MedWorm: Acute Myeloid Leukemia

FDA Staff Says Decitabine No Help in AML

MedPage Today Hematology/Oncology — Wed, 08 Feb 2012 17:40:56 +0100

WASHINGTON (MedPage Today) -- Decitabine (Dacogen), a hypomethylating agent, does not appear to improve mortality in older patients with acute myelogenous leukemia, FDA reviewers concluded. (Source: MedPage Today Hematology/Oncology)

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Nine years interval between first and second bone marrow transplantations and subsequent long-term survival—a case of acute myeloid leukemia with MLL-AF6 fusion gene

Annals of Hematology — Fri, 03 Feb 2012 17:12:41 +0100

Content Type Journal ArticleCategory Letter to the EditorPages 1-3DOI 10.1007/s00277-012-1417-2Authors Yasuhisa Yokoyama, Department of Hematology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, JapanKazumi Suzukawa, Department of Hematology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, JapanYasushi Okoshi, Department of Hematology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, JapanToru Nanmoku, Department of Clinical Laboratory, Tsukuba University Hospital, Tsukuba, Ibaraki, JapanNaoshi Obara, Department of Hematology, Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Ibaraki, JapanTerukazu Enami, Department of Hematology, Faculty of Medicine, University of Tsukuba, ...

Cytidine deaminase genetic variants influence RNA expression and cytarabine cytotoxicity in acute myeloid leukemia

Future Medicine: Pharmacogenomics — Fri, 03 Feb 2012 14:36:38 +0100

Pharmacogenomics , February 2012, Vol. 13, No. 3, Pages 269-282. (Source: Future Medicine: Pharmacogenomics)

Childhood Blastic Plasmacytoid Dendritic Cell Neoplasm Treated with Allogenic Stem Cell Transplantation

Pediatric Dermatology — Fri, 03 Feb 2012 05:00:00 +0100

We report a 15‐year‐old boy with blastic plasmacytoid dendritic cell neoplasm who was treated with acute myeloid leukemia‐based polychemotherapy and subsequent allogenic stem cell transplantation. (Source: Pediatric Dermatology)

Massive cystic granulocytic sarcoma in a newly diagnosed patient with acute myeloid leukaemia

European Journal of Haematology — Thu, 02 Feb 2012 05:00:00 +0100

(Source: European Journal of Haematology)

A small molecule screening strategy with validation on human leukemia stem cells uncovers the therapeutic efficacy of kinetin riboside

Blood — Thu, 02 Feb 2012 05:00:00 +0100

Gene regulatory networks that govern hematopoietic stem cells (HSCs) and leukemia-initiating cells (L-ICs) are deeply entangled. Thus, the discovery of compounds that target L-ICs while sparing HSC is an attractive but difficult endeavor. Presently, most screening approaches fail to counter-screen compounds against normal hematopoietic stem/progenitor cells (HSPCs). Here, we present a multistep in vitro and in vivo approach to identify compounds that can target L-ICs in acute myeloid leukemia (AML). A high-throughput screen of 4000 compounds on novel leukemia cell lines derived from human experimental leukemogenesis models yielded 80 hits, of which 10 were less toxic to HSPC. We characterized a single compound, kinetin riboside (KR), on AML L-ICs and HSPCs. KR demonstrated comparable effic...

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Loss-of-function germline GATA2 mutations in patients with MDS/AML or MonoMAC syndrome and primary lymphedema reveal a key role for GATA2 in the lymphatic vasculature

Blood — Thu, 02 Feb 2012 05:00:00 +0100

Recent work has established that heterozygous germline GATA2 mutations predispose carriers to familial myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML), "MonoMAC" syndrome, and DCML deficiency. Here, we describe a previously unreported MDS family carrying a missense GATA2 mutation (p.Thr354Met), one patient with MDS/AML carrying a frameshift GATA2 mutation (p.Leu332Thrfs*53), another with MDS harboring a GATA2 splice site mutation, and 3 patients exhibiting MDS or MDS/AML who have large deletions encompassing the GATA2 locus. Intriguingly, 2 MDS/AML or "MonoMAC" syndrome patients with GATA2 deletions and one with a frameshift mutation also have primary lymphedema. Primary lymphedema occurs as a result of aberrations in the development and/or function of lymphatic vessels, spurri...

Current understanding of the mechanism of benzene-induced leukemia in humans: implications for risk assessment

Carcinogenesis — Thu, 02 Feb 2012 05:00:00 +0100

Benzene causes acute myeloid leukemia and probably other hematological malignancies. As benzene also causes hematotoxicity even in workers exposed to levels below the US permissible occupational exposure limit of 1 part per million, further assessment of the health risks associated with its exposure, particularly at low levels, is needed. Here, we describe the probable mechanism by which benzene induces leukemia involving the targeting of critical genes and pathways through the induction of genetic, chromosomal or epigenetic abnormalities and genomic instability, in a hematopoietic stem cell (HSC); stromal cell dysregulation; apoptosis of HSCs and stromal cells and altered proliferation and differentiation of HSCs. These effects modulated by benzene-induced oxidative stress, aryl hydrocarb...

UCSB Researchers Discover The Processes Leading To Acute Myeloid Leukemia

Health News from Medical News Today — Wed, 01 Feb 2012 08:00:00 +0100

Researchers at UC Santa Barbara have discovered a molecular pathway that may explain how a particularly deadly form of cancer develops. The discovery may lead to new cancer therapies that reprogram cells instead of killing them. The findings are published in a recent paper in the Journal of Biological Chemistry. The UCSB research team described how a certain mutation in DNA disrupts cellular function in patients with acute myeloid leukemia (AML)... (Source: Health News from Medical News Today)

De novo acute myeloid leukemia risk factors

Cancer — Wed, 01 Feb 2012 05:00:00 +0100

CONCLUSIONS:The current results suggested that several factors play a role in AML predisposition with possible joint effects. Risk profiles for AML differed by sex and WHO subtype. Cancer 2012. © 2012 American Cancer Society. (Source: Cancer)

[Comment] Renaissance of autologous stem cell transplantation for AML?

The Lancet Oncology — Wed, 01 Feb 2012 05:00:00 +0100

After intensive induction chemotherapy, 70–80% of young adult patients with newly diagnosed acute myeloid leukaemia (AML) achieve complete remission (CR); however, without additional treatment, most will relapse within a few months. Accordingly, the aim of post-remission treatment (PRT) is to eradicate residual disease, which persists after induction and is not detectable at examination of the bone marrow morphology. (Source: The Lancet Oncology)

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[Comment] A tale of two tumours and a plea for progress

The Lancet Oncology — Wed, 01 Feb 2012 05:00:00 +0100

Melanoma and acute myeloid leukaemia (AML) share important characteristics: both are non-epithelial malignancies and affect a substantial proportion of young people, with roughly a third of patients diagnosed younger than 60 years. Notably, the incidence of primary melanoma is rising faster than that of any other common cancer and has quadrupled since the 1970s. Although most people with primary melanoma are cured, the incidence of metastatic disease is roughly equal to that of acute myeloid leukaemia, with about 2000 new cases per year in the UK. (Source: The Lancet Oncology)

[News] Qiagen acquires new rights for personalised cancer care

The Lancet Oncology — Wed, 01 Feb 2012 05:00:00 +0100

As the push towards personalised healthcare in many developed and emerging economies continues, the race to develop quick and accurate companion diagnostic tests is hotting up, with cancer diagnostics at the forefront. In the past week Qiagen (Hilden, Germany) announced its acquisition of worldwide exclusive rights to develop a genetic test for the anaplastic lymphoma kinase (ALK) biomarker, which would potentially be used in conjunction with a new class of lung-cancer drugs, and similar rights to develop a test for mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2), which have been implicated in low-grade gliomas, anaplastic gliomas, secondary glioblastoma, and acute myeloid leukaemia. (Source: The Lancet Oncology)

[Articles] Prediction of post-remission survival in acute myeloid leukaemia: a post-hoc analysis of the AML96 trial

The Lancet Oncology — Wed, 01 Feb 2012 05:00:00 +0100

The PRT score groups could help physicians to tailor treatment for patients with AML and our results lend support to the use of autologous HSCT in patients aged 60 years or younger with an intermediate PRT score. (Source: The Lancet Oncology)

Array-Based Cytogenetic Approaches in Acute Myeloid Leukemia: Clinical Impact and Biological Insights

Seminars in Oncology — Wed, 01 Feb 2012 05:00:00 +0100

Conventional cytogenetic studies have shown that the clinical and biological diversity of acute myeloid leukemia (AML) can be attributed, in part, to distinct chromosome aberrations, several of which are now routinely used for diagnosis, risk stratification, and outcome prediction. Although chromosome banding analysis has recently been complemented by the identification of point mutations in a growing number of hematopoiesis-associated genes, current genetic categories do not fully reflect the heterogeneity of AML. To close the gap between standard karyotyping and molecular analyses at the single–base-pair level and gain additional insight into the genetics underlying myeloid leukemogenesis, AML is increasingly being studied using genome-wide, microarray-based cytogenetic methods. These ...

p53-Independent, Normal Stem Cell Sparing Epigenetic Differentiation Therapy for Myeloid and Other Malignancies

Seminars in Oncology — Wed, 01 Feb 2012 05:00:00 +0100

Cytotoxic chemotherapy for acute myeloid leukemia (AML) usually produces only temporary remissions, at the cost of significant toxicity and risk for death. One fundamental reason for treatment failure is that it is designed to activate apoptosis genes (eg, TP53) that may be unavailable because of mutation or deletion. Unlike deletion of apoptosis genes, genes that mediate cell cycle exit by differentiation are present in myelodysplastic syndrome (MDS) and AML cells but are epigenetically repressed: MDS/AML cells express high levels of key lineage-specifying transcription factors. Mutations in these transcription factors (eg, CEBPA) or their cofactors (eg., RUNX1) affect transactivation function and produce epigenetic repression of late-differentiation genes that antagonize MYC. Importantly...

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Clinical Applications of Epigenetic Markers and Epigenetic Profiling in Myeloid Malignancies

Seminars in Oncology — Wed, 01 Feb 2012 05:00:00 +0100

Aberrant DNA methylation is frequent in the myeloid malignancies, particularly myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Promoter CpG methylation is correlated with silencing of tumor-suppressor genes (TSGs) in specific pathways that are also targets of mutation or other mechanisms of inactivation, and is thought to contribute to disease progression and poor prognosis. Epigenetic contributions to myeloid pathogenesis are more complex. Examples include TSG inactivation and oncogenic activation associated with formation of altered chromatin separate from CpG methylation. Epigenetic dysregulation occurs at multiple disease stages and at non-CpG island genomic sites, and also includes genomic hypomethylation and small RNA mechanisms of epigenetic regulation. Identifi...

