Posted by rob on December 31, 2010 under Uncategorized | 
Bendamustine produces durable responses with an acceptable safety profile in patients with rituximab-refractory indolent non-Hodgkin lymphoma.
Clin Lymphoma Myeloma Leuk. 2010 Dec;10(6):452-7
Authors: Cheson BD, Friedberg JW, Kahl BS, Van der Jagt RH, Tremmel L
Although initially responsive to therapy, indolent non-Hodgkin lymphomas (NHLs) are generally incurable. Therefore, active and tolerable treatments for patients with relapsed or refractory disease are needed. Bendamustine, a mechlorethamine alkylator with novel mechanisms of action, is approved in the United States for rituximab-refractory indolent B-cell NHL.
PMID: 21189660 [PubMed - in process]
More
Posted by rob on under Uncategorized |
BAX/BCL-XL gene expression ratio inversely correlates with disease progression in chronic myeloid leukemia.
Blood Cells Mol Dis. 2010 Oct 15;45(3):192-6
Authors: Gonzalez MS, De Brasi CD, Bianchini M, Gargallo P, Moiraghi B, Bengió R, Larripa IB
BCR-ABL fusion gene is implicated in the pathogenesis of chronic myeloid leukemia (CML), encoding the oncoprotein p210(BCR-ABL) with anti-apoptotic activity. The inability to undergo apoptosis is an important mechanism of drug resistance and neoplastic evolution in CML. The gene transcript expression of mitochondrial apoptotic related genes BAX and BCL-XL was evaluated by quantitative Real Time PCR (qPCR) in vitro in K562 cells and in vivo in peripheral blood of 66 CML patients in different stages of the disease: 13 cases at diagnosis, 34 in chronic phase (CP), 10 in accelerated phase (AP) and 9 in blast crisis (BC). Our results in K562 cells showed that all treatments with different tyrosine kinase inhibitors (TKIs) induced a decreased expression of the antiapoptotic oncogene BCL-XL, whereas the proapoptotic gene BAX remains constant with minor modifications. A significantly lower BAX/BCL-XL expression ratio (mean±SEM) than a group of healthy individuals (4.8±0.59) were observed in CML patients at diagnosis (1.28 ± 0.16), in AP (1.14±0.20), in BC (1.16±0.30) and in 18% of cases of patients in CP (2.71±0.40). Most CP cases (82%) showed a significantly increased ratio (10.03±1.30), indicating that the treatment with TKIs efficiently inhibited the expression of BCL-XL by blocking BCR-ABL oncoprotein. The BAX/BCL-XL ratio showed a significant inverse correlation (Spearman P<0.0001) with BCR-ABL/ABL relative expression indicating that low BAX/BCL-XL was associated with disease progression. Accordingly, the follow up of a cohort of eight cases during 6months from diagnosis showed that while the BAX/BCL-XL ratio rapidly increased after treatment in seven cases with good evolution, it decreased in the single case that showed rapid evolution and short survival. Our data suggest that BAX/BCL-XL expression ratio may be a sensitive monitor of disease progression and an early predictor of TKI therapy responsiveness in CML patients.
PMID: 20728382 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
A pilot study of carboplatin and mitoxantrone in blast crisis of chronic myeloid leukemia.
