Roundup Of Articles

Posted by rob on October 19, 2004 under Uncategorized | Be the First to Comment

 

Activation of the PI3K/mTOR pathway by BCR-ABL contributes to increased production of reactive oxygen species.

Blood. 2004 10 14;
Kim JH, Chu SC, Gramlich JL, Pride YB, Babendreier E, Chauhan D, Salgia R, Podar K, Griffin JD, Sattler M

BCR-ABL oncoprotein expressing cells are associated with a relative increase of intracellular reactive oxygen species (ROS), which is thought to play a role in transformation. Elevated ROS levels in BCR-ABL-transformed cells were found to be blocked by the mitochondrial complex I inhibitor rotenone as well as the glucose transport inhibitor phloretin, suggesting that the source of increased ROS might be related to increased glucose metabolism. The glucose analog 2-deoxyglucose (2-DOG) reduced ROS to levels found in non-BCR-ABL-transformed cells and inhibited cell growth alone or in cooperation with imatinib mesylate (Gleevec). A mutant of BCR-ABL that is defective in transformation of myeloid cells, Tyr177Phe, was also found to be defective in raising intracellular ROS levels. Glucose metabolism in BCR-ABL-transformed cells is likely to be mediated by activation of the phosphatidylinositol-3′-kinase (PI3K) pathway, which is regulated through this site. Inhibition of PI3K or mTOR led to a significant decrease in ROS levels. Overall, our results suggest that elevated levels of ROS in BCR-ABL-transformed cells are secondary to a transformation-associated increase in glucose metabolism and an over-active mitochondrial electron transport chain and is specifically regulated by PI3K. Finally, these results hint at novel targets for drug development that may aid traditional therapy.

  • Posted on: Sat, Oct 16 2004 1:34 AM
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Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial.

Lancet. 2004 Sep 25; 364(9440): 1127-34
Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, Issels R, van Oosterom A, Hogendoorn PC, Van Glabbeke M, Bertulli R, Judson I

BACKGROUND: Imatinib is approved worldwide for use in gastrointestinal stromal tumours (GIST). We aimed to assess dose dependency of response and progression-free survival with imatinib for metastatic GIST. METHODS: 946 patients were randomly allocated imatinib 400 mg either once or twice a day. Those assigned the once a day regimen who had progression were offered the option of crossover. The primary endpoint was progression-free survival. Analysis was by intention to treat. FINDINGS: At median follow-up of 760 days (IQR 644-859), 263 (56%) of 473 patients allocated imatinib once a day had progressed compared with 235 (50%) of 473 who were assigned treatment twice a day (estimated hazard ratio 0.82 [95% CI 0.69-0.98]; p=0.026). Side-effects arose in 465/470 (99%) patients allocated the once daily regimen compared with 468/472 (99%) assigned treatment twice a day. By comparison with the group treated once a day, more dose reductions (77 [16%] vs 282 [60%]) and treatment interruptions (189 [40%] vs 302 [64%]) were recorded in patients allocated the twice daily regimen, but treatment in both arms was fairly well tolerated. 52 (5%) patients achieved a complete response, 442 (47%) a partial response, and 300 (32%) stable disease, with no difference between groups. Median time to best response was 107 days (IQR 58-172). INTERPRETATION: If response induction is the only aim of treatment, a daily dose of 400 mg of imatinib is sufficient; however, a dose of 400 mg twice a day achieves significantly longer progression-free survival.

  • Posted on: Thu, Oct 14 2004 10:39 AM
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Pushing the imatinib envelope.

Lancet. 2004 Sep 25; 364(9440): 1101-2
Kitamura Y, Hayashi K
  • Posted on: Thu, Oct 14 2004 10:39 AM
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Imatinib (STI571)-Mediated Changes in Glucose Metabolism in Human Leukemia BCR-ABL-Positive Cells.

Clin Cancer Res. 2004 10 1; 10(19): 6661-6668
Gottschalk S, Anderson N, Hainz C, Eckhardt SG, Serkova NJ

The therapeutic efficacy of imatinib mesylate (Gleevec) is based on its specific inhibition of the BCR-ABL oncogene protein, a widely expressed tyrosine kinase in chronic myelogenous leukemia (CML) cells. The goal of this study was to evaluate glucose metabolism in BCR-ABL-positive cells that are sensitive to imatinib exposure. Two human BCR-ABL-positive cell lines (CML-T1 and K562) and one BCR-ABL-negative cell line (HC-1) were incubated with different imatinib concentrations for 96 hours. Magnetic resonance spectroscopy on cell acid extracts was performed to evaluate [1-(13)C]glucose metabolism, energy state, and changes in endogenous metabolites after incubation with imatinib. Imatinib induced a concentration-dependent inhibition of cell proliferation in CML-T1 (IC(50), 0.69 +/- 0.06 μmol/L) and K562 cells (IC(50), 0.47 +/- 0.04 μmol/L), but not in HC-1 cells. There were no metabolic changes in imatinib-treated HC-1 cells. In BCR-ABL-positive cells, the relevant therapeutic concentrations of imatinib (0.1-1.0 μmol/L) decreased glucose uptake from the media by suppressing glycolitic cell activity (C3-lactate at 0.25 mmol/L, 65% for K562 and 77% for CML-T1 versus control). Additionally, the activity of the mitochondrial Krebs cycle was increased (C4-glutamate at 0.25 μmol/L, 147% for K562 and 170% for CML-T1). The improvement in mitochondrial glucose metabolism resulted in an increased energy state (nucleoside triphosphate/nucleoside diphosphate at 0.25 μmol/L, 130% for K562 and 125% for CML-T1). Apoptosis was observed at higher concentrations. Unlike standard chemotherapeutics, imatinib, without cytocidal activity, reverses the Warburg effect in BCR-ABL-positive cells by switching from glycolysis to mitochondrial glucose metabolism, resulting in decreased glucose uptake and higher energy state.

  • Posted on: Tue, Oct 12 2004 5:37 AM
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Establishment and characterization of a new human erythroleukemic cell line, ERY-1.

Leuk Res. 2004 12; 28(12): 1329-1339
Ribadeau Dumas A, Hamouda NB, Leriche L, Piffaut MC, Bonnemye P, Kuen RL, Tricottet V, Merle-Beral H, Khac FN, Arock M

The growth factor-independent erythroleukemic cell line ERY-1 was established from the peripheral blood of a 87-year-old woman with chronic myeloid leukemia (CML) in the acute phase. Immunophenotyping showed that fresh leukemic cells were positive for CD13, CD33, CD36 and CD235a (glycophorin A), a phenotype compatible with that of erythroblastic cells. Cytogenetic and fluorescence in situ hybridization (FISH) analysis demonstrated classical t(9;22)(q34;q11) chromosomic translocation associated with a duplication of the BCR-ABL fusion gene. Other cytogenetic abnormalities were detected in all analyzed mitosis, the most frequent being a trisomy of chromosome 8. The established ERY-1 cell line retains these immunophenotypic and cytogenetic features, and light and electron microscopy confirmed the relatively mature erythroblastic phenotype of the cells. In addition, ERY-1 cell line expressed beta-globin mRNA and a non-phosphorylable form of the erythropoietin receptor, even in presence of erythropoietin. Of note, the proliferation of ERY-1 cells was inhibited by TGFbeta1 or STI-571 (Gleevec), without significant induction of further differenciation. In conclusion, ERY-1 is a new growth factor-independent human erythroleukemic cell line with a relatively mature phenotype that may be useful to study the molecular events involved in erythroblastic differentiation.

  • Posted on: Tue, Oct 12 2004 5:37 AM
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Activation of the neuronal c-Abl tyrosine kinase by amyloid-beta-peptide and reactive oxygen species.

Neurobiol Dis. 2004 Nov; 17(2): 326-36
Alvarez AR, Sandoval PC, Leal NR, Castro PU, Kosik KS

The deposition and accumulation of amyloid-beta-peptide (Abeta) in the brain are considered a sine qua non for Alzheimer’s disease. The experimental delivery of fibrilized Abeta serves as a cellular model for several facets of the disease including the induction of synaptic dysfunction and apoptosis. c-Abl kinase is involved in the regulation of apoptosis and its pro-apoptotic function is in part mediated by its interaction with p73, a p53 homologue. We found that c-Abl activation is involved in cell signals that regulate neuronal death response to Abeta fibrils. Abeta peptide fibrils induced an increase of the c-Abl activity in rat hippocampal neurons as well as an increase in nuclear p73 protein levels and the p73-c-Abl complex. The neuronal cell death induced by Abeta fibrils was prevented by the inhibition of c-Abl with imatinib mesylate (Gleevec or STI571) and by the inhibition c-Abl expression by RNAi. These results directly point to a therapeutic strategy for the treatment of Alzheimer’s disease.

  • Posted on: Tue, Oct 12 2004 5:37 AM
  • Updated: Wed, Oct 13 2004 8:39 AM
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Successful outcome of pregnancy in chronic myeloid leukaemia treated with imatinib.

Leuk Lymphoma. 2004 Jun; 45(6): 1307-8
Heartin E, Walkinshaw S, Clark RE
  • Posted on: Sat, Oct 9 2004 12:36 PM
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Heterogeneity of response to imatinib-mesylate (glivec) in patients with hypereosinophilic syndrome: implications for dosing and pathogenesis.

Leuk Lymphoma. 2004 Jun; 45(6): 1219-22
Musto P, Falcone A, Sanpaolo G, Bodenizza C, Perla G, Minervini MM, Cascavilla N, Dell’Olio M, La Sala A, Mantuano S, Melillo L, Nobile M, Scalzulli PR, Bisceglia M, Carella AM

Four cases of hypereosinophilic syndrome (HES) treated with the tyrosine-kinase inhibitor imatinib-mesylate are reported. The drug was effective in three patients, but a prolonged clinical and hematological remission was obtained only in one patient, due to appearance of resistance or poor tolerability in the other cases. The dose of imatinib necessary to achieve a response ranged from 100 to 600 mg/d. One patient with evidence of a clonal T-cell population did not respond at all. We confirm the efficacy of imatinib in HES, but we also underline that type and duration of response may be variable. This could be due to different pathogenetic mechanisms of the disease in single patients.

  • Posted on: Sat, Oct 9 2004 12:36 PM
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Biology of gastrointestinal stromal tumors.

J Clin Oncol. 2004 Sep 15; 22(18): 3813-25
Corless CL, Fletcher JA, Heinrich MC

Once a poorly defined pathologic oddity, in recent years, gastrointestinal stromal tumor (GIST) has emerged as a distinct oncogenetic entity that is now center stage in clinical trials of kinase-targeted therapies. This review charts the rapid progress that has established GIST as a model for understanding the role of oncogenic kinase mutations in human tumorigenesis. Approximately 80% to 85% of GISTs harbor activating mutations of the KIT tyrosine kinase. In a series of 322 GISTs (including 140 previously published cases) studied by the authors in detail, mutations in the KIT gene occurred with decreasing frequency in exons 11 (66.1%), 9 (13%), 13 (1.2%), and 17 (0.6%). In the same series, a subset of tumors had mutations in the KIT-related kinase gene PDGF receptor alpha (PDGFRA), which occurred in either exon 18 (5.6%) or 12 (1.5%). The remainder of GISTs (12%) were wild type for both KIT and PDGFRA. Comparative studies of KIT-mutant, PDGFRA-mutant, and wild-type GISTs indicate that there are many similarities between these groups of tumors but also important differences. In particular, the responsiveness of GISTs to treatment with the kinase inhibitor imatinib varies substantially depending on the exonic location of the KIT or PDGFRA mutation. Given these differences, which have implications both for the diagnosis and treatment of GISTs, we propose a molecular-based classification of GIST. Recent studies of familial GIST, pediatric GIST, and variant forms of GIST related to Carney’s triad and neurofibromatosis type 1 are discussed in relationship to this molecular classification. In addition, the role of mutation screening in KIT and PDGFRA as a diagnostic and prognostic aid is emphasized in this review.