Primary granulocytic sarcoma of the peritoneum: a case report and literature review.

Annales de Biologie Clinique — Wed, 01 Feb 2012 05:00:00 +0100

We report the case of a 20 years old man without particular previous pathologies, which brutally presented an ascitic syndrome in a context of health impairment state. The laparoscopy showes many white nodules on all the peritoneum. The histologic examination of one of these nodules showed granulocytic sarcoma. The blood and bone marrow cell count are without any anomaly. The treatment consisted of a standard acute myeloid leukaemia's chemotherapy with very good evolution. The rarity of peritoneal chloroma causes a diagnostic problem, especially in the absence of hematologic abnormalities. It must be mentioned in the presence of peritoneal nodules even if the blood count and bone marrow are normal. PMID: 22294142 [PubMed - as supplied by publisher] (Source: Annales de Biologie Clinique...

Midostaurin does not prolong cardiac repolarization defined in a thorough electrocardiogram trial in healthy volunteers

Cancer Chemotherapy and Pharmacology — Tue, 31 Jan 2012 16:48:29 +0100

Conclusion Midostaurin demonstrated a good safety profile in healthy volunteers, with no prolonged cardiac repolarization or other changes on the electrocardiogram. Content Type Journal ArticleCategory Original ArticlePages 1-9DOI 10.1007/s00280-012-1825-yAuthors Adam del Corral, Novartis Oncology, East Hanover, NJ, USACatherine Dutreix, Novartis Oncology, Basel, SwitzerlandAlice Huntsman-Labed, Novartis Oncology, Basel, SwitzerlandSebastien Lorenzo, Novartis Oncology, Basel, SwitzerlandJoel Morganroth, ERT, East Bridgewater, NJ, USARobert Harrell, Osborne Research Center, LLC, Little Rock, AR, USAYanfeng Wang, Novartis Oncology, East Hanover, NJ, USA Journal Cancer Chemotherapy and PharmacologyOnline ISSN 1432-0843Print ISSN 0344-5704 (Source: Cancer Chemothe...

Undiagnosed, Untreated Acute Promyelocytic Leukemia Presenting as a Suspicious Sudden Death*

Journal of Forensic Sciences — Tue, 31 Jan 2012 05:00:00 +0100

We report the sudden death of a 40-year-old male without significant medical history in which foul play had been initially suspected. A thorough postmortem investigation performed on the decedent lead to the diagnosis of APL. Cause of death was a cerebellar hematoma. Underlying APL should be considered in the differential diagnosis when unexplained bleeding is encountered in a decedent. This case emphasizes the value of routinely collecting bone marrow during an autopsy to enable accurate testing and diagnosis. PMID: 22292852 [PubMed - as supplied by publisher] (Source: Journal of Forensic Sciences)

Processes leading to acute myeloid leukemia discovered

ScienceDaily Headlines — Mon, 30 Jan 2012 14:43:43 +0100

Researchers have discovered a molecular pathway that may explain how a particularly deadly form of cancer develops. The discovery may lead to new cancer therapies that reprogram cells instead of killing them. (Source: ScienceDaily Headlines)

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UCSB researchers discover the processes leading to acute myeloid leukemia

EurekAlert! - Medicine and Health — Mon, 30 Jan 2012 05:00:00 +0100

(University of California - Santa Barbara) Researchers at UC Santa Barbara have discovered a molecular pathway that may explain how a particularly deadly form of cancer develops. The discovery may lead to new cancer therapies that reprogram cells instead of killing them. The findings are published in a recent paper in the Journal of Biological Chemistry. (Source: EurekAlert! - Medicine and Health)

Routine use of microarray-based gene expression profiling to identify patients with low cytogenetic risk acute myeloid leukemia: accurate results can be obtained even with suboptimal samples

BMC Medical Genomics — Mon, 30 Jan 2012 05:00:00 +0100

Conclusion: Gene expression profiling and a supervised method requiring 10-marker classifiers enable the identification of favorable cytogenetic risk acute myeloid leukemia even when samples contain low leukemic blast loads or display poor quality control criterion. (Source: BMC Medical Genomics)

Factors influencing the pharmacokinetics of prophylactic posaconazole oral suspension in patients with acute myeloid leukemia or myelodysplastic syndrome

European Journal of Clinical Pharmacology — Fri, 27 Jan 2012 17:52:02 +0100

Conclusion We developed a prediction basis for mean posaconazole concentrations in AML/MDS patients. Patient weight, presence of diarrhea, and concomitant medication (chemotherapy and pantoprazole) showed significant effects on posaconazole exposure. Corresponding adjustments of the starting dose according to the presence of diarrhea and during the co-administration of chemotherapy or proton-pump inhibitors appear justified before therapeutic drug monitoring results are available. Further investigation of the interaction between different chemotherapeutic regimens and posaconazole is warranted. Content Type Journal ArticleCategory Pharmacokinetics and DispositionPages 1-9DOI 10.1007/s00228-012-1212-yAuthors J. J. Vehreschild, Department I of Internal Medicine, Uni...

Clinical features and prognostic factors of Asian patients with paroxysmal nocturnal hemoglobinuria: results from a single center in China

Annals of Hematology — Fri, 27 Jan 2012 06:53:43 +0100

Abstract Although all patients with paroxysmal nocturnal hemoglobinuria (PNH) have acquired mutations in the phosphatidylinositol glycan class-A(PIG-A)gene, their clinical courses are highly variable. We reviewed 280 PNH cases referred to our hospital from January 1990 through June 2010 to assess clinical presentations, prognostic factors influencing survival, difference among subcategories, and clinical significance of PNH clone size. The overall survival at 10 years after diagnosis estimated by Kaplan–Meier was 77.6%. Both univariate and multivariate analyses identified risk factors affecting survival, including age >40 years, absolute neutrophil count<0.5 × 109 cells/L, development of thrombotic events, evolution to myelodysplastic syndrome or acut...

Introduction

Seminars in Diagnostic Pathology — Fri, 27 Jan 2012 05:38:40 +0100

This issue is the second part of the two issues on bone marrow disorders. As mentioned in the Introduction to Part I (Bone Marrow Disorders: Recent Advances, Part I), a lot of hard work and many hours of discussion have preceded the publication of the WHO series of classifications of human neoplasms. However, advances in our understanding of molecular events that are characteristic of, precede, or define a disease or disease group have nowhere else had such a profound impact on disease classification as in the WHO classification of tumors of the hematopoietic and lymphoid tissues. In the case of the myeloid neoplasms, the classification has categorized some entities, e.g. acute myeloid leukemia, into different types based not only on their morphology, but also on molecular genetic and some...

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Hydroquinone, a benzene metabolite, and leukemia: A case report and review of the literature

Toxicology and Industrial Health current issue — Fri, 27 Jan 2012 05:00:00 +0100

We report a case of a 43-year-old male diagnosed with antecedent myelodysplastic syndrome and acute myeloid leukemia following 16 years of occupational exposure to hydroquinone in radiographic developer solution. Cytogenetic studies revealed aberrations in chromosome 5 and chromosome 7. We review the literature on hydroquinone as a potential cause of hematolymphatic cancers and discuss the role of hydroquinone as a genotoxic and leukemogenic agent. (Source: Toxicology and Industrial Health current issue)

Prediction of Early Death in Acute Myeloid Leukemia [CORRESPONDENCE]

Journal of Clinical Oncology — Fri, 27 Jan 2012 05:00:00 +0100

(Source: Journal of Clinical Oncology)

High-dose therapy with autologous stem cell transplantation versus chemotherapy or immuno-chemotherapy for follicular lymphoma in adults.

Cochrane Database of Systematic Reviews — Thu, 26 Jan 2012 08:18:08 +0100

CONCLUSIONS: In summary, the currently available evidence suggests a strong PFS benefit for HDT + ASCT compared with chemotherapy or immuno-chemotherapy in previously untreated patients with FL. No statistically significant differences in terms of OS, TRM and secondary cancers were detected. These effects are confirmed in a subgroup analysis (one trial) adding rituximab to both treatment arms. Further trials evaluating this approach are needed to determine this effect more precisely in the era of rituximab. Moreover, longer follow-up data are necessary to find out whether the PFS advantage will translate into an OS advantage in previously untreated patients with FL.There is evidence that HDT + ASCT is advantageous in patients with relapsed FL. PMID: 22258971 [PubMed - in process] (Sour...

Response: high ERG gene expression is an unfavorable prognostic marker in pediatric acute myeloid leukemia

Blood — Thu, 26 Jan 2012 05:00:00 +0100

(Source: Blood)

CMV-specific cellular therapy for acute myeloid leukemia?

Blood — Thu, 26 Jan 2012 05:00:00 +0100

(Source: Blood)

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Clofarabine plus low‐dose cytarabine followed by clofarabine plus low‐dose cytarabine alternating with decitabine in acute myeloid leukemia frontline therapy for older patients

Cancer — Thu, 26 Jan 2012 05:00:00 +0100

CONCLUSIONS:Clofarabine plus low‐dose cytarabine alternating with decitabine in consolidation is active in older patients with newly diagnosed AML. The benefits of a prolonged consolidation remain unproven. Cancer 2012;. © 2012 American Cancer Society. (Source: Cancer)

Anti-apoptotic Mcl-1 is essential for the development and sustained growth of acute myeloid leukemia [Research Communications]

Genes and Development — Wed, 25 Jan 2012 05:00:00 +0100

Acute myeloid leukemia (AML) frequently relapses after initial treatment. Drug resistance in AML has been attributed to high levels of the anti-apoptotic Bcl-2 family members Bcl-xL and Mcl-1. Here we report that removal of Mcl-1, but not loss or pharmacological blockade of Bcl-xL, Bcl-2, or Bcl-w, caused the death of transformed AML and could cure disease in AML-afflicted mice. Enforced expression of selective inhibitors of prosurvival Bcl-2 family members revealed that Mcl-1 is critical for survival of human AML cells. Thus, targeting of Mcl-1 or regulators of its expression may be a useful strategy for the treatment of AML. (Source: Genes and Development)

Hierarchical Bayesian formulations for selecting variables in regression models

Statistics in Medicine — Wed, 25 Jan 2012 05:00:00 +0100

The objective of finding a parsimonious representation of the observed data by a statistical model that is also capable of accurate prediction is commonplace in all domains of statistical applications. The parsimony of the solutions obtained by variable selection is usually counterbalanced by a limited prediction capacity. On the other hand, methodologies that assure high prediction accuracy usually lead to models that are neither simple nor easily interpretable. Regularization methodologies have proven to be useful in addressing both prediction and variable selection problems. The Bayesian approach to regularization constitutes a particularly attractive alternative as it is suitable for high‐dimensional modeling, offers valid standard errors, and enables simultaneous estimation of regre...