Med Oncol. 2010 Sep;27(3):728-35
Authors: Dutcher JP, Morris EL, Gaynor B, Paietta E, Wiernik PH
The efficacy and toxicity of carboplatin plus mitoxantrone in blast crisis of chronic myeloid leukemia (CMLBC) were evaluated. Between 1990 and 1996, 20 patients (11 males and nine females, median age of 49 years [range 30-75 years]) were treated with carboplatin, 250 mg/m(2)/day x 5 days as an infusion and mitoxantrone, 10 mg/m(2)/day x 3 days, IV bolus. Median time from diagnosis of CML to BC was 4.25 years (range 0-11 years). CMLBC was myeloid in 13 patients, lymphoid in six, and megakaryocytic in one. All patients were Philadelphia (Ph) chromosome positive; four had a single Ph chromosome, five had double Ph chromosome, three had abnormalities of chromosome 17, and eight had complex cytogenetic abnormalities. Prior treatment for chronic phase included hydroxyurea (12 patients), interferon-alpha (11 patients), cytarabine or all-trans retinoic acid, three patients each and other agents (four patients). Eight patients (five myeloid and three lymphoid) had an objective response (median duration, 3 months). Five had complete responses (CR) of 2, 3, 3, 6, and 6+ months duration, and three had partial responses (PR) for 1, 2, and 4 months. Seven patients died too early to evaluate (TETE): three died pancytopenic in <30 days from initiation of chemotherapy, two patients had pancytopenia for >30 days but had only blasts in their day 30 bone marrow, and two patients were pancytopenic >30 days but demonstrated trilineage marrow regeneration. Three of eight responders survived > or =1 year. Toxicity was primarily hematologic. The objective response rate was 61% (8/13) among those who did not die TETE and 40% among all treated patients. Carboplatin plus mitoxantrone are highly active in CMLBC, with marrow aplasia as the dose-limiting toxicity, and these agents deserve further study in CMLBC, perhaps in combination with tyrosine kinase inhibitors.
PMID: 19697165 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
The role of heterogeneous nuclear ribonucleoprotein K in the progression of chronic myeloid leukemia.
Med Oncol. 2010 Sep;27(3):673-9
Authors: Du Q, Wang L, Zhu H, Zhang S, Xu L, Zheng W, Liu X
Chronic myeloid leukemia (CML) is a neoplastic disease of the hematopoietic stem cell. Heterogeneous nuclear ribonucleoprotein K (hnRNPK) may up-regulate the transcriptional activity of some oncogenes in cancerous cells. The aim of this study was to verify the expression pattern of hnRNPK in patients with CML, to explore its association with BCR-ABL and some abnormal signaling pathways, and to discover how hnRNPK contributes to the progression of CML. In this study, 15 patients with CML (9 in chronic phase and 6 in blast crisis) were enrolled in this study. The expression of hnRNPK in mononuclear cells (MNCs) from these patients was detected by Western blotting and fluorimeter-based quantitative real-time reverse transcriptase polymerase chain reaction. hnRNPK expression levels in K562 cell line and imatinib-resistant leukemic cell line K562R, following the treatments with the inhibitors of Ras-MAPK (PD98059), PI3K/AKT (LY294002), JAK/STAT (AG490) signaling pathways, and BCR-ABL [imatinib mesylate (IM)], were also determined. As the results, the overexpression of hnRNPK in protein and gene patterns was detected in MNCs from patients with CML comparing with normal donors. Especially, its level in MNCs from patients with CML-blast crisis was significantly higher than in CML-chronic phase cells (P < 0.01). After the treatment with PD98059 (at 4, 8, 24, and 48 h) and IM (at 48 h), the expression levels of hnRNPK in leukemic cell lines were decreased, comparing with DMSO control group (P < 0.05). In conclusion, the results suggest that the overexpression of hnRNPK, which is regulated by BCR-ABL and Ras-MAPK signaling pathways, may promote the progression of CML. hnRNPK would be a potential marker and therapeutic target of CML evolution.
PMID: 19653139 [PubMed - indexed for MEDLINE]
More
Posted by rob on December 30, 2010 under Uncategorized |
The genetics and clinical manifestations of telomere biology disorders.