  • Posted on: Fri, Oct 8 2004 10:42 AM
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[Current strategy of chemotherapy for reflactory bone and soft tissue sarcomas]

Gan To Kagaku Ryoho. 2004 Sep; 31(9): 1331-9
Chuman H

Pulmonary metastases have been curative in some patients of osteosarcoma with aggressive surgical excision and intensive chemotherapy. But several retrospective studies and randomized II studies did not prove survival advantages of advanced cases with bone and soft tissue sarcoma. In treatment for refractory and advanced osteosarcoma after conventional treatments, clinical phase II trials showed 20-30% response ratio of high-dose ifosfamide and etoposide combination or carboplatin combination. In soft tissue sarcomas, high-dose ifosfamide and doxorubicin have over 50% response rate to advanced soft tissue sarcoma and total surgical excision of residual lung metastases prolong the survival. But new drugs active to refractory sarcoma had not reported in a recent decade.

  • Posted on: Wed, Oct 6 2004 1:35 AM
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A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors.

Cancer Res. 2004 Sep 1; 64(17): 5913-9
Chen LL, Trent JC, Wu EF, Fuller GN, Ramdas L, Zhang W, Raymond AK, Prieto VG, Oyedeji CO, Hunt KK, Pollock RE, Feig BW, Hayes KJ, Choi H, Macapinlac HA, Hittelman W, Velasco MA, Patel S, Burgess MA, Benjamin RS, Frazier ML

KIT gain of function mutations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). Imatinib is a selective tyrosine kinase inhibitor of ABL, platelet-derived growth factor receptor (PDGFR), and KIT and represents a new paradigm of targeted therapy against GISTs. Here we report for the first time that, after imatinib treatment, an additional specific and novel KIT mutation occurs in GISTs as they develop resistance to the drug. We studied 12 GIST patients with initial near-complete response to imatinib. Seven harbored mutations in KIT exon 11, and 5 harbored mutations in exon 9. Within 31 months, six imatinib-resistant rapidly progressive peritoneal implants (metastatic foci) developed in five patients. Quiescent residual GISTs persisted in seven patients. All six rapidly progressive imatinib-resistant implants from five patients show an identical novel KIT missense mutation, 1982T–>C, that resulted in Val654Ala in KIT tyrosine kinase domain 1. This novel mutation has never been reported before, is not present in pre-imatinib or post-imatinib residual quiescent GISTs, and is strongly correlated with imatinib resistance. Allelic-specific sequencing data show that this new mutation occurs in the allele that harbors original activation mutation of KIT.

  • Posted on: Wed, Oct 6 2004 1:35 AM
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Gastrointestinal stromal tumours: Etiology, pathology and clinical management.

Can J Gastroenterol. 2004 Sep; 18 Suppl B: 3B-8B
Blackstein ME, Dubé P, Fletcher JA, Keller OR, Knowling M, Létourneau R, Morris D, Riddell R, Rorke S, Swallow CJ

Investigation of the regulation of cell growth, differentiation and death by signalling pathways has led to a greater understanding of how alterations in these pathways play a critical role in the development of some cancers, and has opened new opportunities for their treatment. In the present review, results with the prototype drug of this class, imatinib (Gleevec, Glivec [formerly STI571]; Novartis, Switzerland), in metastatic gastrointestinal stromal tumours are presented. The present review originated from a conference of the authors held in Montreal, Quebec in June 2003, under the sponsorship of Novartis.

  • Posted on: Fri, Oct 1 2004 4:33 AM
  • Updated: Fri, Oct 1 2004 6:33 PM
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Association of platelet-derived growth factor-B chain with simian human immunodeficiency virus encephalitis.

Am J Pathol. 2004 Sep; 165(3): 815-24
Potula R, Dhillion N, Sui Y, Zien CA, Funa K, Pinson D, Mayo MS, Singh DK, Narayan O, Buch S

Chemokines and cytokines play a critical role in HIV infection, serving both to modulate virus replication and to recruit target cells to the site of infection. Platelet-derived growth factor (PDGF), a mitogen and chemoattractant for a wide variety of cells, is secreted by macrophages. Since macrophages are the target cells for lentiviral infection in the brain and PDGF is a known inducer of macrophage chemoattractant protein-1 (MCP)-1, a potent chemokine closely associated with HIV encephalitis, we investigated the association of PDGF-B chain (PDGF-B) with encephalitis in macaques caused by simian human immunodeficiency virus (SHIV), a chimera of HIV and SIV. Northern blot analysis confirmed elevated expression of PDGF-B chain mRNA in the brains from encephalitic macaques. Validation of these in vivo studies was confirmed in rhesus macrophage cultures infected with SHIV(KU2) in which we demonstrated heightened expression of PDGF-B chain mRNA. Nuclear run-off analysis established transcriptional up-regulation of PDGF-B chain in virus-inoculated macrophage cultures. Reciprocally, addition of exogenous PDGF enhanced virus replication and MCP-1 expression in these cells. Inhibition of virus replication by tyrosine kinase inhibitor, STI-571, and by PDGF-B antisense oligonucleotides confirmed the specificity of the PDGF effect. Relevance of these findings was confirmed by analysis of archival brain tissue from SHIV encephalitic and non-encephalitic macaques for PDGF-B chain expression. PDGF-B chain protein expression was observed in the virus-infected cells in microglial nodules in the brains of SHIV-encephalitic macaques.

  • Posted on: Fri, Oct 1 2004 4:33 AM
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Research unveils the ‘who’ and ‘why’ of gefitinib.

J Natl Cancer Inst. 2004 Sep 15; 96(18): 1352-4
Vastag B
  • Posted on: Thu, Sep 30 2004 2:35 AM
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New generation leukaemia drugs are on their way.

Drug Discov Today. 2004 Sep 1; 9(17): 732-3
Nelson L

Since Gleevec was first introduced as the leukaemia-wonder drug, its use has been tarnished by resistance in patients. However, a new drug (BMS-354825) that is currently in development could be the answer to the resistance problems encountered with Gleevec.

  • Posted on: Wed, Sep 29 2004 1:43 PM
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Sensitivity to imatinib therapy may be predicted by testing Wilms tumor gene expression and colony growth after a short in vitro incubation.

Cancer. 2004 Sep 1; 101(5): 979-88
Cilloni D, Messa F, Gottardi E, Fava M, Arruga F, Defilippi I, Carturan S, Messa E, Morotti A, Giugliano E, Rege-Cambrin G, Alberti D, Baccarani M, Saglio G

BACKGROUND: The objective of the current study was to verify the ability to predict response to imatinib therapy using in vitro assays to evaluate the inhibition of Wilms tumor gene (WT1) expression and colony growth after samples obtained from patients with chronic myelogenous leukemia (CML) before the start of treatment were subjected to short-term incubation with imatinib. METHODS: WT1 transcript levels and colony growth in bone marrow (BM) samples from 23 patients with CML that was later identified as being responsive to imatinib and from 13 patients with CML that was later identified as not being responsive to imatinib were evaluated after incubation of these samples with imatinib at a concentration of 1 microM for 18 hours. In addition, real-time quantitative polymerase chain reaction (RQ-PCR) analysis of WT1 expression was performed during follow-up, and the results were analyzed for associations with cytogenetic response and with BCR/ABL transcript levels as determined using RQ-PCR analysis. RESULTS: Before treatment, it was found that WT1 expression was elevated in BM samples obtained from all patients with CML. WT1 expression and colony growth were reduced significantly after an 18-hour incubation with imatinib in samples obtained from patients who were later identified as responders to treatment, but not in samples obtained from patients who did not experience responses to treatment. Inhibition of WT1 expression in vitro was associated with inhibition of imatinib-induced BCR-ABL tyrosine kinase activity, a finding that also has been made in studies involving certain Philadelphia chromosome (Ph)-positive and Ph-negative cell lines. CONCLUSIONS: Inhibition of WT1 transcript levels after a short period of in vitro exposure of pretherapy BM samples to imatinib was correlated with inhibition of colony growth and may represent the basis for an easy test that is capable of predicting the sensitivity of CML to treatment with imatinib for individual patients.

  • Posted on: Wed, Sep 29 2004 1:43 PM
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Case of chronic-phase chronic myelogenous leukemia with an abdominal hematopoietic tumor of leukemic clone origin.

Am J Hematol. 2004 Oct; 77(2): 167-70
Sakakura M, Ohishi K, Nomura K, Katayama N, Nishii K, Masuya M, Nakase K, Shiku H

We report a 59-year-old man with chronic myelogenous leukemia (CML) in chronic phase who presented with a large abdominal tumor. Biopsy revealed proliferation of granulocytic-, erythroid-, and megakaryocytic-lineage cells in a retroperitoneal lymph node. The BCR/ABL fusion gene was detected on a paraffin-embedded tissue section of the lymph node by double-color fluorescence in situ hybridization, indicating an extramedullary hematopoietic tumor of CML origin. This patient has achieved a complete cytogenetic response for 19 months with imatinib mesylate (STI571; Gleevec), in association with the regression of the tumor. However, the development of an extramedullary tumor in chronic-phase CML generally indicates a poor prognosis, because it commonly consists of blast proliferation and is followed by blast crisis in the marrow within a few months. This case, therefore, points to the importance of histological examination of extramedullary tumors in CML for evaluation of disease status and for therapeutic decisions.

  • Posted on: Sat, Sep 25 2004 5:34 AM
  • Updated: Sat, Oct 16 2004 1:34 AM
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Expression of C-kit in Ewing Family of Tumors: A Comparison of Different Immunohistochemical Protocols.

Pediatr Dev Pathol. 2004 Jul-Aug; 7(4): 342-7
Ahmed A, Gilbert-Barness E, Lacson A

Ewing sarcoma is a small round blue cell tumor with a high incidence of metastasis and poor survival. The tyrosine kinase receptor, c-kit, is a growth factor receptor that is expressed in a variety of tumors including Ewing sarcoma. Blockade of c-kit by imatinib mesylate (Gleevec; Novartis Pharmaceuticals Corp, East Hanover, NJ) has been successfully used in the treatment of chronic myelogenous leukemia and gastrointestinal tumors. Detection of c-kit expression in Ewing sarcoma indicates a possible role of c-kit in tumor progression and a potential use of anti-c-kit therapy in Ewing sarcoma. Ki-67 is a proliferation marker found at all stages of the cell cycle. Expression of c-kit and Ki-67 was studied in 17 patients with Ewing sarcoma. Sections from paraffin-embedded tumor samples were immunostained, using standard immunohistochemical protocols, with c-kit and Ki-67 monoclonal antibodies, polyclonal c-kit antibody without antigen retrieval, and c-kit polyclonal antibody with antigen retrieval. Eleven out of 17 cases (65%) stained with c-kit monoclonal antibody; the staining was diffuse in 6/17 (35%) cases. C-kit expression did not correlate with Ki-67 proliferation rates. Using the polyclonal c-kit-antibody without antigen retrieval methods, c-kit expression was demonstrated in 1/11 (9%) cases. Incorporating antigen retrieval methods, c-kit expression increased to 53%. Concordance between monoclonal antibodies in detecting c-kit expression was observed in 12/17 cases (71%). We conclude that c-kit is variably expressed in Ewing sarcoma, using either monoclonal or polyclonal antibodies. Detection of c-kit expression in Ewing sarcoma improves with the use of antigen retrieval methods.

  • Posted on: Fri, Sep 24 2004 2:34 AM
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Treatment of CML in pediatric patients: Should imatinib mesylate (STI-571, Gleevec) or allogeneic hematopoietic cell transplant be front-line therapy?