Risk of second cancers in Waldenstrom macroglobulinemia

Annals of Oncology — Tue, 24 Jan 2012 05:00:00 +0100

Conclusions: WM patients are at higher risk of second cancers as compared with the general population. The sample size does not allow firm conclusions about the effect of therapy on the development of second cancers. (Source: Annals of Oncology)

Caregiving Burden, Stress, and Health Effects Among Family Caregivers of Adult Cancer Patients [Grand Rounds]

JAMA — Tue, 24 Jan 2012 05:00:00 +0100

This report describes a case that exemplifies caregiving burden and discusses the importance of identifying caregivers at risk of negative health outcomes and intervening to attenuate the stress associated with the caregiving experience. (Source: JAMA)

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Angiogenesis and Survival in Patients with Myelodysplastic Syndrome.

Pathology Oncology Research — Tue, 24 Jan 2012 05:00:00 +0100

This study confirmed increased MVD in MDS. It does not support an independent prognostic role of angiogenesis in MDS. PMID: 22270865 [PubMed - as supplied by publisher] (Source: Pathology Oncology Research)

Germ-line GATA2 p.THR354MET mutation in familial myelodysplastic syndrome with acquired monosomy 7 and ASXL1 mutation demonstrating rapid onset and poor survival.

Haematologica — Sun, 22 Jan 2012 05:00:00 +0100

Authors: Bödör C, Renneville A, Smith M, Charazac A, Iqbal S, Etancelin P, Cavenagh J, Barnett MJ, Kramarzova K, Krishnan B, Matolcsy A, Preudhomme C, Fitzgibbon J, Owen C Abstract While most myelodysplastic syndrome/acute myeloid leukemia cases are sporadic, rare familial cases occur and provide insight into leukemogenesis. The most clearly defined familial cases result from inherited mutations in RUNX1 or CEBPA. Recently, novel germline mutations in GATA2 were reported. We thus investigated individuals from families with ≥ 1 first-degree relative with myelodysplastic syndrome/acute myeloid leukemia with wildtype RUNX1 and CEBPA, for GATA2 mutations. Screening for other recurrent mutations was also performed. A GATA2 p.Thr354Met mutation was observed in a pedigree in which 2 f...

In Acute Myeloid Leukemia Study Pinpoints And Plugs Mechanism Of Cancer Cell Escape

Health News from Medical News Today — Fri, 20 Jan 2012 09:00:00 +0100

A study published this week in the journal Leukemia identifies a mechanism that acute myeloid leukemia (AML) cells use to evade chemotherapy - and details how to close this escape route. "Introducing chemotherapy to cells is like putting a curve in front of a speeding car," says Christopher Porter, MD, investigator at the University of Colorado Cancer Center and assistant professor of pediatrics at the University of Colorado School of Medicine. "Cells that can put on the brakes make it around the corner and cells that can't speed off the track... (Source: Health News from Medical News Today)

miR‐199b‐5p directly targets podxl and ddr1 and decreased levels of miR‐199b‐5p correlate with elevated expressions of podxl and ddr1 in acute myeloid leukemia

American Journal of Hematology — Fri, 20 Jan 2012 05:00:00 +0100

(Source: American Journal of Hematology)

Association of CYP3A5*3 polymorphism with development of acute leukemia

Indian Journal of Human Genetics — Fri, 20 Jan 2012 05:00:00 +0100

Conclusion : The results suggest that the CYP3A5*3 polymorphism might confer the risk to develop ALL or AML emphasizing the significance of effective phase I detoxification in carcinogenesis. Association of the polymorphism with clinical variables indicate that the 3/3 genotype might also contribute to poorer survival of the patients. (Source: Indian Journal of Human Genetics)

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Inducible knockout of GRP78/BiP in the hematopoietic system suppresses Pten-null leukemogenesis and AKT oncogenic signaling

Blood — Thu, 19 Jan 2012 05:00:00 +0100

Traditionally, GRP78 is regarded as protective against hypoxia and nutrient starvation prevalent in the microenvironment of solid tumors; thus, its role in the development of hematologic malignancies remains to be determined. To directly elucidate the requirement of GRP78 in leukemogenesis, we created a biallelic conditional knockout mouse model of GRP78 and PTEN in the hematopoietic system. Strikingly, heterozygous knockdown of GRP78 in PTEN null mice is sufficient to restore the hematopoietic stem cell population back to the normal percentage and suppress leukemic blast cell expansion. AKT/mTOR activation in PTEN null BM cells is potently inhibited by Grp78 heterozygosity, corresponding with suppression of the PI3K/AKT pathway by GRP78 knockdown in leukemia cell lines. This is the first ...

Monitoring of methylation changes in 9p21 region in patients with myelodysplastic syndromes and acute myeloid leukemia.

Neoplasma — Thu, 19 Jan 2012 04:30:02 +0100

Authors: Cechova H, Lassuthova P, Novakova L, Belickova M, Stemberkova R, Jencik J, Stankova M, Hrabakova P, Pegova K, Zizkova H, Cermak J Abstract Epigenetic de novo methylation of CpG islands is an important event in malignant transformation. Two genes are frequently methylated: cyclin-dependent kinase inhibitor 2B (CDKN2B) and cyclin-dependent kinase inhibitor 2A (CDKN2A). In our study methylation of these genes was studied in 63 patients with myelodysplastic syndromes (MDS), 2 with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) and 13 with acute myeloid leukemia (AML). Five patients were monitored during 5-azacytidine treatment. Twenty-six healthy donors were tested in a control group. Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) met...

New Achilles Heel In Acute Myeloid Leukaemia Identified By Cell Death Researchers

Health News from Medical News Today — Wed, 18 Jan 2012 10:00:00 +0100

Melbourne researchers have discovered that acute myeloid leukaemia (AML), an aggressive blood cancer with poor prognosis, may be susceptible to medications that target a protein called Mcl-1. The research team at the institute was led by Dr Stefan Glaser, from the institute's Cancer and Haematology division, and Professor Andreas Strasser, joint head of the institute's Molecular Genetics of Cancer division, working in collaboration with scientists from the Australian Centre for Blood Diseases and St... (Source: Health News from Medical News Today)

Study pinpoints and plugs mechanism of AML cancer cell escape

EurekAlert! - Medicine and Health — Wed, 18 Jan 2012 05:00:00 +0100

(University of Colorado Denver) Turning off the gene that codes for WEE1 sensitizes acute myeloid leukemia cells to chemotherapy. (Source: EurekAlert! - Medicine and Health)

From cryptic chromosomal lesions to pathologically relevant genes: Integration of SNP‐array with gene expression profiling in myelodysplastic syndrome with normal karyotype

Genes, Chromosomes and Cancer — Tue, 17 Jan 2012 05:00:00 +0100

AbstractMyelodysplastic syndrome (MDS), a clonal disorder originating from hematopoietic stem cell, is characterized by a progressive character often leading to transformation to acute myeloid leukemia. We used single nucleotide polymorphism arrays (SNP‐A) to identify previously cryptic chromosomal abnormalities such as copy number alterations and uniparental disomies (UPD) in cytogenetically normal MDS. In the aberrant regions, we attempted to localize candidate genes with potential relevance to the disease. Using SNP‐A, we analyzed peripheral blood granulocytes from 37 MDS patients. The analysis identified 13 cryptic chromosomal defects in 10 patients (27%). Four UPD (affecting chromosomes 3q, 7q, 17q, and 20p), 5 deletions and 4 duplications were detected. Gene expression data measu...

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Isolated granulocytic sarcoma of the pancreas: A tricky diagnostic for primary pancreatic extramedullary acute myeloid leukemia

World Journal of Surgical Oncology — Mon, 16 Jan 2012 05:00:00 +0100

We report two clinical cases of primary granulocytic sarcoma of the pancreas that were diagnosed on the surgical specimen. Atypical clinical and morphological presentations may have lead to pretherapeutic biopsies of the pancreatic mass in order to indicate primary chemotherapy. Literature review of this rare clinical presentation may help physicians to anticipate diagnostic and therapeutic strategies. (Source: World Journal of Surgical Oncology)

Cell death researchers identify new Achilles heel in acute myeloid leukemia

EurekAlert! - Medicine and Health — Mon, 16 Jan 2012 05:00:00 +0100

(Walter and Eliza Hall Institute) Melbourne researchers have discovered that acute myeloid leukemia, an aggressive blood cancer with poor prognosis, may be susceptible to medications that target a protein called Mcl-1. (Source: EurekAlert! - Medicine and Health)

A novel murine model of myeloproliferative disorders generated by overexpression of the transcription factor NF-E2

The Journal of Experimental Medicine — Mon, 16 Jan 2012 05:00:00 +0100

The molecular pathophysiology of myeloproliferative neoplasms (MPNs) remains poorly understood. Based on the observation that the transcription factor NF-E2 is often overexpressed in MPN patients, independent of the presence of other molecular aberrations, we generated mice expressing an NF-E2 transgene in hematopoietic cells. These mice exhibit many features of MPNs, including thrombocytosis, leukocytosis, Epo-independent colony formation, characteristic bone marrow histology, expansion of stem and progenitor compartments, and spontaneous transformation to acute myeloid leukemia. The MPN phenotype is transplantable to secondary recipient mice. NF-E2 can alter histone modifications, and NF-E2 transgenic mice show hypoacetylation of histone H3. Treatment of mice with the histone deacetylase...

Acute myeloid leukemia versus professional occupation: the profile of workers treated at the Recife Hematology Hospital

Revista da Escola de Enfermagem da USP — Sat, 14 Jan 2012 11:51:43 +0100

The objective of this study was to learn the profile of workers in the economically active age group admitted from 1997 to 2007 to a hematology hospital, diagnosed with acute myeloid leukemia (AML); check which professions have the highest prevalence among the assisted workers who died; and identify the occupational risks compatible with the appearance of AML in the prevalent professions. This is a quantitative, exploratory study. Most profiles were characterized as originally from the agreste and the metropolitan region of the state of Pernambuco, male, white, and with incomplete primary education. The most common occupations were related to agriculture and domestic work, both of which involve the use of chemical substances that, according to literature, are possible factors involved in t...