Genet Med. 2010 Dec;12(12):753-64
Authors: Savage SA, Bertuch AA
Telomere biology disorders are a complex set of illnesses defined by the presence of very short telomeres. Individuals with classic dyskeratosis congenita have the most severe phenotype, characterized by the triad of nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. More significantly, these individuals are at very high risk of bone marrow failure, cancer, and pulmonary fibrosis. A mutation in one of six different telomere biology genes can be identified in 50–60% of these individuals. DKC1, TERC, TERT, NOP10, and NHP2 encode components of telomerase or a telomerase-associated factor and TINF2, a telomeric protein. Progressively shorter telomeres are inherited from generation to generation in autosomal dominant dyskeratosis congenita, resulting in disease anticipation. Up to 10% of individuals with apparently acquired aplastic anemia or idiopathic pulmonary fibrosis also have short telomeres and mutations in TERC or TERT. Similar findings have been seen in individuals with liver fibrosis or acute myelogenous leukemia. This report reviews basic aspects of telomere biology and telomere length measurement, and the clinical and genetic features of those disorders that constitute our current understanding of the spectrum of illness caused by defects in telomere biology. We also suggest a grouping schema for the telomere disorders.
PMID: 21189492 [PubMed - in process]
More
Posted by rob on under Uncategorized |
Dasatinib is a potent inhibitor of the BCR-ABL tyrosine kinase and is effective treatment for patients with chronic myelogenous leukemia (CML) resistant to or intolerant of treatment with imatinib. Large granular lymphocytes (LGLs) normally account for only 10–15% of circulating mononuclear cells in adults with most LGLs having an NK-cell phenotype (CD3?, CD16+, CD56+). Proliferation of LGLs has been reported in a small number of patients treated with dasatinib. Mustjoki et al demonstrated that LGL proliferation occurred in both CML and Philadelphia chromosome positive ALL patients treated with dasatinib . Both T- and NK-cell phenotypes were observed in patients with LGL lymphocytosis. In patients with T-cell phenotypes, clonality was demonstrated through T-cell receptor gene rearrange…
More
Posted by rob on under Uncategorized |
Imatinib, a selective inhibitor of Bcr-Abl tyrosine kinase, has dramatically changed the treatment of chronic myelogenous leukemia (CML). The estimated 6-year overall survival is 95% when only CML-related deaths were considered . However, imatinib is a very expensive agent (standard daily dose (400mg) costs 12,512 yen=140 US$ in Japan). Therefore, in developing countries, allogeneic hematopoietic stem cell transplantation is still performed as a first-line treatment for CML, since many patients are unable to afford the continuing treatment with imatinib. (Source: Leukemia Research)
More
Posted by rob on under Uncategorized |
This report aims to more accurately define the frequency of the involvement of SRC Family Kinases (SFKs) in imatinib- and dasatinib-resistant CML patients. Clinical samples were analysed during in vivo treatment. We confirmed the high frequency of SFKs involvement in Tyrosine kinase inhibitor-resistant CML (52% of the cases) and even further in progressive disease and blast crises (60% of the cases). The SFKs deregulation is also observed in patients harboring BCR-ABL mutations. In T315I and F317L mutated patients, CML-resistance appears to be promoted by SFKs kinase protein reactivation once the BCR-ABL mutated clone has decreased on Omacetaxine. (Source: Leukemia Research)
More
Posted by rob on under Uncategorized |
In conclusion, our study points to p57Kip2 as a novel and precocious effector of BCR–ABL targeting drugs. (Source: Carcinogenesis)
More
Posted by rob on December 29, 2010 under Uncategorized |
Tumor-specific Cytotoxicity and Type of Cell Death Induced by Benzaldehyde.