Pediatr Blood Cancer. 2004 Oct; 43(5): 523
Pulsipher MA

BACKGROUND: Long-term survival of pediatric patients with chronic myelogenous leukemia (CML) receiving myeloablative hematopoietic stem cell transplantation from fully-matched related and unrelated donors has been reported between 60 and 75%, but is associated with significant morbidity. Imatinib mesylate (STI-571, Gleevec) and reduced intensity conditioning stem cell transplantation (RIC) are two promising new tools that offer potential for decreasing therapy associated morbidity for patients with CML. RESULTS: Large trials have shown significant responses in chronic phase patients treated with imatinib and reasonable but short-lived responses in advanced phase CML. Data from adult studies is beginning to define populations likely to progress or have prolonged responses to imatinib, and some adult treatment paradigms are moving toward reserving transplantation until patients are at risk of failure with imatinib. Early trials of RIC transplantation in CML show decreased transplant related morbidity with efficacy similar to conventional transplantation, but the approach has yet to be verified in phase III studies. Data in pediatric patients with imatinib and RIC transplantation is limited. CONCLUSIONS: Studies with imatinib are underway in pediatrics, but whether pediatric dosing schemes will lead to outcomes similar to adults is unknown. Because HLA-matched myeloablative transplantation offers a high rate of cure in the pediatric population, clinical studies assessing the role of imatinib mesylate and RIC transplantation should be planned carefully in order to avoid sub-optimal outcomes. Copyright 2004 Wiley-Liss, Inc.

  • Posted on: Fri, Sep 24 2004 2:34 AM
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Establishment and characterization of an STI571-resistant human myelogenous leukemia cell line, SR-1.

Cancer Genet Cytogenet. 2004 Oct 1; 154(1): 52-6
Kwon HC, Kim SH, Kim JS, Han H, Sook Roh M, Han JY, Seo SY, Lee YH, Kim HJ

The tyrosine kinase inhibitor STI571 is an effective agent for the treatment of chronic myelogenous leukemia (CML). However, a lack of response to STI571 or the recurrence of the disease after a transient initial response is usually seen in patients with advanced stage CML. We have established a novel STI571 (Gleevec/Glivec, imatinib mesylate)-resistant acute myelocytic leukemia cell line (SR-1) from an STI571-resistant blast crisis patient. By flow cytometry, the immunophenotype of SR-1 was found to be compatible with a myeloid lineage (CD13(+), CD33(+), HLA-DR(+), anti-MPO(+)). Conventional cytogenetics showed a three-way reciprocal translocation involving 7p22, 9q34, and 22q11.2, i.e., a variant Philadelphia chromosome translocation. The BCR/ABL rearrangement was detected by fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction. To determine the tumorigenicity of the SR-1 cell line in vivo, cells were injected subcutaneously into severe combined immunodeficiency mice. Four weeks later, tumors had grown and showed the same laboratory findings as in SR-1. Although STI571 resistance is a known treatment complication, in vivo STI571-resistant cell lines have not been fully established. We hope that our SR-1 cell line may be useful in molecular pathogenetic investigations of STI571-resistant CML.

  • Posted on: Fri, Sep 24 2004 2:34 AM
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Imatinib results in better quality of life for CML patients than interferon/Ara-C.

J Support Oncol. 2003 May-Jun; 1(1): 77
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Trisomy 8 in Philadelphia-negative cells during imatinib therapy.

Am J Hematol. 2004 Sep; 77(1): 88-9
Bernardeschi P, Fiorentini G, Rossi S, Dentico P, Simi P, Guidi S

Targeted therapy with imatinib selectively suppresses Philadelphia-positive cells in chronic myeloid leukemia cells, with reappearance of apparently normal hemopoiesis in a considerable number of patients. Recently, clonal abnormalities have been observed in Philadelphia-negative cells during imatinib therapy, the biologic and prognostic significance of which is actually unknown. A case of trisomy 8 occurring in Philadelphia-negative cells, which was treated by bone marrow transplantation, is reported. Chromosomal abnormalities in Philadelphia-negative cells do not seem to herald disease transformation, but the long-term prognosis may be influenced by an increased incidence of myelodysplasia in younger patients.

  • Posted on: Fri, Sep 24 2004 2:34 AM
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Relationship between idiopathic hypereosinophilic syndrome, eosinophilic leukemia, and systemic mastocytosis.

Am J Hematol. 2004 Sep; 77(1): 82-5
Bain BJ

Chronic eosinophilic leukemia is a neoplastic condition with persistent eosinophilia as the major hematological abnormality and with the eosinophils being part of the neoplastic clone. Some cases can be recognized by traditional hematological criteria, but many can be recognized only when a clonal cytogenetic or molecular genetic abnormality is demonstrated. A range of cytogenetic and molecular genetic abnormalities has been recognized, including both those seen in other myeloid malignancies (such as trisomy 8, monosomy 7, and 20q-) and those that are particularly linked to eosinophil differentiation (such as rearrangements of PDGFRB, FGFR1, and PDGFRA, the latter with formation of a FIP1L1-PDGFRA fusion gene). The discovery of the FIP1L1-PDGFRA fusion gene has led to the recognition that many patients who would previously have been regarded as having idiopathic hypereosinophilia actually have chronic eosinophilic leukemia. The same fusion gene has also been found in patients with hypereosinophilia and atypical bone marrow mast cells but whether this syndrome should be regarded as a variant of eosinophilic leukemia or as a variant of systemic mastocytosis remains to be established.

  • Posted on: Fri, Sep 24 2004 2:34 AM
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Management of life-threatening pulmonary leukostasis with single agent imatinib mesylate during CML myeloid blast crisis.

Haematologica. 2004 Sep; 89(9): ECR30
Leis JF, Primack SL, Schubach SE, Curtin PT, Druker BJ, Maziarz RT

Pulmonary leukostasis is a rare but serious and often fatal complication of chronic myeloid leukemia (CML) in blast crisis and acute myeloid leukemia. Treatment options are limited for these patients. Imatinib mesylate (STI-571, Gleevec, Novartis) is a potent and selective inhibitor of the BCR-abl tyrosine kinase, the molecular abnormality that causes CML. The case of a 74-year-old man with a history of CML who presented in myeloid blast crisis with pulmonary leukostasis characterized by increasing dyspnea, hypoxemia, fever, and impending respiratory failure is reported. The patient was treated with single agent imatinib mesylate (IM) with rap

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Activation of the PI3K/mTOR pathway by BCR-ABL contributes to increased production of reactive oxygen species.

Blood. 2004 10 14;
Kim JH, Chu SC, Gramlich JL, Pride YB, Babendreier E, Chauhan D, Salgia R, Podar K, Griffin JD, Sattler M

BCR-ABL oncoprotein expressing cells are associated with a relative increase of intracellular reactive oxygen species (ROS), which is thought to play a role in transformation. Elevated ROS levels in BCR-ABL-transformed cells were found to be blocked by the mitochondrial complex I inhibitor rotenone as well as the glucose transport inhibitor phloretin, suggesting that the source of increased ROS might be related to increased glucose metabolism. The glucose analog 2-deoxyglucose (2-DOG) reduced ROS to levels found in non-BCR-ABL-transformed cells and inhibited cell growth alone or in cooperation with imatinib mesylate (Gleevec). A mutant of BCR-ABL that is defective in transformation of myeloid cells, Tyr177Phe, was also found to be defective in raising intracellular ROS levels. Glucose metabolism in BCR-ABL-transformed cells is likely to be mediated by activation of the phosphatidylinositol-3′-kinase (PI3K) pathway, which is regulated through this site. Inhibition of PI3K or mTOR led to a significant decrease in ROS levels. Overall, our results suggest that elevated levels of ROS in BCR-ABL-transformed cells are secondary to a transformation-associated increase in glucose metabolism and an over-active mitochondrial electron transport chain and is specifically regulated by PI3K. Finally, these results hint at novel targets for drug development that may aid traditional therapy.

  • Posted on: Sat, Oct 16 2004 1:34 AM
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Progression-free survival in gastrointestinal stromal tumours with high-dose imatinib: randomised trial.

Lancet. 2004 Sep 25; 364(9440): 1127-34
Verweij J, Casali PG, Zalcberg J, LeCesne A, Reichardt P, Blay JY, Issels R, van Oosterom A, Hogendoorn PC, Van Glabbeke M, Bertulli R, Judson I

BACKGROUND: Imatinib is approved worldwide for use in gastrointestinal stromal tumours (GIST). We aimed to assess dose dependency of response and progression-free survival with imatinib for metastatic GIST. METHODS: 946 patients were randomly allocated imatinib 400 mg either once or twice a day. Those assigned the once a day regimen who had progression were offered the option of crossover. The primary endpoint was progression-free survival. Analysis was by intention to treat. FINDINGS: At median follow-up of 760 days (IQR 644-859), 263 (56%) of 473 patients allocated imatinib once a day had progressed compared with 235 (50%) of 473 who were assigned treatment twice a day (estimated hazard ratio 0.82 [95% CI 0.69-0.98]; p=0.026). Side-effects arose in 465/470 (99%) patients allocated the once daily regimen compared with 468/472 (99%) assigned treatment twice a day. By comparison with the group treated once a day, more dose reductions (77 [16%] vs 282 [60%]) and treatment interruptions (189 [40%] vs 302 [64%]) were recorded in patients allocated the twice daily regimen, but treatment in both arms was fairly well tolerated. 52 (5%) patients achieved a complete response, 442 (47%) a partial response, and 300 (32%) stable disease, with no difference between groups. Median time to best response was 107 days (IQR 58-172). INTERPRETATION: If response induction is the only aim of treatment, a daily dose of 400 mg of imatinib is sufficient; however, a dose of 400 mg twice a day achieves significantly longer progression-free survival.

  • Posted on: Thu, Oct 14 2004 10:39 AM
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Pushing the imatinib envelope.

Lancet. 2004 Sep 25; 364(9440): 1101-2
Kitamura Y, Hayashi K
  • Posted on: Thu, Oct 14 2004 10:39 AM
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Imatinib (STI571)-Mediated Changes in Glucose Metabolism in Human Leukemia BCR-ABL-Positive Cells.

Clin Cancer Res. 2004 10 1; 10(19): 6661-6668
Gottschalk S, Anderson N, Hainz C, Eckhardt SG, Serkova NJ

The therapeutic efficacy of imatinib mesylate (Gleevec) is based on its specific inhibition of the BCR-ABL oncogene protein, a widely expressed tyrosine kinase in chronic myelogenous leukemia (CML) cells. The goal of this study was to evaluate glucose metabolism in BCR-ABL-positive cells that are sensitive to imatinib exposure. Two human BCR-ABL-positive cell lines (CML-T1 and K562) and one BCR-ABL-negative cell line (HC-1) were incubated with different imatinib concentrations for 96 hours. Magnetic resonance spectroscopy on cell acid extracts was performed to evaluate [1-(13)C]glucose metabolism, energy state, and changes in endogenous metabolites after incubation with imatinib. Imatinib induced a concentration-dependent inhibition of cell proliferation in CML-T1 (IC(50), 0.69 +/- 0.06 μmol/L) and K562 cells (IC(50), 0.47 +/- 0.04 μmol/L), but not in HC-1 cells. There were no metabolic changes in imatinib-treated HC-1 cells. In BCR-ABL-positive cells, the relevant therapeutic concentrations of imatinib (0.1-1.0 μmol/L) decreased glucose uptake from the media by suppressing glycolitic cell activity (C3-lactate at 0.25 mmol/L, 65% for K562 and 77% for CML-T1 versus control). Additionally, the activity of the mitochondrial Krebs cycle was increased (C4-glutamate at 0.25 μmol/L, 147% for K562 and 170% for CML-T1). The improvement in mitochondrial glucose metabolism resulted in an increased energy state (nucleoside triphosphate/nucleoside diphosphate at 0.25 μmol/L, 130% for K562 and 125% for CML-T1). Apoptosis was observed at higher concentrations. Unlike standard chemotherapeutics, imatinib, without cytocidal activity, reverses the Warburg effect in BCR-ABL-positive cells by switching from glycolysis to mitochondrial glucose metabolism, resulting in decreased glucose uptake and higher energy state.