Leukemia Relapse May Be Influenced By Chemotherapy

Health News from Medical News Today — Fri, 13 Jan 2012 08:00:00 +0100

The chemotherapy drugs required to push a common form of adult leukemia into remission may contribute to DNA damage that can lead to a relapse of the disease in some patients, findings of a new study suggest. The research, by a team of physicians and scientists at Washington University School of Medicine in St. Louis, is published in the advance online edition of Nature. For patients with acute myeloid leukemia (AML), initial treatment with chemotherapy is essential for putting the cancer into remission. Without it, most patients would die within several months... (Source: Health News from Medical News Today)

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DNA Damage From Chemo May Help Spur Leukemia’s Return

The Doctors Lounge - Oncology — Fri, 13 Jan 2012 05:00:00 +0100

The treatment can achieve acute myeloid leukemia remission, but better options needed, experts say (Source: The Doctors Lounge - Oncology)

Prognostic significance of DNA methyltransferase 3A mutations in cytogenetically normal acute myeloid leukemia: a study by the Acute Leukemia French Association

Leukemia — Fri, 13 Jan 2012 05:00:00 +0100

Authors: A Renneville, N Boissel, O Nibourel, C Berthon, N Helevaut, C Gardin, J-M Cayuela, S Hayette, O Reman, N Contentin, D Bordessoule, C Pautas, S de Botton, T de Revel, C Terre, P Fenaux, X Thomas, S Castaigne, H Dombret & C Preudhomme (Source: Leukemia)

Integrated genomic analyses identify WEE1 as a critical mediator of cell fate and a novel therapeutic target in acute myeloid leukemia

Leukemia — Fri, 13 Jan 2012 05:00:00 +0100

Authors: C C Porter, J Kim, S Fosmire, C M Gearheart, A van Linden, D Baturin, V Zaberezhnyy, P R Patel, D Gao, A C Tan & J DeGregori (Source: Leukemia)

DNA Damage From Chemo May Help Spur Leukemia's Return

Cancercompass News: Other Cancer — Fri, 13 Jan 2012 00:00:00 +0100

The treatment can achieve acute myeloid leukemia remission, but better options needed, experts say (Source: Cancercompass News: Other Cancer)

DNA Damage from Chemo May Help Spur Leukemia's Return

MedlinePlus Health News — Thu, 12 Jan 2012 19:00:00 +0100

The treatment can achieve acute myeloid leukemia remission, but better options needed, experts say Source: HealthDay Related MedlinePlus Pages: Acute Myeloid Leukemia, Cancer Chemotherapy (Source: MedlinePlus Health News)

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Prognostic and therapeutic implications of minimal residual disease detection in acute myeloid leukemia

Blood — Thu, 12 Jan 2012 05:00:00 +0100

The choice of either induction or postremission therapy for adults with acute myeloid leukemia is still largely based on the "one size fits all" principle. Moreover, pretreatment prognostic parameters, especially chromosome and gene abnormalities, may fail in predicting individual patient outcome. Measurement of minimal residual disease (MRD) is nowadays recognized as a potential critical tool to assess the quality of response after chemotherapy and to plan postremission strategies that are, therefore, driven by the individual risk of relapse. PCR and multiparametric flow cytometry have become the most popular methods to investigate MRD because they have been established as sensitive and specific enough to allow MRD to be studied serially. In the present review, we examine the evidence sup...

Functional inhibition of osteoblastic cells in an in vivo mouse model of myeloid leukemia

Blood — Thu, 12 Jan 2012 05:00:00 +0100

Pancytopenia is a major cause of morbidity in acute myeloid leukemia (AML), yet its cause is unclear. Normal osteoblastic cells have been shown to support hematopoiesis. To define the effects of leukemia on osteoblastic cells, we used an immunocompetent murine model of AML. Leukemic mice had inhibition of osteoblastic cells, with decreased serum levels of the bone formation marker osteocalcin. Osteoprogenitor cells and endosteal-lining osteopontin+ cells were reduced, and osteocalcin mRNA in CD45– marrow cells was diminished. This resulted in severe loss of mineralized bone. Osteoclasts were only transiently increased without significant increases in bone resorption, and their inhibition only partially rescued leukemia-induced bone loss. In vitro data suggested that a leukemia-derive...

Monosomal karyotype in adult acute myeloid leukemia: prognostic impact and outcome after different treatment strategies

Blood — Thu, 12 Jan 2012 05:00:00 +0100

We aimed to determine the prognostic impact of monosomal karyotype (MK) in acute myeloid leukemia (AML) in the context of the current World Health Organization (WHO) classification and to evaluate the outcome of MK+ patients after allogeneic HSCT. Of 1058 patients with abnormal cytogenetics, 319 (30%) were MK MK+. MK+ patients were significantly older (P = .0001), had lower white blood counts (P = .0006), and lower percentages of BM blasts (P = .0004); MK was associated with the presence of –5/5q–, –7, 7q–, abnl(12p), abnl(17p), –18/18q–, –20/20q–, inv(3)/t(3;3), complex karyotype (CK), and myelodysplasia (MDS)–related cytogenetic abnormalities (P < .0001, each); and NPM1 mutations (P < .0001), FLT3 internal tandem duplications (P...

DNMT3A mutations in acute myeloid leukemia: stability during disease evolution and clinical implications

Blood — Thu, 12 Jan 2012 05:00:00 +0100

In conclusion, DNMT3A mutations are associated with distinct clinical and biologic features and poor prognosis in de novo AML patients. Furthermore, the DNMT3A mutation may be a potential biomarker for monitoring of minimal residual disease. (Source: Blood)

Prolonged Survival with Imatinib Mesylate Combined with Chemotherapy and Allogeneic Stem Cell Transplantation in de novo Ph+ Acute Myeloid Leukemia.

Acta Haematologica — Thu, 12 Jan 2012 05:00:00 +0100

Conclusions: Our cases indicate that IM combined with daunorubicin-based chemotherapy followed by allo-HSCT and IM maintenance treatment is associated with a favorable outcome for de novo Ph+ AML, especially when IM is used in an early phase of AML. PMID: 22248505 [PubMed - as supplied by publisher] (Source: Acta Haematologica)

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Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing

Nature AOP — Wed, 11 Jan 2012 05:00:00 +0100

Authors: Li Ding, Timothy J. Ley, David E. Larson, Christopher A. Miller, Daniel C. Koboldt, John S. Welch, Julie K. Ritchey, Margaret A. Young, Tamara Lamprecht, Michael D. McLellan, Joshua F. McMichael, John W. Wallis, Charles Lu, Dong Shen, Christopher C. Harris, David J. Dooling, Robert S. Fulton, Lucinda L. Fulton, Ken Chen, Heather Schmidt, Joelle Kalicki-Veizer, Vincent J. Magrini, Lisa Cook, Sean D. McGrath, Tammi L. Vickery, Michael C. Wendl, Sharon Heath, Mark A. Watson, Daniel C. Link, Michael H. Tomasson, William D. Shannon, Jacqueline E. Payton, Shashikant Kulkarni, Peter Westervelt, Matthew J. Walter, Timothy A. Graubert, Elaine R. Mardis, Richard K. Wilson & John F. DiPersio Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, whic...

Hematological cancer: Germline genes likely have a role in young patients with AML

Nature Clinical Practice Oncology — Tue, 10 Jan 2012 05:00:00 +0100

Nature Reviews Clinical Oncology 9, 66 (2012). doi:10.1038/nrclinonc.2011.208 A large population study has been completed in Sweden that aimed to identify whether there is a familial link for acute myeloid leukemia (AKL) and myelodysplastic syndromes (MDS). Interestingly, having a first-degree relative with AML or MDS did not increase the risk of developing either (Source: Nature Clinical Practice Oncology)

Novel targeted therapy for acute myeloid leukemia with a dual FLT3 and JAK2 inhibitor.

Acta Pharmacologica Sinica — Mon, 09 Jan 2012 05:00:00 +0100

Authors: Lou YJ PMID: 22231396 [PubMed - as supplied by publisher] (Source: Acta Pharmacologica Sinica)

Hypomethylation mediated by decreased DNMTs involves in the activation of proto-oncogene MPL in TK6 cells treated with hydroquinone.

Toxicology Letters — Sun, 08 Jan 2012 05:00:00 +0100

In conclusion, hypomethylation, including global and specific hypomethylation, might be involved in the activation of MPL, and the hypomethylation could be induced by decreased DNMTs in TK6 cells exposed to HQ. PMID: 22245671 [PubMed - as supplied by publisher] (Source: Toxicology Letters)

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Combination strategies in myelodysplastic syndromes.

International Journal of Hematology — Fri, 06 Jan 2012 05:00:00 +0100

Authors: Ornstein MC, Sekeres MA Abstract The myelodysplastic syndromes (MDS) consist of an array of clonal hematological malignancies resulting from disorders of pluripotent hematopoietic stem cells. MDS is associated with a poor overall prognosis and patients are categorized as higher risk and lower risk on the basis of the International Prognostic Scoring System. Currently, lenalidomide, azacitidine, and decitabine are the only three FDA-approved drugs for MDS. Traditional therapies for MDS involve the administration of single agents providing either supportive measures or disease-modifying effects directed to slowing progression to acute myeloid leukemia (AML) and improving survival. Recently, however, there has been increasing evidence suggesting that the combination of drugs ...

MicroRNA control of myelopoiesis and the differentiation block in Acute Myeloid Leukaemia

Journal of Cellular and Molecular Medicine — Fri, 06 Jan 2012 05:00:00 +0100

AbstractIn the relatively short period of time since their discovery microRNAs have been shown to control many important cellular functions such as cell differentiation, growth, proliferation and apoptosis. Additionally, microRNAs have been demonstrated as key drivers of many malignancies and can function as either tumour suppressors or oncogenes. The haematopoietic system is not outside the realm of microRNA control with microRNAs controlling aspects of stem cell and progenitor self‐renewal and differentiation; with many, if not all haematological disorders associated with aberrant microRNA expression and function. In this review we focus on the current understanding of microRNA control of haematopoiesis and detail the evidence for the contribution and clinical relevance of aberrant mic...

Familial Aggregation of Acute Myeloid Leukemia and Myelodysplastic Syndromes [Hematologic Malignancies]

Journal of Clinical Oncology — Fri, 06 Jan 2012 05:00:00 +0100

Conclusion We did not find evidence for familial aggregation of the severe end of the spectrum of myeloid malignancies (AML and MDS). The risks of myeloproliferative neoplasms were modestly increased with trends toward significance, suggesting a possible role of inheritance. In contrast, although limited in sample size, relatives of young patients with AML were at increased risk of AML/MDS, suggesting that germline genes may play a stronger role in these patients. The increased risk of all hematologic malignancies and of solid tumors among relatives of patients with AML suggests that genes for malignancy in general and/or other environmental factors may be shared. (Source: Journal of Clinical Oncology)

Flt3-ITD mutations in a mouse model of radiation-induced acute myeloid leukaemia

Leukemia — Fri, 06 Jan 2012 05:00:00 +0100

Authors: R Finnon, N Brown, J Moody, C Badie, C-H Olme, R Huiskamp, E Meijne, M Sutmuller, M Rosemann & S D Bouffler (Source: Leukemia)

MicroRNA control of myelopoiesis and the differentiation block in Acute Myeloid Leukaemia.