Anticancer Res. 2010 Dec;30(12):5069-76
Authors: Ariyoshi-Kishino K, Hashimoto K, Amano O, Saitoh J, Kochi M, Sakagami H
We have previously reported that sodium 5,6-benzylidene-L-ascorbate (SBA) induced dramatic antitumor activity in inoperable cancer patients, but induced only marginal tumor specificity in vitro. Here the tumor specificity and type of cell death induced by benzaldehyde (BA), a degradation product of SBA, was investigated, using human tumor cell lines (oral squamous cell carcinoma [OSCC], glioblastoma, myelogenous leukemia) and human normal oral cells (gingival fibroblast, pulp cell, periodontal ligament fibroblast). BA showed much higher tumor-specific cytotoxicity than SBA. BA induced the formation of autophagosomes, the destruction of mitochondrial structure and digestion of broken organelles, without any apparent induction of internucleosomal DNA fragmentation and caspase activation in an OSCC cell line HSC-2, in a similar manner to SBA. However, pretreatment with 3-methyladenine or bafilomycin A(1), autophagy inhibitors, did not completely rescue the cells from the cytotoxicity induced by BA. The study suggests that BA may play an important role in the induction of antitumor activity of SBA in vivo, although the autophagic phenotypes induced by BA may be involved in both cell death and survival.
PMID: 21187492 [PubMed - in process]
More
Posted by rob on under Uncategorized |
Significant association between polymorphism of the erythropoietin gene promoter and myelodysplastic syndrome.
BMC Med Genet. 2010;11:163
Authors: Ma W, Kantarjian H, Zhang K, Zhang X, Wang X, Chen C, Donahue AC, Zhang Z, Yeh CH, O’Brien S, Garcia-Manero G, Caporaso N, Landgren O, Albitar M
Myelodysplastic syndrome (MDS) may be induced by certain mutagenic environmental or chemotherapeutic toxins; however, the role of susceptibility genes remains unclear. The G/G genotype of the single-nucleotide polymorphism (SNP) rs1617640 in the erythropoietin (EPO) promoter has been shown to be associated with decreased EPO expression. We examined the association of rs1617640 genotype with MDS.
PMID: 21078205 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
Dasatinib, even at low doses, is an effective second-line therapy for chronic myeloid leukemia patients resistant or intolerant to imatinib. Results from a real life-based Italian multicenter retrospective study on 114 patients.
Am J Hematol. 2010 Dec;85(12):960-3
Authors: Visani G, Breccia M, Gozzini A, Specchia G, Montefusco E, Morra E, Annunziata M, Camera A, Cavazzini F, Stagno F, Pregno P, Usala E, Santini V, Piccaluga PP, Isidori A
PMID: 21069865 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
[Leukemia and lymphoma].
Nippon Rinsho. 2010 Aug;68 Suppl 8:481-4
Authors: Kato M, Ogawa S
PMID: 20979299 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
An asymptomatic 61-year-old man with BCR-ABL-positive bone marrow following autologous transplantation for multiple myeloma.
Am J Hematol. 2010 Dec;85(12):944-6
Authors: Roper N, DeAngelo DJ, Kuo F, Dal Cin P, Ghobrial I, Aster JC
PMID: 20730794 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
Development of severe sclerotic chronic GVHD during treatment with dasatinib.
Bone Marrow Transplant. 2010 Sep;45(9):1469-70
Authors: Pulanic D, Cowen EW, Baird K, Bishop MR, Pavletic SZ
PMID: 20062096 [PubMed - indexed for MEDLINE]
More
Posted by rob on December 25, 2010 under Uncategorized |
Acquired growth hormone deficiency in a girl with chronic myelogenous leukemia treated with tyrosine kinase inhibitor therapy.
Pediatr Blood Cancer. 2010 Dec 22;
Authors: Hobernicht SL, Schweiger B, Zeitler P, Wang M, Hunger SP
Chronic myelogenous leukemia (CML) is caused by the BCR-ABL1 fusion gene that encodes for a constitutively-active tyrosine kinase. Adults and children with CML are typically treated with imatinib mesylate, a BCR-ABL1 tyrosine kinase inhibitor (TKI), or a second-generation TKI. Several case reports have documented growth delay of unknown mechanism in children with CML treated with imatinib. We report a seven-year-old identical twin with CML who developed significant growth delay, as compared to her twin, during five years of TKI therapy. Detailed endocrine evaluation showed acquired growth hormone deficiency, a pathway potentially inhibited by TKIs. Pediatr Blood Cancer © 2010 Wiley-Liss, Inc.