  • Posted on: Tue, Oct 12 2004 5:37 AM
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Establishment and characterization of a new human erythroleukemic cell line, ERY-1.

Leuk Res. 2004 12; 28(12): 1329-1339
Ribadeau Dumas A, Hamouda NB, Leriche L, Piffaut MC, Bonnemye P, Kuen RL, Tricottet V, Merle-Beral H, Khac FN, Arock M

The growth factor-independent erythroleukemic cell line ERY-1 was established from the peripheral blood of a 87-year-old woman with chronic myeloid leukemia (CML) in the acute phase. Immunophenotyping showed that fresh leukemic cells were positive for CD13, CD33, CD36 and CD235a (glycophorin A), a phenotype compatible with that of erythroblastic cells. Cytogenetic and fluorescence in situ hybridization (FISH) analysis demonstrated classical t(9;22)(q34;q11) chromosomic translocation associated with a duplication of the BCR-ABL fusion gene. Other cytogenetic abnormalities were detected in all analyzed mitosis, the most frequent being a trisomy of chromosome 8. The established ERY-1 cell line retains these immunophenotypic and cytogenetic features, and light and electron microscopy confirmed the relatively mature erythroblastic phenotype of the cells. In addition, ERY-1 cell line expressed beta-globin mRNA and a non-phosphorylable form of the erythropoietin receptor, even in presence of erythropoietin. Of note, the proliferation of ERY-1 cells was inhibited by TGFbeta1 or STI-571 (Gleevec), without significant induction of further differenciation. In conclusion, ERY-1 is a new growth factor-independent human erythroleukemic cell line with a relatively mature phenotype that may be useful to study the molecular events involved in erythroblastic differentiation.

  • Posted on: Tue, Oct 12 2004 5:37 AM
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Activation of the neuronal c-Abl tyrosine kinase by amyloid-beta-peptide and reactive oxygen species.

Neurobiol Dis. 2004 Nov; 17(2): 326-36
Alvarez AR, Sandoval PC, Leal NR, Castro PU, Kosik KS

The deposition and accumulation of amyloid-beta-peptide (Abeta) in the brain are considered a sine qua non for Alzheimer’s disease. The experimental delivery of fibrilized Abeta serves as a cellular model for several facets of the disease including the induction of synaptic dysfunction and apoptosis. c-Abl kinase is involved in the regulation of apoptosis and its pro-apoptotic function is in part mediated by its interaction with p73, a p53 homologue. We found that c-Abl activation is involved in cell signals that regulate neuronal death response to Abeta fibrils. Abeta peptide fibrils induced an increase of the c-Abl activity in rat hippocampal neurons as well as an increase in nuclear p73 protein levels and the p73-c-Abl complex. The neuronal cell death induced by Abeta fibrils was prevented by the inhibition of c-Abl with imatinib mesylate (Gleevec or STI571) and by the inhibition c-Abl expression by RNAi. These results directly point to a therapeutic strategy for the treatment of Alzheimer’s disease.

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  • Updated: Wed, Oct 13 2004 8:39 AM
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Successful outcome of pregnancy in chronic myeloid leukaemia treated with imatinib.

Leuk Lymphoma. 2004 Jun; 45(6): 1307-8
Heartin E, Walkinshaw S, Clark RE
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Heterogeneity of response to imatinib-mesylate (glivec) in patients with hypereosinophilic syndrome: implications for dosing and pathogenesis.

Leuk Lymphoma. 2004 Jun; 45(6): 1219-22
Musto P, Falcone A, Sanpaolo G, Bodenizza C, Perla G, Minervini MM, Cascavilla N, Dell’Olio M, La Sala A, Mantuano S, Melillo L, Nobile M, Scalzulli PR, Bisceglia M, Carella AM

Four cases of hypereosinophilic syndrome (HES) treated with the tyrosine-kinase inhibitor imatinib-mesylate are reported. The drug was effective in three patients, but a prolonged clinical and hematological remission was obtained only in one patient, due to appearance of resistance or poor tolerability in the other cases. The dose of imatinib necessary to achieve a response ranged from 100 to 600 mg/d. One patient with evidence of a clonal T-cell population did not respond at all. We confirm the efficacy of imatinib in HES, but we also underline that type and duration of response may be variable. This could be due to different pathogenetic mechanisms of the disease in single patients.

  • Posted on: Sat, Oct 9 2004 12:36 PM
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Biology of gastrointestinal stromal tumors.

J Clin Oncol. 2004 Sep 15; 22(18): 3813-25
Corless CL, Fletcher JA, Heinrich MC

Once a poorly defined pathologic oddity, in recent years, gastrointestinal stromal tumor (GIST) has emerged as a distinct oncogenetic entity that is now center stage in clinical trials of kinase-targeted therapies. This review charts the rapid progress that has established GIST as a model for understanding the role of oncogenic kinase mutations in human tumorigenesis. Approximately 80% to 85% of GISTs harbor activating mutations of the KIT tyrosine kinase. In a series of 322 GISTs (including 140 previously published cases) studied by the authors in detail, mutations in the KIT gene occurred with decreasing frequency in exons 11 (66.1%), 9 (13%), 13 (1.2%), and 17 (0.6%). In the same series, a subset of tumors had mutations in the KIT-related kinase gene PDGF receptor alpha (PDGFRA), which occurred in either exon 18 (5.6%) or 12 (1.5%). The remainder of GISTs (12%) were wild type for both KIT and PDGFRA. Comparative studies of KIT-mutant, PDGFRA-mutant, and wild-type GISTs indicate that there are many similarities between these groups of tumors but also important differences. In particular, the responsiveness of GISTs to treatment with the kinase inhibitor imatinib varies substantially depending on the exonic location of the KIT or PDGFRA mutation. Given these differences, which have implications both for the diagnosis and treatment of GISTs, we propose a molecular-based classification of GIST. Recent studies of familial GIST, pediatric GIST, and variant forms of GIST related to Carney’s triad and neurofibromatosis type 1 are discussed in relationship to this molecular classification. In addition, the role of mutation screening in KIT and PDGFRA as a diagnostic and prognostic aid is emphasized in this review.

  • Posted on: Fri, Oct 8 2004 10:42 AM
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[Current strategy of chemotherapy for reflactory bone and soft tissue sarcomas]

Gan To Kagaku Ryoho. 2004 Sep; 31(9): 1331-9
Chuman H

Pulmonary metastases have been curative in some patients of osteosarcoma with aggressive surgical excision and intensive chemotherapy. But several retrospective studies and randomized II studies did not prove survival advantages of advanced cases with bone and soft tissue sarcoma. In treatment for refractory and advanced osteosarcoma after conventional treatments, clinical phase II trials showed 20-30% response ratio of high-dose ifosfamide and etoposide combination or carboplatin combination. In soft tissue sarcomas, high-dose ifosfamide and doxorubicin have over 50% response rate to advanced soft tissue sarcoma and total surgical excision of residual lung metastases prolong the survival. But new drugs active to refractory sarcoma had not reported in a recent decade.

  • Posted on: Wed, Oct 6 2004 1:35 AM
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A missense mutation in KIT kinase domain 1 correlates with imatinib resistance in gastrointestinal stromal tumors.

Cancer Res. 2004 Sep 1; 64(17): 5913-9
Chen LL, Trent JC, Wu EF, Fuller GN, Ramdas L, Zhang W, Raymond AK, Prieto VG, Oyedeji CO, Hunt KK, Pollock RE, Feig BW, Hayes KJ, Choi H, Macapinlac HA, Hittelman W, Velasco MA, Patel S, Burgess MA, Benjamin RS, Frazier ML

KIT gain of function mutations play an important role in the pathogenesis of gastrointestinal stromal tumors (GISTs). Imatinib is a selective tyrosine kinase inhibitor of ABL, platelet-derived growth factor receptor (PDGFR), and KIT and represents a new paradigm of targeted therapy against GISTs. Here we report for the first time that, after imatinib treatment, an additional specific and novel KIT mutation occurs in GISTs as they develop resistance to the drug. We studied 12 GIST patients with initial near-complete response to imatinib. Seven harbored mutations in KIT exon 11, and 5 harbored mutations in exon 9. Within 31 months, six imatinib-resistant rapidly progressive peritoneal implants (metastatic foci) developed in five patients. Quiescent residual GISTs persisted in seven patients. All six rapidly progressive imatinib-resistant implants from five patients show an identical novel KIT missense mutation, 1982T–>C, that resulted in Val654Ala in KIT tyrosine kinase domain 1. This novel mutation has never been reported before, is not present in pre-imatinib or post-imatinib residual quiescent GISTs, and is strongly correlated with imatinib resistance. Allelic-specific sequencing data show that this new mutation occurs in the allele that harbors original activation mutation of KIT.

  • Posted on: Wed, Oct 6 2004 1:35 AM
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Gastrointestinal stromal tumours: Etiology, pathology and clinical management.

Can J Gastroenterol. 2004 Sep; 18 Suppl B: 3B-8B
Blackstein ME, Dubé P, Fletcher JA, Keller OR, Knowling M, Létourneau R, Morris D, Riddell R, Rorke S, Swallow CJ

Investigation of the regulation of cell growth, differentiation and death by signalling pathways has led to a greater understanding of how alterations in these pathways play a critical role in the development of some cancers, and has opened new opportunities for their treatment. In the present review, results with the prototype drug of this class, imatinib (Gleevec, Glivec [formerly STI571]; Novartis, Switzerland), in metastatic gastrointestinal stromal tumours are presented. The present review originated from a conference of the authors held in Montreal, Quebec in June 2003, under the sponsorship of Novartis.

  • Posted on: Fri, Oct 1 2004 4:33 AM
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Association of platelet-derived growth factor-B chain with simian human immunodeficiency virus encephalitis.

Am J Pathol. 2004 Sep; 165(3): 815-24
Potula R, Dhillion N, Sui Y, Zien CA, Funa K, Pinson D, Mayo MS, Singh DK, Narayan O, Buch S

Chemokines and cytokines play a critical role in HIV infection, serving both to modulate virus replication and to recruit target cells to the site of infection. Platelet-derived growth factor (PDGF), a mitogen and chemoattractant for a wide variety of cells, is secreted by macrophages. Since macrophages are the target cells for lentiviral infection in the brain and PDGF is a known inducer of macrophage chemoattractant protein-1 (MCP)-1, a potent chemokine closely associated with HIV encephalitis, we investigated the association of PDGF-B chain (PDGF-B) with encephalitis in macaques caused by simian human immunodeficiency virus (SHIV), a chimera of HIV and SIV. Northern blot analysis confirmed elevated expression of PDGF-B chain mRNA in the brains from encephalitic macaques. Validation of these in vivo studies was confirmed in rhesus macrophage cultures infected with SHIV(KU2) in which we demonstrated heightened expression of PDGF-B chain mRNA. Nuclear run-off analysis established transcriptional up-regulation of PDGF-B chain in virus-inoculated macrophage cultures. Reciprocally, addition of exogenous PDGF enhanced virus replication and MCP-1 expression in these cells. Inhibition of virus replication by tyrosine kinase inhibitor, STI-571, and by PDGF-B antisense oligonucleotides confirmed the specificity of the PDGF effect. Relevance of these findings was confirmed by analysis of archival brain tissue from SHIV encephalitic and non-encephalitic macaques for PDGF-B chain expression. PDGF-B chain protein expression was observed in the virus-infected cells in microglial nodules in the brains of SHIV-encephalitic macaques.