J Cell Mol Med — Fri, 06 Jan 2012 05:00:00 +0100

Authors: Palma CA, Tonna EJ, Ma DF, Lutherborrow M Abstract In the relatively short period of time since their discovery microRNAs have been shown to control many important cellular functions such as cell differentiation, growth, proliferation and apoptosis. Additionally, microRNAs have been demonstrated as key drivers of many malignancies and can function as either tumour suppressors or oncogenes. The haematopoietic system is not outside the realm of microRNA control with microRNAs controlling aspects of stem cell and progenitor self-renewal and differentiation; with many, if not all haematological disorders associated with aberrant microRNA expression and function. In this review we focus on the current understanding of microRNA control of haematopoiesis and detail the evidence f...

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VX-322: A Novel Dual Receptor Tyrosine Kinase Inhibitor for the Treatment of Acute Myelogenous Leukemia

Journal of Medicinal Chemistry — Thu, 05 Jan 2012 19:44:24 +0100

Journal of Medicinal ChemistryDOI: 10.1021/jm201198w (Source: Journal of Medicinal Chemistry)

In Vitro and In Vivo Antitumor Effect of Anti-CD33 Chimeric Receptor-Expressing EBV-CTL against CD33+ Acute Myeloid Leukemia

Advances in Pharmacological Sciences — Thu, 05 Jan 2012 14:27:21 +0100

In conclusion, targeting CD33 by CAR-modified EBV-specific T cells may provide additional therapeutic benefit to AML patients as compared to conventional chemotherapy or transplantation regimens alone. (Source: Advances in Pharmacological Sciences)

Acute leukemia incidence and patient survival among children and adults in the United States, 2001-2007

Blood — Thu, 05 Jan 2012 05:00:00 +0100

Since 2001, the World Health Organization classification for hematopoietic and lymphoid neoplasms has provided a framework for defining acute leukemia (AL) subtypes, although few population-based studies have assessed incidence patterns and patient survival accordingly. We assessed AL incidence rates (IRs), IR ratios (IRRs), and relative survival in the United States (2001-2007) in one of the first population-based, comprehensive assessments. Most subtypes of acute myeloid leukemia (AML) and acute lymphoblastic leukemia/lymphoma (ALL/L) predominated among males, from twice higher incidence of T-cell ALL/L among males than among females (IRR = 2.20) to nearly equal IRs of acute promyelocytic leukemia (APL; IRR = 1.08). Compared with non-Hispanic whites, Hispanics had significantly higher in...

Multi-institutional phase 2 clinical and pharmacogenomic trial of tipifarnib plus etoposide for elderly adults with newly diagnosed acute myelogenous leukemia

Blood — Thu, 05 Jan 2012 05:00:00 +0100

This study is registered at www.clinicaltrials.gov as #NCT00602771. (Source: Blood)

A functional variant in the core promoter of the CD95 cell death receptor gene predicts prognosis in acute promyelocytic leukemia

Blood — Thu, 05 Jan 2012 05:00:00 +0100

Up to 15% of acute promyelocytic leukemia (APL) patients fail to achieve or maintain remission. We investigated a common G > A polymorphism at position –1377 (rs2234767) in the core promoter of the CD95 cell death receptor gene in 708 subjects with acute myeloid leukemia, including 231 patients with APL. Compared with the GG genotype, carrier status for the –1377A variant was associated with a significantly worse prognosis in APL patients. Carriers were more likely to fail remission induction (odds ratio = 4.22; 95% confidence interval, 1.41-12.6, P = .01), were more likely to die during the first 8 weeks of remission induction therapy (hazard ratio = 7.26; 95% confidence interval, 2.39-22.9, P = .0005), and had a significantly worse 5-year overall survival (odds ratio = 2.1...

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Allelic methylation levels of the noncoding VTRNA2-1 located on chromosome 5q31.1 predict outcome in AML

Blood — Thu, 05 Jan 2012 05:00:00 +0100

Deletions of chromosome 5q are associated with poor outcomes in acute myeloid leukemia (AML) suggesting the presence of tumor suppressor(s) at the locus. However, definitive identification of putative tumor suppressor genes remains controversial. Here we show that a 106-nucleotide noncoding RNA vault RNA2-1 (vtRNA2-1), previously misannotated as miR886, could potentially play a role in the biology and prognosis of AML. vtRNA2-1 is transcribed by polymerase III and is monoallelically methylated in 75% of healthy individuals whereas the remaining 25% of the population have biallelic hypomethylation. AML patients without methylation of VTRNA2-1 have a considerably better outcome than those with monoallelic or biallelic methylation (n = 101, P = .001). We show that methylation is inversely cor...

Generation of single-chain bispecific green fluorescent protein fusion antibodies for imaging of antibody-induced T cell synapses.

Analytical Biochemistry — Wed, 04 Jan 2012 05:00:00 +0100

Authors: Stamova S, Feldmann A, Cartellieri M, Arndt C, Koristka S, Apel F, Wehner R, Schmitz M, Bornhäuser M, von Bonin M, Ehninger G, Bartsch H, Bachmann M Abstract There is growing interest in the development of novel single-chain bispecific antibodies for retargeting of immune effector T cells to tumor cells. Until today, functional fusion constructs consisting of a single-chain bispecific antibody and a fluorescent protein were not reported. Such molecules could be useful for an in vivo visualization of this retargeting process. Recently, we established two novel single-chain bispecific antibodies. One is capable of retargeting T cells to CD33, and the other is capable of retargeting T cells to the prostate stem cell antigen (PSCA). CD33 is an attractive immunotarget on the s...

Autologous Stem Cell Transplantation in Follicular Lymphoma: a Systematic Review and Meta-analysis

JNCI — Tue, 03 Jan 2012 05:00:00 +0100

Conclusions Available evidence suggests that high-dose therapy and ASCT as part of FL initial treatment does not improve overall survival. Future trials of ASCT in the context of current chemoimmunotherapy approaches to FL are needed. (Source: JNCI)

Population pharmacokinetics of cytarabine, etoposide, and daunorubicin in the treatment for acute myeloid leukemia

Cancer Chemotherapy and Pharmacology — Mon, 02 Jan 2012 16:46:10 +0100

Conclusions Population-based models characterized the PK for all three drugs. bWBC was a significant covariate for etoposide and cytarabine and showed a trend for daunorubicin. Linking the significant bWBC relationships and the relationship between kidney function and etoposide clearance to clinical end points would support dose individualization. Patients with above-normal creatinine clearances and high bWBC may receive sub-optimal treatment due to elevated etoposide clearances. Content Type Journal ArticleCategory Original ArticlePages 1-9DOI 10.1007/s00280-011-1800-zAuthors Mikkel Krogh-Madsen, Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences, University of Copenhagen, Jagtvej 160, 2100 Copenhagen, DenmarkBrendan Bender, Departm...

[News] 53rd ASH annual meeting

The Lancet Oncology — Sun, 01 Jan 2012 05:00:00 +0100

Gemtuzumab ozogamicin (GO), an anti-CD33 monoclonal antibody linked to the cytotoxic agent chalicheamicin, was withdrawn from market in 2010 after results of SWOG S0106 raised concerns that it lacked efficacy and increased the risk of veno-occlusive disease (VOD). However, results of a randomised phase 3 trial presented by Sylvie Castaigne (Le Chesnay, France) and colleagues indicate that GO might still have a role in therapy for acute myeloid leukaemia (AML). Elderly patients were treated with standard induction and consolidation chemotherapy with or without the addition of GO, which was given in a fractionated dose at induction, over 3 days. (Source: The Lancet Oncology)

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FMS-Like Tyrosine Kinase 3 Internal Tandem Duplication and the Patterns of Its Gene Sequence in 207 Chinese Patients With De Novo Acute Myeloid Leukemia.

Archives of Pathology and Laboratory Medicine — Sun, 01 Jan 2012 05:00:00 +0100

Conclusion.-Detection of FLT3 mutation is fast, easy, and inexpensive. The mutant to wild-type ratio is helpful for performing detailed risk stratification. DNA sequence analysis is more precise for confirming and evaluating the mutation pattern. PMID: 22208491 [PubMed - in process] (Source: Archives of Pathology and Laboratory Medicine)

A hearty solution for acute myeloid leukemia.

Acta Pharmacologica Sinica — Sun, 01 Jan 2012 05:00:00 +0100

Authors: Hung YJ, Liu HE PMID: 22212427 [PubMed - in process] (Source: Acta Pharmacologica Sinica)

The corepressors BCOR and BCORL1: two novel players in acute myeloid leukemia.

Haematologica — Sun, 01 Jan 2012 05:00:00 +0100

Authors: Tiacci E, Grossmann V, Martelli MP, Kohlmann A, Haferlach T, Falini B PMID: 22210327 [PubMed - in process] (Source: Haematologica)

Disease‐stabilizing treatment with all‐trans retinoic acid and valproic acid in acute myeloid leukemia: Serum HSP70 and HSP90 levels and serum cytokine profiles are determined by the disease, patient age and antileukemic treatment

American Journal of Hematology — Sun, 01 Jan 2012 05:00:00 +0100

AbstractHeat shock protein (HSP) 70 and HSP90 are released by primary human acute myeloid leukemia (AML) cells during stress‐induced spontaneous in vitro apoptosis. The AML cells also show constitutive release of several cytokines, and the systemic serum levels of several soluble mediators are altered in patients with untreated AML. In the present study we investigated serum levels of HSP70/HSP90 and the serum cytokine profiles of patients with untreated AML and patients receiving AML‐stabilizing palliative treatment based on all‐trans retinoic acid (ATRA) plus valproic acid. Patients with untreated AML showed increased HSP90 levels and a distinct serum cytokine profile compared with healthy controls, and low pre‐therapy HSP90 levels were associated with a prolonged survival during...

Phase II study of 2‐chlorodeoxyadenosine plus idarubicin for children with acute myeloid leukaemia in first relapse: a Paediatric Oncology Group study

British Journal of Haematology — Sat, 31 Dec 2011 19:54:11 +0100

This study demonstrated that the novel combination of 2‐CDA/Ida was effective and should be considered for incorporation in front line therapy for children with AML. (Source: British Journal of Haematology)

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Distinctive microRNA signature is associated with the diagnosis and prognosis of acute leukemia

Medical Oncology — Fri, 30 Dec 2011 16:43:29 +0100

Abstract MicroRNAs (miRNAs) are of great importance in pathogenesis, diagnosis and prognosis of acute leukemia (AL). We studied five AL-related miRNAs to confirm the significance of these miRNAs in AL. Samples tested included acute myeloid leukemia (AML), 107 cases; acute lymphoblastic leukemia (ALL), 40 cases. Five AL-related miRNAs: miR-128, let-7b, miR-223, miR-181a and miR-155 expression were detected by qRT-PCR. Analysis showed that miRNA-128 expression was significantly higher in ALL (P < 0.001). However, the let-7b and miR-223 expressions in ALL were significantly lower than in AML (P < 0.001). Compared with normal controls, miR-128 expression was significantly higher in ALL (P < 0.001), but there was no significant difference in ...

