. AT9283 inhibited proliferation in a panel of BaF3 and human BCR-ABL(+) cell lines both sensitive and resistant to imatinib because of a variety of mechanisms. In BCR-ABL(+) cells, we confirmed inhibition of substrates of both BCR-ABL (signal transducer and activator of transcription-5) and Aurora B (histone H3) at physiologically achievable concentrations. The in vivo effects of AT9283 were examined in several mouse models engrafted either subcutaneously or intravenously with BaF3/BCR-ABL, human BCR-ABL(+) cell lines, or primary patient samples expressing BCR-ABL/T315I or glutamic acid 255 to lysine, another imatinib-resistant mutation. These data together support further clinical investigation of AT9283 in patients with imatinib- and second-generation ABL TKI-resistant BCR-ABL(+) cells, including T315I.
PMID: 20548094 [PubMed - indexed for MEDLINE]
Posted by rob on October 26, 2010 under Uncategorized | Comments are off for this article
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The low frequency of clinical resistance to PDGFR inhibitors in myeloid neoplasms with abnormalities of PDGFRA might be related to the limited repertoire of possible PDGFRA kinase domain mutations in vitro.
Oncogene. 2010 Oct 25;
Authors: von Bubnoff N, Gorantla SP, Engh RA, Oliveira TM, Thöne S, Aberg E, Peschel C, Duyster J
Myeloproliferation with prominent eosinophilia is associated with rearrangements of PDGFR-A or -B. The most common rearrangement is FIP1L1-PDGFRA (FP). The majority of patients with PDGFR-rearranged myeloproliferation respond to treatment with imatinib. In contrast to BCR-ABL-positive chronic myelogenous leukemia, only few cases of imatinib resistance and mutations of the FP kinase domain have been described so far. We hypothesized that the number of critical residues mediating imatinib resistance in FP in contrast to BCR-ABL might be limited. We performed an established systematic and comprehensive in vitro resistance screen to determine the pattern and frequency of possible TKI resistance mutations in FP. We identified 27 different FP kinase domain mutations including 25 novel variants, which attenuated response to imatinib, nilotinib or sorafenib. However, the majority of these exchanges did not confer complete inhibitor resistance. At clinically achievable drug concentrations, FP/T674I predominated with imatinib, whereas with nilotinib and sorafenib, FP/D842V and the compound mutation T674I+T874I became prevalent. Our results suggest that the PDGFR kinase domain contains a limited number of residues where exchanges critically interfere with binding of and inhibition by available PDGFR kinase inhibitors at achievable concentrations, which might explain the low frequency of imatinib resistance in this patient population. In addition, these findings would help to select the appropriate second-line drug in cases of imatinib-resistant disease and may be translated to other neoplasms driven by activated forms of PDGFR-A or -B.Oncogene advance online publication, 25 October 2010; doi:10.1038/onc.2010.476.
PMID: 20972453 [PubMed - as supplied by publisher]
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Response to dasatinib in a patient with concomitant chronic myeloid leukemia and chronic lymphocytic leukemia.
Acta Haematol. 2010;124(2):105-9
Authors: Serpa M, Bendit I, Seguro F, Xavier F, Cavalcante M, Steinbaum D, Nardinelli L, Aldred VL, de Paula HM, Dorlhiac-Llacer PE
While chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) are common diseases in the elderly, they rarely occur simultaneously in the same patient. Here we present the case of a 77-year-old patient diagnosed with CML in the chronic phase who showed an optimal response to 400 mg/day of imatinib. This patient progressed to Binet B-CLL with an 11q22.3 deletion and CD38 positivity in the 4th month of treatment. During the follow-up, his lymphocyte number doubled in <6 months. Based on previous reports, dasatinib was chosen instead of imatinib. After 6 months of treatment with 100 mg/day of dasatinib, the patient demonstrated a partial response, characterized by the regression of lymph node enlargement, a hemoglobin level of 10.7 g/dl, neutrophils of 1.7 × 10(9)/l, a 82% reduction in the lymphocyte number and an increase in cytotoxic CD8+ and large granular lymphocytes. This partial response has persisted to the present time. While little data have been published regarding the in vitro effect of dasatinib monotherapy for CLL, this case report provides some evidence of the clinical activity of dasatinib in CLL.