  • Posted on: Fri, Oct 1 2004 4:33 AM
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Research unveils the ‘who’ and ‘why’ of gefitinib.

J Natl Cancer Inst. 2004 Sep 15; 96(18): 1352-4
Vastag B
  • Posted on: Thu, Sep 30 2004 2:35 AM
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New generation leukaemia drugs are on their way.

Drug Discov Today. 2004 Sep 1; 9(17): 732-3
Nelson L

Since Gleevec was first introduced as the leukaemia-wonder drug, its use has been tarnished by resistance in patients. However, a new drug (BMS-354825) that is currently in development could be the answer to the resistance problems encountered with Gleevec.

  • Posted on: Wed, Sep 29 2004 1:43 PM
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Sensitivity to imatinib therapy may be predicted by testing Wilms tumor gene expression and colony growth after a short in vitro incubation.

Cancer. 2004 Sep 1; 101(5): 979-88
Cilloni D, Messa F, Gottardi E, Fava M, Arruga F, Defilippi I, Carturan S, Messa E, Morotti A, Giugliano E, Rege-Cambrin G, Alberti D, Baccarani M, Saglio G

BACKGROUND: The objective of the current study was to verify the ability to predict response to imatinib therapy using in vitro assays to evaluate the inhibition of Wilms tumor gene (WT1) expression and colony growth after samples obtained from patients with chronic myelogenous leukemia (CML) before the start of treatment were subjected to short-term incubation with imatinib. METHODS: WT1 transcript levels and colony growth in bone marrow (BM) samples from 23 patients with CML that was later identified as being responsive to imatinib and from 13 patients with CML that was later identified as not being responsive to imatinib were evaluated after incubation of these samples with imatinib at a concentration of 1 microM for 18 hours. In addition, real-time quantitative polymerase chain reaction (RQ-PCR) analysis of WT1 expression was performed during follow-up, and the results were analyzed for associations with cytogenetic response and with BCR/ABL transcript levels as determined using RQ-PCR analysis. RESULTS: Before treatment, it was found that WT1 expression was elevated in BM samples obtained from all patients with CML. WT1 expression and colony growth were reduced significantly after an 18-hour incubation with imatinib in samples obtained from patients who were later identified as responders to treatment, but not in samples obtained from patients who did not experience responses to treatment. Inhibition of WT1 expression in vitro was associated with inhibition of imatinib-induced BCR-ABL tyrosine kinase activity, a finding that also has been made in studies involving certain Philadelphia chromosome (Ph)-positive and Ph-negative cell lines. CONCLUSIONS: Inhibition of WT1 transcript levels after a short period of in vitro exposure of pretherapy BM samples to imatinib was correlated with inhibition of colony growth and may represent the basis for an easy test that is capable of predicting the sensitivity of CML to treatment with imatinib for individual patients.

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Case of chronic-phase chronic myelogenous leukemia with an abdominal hematopoietic tumor of leukemic clone origin.

Am J Hematol. 2004 Oct; 77(2): 167-70
Sakakura M, Ohishi K, Nomura K, Katayama N, Nishii K, Masuya M, Nakase K, Shiku H

We report a 59-year-old man with chronic myelogenous leukemia (CML) in chronic phase who presented with a large abdominal tumor. Biopsy revealed proliferation of granulocytic-, erythroid-, and megakaryocytic-lineage cells in a retroperitoneal lymph node. The BCR/ABL fusion gene was detected on a paraffin-embedded tissue section of the lymph node by double-color fluorescence in situ hybridization, indicating an extramedullary hematopoietic tumor of CML origin. This patient has achieved a complete cytogenetic response for 19 months with imatinib mesylate (STI571; Gleevec), in association with the regression of the tumor. However, the development of an extramedullary tumor in chronic-phase CML generally indicates a poor prognosis, because it commonly consists of blast proliferation and is followed by blast crisis in the marrow within a few months. This case, therefore, points to the importance of histological examination of extramedullary tumors in CML for evaluation of disease status and for therapeutic decisions.

  • Posted on: Sat, Sep 25 2004 5:34 AM
  • Updated: Sat, Oct 16 2004 1:34 AM
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Expression of C-kit in Ewing Family of Tumors: A Comparison of Different Immunohistochemical Protocols.

Pediatr Dev Pathol. 2004 Jul-Aug; 7(4): 342-7
Ahmed A, Gilbert-Barness E, Lacson A

Ewing sarcoma is a small round blue cell tumor with a high incidence of metastasis and poor survival. The tyrosine kinase receptor, c-kit, is a growth factor receptor that is expressed in a variety of tumors including Ewing sarcoma. Blockade of c-kit by imatinib mesylate (Gleevec; Novartis Pharmaceuticals Corp, East Hanover, NJ) has been successfully used in the treatment of chronic myelogenous leukemia and gastrointestinal tumors. Detection of c-kit expression in Ewing sarcoma indicates a possible role of c-kit in tumor progression and a potential use of anti-c-kit therapy in Ewing sarcoma. Ki-67 is a proliferation marker found at all stages of the cell cycle. Expression of c-kit and Ki-67 was studied in 17 patients with Ewing sarcoma. Sections from paraffin-embedded tumor samples were immunostained, using standard immunohistochemical protocols, with c-kit and Ki-67 monoclonal antibodies, polyclonal c-kit antibody without antigen retrieval, and c-kit polyclonal antibody with antigen retrieval. Eleven out of 17 cases (65%) stained with c-kit monoclonal antibody; the staining was diffuse in 6/17 (35%) cases. C-kit expression did not correlate with Ki-67 proliferation rates. Using the polyclonal c-kit-antibody without antigen retrieval methods, c-kit expression was demonstrated in 1/11 (9%) cases. Incorporating antigen retrieval methods, c-kit expression increased to 53%. Concordance between monoclonal antibodies in detecting c-kit expression was observed in 12/17 cases (71%). We conclude that c-kit is variably expressed in Ewing sarcoma, using either monoclonal or polyclonal antibodies. Detection of c-kit expression in Ewing sarcoma improves with the use of antigen retrieval methods.

  • Posted on: Fri, Sep 24 2004 2:34 AM
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Treatment of CML in pediatric patients: Should imatinib mesylate (STI-571, Gleevec) or allogeneic hematopoietic cell transplant be front-line therapy?

Pediatr Blood Cancer. 2004 Oct; 43(5): 523
Pulsipher MA

BACKGROUND: Long-term survival of pediatric patients with chronic myelogenous leukemia (CML) receiving myeloablative hematopoietic stem cell transplantation from fully-matched related and unrelated donors has been reported between 60 and 75%, but is associated with significant morbidity. Imatinib mesylate (STI-571, Gleevec) and reduced intensity conditioning stem cell transplantation (RIC) are two promising new tools that offer potential for decreasing therapy associated morbidity for patients with CML. RESULTS: Large trials have shown significant responses in chronic phase patients treated with imatinib and reasonable but short-lived responses in advanced phase CML. Data from adult studies is beginning to define populations likely to progress or have prolonged responses to imatinib, and some adult treatment paradigms are moving toward reserving transplantation until patients are at risk of failure with imatinib. Early trials of RIC transplantation in CML show decreased transplant related morbidity with efficacy similar to conventional transplantation, but the approach has yet to be verified in phase III studies. Data in pediatric patients with imatinib and RIC transplantation is limited. CONCLUSIONS: Studies with imatinib are underway in pediatrics, but whether pediatric dosing schemes will lead to outcomes similar to adults is unknown. Because HLA-matched myeloablative transplantation offers a high rate of cure in the pediatric population, clinical studies assessing the role of imatinib mesylate and RIC transplantation should be planned carefully in order to avoid sub-optimal outcomes. Copyright 2004 Wiley-Liss, Inc.

  • Posted on: Fri, Sep 24 2004 2:34 AM
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Establishment and characterization of an STI571-resistant human myelogenous leukemia cell line, SR-1.

Cancer Genet Cytogenet. 2004 Oct 1; 154(1): 52-6
Kwon HC, Kim SH, Kim JS, Han H, Sook Roh M, Han JY, Seo SY, Lee YH, Kim HJ

The tyrosine kinase inhibitor STI571 is an effective agent for the treatment of chronic myelogenous leukemia (CML). However, a lack of response to STI571 or the recurrence of the disease after a transient initial response is usually seen in patients with advanced stage CML. We have established a novel STI571 (Gleevec/Glivec, imatinib mesylate)-resistant acute myelocytic leukemia cell line (SR-1) from an STI571-resistant blast crisis patient. By flow cytometry, the immunophenotype of SR-1 was found to be compatible with a myeloid lineage (CD13(+), CD33(+), HLA-DR(+), anti-MPO(+)). Conventional cytogenetics showed a three-way reciprocal translocation involving 7p22, 9q34, and 22q11.2, i.e., a variant Philadelphia chromosome translocation. The BCR/ABL rearrangement was detected by fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction. To determine the tumorigenicity of the SR-1 cell line in vivo, cells were injected subcutaneously into severe combined immunodeficiency mice. Four weeks later, tumors had grown and showed the same laboratory findings as in SR-1. Although STI571 resistance is a known treatment complication, in vivo STI571-resistant cell lines have not been fully established. We hope that our SR-1 cell line may be useful in molecular pathogenetic investigations of STI571-resistant CML.

  • Posted on: Fri, Sep 24 2004 2:34 AM
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Imatinib results in better quality of life for CML patients than interferon/Ara-C.

J Support Oncol. 2003 May-Jun; 1(1): 77
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Trisomy 8 in Philadelphia-negative cells during imatinib therapy.

Am J Hematol. 2004 Sep; 77(1): 88-9
Bernardeschi P, Fiorentini G, Rossi S, Dentico P, Simi P, Guidi S

Targeted therapy with imatinib selectively suppresses Philadelphia-positive cells in chronic myeloid leukemia cells, with reappearance of apparently normal hemopoiesis in a considerable number of patients. Recently, clonal abnormalities have been observed in Philadelphia-negative cells during imatinib therapy, the biologic and prognostic significance of which is actually unknown. A case of trisomy 8 occurring in Philadelphia-negative cells, which was treated by bone marrow transplantation, is reported. Chromosomal abnormalities in Philadelphia-negative cells do not seem to herald disease transformation, but the long-term prognosis may be influenced by an increased incidence of myelodysplasia in younger patients.

  • Posted on: Fri, Sep 24 2004 2:34 AM
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Relationship between idiopathic hypereosinophilic syndrome, eosinophilic leukemia, and systemic mastocytosis.

Am J Hematol. 2004 Sep; 77(1): 82-5
Bain BJ

Chronic eosinophilic leukemia is a neoplastic condition with persistent eosinophilia as the major hematological abnormality and with the eosinophils being part of the neoplastic clone. Some cases can be recognized by traditional hematological criteria, but many can be recognized only when a clonal cytogenetic or molecular genetic abnormality is demonstrated. A range of cytogenetic and molecular genetic abnormalities has been recognized, including both those seen in other myeloid malignancies (such as trisomy 8, monosomy 7, and 20q-) and those that are particularly linked to eosinophil differentiation (such as rearrangements of PDGFRB, FGFR1, and PDGFRA, the latter with formation of a FIP1L1-PDGFRA fusion gene). The discovery of the FIP1L1-PDGFRA fusion gene has led to the recognition that many patients who would previously have been regarded as having idiopathic hypereosinophilia actually have chronic eosinophilic leukemia. The same fusion gene has also been found in patients with hypereosinophilia and atypical bone marrow mast cells but whether this syndrome should be regarded as a variant of eosinophilic leukemia or as a variant of systemic mastocytosis remains to be established.