Diffuse Osteosclerosis-Associated Acute Myeloid Leukemia [DIAGNOSIS IN ONCOLOGY]

Journal of Clinical Oncology — Thu, 29 Dec 2011 05:00:00 +0100

(Source: Journal of Clinical Oncology)

The role of Sirtuin 2 activation by nicotinamide phosphoribosyltransferase in the aberrant proliferation and survival of myeloid leukemia cells.

Haematologica — Thu, 29 Dec 2011 05:00:00 +0100

Conclusions. Our results provide strong evidence that NAMPT and SIRT2 participate in the aberrant proliferation and survival of leukemic cells, and suggest that the AKT/GSK-3β/β-catenin pathway is a target in FK866- and AC93253-induced inhibition of leukemia cell proliferation. PMID: 22207684 [PubMed - as supplied by publisher] (Source: Haematologica)

Targeting Ion Channels in Leukemias: A New Challenge for Treatment.

Current Medicinal Chemistry — Thu, 29 Dec 2011 05:00:00 +0100

Authors: Arcangeli A, Pillozzi S, Becchetti A Abstract Leukemias, as other cancers, bear several genetic alterations of tumor-related genes, such as point mutations, translocations, epigenetic modifications, often accompanied by gene amplification or inactivation. The identification of tumor-related genes provides considerable insight into the biology of leukemias and opens the way to more specific pharmacological treatments. These genes comprise several ion channels and pumps, as the transport mechanisms associated with volume control, proliferation and apoptosis are often altered in cancers. In leukemic cells, such changes are observed as early as the stem cell stage. Ion channels can regulate other malignant features, such as lack of differentiation, increased migratory and inva...

Molecular and genetic features of myelodysplastic syndromes

Clinical and Laboratory Haematology — Wed, 28 Dec 2011 13:53:50 +0100

SummaryMultifactorial pathogenetic features underlying myelodysplastic syndromes (MDS) relate to inherent abnormalities within the hematopoietic precursor cell population. The predominant final common pathogenetic pathway causing ineffective hematopoiesis in MDS has been the varying degrees of apoptosis of the hematopoietic precursors and their progeny. A variety of molecular abnormalities have been demonstrated in MDS. These lesions are attributable to nonrandom cytogenetic and oncogenic mutations, indicative of chromosomal and genetic instability, transcriptional RNA splicing abnormalities, and epigenetic changes. Evolutionary cytogenetic changes may occur during the course of the disorder, which are associated with disease progression. These genetic derangements reflect a multistep proc...

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Phosphorylation of serine 21 modulates the proliferation inhibitory more than the differentiation inducing effects of C/EBPα in K562 cells

Journal of Cellular Biochemistry — Wed, 28 Dec 2011 05:00:00 +0100

AbstractThe CCAAT/Enhancer binding protein α (C/EBPα) is a transcription factor required for differentiation of myeloid progenitors. In acute myeloid leukemia (AML) cells expressing the constitutively active FLT3‐ITD receptor tyrosine kinase, MAP kinase‐dependent phosphorylation of serine 21 (S21) inhibits the ability of C/EBPα to induce granulocytic differentiation To assess whether this post‐translational modification also modulates the activity of C/EBPα in BCR/ABL‐expressing cells, we tested the biological effects of wild type and mutant C/EBPα mimicking phosphorylated or non–phosphorylatable serine 21 (S21D and S21A, respectively) in K562 cells ectopically expressing tamoxifen‐regulated C/EBPα‐ER chimeric proteins.We show here that S21D C/EBPα‐ER induced termi...

Breast cancer in a case of Shwachman Diamond syndrome

Pediatric Blood and Cancer — Tue, 27 Dec 2011 05:00:00 +0100

We report a novel case of a solid tumor in a patient with SDS and biallelic mutations in the Shwachman Bodian Diamond Syndrome gene (SBDS). Whether the development of breast cancer in this patient is due to SDS or an isolated case due to unknown factors requires further study. Pediatr Blood Cancer © 2011 Wiley Periodicals, Inc. (Source: Pediatric Blood and Cancer)

Acquisition of a BCR-ABL1 Transcript in a Patient with Disease Progression from MDS with Fibrosis to AML with Myelodysplasia-Related Changes.

Annals of Clinical and Laboratory Science — Fri, 23 Dec 2011 21:54:02 +0100

We report the case of a 66-year-old male patient diagnosed with refractory anemia with excess blasts-2 with fibrosis (MDS RAEB-2-F) with a normal karyotype and negative findings for both BCR-ABL1 transcript and JAK2 V617F mutations. He refused therapy upon his diagnosis and, after 5 months, his disease progressed to leukemia. The patient was diagnosed with acute myeloid leukemia with myelodysplasia-related changes (AML-MRC), based on a bone marrow exam revealing increased blasts (32.8%). Cytogenetic study revealed a complex karyotype, and molecular studies identified a minor BCRABL1 fusion transcript. The patient's general condition deteriorated despite the initiation of induction chemotherapy, and he died approximately 2 weeks after the diagnosis of AML-MRC. This patient's poor clinical o...

Lymphodepletion is permissive to the development of spontaneous T-cell responses to the self-antigen PR1 early after allogeneic stem cell transplantation and in patients with acute myeloid leukemia undergoing WT1 peptide vaccination following chemotherapy

Cancer Immunology, Immunotherapy — Fri, 23 Dec 2011 16:51:28 +0100

Abstract PR1, an HLA-A*0201 epitope shared by proteinase-3 (PR3) and elastase (ELA2) proteins, is expressed in normal neutrophils and overexpressed in myeloid leukemias. PR1-specific T cells have been linked to graft-versus-leukemia (GVL) effect. We hypothesized that lymphopenia induced by chemo-radiotherapy can enhance weak autoimmune responses to self-antigens such as PR1. We measured PR1-specific responses in 27 patients 30–120 days following allogeneic stem cell transplant (SCT) and correlated these with ELA2 and PR3 expression and minimal residual disease (MRD). Post-SCT 10/13 CML, 6/9 ALL, and 4/5 solid tumor patients had PR1 responses correlating with PR3 and ELA2 expression. At day 180 post-SCT, 8/8 CML patients with PR1 responses were BCR-ABL-negative compar...

Gemtuzumab Boosts Survival in AMLGemtuzumab Boosts Survival in AML

Medscape Today Headlines — Fri, 23 Dec 2011 15:39:20 +0100

Dr. Richard Stone reports on new findings in acute myeloid leukemia as presented at ASH 2011. Medscape Hematology-Oncology (Source: Medscape Today Headlines)

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Natural history of transient myeloproliferative disorder clinically diagnosed in Down syndrome neonates: a report from the Children's Oncology Group Study A2971

Blood — Thu, 22 Dec 2011 05:00:00 +0100

Transient myeloproliferative disorder (TMD), restricted to newborns with trisomy 21, is a megakaryocytic leukemia that although lethal in some is distinguished by its spontaneous resolution. Later development of acute myeloid leukemia (AML) occurs in some. Prospective enrollment (n = 135) elucidated the natural history in Down syndrome (DS) patients diagnosed with TMD via the use of uniform monitoring and intervention guidelines. Prevalent at diagnosis were leukocytosis, peripheral blast exceeding marrow blast percentage, and hepatomegaly. Among those with life-threatening symptoms, most (n = 29/38; 76%) received intervention therapy until symptoms abated and then were monitored similarly. Organomegaly with cardiopulmonary compromise most frequently led to intervention (43%). Death occurre...

ASXL1 mutations identify a high-risk subgroup of older patients with primary cytogenetically normal AML within the ELN Favorable genetic category

Blood — Thu, 22 Dec 2011 05:00:00 +0100

The associations of mutations in the enhancer of trithorax and polycomb family gene ASXL1 with pretreatment patient characteristics, outcomes, and gene-/microRNA-expression profiles in primary cytogenetically normal acute myeloid leukemia (CN-AML) are unknown. We analyzed 423 adult patients for ASXL1 mutations, other prognostic gene mutations, and gene-/microRNA-expression profiles. ASXL1 mutations were 5 times more common in older (≥ 60 years) patients (16.2%) than those younger than 60 years (3.2%; P < .001). Among older patients, ASXL1 mutations associated with wild-type NPM1 (P < .001), absence of FLT3-internal tandem duplications (P = .002), mutated CEBPA (P = .01), and with inferior complete remission (CR) rate (P = .04), disease-free survival (DFS; P = .03), overall surviva...

ALDH, CA I, and CD2AP: Novel, Diagnostically Useful Immunohistochemical Markers to Identify Erythroid Precursors in Bone Marrow Biopsy Specimens.

American Journal of Clinical Pathology — Tue, 20 Dec 2011 15:15:07 +0100

Authors: Rollins-Raval MA, Fuhrer K, Marafioti T, Roth CG Abstract Neoplastic erythroid proliferations may represent a diagnostic challenge owing to the difficulty in characterizing immature erythroblasts. Immunohistochemical expression of aldehyde dehydrogenase (ALDH), carbonic anhydrase isoenzyme I (CA I), and CD2-associated protein (CD2AP) was assessed in 66 bone marrow biopsy specimens and compared with glycophorin A and E-cadherin. ALDH, CA I, and CD2AP labeled neoplastic erythroblasts in most acute erythroid leukemias (AELs) and myelodysplasias and highlighted benign erythroid precursors within normal marrows, erythroid hyperplasias, acute lymphoblastic leukemias (ALLs), blastic plasmacytoid dendritic cell neoplasm, and most acute myeloid leukemias (AMLs). In 2 AELs, CD2AP wa...

NRP-1/CD304 Expression in Acute Leukemia: A Potential Marker for Minimal Residual Disease Detection in Precursor B-Cell Acute Lymphoblastic Leukemia.