PMID: 20720403 [PubMed - indexed for MEDLINE]
Posted by rob on October 25, 2010 under Uncategorized | Comments are off for this article
Bristol-Myers Squibb today announced that SPRYCEL (dasatinib) received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive Chronic Myelogenous Leukaemia in Chronic Phase (CML-CP)… (Source: Health News from Medical News Today)
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Kulachart Jangpatarapongsa, Duangporn Polpanich, Vichanan Yamkamon, Yuranun Dittharot, Jutharat Peng-On, Raweewan Thiramanas, Suradej Hongeng, Saengsuree Jootar, Lalida Charoenmak, Pramuan Tangboriboonrat
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Kulachart Jangpatarapongsa, Analyst, 2011, DOI: 10.1039/c0an00374c
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Posted by rob on October 24, 2010 under Uncategorized | Comments are off for this article
Cost and effectiveness of reduced-intensity and conventional allogeneic hematopoietic stem cell transplantation for acute myelogenous leukemia and myelodysplastic syndrome.
Support Care Cancer. 2010 Dec;18(12):1565-9
Authors: Imataki O, Kamioka T, Fukuda T, Tanosaki R, Takaue Y
GOALS OF WORK: Allogeneic stem cell transplantation with a reduced-intensity regimen (RIST) has been evaluated mostly in terms of its clinical benefit, and the pharmacoeconomic aspects of this procedure remain unclear. We compared the cost and effectiveness of RIST with those of stem cell transplantation using a conventional myeloablative regimen (CST). PATIENTS AND METHODS: Fifty consecutive patients who underwent transplantation for myeloid malignancy were included. Life years and medical costs during the entire treatment course for up to 2 years after transplantation were evaluated, and cost-effectiveness was assessed from the payer’s perspective. MAIN RESULTS: Of these 50 cases, 35 were treated with CST and 15 were treated with RIST. The mean survival time was 1.5 years in CST and 1.2 years in RIST, while the mean total cost per patient within the first 2 years was $29,630 for CST and $29,466 for RIST, with no significant difference. The duration of total hospitalization was shorter in RIST than in CST; then, the cost for hospitalization represented a lower proportion of the total cost in RIST (49% of total cost) than in CST (63%). In contrast, the cost related to the conditioning regimen was significantly higher in RIST than in CST. CONCLUSIONS: This result suggests that the increased cost of the conditioning regimen offsets the reduced cost of hospitalization in RIST. Although some differences were observed in the details of the cost, the total cost and mean survival were comparable between CST and RIST, and this result was confirmed by a probabilistic sensitivity analysis.
PMID: 20967555 [PubMed - in process]
Posted by rob on October 22, 2010 under Uncategorized | Comments are off for this article
Protein Tyrosine Phosphatase Receptor Type {gamma} Is a Functional Tumor Suppressor Gene Specifically Downregulated in Chronic Myeloid Leukemia.
Cancer Res. 2010 Oct 19;
Authors: Della Peruta M, Martinelli G, Moratti E, Pintani D, Vezzalini M, Mafficini A, Grafone T, Iacobucci I, Soverini S, Murineddu M, Vinante F, Tecchio C, Piras G, Gabbas A, Monne M, Sorio C
Chronic myelogenous leukemia (CML) is the most common myeloproliferative disease. Protein tyrosine phosphatase receptor type ? (PTPRG) is a tumor suppressor gene and a myeloid cell marker expressed by CD34(+) cells. Downregulation of PTPRG increases colony formation in the PTPRG-positive megakaryocytic cell lines MEG-01 and LAMA-84 but has no effect in the PTPRG-negative cell lines K562 and KYO-1. Its overexpression has an oncosuppressive effect in all these cell lines and is associated with myeloid differentiation and inhibition of BCR/ABL-dependent signaling. The intracellular domain of PTPRG directly interacts with BCR/ABL and CRKL, but not with signal transducers and activators of transcription 5. PTPRG is downregulated at the mRNA and protein levels in leukocytes of CML patients in both peripheral blood and bone marrow, including CD34(+) cells, and is reexpressed following molecular remission of disease. Reexpression was associated with a loss of methylation of a CpG island of PTPRG promoter occurring in 55% of the patients analyzed. In K562 cell line, the DNA hypomethylating agent 5-aza-2′-deoxycytidine induced PTPRG expression and caused an inhibition of colony formation, partially reverted by downregulation of PTPRG expression. These findings establish, for the first time, PTPRG as a tumor suppressor gene involved in the pathogenesis of CML, suggesting its use as a potential diagnostic and therapeutic target. Cancer Res; 70(21); 8896-906. ©2010 AACR.
PMID: 20959494 [PubMed - as supplied by publisher]