  • Posted on: Fri, Sep 24 2004 2:34 AM
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Management of life-threatening pulmonary leukostasis with single agent imatinib mesylate during CML myeloid blast crisis.

Haematologica. 2004 Sep; 89(9): ECR30
Leis JF, Primack SL, Schubach SE, Curtin PT, Druker BJ, Maziarz RT

Pulmonary leukostasis is a rare but serious and often fatal complication of chronic myeloid leukemia (CML) in blast crisis and acute myeloid leukemia. Treatment options are limited for these patients. Imatinib mesylate (STI-571, Gleevec, Novartis) is a potent and selective inhibitor of the BCR-abl tyrosine kinase, the molecular abnormality that causes CML. The case of a 74-year-old man with a history of CML who presented in myeloid blast crisis with pulmonary leukostasis characterized by increasing dyspnea, hypoxemia, fever, and impending respiratory failure is reported. The patient was treated with single agent imatinib mesylate (IM) with rap

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Outcome in noninvasively and invasively ventilated hematologic patients with acute respiratory failure.

Chest. 2004 Oct; 126(4): 1299-306
Depuydt PO, Benoit DD, Vandewoude KH, Decruyenaere JM, Colardyn FA

STUDY OBJECTIVES: The survival rate of patients with a hematologic malignancy requiring mechanical ventilation (MV) in the ICU has improved over the last few decades. The objective of this study was to identify the factors affecting the in-hospital mortality of these particular patients, and to assess whether the use of noninvasive positive pressure ventilation (NPPV) was protective in our study population. DESIGN: We retrospectively collected variables in 166 consecutive patients with hematologic malignancies who had acute respiratory failure (ARF) requiring MV, and identified factors obtained within 24 h of ICU admission affecting in-hospital mortality in univariate and multivariate stepwise logistic regression analyses. The effect of NPPV on mortality was assessed using a pair-wise matched exposed-unexposed analysis. RESULTS: The mean simplified acute physiology score (SAPS) II was 58.9. The in-hospital mortality rate was 71%. In a multivariate logistic regression analysis, the in-hospital mortality rate was predicted by increasing severity of illness, as measured by SAPS II (odds ratio [OR] per point of increase, 1.07; 95% confidence interval [CI], 1.04 to 1.11) and a diagnosis of acute myelogenous leukemia (OR, 2.73; 95% CI, 1.05 to 7.11). Female sex (OR, 0.36; 95% CI, 0.16 to 0.82), endotracheal intubation (ETI) within 24 h of ICU admission (OR, 0.29; 95% CI, 0.11 to 0.78), and recent bacteremia (defined as blood cultures positive for bacteria < 48h before or < 24h after ICU admission) [OR, 0.22; 95% CI, 0.08 to 0.61] were associated with a lower mortality rate. Twenty-seven patients who received NPPV were matched for SAPS II (+/- 3) with 52 patients who required immediate ETI on a 1:2 basis. The crude in-hospital mortality rate was 65.4% in both groups. CONCLUSION: Although the in-hospital mortality rate in hematologic patients who develop ARF remains high, the reluctance to intubate and start treatment with invasive MV in this population is unjustified, especially when bacteremia has precipitated ICU admission.

  • Posted on: Sat, Oct 16 2004 5:27 AM
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Role of farnesyltransferase inhibitors in hematologic malignancies.

Expert Rev Anticancer Ther. 2004 Oct; 4(5): 843-56
Santos ES, Rosenblatt JD, Goodman M

The treatment of hematologic malignancies has progressed in the last few years. Identification of new pathways and target molecules in leukemia has ushered in a promising new era of therapy. Ras mutations have recently been implicated in the pathogenesis of acute leukemia, and inhibition of Ras signaling through the use of farnesyltransferase inhibitors (FTIs) has shown promise in early trials in acute myeloid leukemia (AML). Responses have not correlated with the presence of Ras mutations, suggesting that novel pathways are involved. In several early trials, FTIs have shown activity as single agents in poor-risk AML, suggesting a potential role in combination with standard chemotherapy. FTIs are now being tested in other clinical settings, such as myelodysplasia, chronic myelogenous leukemia and multiple myeloma, with encouraging preliminary activity.

  • Posted on: Sat, Oct 16 2004 5:27 AM
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Hematopoietic stem cell transplantation among patients with leukemia of all ages in Texas.

Cancer. 2004 10 13;
Hwang JP, Lam TP, Cohen DS, Donato ML, Geraci JM

BACKGROUND: Hematopoietic stem cell transplantation (HSCT) is an effective but expensive medical procedure to which some ethnic minorities, the elderly, and those without insurance have been shown to have limited access. The purpose of the current study was to determine whether socioeconomic factors were associated with HSCT usage rates in patients with leukemia. METHODS: The authors identified 6574 patients with acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myelogenous leukeima, chronic myelogenous leukemia, or other leukemias from the 1999 Texas Hospital Inpatient Discharge Public Use Data File. Of these patients, 1604 received an autologous or allogeneic HSCT. The authors assessed patients’ ethnicity, payer status, age, gender, and comorbid medical conditions. Logistic regression was used to control for patient characteristics and to evaluate associations among payer status, ethnicity, and HSCT use. P

  • Posted on: Sat, Oct 16 2004 5:27 AM
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Philadelphia (Ph(1))-negative myeloid/natural killer cell precursor leukemia evolving during Ph(1)-positive chronic myelogenous leukemia: report of two cases.

Leukemia. 2004 10 14;
Matsuda M, Morita Y, Sano T, Tanaka M, Tatsumi Y, Maeda Y, Kanamaru A
  • Posted on: Sat, Oct 16 2004 5:27 AM
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Putting the rap on akt.

J Clin Oncol. 2004 Oct 15; 22(20): 4217-26
Thompson JE, Thompson CB

The protein kinase Akt is activated in a wide variety of cancers, and this activation results in enhanced resistance to apoptosis through multiple mechanisms. This article reviews the control of Akt activation by the opposing actions of the oncogene phosphoinositide 3-kinase (PI3-K) and the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10. The activation of Akt by transforming mutations, such as the amplification of HER-2/neu in breast cancer and the formation of the BCR/ABL fusion gene in chronic myelogenous leukemia, seems to be essential for the transforming activity of these oncogenes. We discuss several of the proposed mechanisms for the antiapoptotic effect of activated Akt, including the inhibition of the proapoptotic protein Bad, downregulation of death receptors, and enhancement of the glycolytic rate. Increased glycolysis is seen in many malignancies and forms the basis for the increasing use of positron emission tomography imaging for diagnosis and staging. Finally, we discuss rapamycin and its analogs, which are now in trials as antineoplastic therapy; these agents show particular promise in tumors in which Akt has been activated.

  • Posted on: Sat, Oct 16 2004 5:27 AM
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Cutaneous sarcoidosis and polycythemia vera.

J Eur Acad Dermatol Venereol. 2004 Nov; 18(6): 700-1
Pascual J, Belinchón I, Albares P, Vergara G, Betlloch I, Bañuls J

ABSTRACT Polycythemia vera is classified with myelogenous leukaemia, agnogenic myeloid metaplasia and primary thrombocythemia as a myeloproliferative syndrome. Cutaneous symptoms have been reported with polycythemia vera, including facial plethora, aquagenic pruritus, urticaria, purpura, Sweet’s syndrome and pyoderma gangrenosum. However, polycythemia vera associated with systemic sarcoidosis has been rarely reported. An unusual case of polycythemia vera associated with cutaneous sarcoidosis is described.

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Successful allogeneic bone marrow transplantation in a patient with acute myelogenous leukemia and cytomegalovirus retinitis.

Int J Hematol. 2004 Aug; 80(2): 190-2
Matsubara H, Adachi S, Yano J, Kitamura N, Miyazaki M, Mizushima Y, Hiramatsu H, Kobayashi M, Nakahata T

A 1-year-old boy with acute myeloid leukemia with cytomegalovirus (CMV) retinitis that was refractory because of severely impaired cellular immunity underwent bone marrow transplantation from an HLA-matched donor after a conditioning regimen of busulfan, cyclophosphamide, and etoposide. Although we continued administration of ganciclovir from preparation therapy, retinitis worsened after engraftment. Thereafter retinitis improved gradually as the number of CD4+ T-lymphocytes increased. The findings in this case suggest that stem cell transplantation for a leukemia patient with CMV disease may be effective.

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Meis1-mediated apoptosis is caspase-dependent and can be suppressed by coexpression of HoxA9 in murine and human cell Lines.

Blood. 2004 10 12;
Wermuth PJ, Buchberg AM

Coexpression of the homeodomain protein Meis1 and either HoxA7 or HoxA9 is characteristic of many acute myelogenous leukemias. Although Meis1 can be overexpressed in bone marrow long-term repopulating cells, it is incapable of mediating their transformation. While overexpressing HoxA9 alone transforms murine bone marrow cells, concurrent Meis1 overexpression greatly accelerates oncogenesis. Meis1-HoxA9 cooperation suppresses several myeloid differentiation pathways. We now report that Meis1 overexpression strongly induces apoptosis in a variety of cell types in vitro via a caspase-dependent process. Meis1 requires a functional homeodomain and Pbx-interaction motif to induce apoptosis. Coexpressing HoxA9 with Meis1suppresses this apoptosis and provides protection from several apoptosis inducers. Pbx1, another Meis1 cofactor, also induces apoptosis; however, coexpressing HoxA9 is incapable of rescuing Pbx-mediated apoptosis. This resistance to apoptotic stimuli, coupled with the previously reported ability to suppress multiple myeloid differentiation pathways, would provide a strong selective advantage to Meis1-HoxA9 coexpressing cells, in vivo, leading to leukemogenesis.

  • Posted on: Thu, Oct 14 2004 11:32 AM
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Imatinib (STI571)-Mediated Changes in Glucose Metabolism in Human Leukemia BCR-ABL-Positive Cells.

Clin Cancer Res. 2004 10 1; 10(19): 6661-6668
Gottschalk S, Anderson N, Hainz C, Eckhardt SG, Serkova NJ

The therapeutic efficacy of imatinib mesylate (Gleevec) is based on its specific inhibition of the BCR-ABL oncogene protein, a widely expressed tyrosine kinase in chronic myelogenous leukemia (CML) cells. The goal of this study was to evaluate glucose metabolism in BCR-ABL-positive cells that are sensitive to imatinib exposure. Two human BCR-ABL-positive cell lines (CML-T1 and K562) and one BCR-ABL-negative cell line (HC-1) were incubated with different imatinib concentrations for 96 hours. Magnetic resonance spectroscopy on cell acid extracts was performed to evaluate [1-(13)C]glucose metabolism, energy state, and changes in endogenous metabolites after incubation with imatinib. Imatinib induced a concentration-dependent inhibition of cell proliferation in CML-T1 (IC(50), 0.69 +/- 0.06 μmol/L) and K562 cells (IC(50), 0.47 +/- 0.04 μmol/L), but not in HC-1 cells. There were no metabolic changes in imatinib-treated HC-1 cells. In BCR-ABL-positive cells, the relevant therapeutic concentrations of imatinib (0.1-1.0 μmol/L) decreased glucose uptake from the media by suppressing glycolitic cell activity (C3-lactate at 0.25 mmol/L, 65% for K562 and 77% for CML-T1 versus control). Additionally, the activity of the mitochondrial Krebs cycle was increased (C4-glutamate at 0.25 μmol/L, 147% for K562 and 170% for CML-T1). The improvement in mitochondrial glucose metabolism resulted in an increased energy state (nucleoside triphosphate/nucleoside diphosphate at 0.25 μmol/L, 130% for K562 and 125% for CML-T1). Apoptosis was observed at higher concentrations. Unlike standard chemotherapeutics, imatinib, without cytocidal activity, reverses the Warburg effect in BCR-ABL-positive cells by switching from glycolysis to mitochondrial glucose metabolism, resulting in decreased glucose uptake and higher energy state.