American Journal of Clinical Pathology — Tue, 20 Dec 2011 15:14:56 +0100

Authors: Meyerson HJ, Blidaru G, Edinger A, Osei E, Schweitzer K, Fu P, Ho L Abstract Neuropilin-1 (NRP-1)/CD304 is a marker for plasmacytoid dendritic cells. We determined the distribution of NRP-1/CD304 expression on normal hematopoietic cells and in 167 acute leukemias by flow cytometry. NRP-1/CD304 surface expression was frequent in precursor B-cell acute lymphoblastic leukemia (36/51 [71%]) and uncommon in acute myeloid leukemia (22.9%). In acute myeloid leukemia, expression was noted in all (4/4) acute myeloid leukemias with the M4eo subtype and in 50% of specimens (6/12) with complex cytogenetics. On hematopoietic cells, NRP-1/CD304 was expressed on normal erythroid progenitors, plasma cells, and B-cell progenitors, as well as plasmacytoid dendritic cells. Expression was not...

Clues That Could Improve Therapy Revealed By First Comprehensive DNA Study Of Mast Cell Leukemia

Health News from Medical News Today — Tue, 20 Dec 2011 08:00:00 +0100

Cancer researchers at Cold Spring Harbor Laboratory (CSHL) have carried out the first comprehensive study of the changes seen in the DNA of a patient with mast cell leukemia (MCL), an extremely aggressive subtype of acute myeloid leukemia (AML) with a very poor prognosis. Their genomic survey has helped identify two previously unknown mutations that could directly influence patient response to currently available therapeutic drugs... (Source: Health News from Medical News Today)

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Acute myeloid leukemia: 2012 update on diagnosis, risk stratification, and management

American Journal of Hematology — Mon, 19 Dec 2011 10:31:00 +0100

AbstractDisease Overview: Acute myeloid leukemia (AML) results from accumulation of abnormal immature cells in the marrow. These cells interfere with normal hematopoiesis can escape into the blood and infiltrate lung and CNS. The most common cause of death is bone marrow failure. It is likely that many different mutations and/or epigenetic aberrations can produce the same disease, with these differences responsible for the very variable response to therapy, which is AML's principal clinical feature.Diagnosis: This rests on demonstration that the marrow or blood has >20% blasts of myeloid lineage. Blast lineage is assessed by multiparameter flow cytometry with CD33 and CD13 being surface markers typically expressed by myeloid blasts. It should be realized that clinical/prognostic conside...

Development of an Oral Form of Azacytidine: 2′3′5′Triacetyl-5-Azacytidine

Clinical and Developmental Immunology — Sun, 18 Dec 2011 23:53:19 +0100

This study evaluated 2′,3′,5′-triacetyl-5-azacitidine (TAC) as a potential prodrug for azacitidine. The prodrug demonstrated significant pharmacokinetic improvements in bioavailability, solubility, and stability over the parent compound. In vivo analyses indicated a lack of general toxicity coupled with significantly improved survival. Pharmacodynamic analyses confirmed its ability to suppress global methylation in vivo. These data indicate that esterified nucleoside derivatives may be effective prodrugs for azacitidine and encourages further investigation of TAC into its metabolism, activity, and possible clinical evaluation. (Source: Clinical and Developmental Immunology)

First comprehensive DNA study of mast cell leukemia uncovers clues that could improve therapy

ScienceDaily Headlines — Fri, 16 Dec 2011 16:28:28 +0100

Cancer researchers have carried out the first comprehensive study of the changes seen in the DNA of a patient with mast cell leukemia, an extremely aggressive subtype of acute myeloid leukemia with a very poor prognosis. Their genomic survey has helped identify two previously unknown mutations that could directly influence patient response to currently available therapeutic drugs. (Source: ScienceDaily Headlines)

Quizartinib Monotherapy Produces Response in Both Relapsed and Refractory FLT3-ITD–Positive Acute Myeloid Leukemia

Clinical Care Options Oncology - Leukemia — Fri, 16 Dec 2011 11:51:13 +0100

Capsule Summary - Quizartinib achieved clinically meaningful responses in patients with refractory FLT3-ITD–positive AML, including CRs in 40% and transition to HSCT in 21%. (Source: Clinical Care Options Oncology - Leukemia)

First comprehensive DNA study of mast cell leukemia uncovers clues that could improve therapy

EurekAlert! - Medicine and Health — Fri, 16 Dec 2011 05:00:00 +0100

(Cold Spring Harbor Laboratory) Cancer researchers at Cold Spring Harbor Laboratory have carried out the first comprehensive study of the changes seen in the DNA of a patient with mast cell leukemia, an extremely aggressive subtype of acute myeloid leukemia with a very poor prognosis. Their genomic survey has helped identify two previously unknown mutations that could directly influence patient response to currently available therapeutic drugs. (Source: EurekAlert! - Medicine and Health)

Activity of Alemtuzumab in Acute Myelogenous Leukemia and Myelodysplastic Syndrome With Chromosome 7 Aberrations [CORRESPONDENCE]

Journal of Clinical Oncology — Fri, 16 Dec 2011 05:00:00 +0100

(Source: Journal of Clinical Oncology)

Prognosis of acute myeloid leukemia harboring monosomal karyotype in patients treated with or without allogeneic hematopoietic cell transplantation after achieving complete remission.

Haematologica — Fri, 16 Dec 2011 05:00:00 +0100

Authors: Yanada M, Kurosawa S, Yamaguchi T, Yamashita T, Moriuchi Y, Ago H, Takeuchi J, Nakamae H, Taguchi J, Sakura T, Takamatsu Y, Waki F, Yokoyama H, Watanabe M, Emi N, Fukuda T Abstract To evaluate the prognostic impact of monosomal karyotype on post-remission outcome in acute myeloid leukemia, we retrospectively analyzed 2,099 patients who had achieved complete remission. Monosomal karyotype was noted in 73 patients (4%). Of them, the probability of overall survival from first complete remission was 14% at 4 years, which was significantly inferior to that in patients without monosomal karyotype, primarily due to a high relapse rate of 86%. Monosomal karyotype remained significantly associated with worse overall survival among patients with unfavorable cytogenetics or complex k...

Acute myeloid leukemia developing in patients with autoimmune diseases.

Haematologica — Fri, 16 Dec 2011 05:00:00 +0100

This article will review the data available on acute myeloid leukemia developing in patients with autoimmune diseases. Possible leukemogeneic mechanisms in these patients as well as evidence supporting the association of their primary immunosuppressive status and their exposure to specific therapies will be reviewed as well. This review also supports the idea that it may be misleading to label leukemias that develop in patients with autoimmune diseases who are exposed to cytotoxic agents as therapy related leukemias. A better understanding of the molecular defects in autoimmune disease patients who develop acute leukemia will lead to a thorough appreciation of the association between these two diseases entities. PMID: 22180424 [PubMed - as supplied by publisher] (Source: Haematologica)

Recurrent Pericarditis after Chemotherapy for Acute Myeloid Leukemia: A Case Report and a Modern Approach to Chemotherapy-Induced Pericarditis

Karger Publishers — Thu, 15 Dec 2011 23:00:00 +0100

Cardiology 2011;120:130–134 (DOI:10.1159/000333418) (Source: Karger Publishers)

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Secreted-frizzled related protein 1 is a transcriptional repression target of the t(8;21) fusion protein in acute myeloid leukemia

Blood — Thu, 15 Dec 2011 05:00:00 +0100

In this study, we examined SFRP1, SFRP2, SFRP4, and SFRP5 promoter methylation in 83 patients with AML (59 children and 24 adults) and found preferential SFRP1 methylation and mRNA down-regulation in the prognostically favorable subgroup of AML with t(8;21) translocation. Among the 4 genes, SFRP1 methylation independently predicted prolonged event-free and relapse-free survivals in childhood patients with nonacute promyelocytic leukemia with nonadverse cytogenetics. Mechanistically, we further demonstrated that RUNX1-ETO, the t(8;21) fusion product, specifically bound the SFRP1 promoter and repressed its transcription via a consensus RUNX binding site. In t(8;21)–leukemia cells, SFRP1 selectively inhibited canonical Wnt signaling and cellular proliferation that were associated with c...

MicroRNA-130a-mediated down-regulation of Smad4 contributes to reduced sensitivity to TGF-{beta}1 stimulation in granulocytic precursors

Blood — Thu, 15 Dec 2011 05:00:00 +0100

Smad4 is important in the TGF-β pathway and required for transcriptional activation and inhibition of cell growth after TGF-β1 stimulation. We demonstrate that miR-130a is differentially expressed during granulopoiesis and targets Smad4 mRNA. The transcript for Smad4 is present throughout neutrophil maturation, but Smad4 protein is undetectable in the most immature cells, where miR-130a is highly expressed. Two miR-130a binding sites were identified in the 3'-untranslated region of the Smad4 mRNA. Overexpression of miR-130a in HEK293, A549, and 32Dcl3 cells repressed synthesis of Smad4 protein without affecting Smad4 mRNA level. Repression of Smad4 synthesis in a granulocytic cell line by miR-130a reduced its sensitivity to TGF-β1–induced growth inhibition. This effect...

Erythroleukemia presenting with myeloid sarcoma of the lung as detected by immunophenotypic analysis of bronchoalveolar lavage fluid

Leukemia Research — Thu, 15 Dec 2011 05:00:00 +0100

We report an erythroid/myeloid AEL subtype presenting with pulmonary MS, as detected by BALF immunophenotype. (Source: Leukemia Research)

Atraumatic splenic rupture in patients with myelodysplastic syndromes: Report of a case occurred during treatment with 5-azacitidine and review of the literature

Leukemia Research — Thu, 15 Dec 2011 05:00:00 +0100

A 62-year old Caucasian woman with a previous history of arterial hypertension, dilative cardiomyopathy and cerebral transient ischemic attack, was admitted to our Department because of marked fatigue, in the absence of fever or hemorrhage. The complete blood count (CBC) revealed pancytopenia, with white blood cell (WBC) count 0.8×109/L in the absence of circulating blasts, hemoglobin (Hb) level 5.4g/dl and platelet (Plt) count 78×109/L, without signs of coagulopathy. Neither hepatomegaly nor splenomegaly were observed on abdominal ultrasonography. The morphological, cytochemical and immunophenotypic analyses performed on peripheral blood and bone marrow aspirate and trephine biopsy documented features consistent with a myelodysplastic syndrome (MDS). Conventional G-banding showed a norm...

Transformation of a Chronic Myeloproliferative Neoplasm to Acute Myelogenous Leukemia: Does Anything Work?

Current Hematologic Malignancy Reports — Wed, 14 Dec 2011 16:41:01 +0100

Abstract The BCR/ABL-negative myeloproliferative neoplasms (MPNs) of essential thrombocythemia, polycythemia vera, and primary myelofibrosis, over the natural course of their disease, have an increasing predisposition to transform to overt acute myeloid leukemia (AML)—most appropriately referred to as MPN-blast phase (MPN-BP). Although this transformation is a rare event, once AML has occurred, it is associated with a poor response to therapy and short survival. The molecular events leading to transformation are poorly defined. Currently, no therapy other than allogeneic stem cell transplantation (ASCT) has been demonstrated to alter the natural history of this disease. Multiple therapeutic investigations are currently ongoing, including early ASCT, hypomethylating agent...