PMID: 21182033 [PubMed - as supplied by publisher]
More
Posted by rob on under Uncategorized |
Acquired protein C deficiency in a child with acute myelogenous leukemia, splenic, renal, and intestinal infarction.
Blood Coagul Fibrinolysis. 2010 Dec 21;
Authors: Farah RA, Jalkh KS, Farhat HZ, Sayad PE, Kadri AM
We report the case of a 6-year-old boy diagnosed with acute promyelocytic leukemia (AML-M3V) when he presented with pallor, abdominal pain, anorexia, and fatigue. Induction chemotherapy was started according to the AML-BFM 98 protocol along with Vesanoid (ATRA, All-trans retinoic acid). On the sixth day of induction, he developed splenic and gallbladder infarcts. Splenectomy and cholecystectomy were performed while chemotherapy induction continued as scheduled. Four days later, he developed ischemic areas in the kidneys and ischemic colitis in the sigmoid colon. Hypercoagulation studies showed severe deficiency of protein C. Tests showed protein C 16% (reference range 70-140%), protein S 87% (reference range 70-140%), antithrombin III 122% (reference range 80-120%), prothrombin time 13.6 s (reference = 11.3), INR (international normalized ratio) 1.21, partial thromboplastin time 33 s (reference = 33), fibrinogen 214 mg/dl, D-dimer 970 ?g/ml, factor II 98%, and that antinuclear antibody, antiphospholipid antibodies, mutation for factor II gene (G20210A), and mutation for Arg506 Gln of factor V were all negative (factor V Leiden). There was no evidence of clinical disseminated intravascular coagulation (DIC). He was treated with low molecular weight heparin and did well. He continues to be in complete remission 7 years later with normal protein C levels. Acquired protein C deficiency can occur in a variety of settings and has been reported in acute myelocytic leukemia. However, clinically significant thrombosis in the absence of clinical DIC, such as our case, remains extremely rare.
PMID: 21178585 [PubMed - as supplied by publisher]
More
Posted by rob on under Uncategorized |
Insights into the stem cells of chronic myeloid leukemia.
Leukemia. 2010 Nov;24(11):1823-33
Authors: Sloma I, Jiang X, Eaves AC, Eaves CJ
Chronic myeloid leukemia (CML) has long served as a paradigm for generating new insights into the cellular origin, pathogenesis and improved approaches to treating many types of human cancer. Early studies of the cellular phenotypes and genotypes represented in leukemic populations obtained from CML patients established the concept of an evolving clonal disorder originating in and initially sustained by a rare, multipotent, self-maintaining hematopoietic stem cell (HSC). More recent investigations continue to support this model, while also revealing new insights into the cellular and molecular mechanisms that explain how knowledge of CML stem cells and their early differentiating progeny can predict the differing and variable features of chronic phase and blast crisis. In particular, these emphasize the need for new agents that effectively and specifically target CML stem cells to produce non-toxic, but curative therapies that do not require lifelong treatments.
PMID: 20861912 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
OCT-1 activity measurement provides a superior imatinib response predictor than screening for single-nucleotide polymorphisms of OCT-1.
Leukemia. 2010 Nov;24(11):1962-5
Authors: White DL, Saunders VA, Dang P, Engler J, Hughes TP
PMID: 20811406 [PubMed - indexed for MEDLINE]
More
Posted by rob on under Uncategorized |
We report a seven?year?old identical twin with CML who developed significant growth delay, as compared to her twin, during five years of TKI therapy. Detailed endocrine evaluation showed acquired growth hormone deficiency, a pathway potentially inhibited by TKIs. Pediatr Blood Cancer © 2010 Wiley?Liss, Inc. (Source: Pediatric Blood and Cancer)
More