  • Posted on: Tue, Oct 12 2004 3:31 PM
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Expression of P2X7 in human hematopoietic cell lines and leukemia patients.

Leuk Res. 2004 Dec; 28(12): 1313-22
Zhang XJ, Zheng GG, Ma XT, Yang YH, Li G, Rao Q, Nie K, Wu KF

The P2X7 nucleotide receptor is an adenosine 5′-triphosphate (ATP) -gated ion channel, which is widely expressed in cells of hematopoietic origin and functions as a non-selective cation channel permeable to Na(+), Ca(2+), etc upon stimulation. Here, we investigated P2X7 expression in 11 human hematopoietic cell lines, representing different lineages, as well as bone marrow mononuclear cells (BMMC) samples from 87 leukemia and 10 myelodysplastic syndrome (MDS) patients. Semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) and flow cytometry results showed that both P2X7 mRNA and protein were detected in eight cell lines with a non-lineage-specific manner. Samples from 69 leukemia and 9 MDS patients were P2X7 positive at mRNA level. Moreover, both positive rates and relative expression levels were significantly higher in acute myelogenous leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and MDS groups than that in normal donor group. The expression levels varied among AML subtypes with higher levels being observed in M4, M5, and M6 groups but not in M1 or M2 group. Furthermore, after one course of standard induction therapies, the remission rate in high P2X7 expression group was lower than that in either P2X7 negative group or low P2X7 expression group. Cytoplasmic free calcium increase was detected in five of eight P2X7(+) cell lines as well as P2X7(+) normal donor and patient samples tested, but not in three Epstein-Barr virus (EBV) positive cell lines (J6-1, Namalwa, and LCL-H) in Locke’s solution upon stimulation by extracellular ATP or the more potent and specific agonist, 2′,3′-O-(4-benzoyl)benzoyl-ATP (BzATP). The possible mechanisms causing the loss of P2X7 function were discussed.

  • Posted on: Tue, Oct 12 2004 3:31 PM
  • Updated: Wed, Oct 13 2004 7:30 AM
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Interphase fluorescence in situ hybridization studies for the detection of 9q34 deletions in chronic myelogenous leukemia: a practical approach to clinical diagnosis.

Cancer Genet Cytogenet. 2004 Oct 15; 154(2): 138-43
Aoun P, Wiggins M, Pickering D, Foran J, Rasheed H, Pavletic SZ, Sanger W

Chronic myelogenous leukemia (CML) is characterized by the Philadelphia chromosome (Ph) in more than 90% of cases. Recent studies using fluorescence in situ hybridization (FISH) have shown that in a subset of patients with CML, deletions of 9q34 involving the argininosuccinate synthetase region occur at the time of the Philadelphia translocation and are associated with a poor prognosis. We performed interphase FISH studies in 152 cases of CML using a dual-color, dual-fusion probe system with a third probe directed at 9q34. Cytogenetic studies showed a simple (typical) Ph in 124/152 (82%), a cryptic Ph in 11/152 (7%), and a variant Ph chromosome with a complex translocation in 17/152 (11%) of cases. Interphase FISH studies showed single BCR/ABL fusion patterns in 48/152 (32%) of cases. Deletions of 9q34 were observed in 14% of all the cases and were present in 46% of cases with single BCR/ABL fusion pattern. All the 9q34 deletions occurred in cases with single BCR/ABL fusion signal. However, a single-fusion pattern is not specific for 9q34 deletions, and cases should be routinely screened for the presence of this prognostically significant abnormality by using a third probe directed specifically at 9q34.

  • Posted on: Tue, Oct 12 2004 3:31 PM
  • Updated: Wed, Oct 13 2004 7:30 AM
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Effect of St John’s wort on imatinib mesylate pharmacokinetics.

Clin Pharmacol Ther. 2004 10; 76(4): 323-329
Frye RF, Fitzgerald SM, Lagattuta TF, Hruska MW, Egorin MJ

Objective Imatinib is a potent inhibitor of the Bcr-Abl and c- kit tyrosine kinases and is approved for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia and gastrointestinal stromal tumors. Because imatinib is predominantly metabolized by cytochrome P450 (CYP) 3A4, its pharmacokinetics may be altered when it is coadministered with drugs or herbs (eg, St John’s wort) that modulate CYP3A4 activity.Thus we examined the effects of St John’s wort on imatinib pharmacokinetics. Methods This 2-period, open-label, fixed-sequence study was completed by 12 healthy subjects (6 men and 6 women) aged between 20 and 51 years. Each subject received 400 mg imatinib orally on study day 1, St John’s wort (300 mg 3 times daily) on days 4 to 17, and 400 mg imatinib again on day 15. Serial blood samples were obtained over a 72-hour period after each imatinib dose. Imatinib and N -desmethyl-imatinib (CGP 74588) were quantified in plasma by liquid chromatography-mass spectrometry. Results St John’s wort administration increased imatinib clearance by 43% ( P < .001), from 12.5 +/- 3.6 L/h to 17.9 +/- 5.6 L/h; imatinib area under the concentration versus time curve (AUC) extrapolated to infinity was decreased by 30%, from 34.5 +/- 9.5 μg . h/mL to 24.2 +/- 7.0 μg . h/mL ( P < .001). Imatinib half-life (12.8 hours versus 9.0 hours) and maximum concentration (C max ) (2.2 μg/mL versus 1.8 μg/mL) were also significantly decreased ( P < .005). N -desmethyl-imatinib C max was increased from 285 +/- 95 ng/mL to 318 +/- 95 ng/mL during St John’s wort dosing, but the AUC from 0 to 72 hours was not altered. Conclusions These data indicate that St John’s wort increases imatinib clearance. Thus patients taking imatinib should avoid taking St John’s wort. Concomitant use of enzyme inducers, including St John’s wort, may necessitate an increase in the imatinib dose to maintain clinical effectiveness.

  • Posted on: Fri, Oct 8 2004 1:28 PM
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Loss of SHIP and CIS Recruitment to the Granulocyte Colony-Stimulating Factor Receptor Contribute to Hyperproliferative Responses in Severe Congenital Neutropenia/Acute Myelogenous Leukemia.

J Immunol. 2004 Oct 15; 173(8): 5036-45
Hunter MG, Jacob A, O’donnell LC, Agler A, Druhan LJ, Coggeshall KM, Avalos BR

Mutations in the G-CSF receptor (G-CSFR) in patients with severe congenital neutropenia (SCN) are postulated to contribute to transformation to acute myelogenous leukemia (AML). These mutations result in defective receptor internalization and sustained cellular activation, suggesting a loss of negative signaling by the G-CSFR. In this paper we investigated the roles of SHIP and cytokine-inducible Src homology 2 protein (CIS) in down-modulating G-CSFR signals and demonstrate that loss of their recruitment as a consequence of receptor mutations leads to aberrant signaling. We show that SHIP binds to phosphopeptides corresponding to Tyr(744) and Tyr(764) in the G-CSFR and that Tyr(764) is required for in vivo phosphorylation of SHIP and the formation of SHIP/Shc complexes. Cells expressing a G-CSFR form lacking Tyr(764) exhibited hypersensitivity to G-CSF and enhanced proliferation, but to a lesser degree than observed with the most common mutant G-CSFR form in patients with SCN/AML, prompting us to investigate whether suppressor of cytokine signaling proteins also down-modulate G-CSFR signals. G-CSF was found to induce the expression of CIS and of CIS bound to phosphopeptides corresponding to Tyr(729) and Tyr(744) of the G-CSFR. The expression of CIS was prolonged in cells with the SCN/AML mutant G-CSFR lacking Tyr(729) and Tyr(744), which also correlated with increased G-CSFR expression. These findings suggest that SHIP and CIS interact with distal phosphotyrosine residues in the G-CSFR to negatively regulate G-CSFR signaling by limiting proliferation and modulating surface expression of the G-CSFR, respectively. Novel therapeutic approaches targeting inhibitory pathways that limit G-CSFR signaling may have promise in the treatment of patients with SCN/AML.

  • Posted on: Fri, Oct 8 2004 1:28 PM
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Treatment of Chronic Myeloid Leukemia Cells with Imatinib (STI571) Impairs p53 Accumulation in Response to DNA Damage.

Cell Cycle. 2004 9 2; 3(9):
Goldberg Z, Levav Y, Krichevsky S, Fibach E, Haupt Y

Chronic myelogenous leukaemia (CML) is induced by the Bcr-Abl fusion protein. Inhibition of Bcr-Abl by STI571 is widely used to treat CML patients. Unlike in most cancer types, the frequency of p53 mutations in CML is low. Here, we investigated the effect of STI571 treatment of CML cells on p53 regulation. Exposure of CML cells, including established cell lines and freshly isolated cells from patients, to STI571 reduced p53 protein levels, and severely impaired its accumulation in response to DNA damage. This may be explained by the status of p53 serine 20 phosphorylation. In non-stressed CML cells, serine 20 of p53 is constitutively phosphorylated by Chk1, and is inhibited by STI571. In response to DNA damage, however, this phosphorylation is mediated by Chk1 and Chk2, and is only partially inhibited by STI571. CML cells expressing wild-type p53 are more resistant to treatment with STI571, but moderately more sensitive to DNA damage, than CML cells lacking p53. An enhanced induction of apoptosis by STI571 and DNA damage is observed in CML cells bearing wild-type p53, but not in cells lacking functional p53. This implies that the status of p53 may affect the response of CML cells to this combined treatment.

  • Posted on: Thu, Oct 7 2004 9:30 AM
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Hot-compressed-water decomposed products from bamboo manifest a selective cytotoxicity against acute lymphoblastic leukemia cells.

Toxicol In Vitro. 2004 Dec; 18(6): 765-71
Ando H, Ohba H, Sakaki T, Takamine K, Kamino Y, Moriwaki S, Bakalova R, Uemura Y, Hatate Y

We examined the effect of hot-compressed-water (HCW) extracted and fractionated bamboo products (named as fractions A and B) on the viability of human cultured cell lines, derived from leukemia patients and human peripheral blood lymphocytes, obtained from normal adults. Fraction A was composed of xylose, xylooligosaccharides and water-soluble lignin, determined by high-performance anion exchange chromatography and spectrophotometry. Fraction B was composed of glucose and celooligosaccharides. It was found that Fraction B expressed a negligible cytotoxic effect against leukemia cells, while Fraction A reduced markedly (in a dose-dependent manner) the viability of leukemia cell lines, derived from acute lymphoblastic leukemia (ALL)–Jurkat and MOLT-4. Fraction A did not influence the viability of leukemia cells, derived from myelogenous leukemia (ML-2) or lymphoma (SupT-1), as well as the viability of normal lymphocytes. Furthermore, microscopic examination of ALL-derived cells treated with Fraction A showed typical apoptotic morphological changes such as a condensation of nucleus and membrane blebing, as well as phosphatidylserine (PSer) exposure on the cell surface. The effect of decomposed products of commercially available xylan against ALL-derived Jurkat cells was significantly lower than that of Fraction A. These results suggest that the cytotoxic effect of Fraction A may be attributed to apoptosis, induced by xylooligosaccharides and it is specific for ALL-derived cells. We speculate that the water-soluble lignin is an important factor, potentiating the cytotoxic effect of xylan in HCW-extracts from bamboo.

  • Posted on: Thu, Oct 7 2004 9:30 AM
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Possible involvement of P-glycoprotein in renal excretion of pazufloxacin in rats.

Eur J Pharmacol. 2004 Oct 6; 501(1-3): 151-9
Shimizu A, Miyoshi M, Sugie M, Ueyama J, Yamaguchi T, Sasaki T, Takagi K, Jin M, Miyamoto K, Tsuji A, Hasegawa T

The present study aims to investigate whether pazufloxacin, a new quinolone antimicrobial agent, is a substrate for P-glycoprotein in vitro, and whether it is excreted from kidney by P-glycoprotein and/or multidrug resistance-associated protein (Mrp2) in vivo. The in vitro experiments showed that the intracellular accumulation of pazufloxacin in adriamycin-resistant human chronic myelogenous leukemia cells (K562/ADR) overexpressing P-glycoprotein was significantly lower than that in human chronic myelogenous leukemia cells (K562/S) not expressing P-glycoprotein. When rats received an intravenous injection of pazufloxacin in combination with or without cyclosporine, cyclosporine significantly delayed the disappearance of pazufloxacin from plasma and decreased the systemic clearance and volume of distribution at steady state of pazufloxacin to 50% and 70% of the corresponding control values, respectively. Renal handling experiments revealed that the renal clearance of pazufloxacin was 75% of that corresponding to the systemic clearance, suggesting that the main route of pazufloxacin elimination is the kidney. Cyclosporine significantly increased the steady-state concentration of pazufloxacin in plasma by decreasing the tubular secretion clearance and glomerular filtration rate. These results suggest the possibility that pazufloxacin is excreted into the urine via P-glycoprotein. No significant differences in the renal and tubular secretion clearances of pazufloxacin were observed between normal rats and Eisai hyperbilirubinemic rats (EHBR), which have a hereditary deficiency in Mrp2, indicating the lack of the involvement of Mrp2 in the renal excretion of pazufloxacin. Sparfloxacin, a P-glycoprotein substrate, also significantly decreased the renal and tubular secretion clearances of pazufloxacin, suggesting that pazufloxacin and sparfloxacin share the same transporters, including P-glycoprotein. The present study at least suggests that pazufloxacin is excreted into the urine via P-glycoprotein and some active drug transporters other than Mrp2.

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Biliary excretion of imatinib mesylate and its metabolite CGP 74588 in humans.

Pharmacotherapy. 2004 Sep; 24(9): 1232-5
Ramalingam S, Lagattuta TF, Egorin MJ, Hayes MJ, Ramanathan RK

Imatinib mesylate, licensed to treat chronic myelogenous leukemia and gastrointestinal stromal tumors, is metabolized by cytochrome P450 3A and undergoes little renal excretion, but its biliary excretion by humans is uncharacterized. Liquid chromatography-mass spectrometry was used to quantitate imatinib and its metabolite CGP 74588 in the bile of two patients with biliary stents; the ratio of imatinib:CGP 74588 in each was approximately 9:1. In the first patient, who was receiving long-term therapy with imatinib 400 mg/day and had normal liver function tests, biliary imatinib accounted for 17.7% of the daily dose and CGP 74588 accounted for 2.1%. In the second patient, who had elevated liver function tests and was studied after his first dose of imatinib 300 mg, biliary imatinib accounted for only 1.8% of the daily dose and CGP 74588 accounted for 0.2%. These data show both the qualitative similarities and the quantitative variability in biliary excretion of imatinib and its principal metabolite.

  • Posted on: Wed, Oct 6 2004 5:26 AM
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Functional and morphological cardiac changes in myeloproliferative disorders (clinical study).

Int J Cardiol. 2004 Nov; 97(2): 213-20
Kadikoylu G, Onbasili A, Tekten T, Barutca S, Bolaman Z

Purpose: Cardiac involvement is not well defined in myeloproliferative disorders (MPD). The purpose of this study was to evaluate the cardiac involvement by transthoracic echocardiography in MPD. Materials and methods: The study groups were 36 patients (mean age: 58+/-15 years, 20 female and 16 male) with MPD and 30 age-matched healthy controls. MPD group included 15 essential thrombocythemia (ET), eight chronic phase chronic myelogenous leukemia (CML), seven idiopathic myelofibrosis (MF) and six polcythemia vera patients. Results: Valvular regurgitations were present in 14 patients (39%) and eight controls (27%), (P>0.05). Mitral regurgitation (MR) was more prominent in CML compared to controls (P=0.044). The rates of annular calcifications, valvular thickening, and vegetation like lesions were not different between MPD and control groups. Pulmonary hypertension (PHT) was present in six (17%) patients, but none of the controls (P=0.021). The rates of PHT in CML and MF were significantly higher than controls (P<0.05). The rate of PHT was not different in-between MPD patients with and without thromboembolic events, however, in MPD cases with thromboembolic events PHT was more common compared to controls (P=0.037). Conclusion: This study showed that valvular lesions were not more prevalent in MPD. PHT was the most prominent cardiac pathology in MPD (especially in CML, MF and thromboembolic events subgroups) compared to controls. Further evaluation of the cardiac changes in MPD subgroups with extended studies including trans-oesophageal echocardiography and longer follow-up periods would be appropriate.

  • Posted on: Sat, Oct 2 2004 8:33 AM
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Lipoteichoic acid derived from Enterococcus faecalis modulates the functional characteristics of both normal peripheral blood leukocytes and native human acute myelogenous leukemia blasts.

Eur J Haematol. 2004 Nov; 73(5): 340-350
Bruserud , Wendelbo , Paulsen K

Bruserud Ã?, Wendelbo Ã?, Paulsen K. Lipoteichoic acid derived from Enterococcus faecalis modulates the functional characteristics of both normal peripheral blood leukocytes and native human acute myelogenous leukemia blasts. Eur J Haematol 2004: 73: 340-350. Copyright Blackwell Munksgaard 2004.Abstract: Objectives: Several case reports have described complete hematological remissions for patients with otherwise untreated acute myelogenous leukemia (AML) who receive hematopoietic growth factor therapy during complicating bacterial infections. This may be caused by indirect cytokine effects, but direct effects of infecting agents on the malignant cells are also possible because bacterial molecules can bind to specific receptors expressed by normal and malignant leukocytes. Lipoteichoic acid (LTA) is a cell wall component of gram-positive bacteria, and it can activate normal immunocompetent cells through binding to specific cell membrane receptors. Methods: We investigated effects of LTA derived from Enterococcus faecalis on in vitro cultured (i) normal peripheral blood mononuclear cells (PBMC); (ii) remaining T cells derived from patients with hematologic malignancies and chemotherapy-induced leukopenia; and (iii) native human AML cells. Results: Increased interleukin 1beta (IL1beta) and IL8 release by in vitro cultured normal PBMC was observed after stimulation with LTA at concentrations >/=5 microg/mL; these levels were lower than for lipopolysaccharide (LPS)-stimulated cells and LTA antagonized LPS-induced cytokine release by normal PBMC. In most cases LTA did not alter T-cell proliferation for patients with chemotherapy-induced leukopenia. The LTA effects on AML blasts were investigated for 62 consecutive patients. LTA altered either cytokine (granulocyte-macrophage colony-stimulating factor + stem cell factor + IL3)-dependent proliferation or the release of IL1beta/IL8 for 23 patients; the effects were divergent but increased proliferation/cytokine levels were most commonly observed. Conclusion: The LTA derived from E. faecalis can modulate the functional characteristics of normal leukocytes and native human AML blasts.

  • Posted on: Sat, Oct 2 2004 8:33 AM
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[Therapy of chronic myelogenous leukemia in 2004]

Dtsch Med Wochenschr. 2004 Oct 1; 129(40): 2122-7
Hochhaus A, Berger U, Hehlmann R

Summary. Chronic myelogenous leukemia consitutes a clinical model for other neoplastic diseases. The cytogenetic hallmark of CML, the Ph chromosom with the molecular juxtaposition of BCR and ABL genes and the multistep pathogenesis with the stable chronic phase, the accelerated phase and the terminal blast crisis provide the background for the translation of molecular-cytogenetic findings into clinical practice. The systematic development of the selective BCR-ABL inhibitor imatinib was based on the discovery of the molecular pathogenesis of CML. Promising preclinical data were confirmed in phase I-III trials. Concerning hematologic and cytogenetic response and adverse effects imatinib is superior to interferon alpha. Open questions are treatment duration in patients with good response, long term side effects, persistence of minimal residual disease in almost all patients, development of resistance after long term therapy, and the efficacy of combination treatments. Prospective clinical trials, e. g. CML study IV of the German CML Study Group, should answer these questions. The impact of the various treatment modalities (imatinib, interferon alpha, ara-C, allogeneic stem cell transplantation) will be elucidated. The recruitment of newly diagnosed CML patients into CML-study IV is recommended.

  • Posted on: Thu, Sep 30 2004 3:26 AM
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Genes transcriptionally modulated by interferon ?2a correlate with the cytokine activity

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Genes transcriptionally modulated by interferon ?2a correlate with the cytokine activity.

Haematologica. 2004 Sep; 89(9): 1046-53
Iolascon A, Volinia S, Borriello A, Giordani L, Moretti A, Servedio V, Maiorano N, Cucciolla V, Criniti V, Gasparini P, Indaco S, Della Ragione F

BACKGROUND AND OBJECTIVES: Interferon ?2a (IFN?2a) mediates important antiviral, antiproliferative and immunomodulatory responses and is employed in the treatment of human diseases, including chronic myelogenous leukemia. Here, we report the IFN?2a-dependent expression profiles of three malignant cell lines derived from liver, lymphocytes and muscle. DESIGN AND METHODS: The experiments were performed in the presence of cycloheximide, thus our results exclusively reflect direct transcriptional modulation. The short exposure time i.e. 5 hours evidences only the early events, excluding the effects of complex phenotypic changes on the expression. RESULTS: Our findings indicate that IFN?2a rapidly up-regulates the expression of STAT1, STAT2 and ISGF3G genes. This activity should result in the amplification of the cellular response to the cytokine. Moreover, IFN?2a directly modulates the expression of: (i) important transcriptional factors, e.g. IRF1 and IRF7 which control pivotal cellular events, and (ii) enzymes involved in the IFN?2a-dependent antiviral and apoptotic response. Interestingly, we showed that the cytokine induces transcriptional expression of Sjögren’s syndrome antigen A1, a protein involved in several autoimmune diseases. INTERPRETATION AND CONCLUSIONS: The observed changes induced by IFN?2a could be related to the development of autoimmune syndromes observed during IFN?2a treatment. A number of genes transcriptionally regulated by the cytokine have been identified for the first time; these might represent additional effectors of IFN?2a activity.

http://www.hubmed.org/display.cgi?issn=15928721&uids=15377465

Q fever: a new cause of ‘doughnut’ granulomatous lobular panniculitis.

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Br J Dermatol. 2004 Sep; 151(3): 685-7
Galache C, Santos-Juanes J, Blanco S, Rodríguez E, Martínez A, Soto J

Summary Q fever is an uncommon zoonotic rickettsial disease with no exanthem or specific cutaneous lesions. Only nonspecific cutaneous involvement has been reported to date. A 69-year-old Spanish woman with chronic myelogenous leukaemia developed fever and two subcutaneous nodules. The patient complained of extreme pain. Biopsy revealed a granulomatous lobular panniculitis with a characteristic ‘fibrin ring’ or ‘doughnut’ appearance: fibrin and inflammatory cells arranged around a central clear space. Changes of membranous lipodystrophy were also found. Q fever serological studies were positive. Our patient had panniculitis with singular histopathological features. These histopathological changes have been described in liver and bone marrow of patients with Q fever. To the best of our knowledge, this cutaneous involvement due to Q fever has not previously been described in the literature.

http://www.hubmed.org/display.cgi?issn=00070963&uids=15377359

Pic Of The Day

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A Mechanic of F1 Ferrari team waits to start unpack the stuffs in the boxes of Interlagos racetrack, in Sao Paulo, Brazil.