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A High Risk Of Recurrence In Some Older Acute-Leukemia Patients Signaled By Gene Mutation

Health News from Medical News Today — Wed, 14 Dec 2011 08:00:00 +0100

Older people with acute myeloid leukemia and normal looking chromosomes in their cancer cells have a higher risk of recurrence if they have mutations in a gene called ASXL1, according to a new study by researchers at the Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James). The study is the first to investigate the influence of these gene mutations on prognosis in patients with cytogenetically normal acute myeloid leukemia (CN-AML), and in conjunction with other prognostic gene mutations... (Source: Health News from Medical News Today)

AML Patients Have High Response Rate with Vorinostat Added to Treatment

M. D. Anderson Cancer Center - News Releases — Wed, 14 Dec 2011 05:00:00 +0100

Association of Janus kinase 2 (JAK2) polymorphisms with acute leukemia susceptibility.

International Journal of Laboratory Hematology — Wed, 14 Dec 2011 05:00:00 +0100

Conclusion: The results indicate that the risk of acute leukemia might be associated with JAK2 polymorphisms. PMID: 22168550 [PubMed - as supplied by publisher] (Source: International Journal of Laboratory Hematology)

ASH: Gemtuzumab—A Potential New Use for an Old Drug in AML

Cancer Network — Tue, 13 Dec 2011 12:00:00 +0100

The phase III trial comparing the use of gemtuzumab ozogamicin combined with chemotherapy to chemotherapy alone in newly diagnosed acute myeloid leukemia (AML) patients provides evidence that the combination treatment may be promising in this patient population. (Source: Cancer Network)

A Two-Faced Leukemia?

Health News from Medical News Today — Tue, 13 Dec 2011 11:00:00 +0100

One kind of leukemia sometimes masquerades as another, according to a study published online this week in the Journal of Experimental Medicine*. Leukemia results when normal immune cells accumulate mutations that drive uncontrolled growth. T cell acute lymphoblastic leukemia (T-ALL) derives from immature T cells, whereas acute myeloid leukemia (AML) comes from myeloid cells. Only 50% of adult T-ALL patients can be cured, and a team led by Adolfo Ferrando at Columbia University Institute for Cancer Genetics is trying to understand why... (Source: Health News from Medical News Today)

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Expression profile of heat shock proteins in acute myeloid leukaemia patients reveals a distinct signature strongly associated with FLT3 mutation status – consequences and potentials for pharmacological intervention

British Journal of Haematology — Tue, 13 Dec 2011 10:37:24 +0100

SummaryHeat shock proteins (HSPs) are molecular chaperones that assist proteins in their folding to native structures. HSPs are regarded as possible therapeutic targets in acute myeloid leukaemia (AML). We used bioinformatical approaches to characterize the HSP profile in AML cells from 75 consecutive patients, in addition to the effect of the HSP90 inhibitor 17‐DMAG. Patients harbouring a FLT3‐internal tandem duplication (FLT3‐ITD) were extensively overrepresented in the cluster with high HSP levels, indicating a strong dependence of HSPs in stabilizing FLT3‐ITD encoded oncoproteins. FLT3 ligation further increased the levels of HSP90 and its co‐chaperone HSP70. HSP90 inhibition had a stronger pro‐apoptotic effect for AML cells with FLT3‐ITD than for cells with wild‐type F...

AML Patients Have High Response Rate With Vorinostat Added To Treatment

Health News from Medical News Today — Tue, 13 Dec 2011 09:00:00 +0100

Adding a drug that activates genes to frontline combination therapy for acute myeloid leukemia resulted in an 85 percent remission rate after initial treatment, researchers at The University of Texas MD Anderson Cancer Center reported at the 53rd Annual Meeting of the American Society of Hematology. Results of the Phase II clinical trial of 75 patients set the stage for a national Phase III clinical trial of the new combination compared to standard-of-care frontline combinations used at MD Anderson and elsewhere, said study leader Guillermo Garcia-Manero, M.D... (Source: Health News from Medical News Today)

Long-term WT1 peptide vaccination for patients with acute myeloid leukemia with minimal residual disease

Leukemia — Tue, 13 Dec 2011 05:00:00 +0100

Authors: A Tsuboi, Y Oka, T Kyo, Y Katayama, O A Elisseeva, M Kawakami, S Nishida, S Morimoto, A Murao, H Nakajima, N Hosen, Y Oji & H Sugiyama (Source: Leukemia)

Serotype-specific pneumococcal antibody concentrations in children treated for acute leukaemia

Archives of Disease in Childhood — Tue, 13 Dec 2011 05:00:00 +0100

Children treated for acute leukaemia are at increased risk of infection with Streptococcus pneumoniae. The basis for this may include low levels of pneumococcal antibody but this has not been well studied. The authors measured serotype-specific pneumococcal IgG antibody concentrations in children treated for acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) ≥6 months after completion of standard-dose chemotherapy. Pneumococcal serotype-specific IgG antibody concentrations were low. None of the subjects had protective concentrations against all the heptavalent-pneumococcal conjugate vaccine serotypes. There was no significant difference in antibody concentrations between subjects with ALL and AML (p≥0.05). Children treated for ALL and AML generally have non-protect...

Clofarabine in the Treatment of Newly Diagnosed Acute Myeloid Leukemia in Older Adults (January).

The Annals of Pharmacotherapy — Tue, 13 Dec 2011 05:00:00 +0100

CONCLUSIONS:Based on published data, adverse effect profiles, and cost, clofarabine may be an appropriate alternative to intensive chemotherapy regimens in certain subsets of older patients with newly diagnosed AML. These include patients with a baseline decreased performance status or history of cardiovascular disease who may not tolerate anthracyclines, which are typically a component of most intensive chemotherapy regimens. Additional randomized controlled trials are needed to directly compare the efficacy of clofarabine with that of intensive chemotherapy regimens and to evaluate the potential benefit of combining clofarabine with cytarabine. PMID: 22170975 [PubMed - as supplied by publisher] (Source: The Annals of Pharmacotherapy)

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Single-cell Pharmacodynamic Monitoring of S6 Ribosomal Protein Phosphorylation in AML Blasts During a Clinical Trial Combining the mTOR Inhibitor Sirolimus and Intensive Chemotherapy.

Clinical Cancer Research — Tue, 13 Dec 2011 05:00:00 +0100

CONCLUSIONS: The methodology described is rapid and reproducible. We demonstrate the feasibility of real-time, direct pharmacodynamic monitoring by flow cytometry during clinical trials combining intensive chemotherapy and signal transduction inhibitors. This approach greatly clarifies pharmacokinetic/pharmacodynamic relationships and has broad application to pre-clinical and clinical testing of drugs whose direct or downstream effects disrupt PI3K/AKT/mTOR signaling. PMID: 22167413 [PubMed - as supplied by publisher] (Source: Clinical Cancer Research)

Cancer-Related Pathway Reveals Potential Treatment Target For Rare Pediatric Disease Cherubism

Health News from Medical News Today — Mon, 12 Dec 2011 08:00:00 +0100

Cancer researchers studying genetic mutations that cause leukemia have discovered a connection to the rare disease cherubism, an inherited facial bone disorder in children. The link is the enzyme Tankyrase and its pivotal role in switching on or off the protein that controls two known cancer genes. In normal cells, the protein is vital for bone development. In abnormal cells, it is thought to be involved in two common types of blood cancer - chronic myelogenous leukemia and acute myeloid leukemia. The findings, published online today in CELL (DOI: 10.1016/j.cell.2011.10... (Source: Health News from Medical News Today)

AML patients have high response rate with vorinostat added to treatment

EurekAlert! - Cancer — Mon, 12 Dec 2011 05:00:00 +0100

(University of Texas M. D. Anderson Cancer Center) Adding a drug that activates genes to frontline combination therapy for acute myeloid leukemia resulted in an 85 percent remission rate after initial treatment, researchers at the University of Texas MD Anderson Cancer Center reported at the 53rd Annual Meeting of the American Society of Hematology. (Source: EurekAlert! - Cancer)

Gene mutation signals a high risk of recurrence in some older acute-leukemia patients

EurekAlert! - Cancer — Mon, 12 Dec 2011 05:00:00 +0100

(Ohio State University Medical Center) Older people with acute myeloid leukemia and normal looking chromosomes in their cancer cells have a higher risk of recurrence if they have mutations in the ASXL1gene, according to a new study. The study is the first to investigate the influence of these gene mutations on prognosis in these patients and in conjunction with other prognostic gene mutations. The findings could lead to more effective targeted therapies and improved cure rates for these patients. (Source: EurekAlert! - Cancer)

Erythroid proliferations in myeloid neoplasms

Human Pathology — Mon, 12 Dec 2011 05:00:00 +0100

Summary: Prominent erythroid proliferations (in which erythroid elements comprise ≥50% of total bone marrow cells) can be seen in various hematopoietic stem cell neoplasms. The myeloproliferative neoplasm polycythemia vera exhibits effective, overexuberant erythropoiesis resulting in an increased red blood cell mass; in contrast, most other diseases characterized by erythroid predominance exhibit ineffective hemopoiesis. The latter include acute erythroid leukemia (erythroid-myeloid and pure erythroid leukemia subtypes) as well as some cases of myelodysplastic syndromes, acute myeloid leukemia with myelodysplasia-related changes, and therapy-related myeloid neoplasms. Some nonneoplastic reactive conditions may also manifest a striking bone marrow erythroid predominance. In this article, ...

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ASH: Gemtuzumab Gets New Look in AML (CME/CE)

MedPage Today Hematology/Oncology — Sun, 11 Dec 2011 18:12:19 +0100

SAN DIEGO (MedPage Today) -- Oncologists are re-evaluating gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukemia, with new results presented here suggesting its 2010 withdrawal from the market may have been premature. (Source: MedPage Today Hematology/Oncology)

Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes

Nature Genetics — Sun, 11 Dec 2011 05:00:00 +0100

Authors: Timothy A Graubert, Dong Shen, Li Ding, Theresa Okeyo-Owuor, Cara L Lunn, Jin Shao, Kilannin Krysiak, Christopher C Harris, Daniel C Koboldt, David E Larson, Michael D McLellan, David J Dooling, Rachel M Abbott, Robert S Fulton, Heather Schmidt, Joelle Kalicki-Veizer, Michelle O'Laughlin, Marcus Grillot, Jack Baty, Sharon Heath, John L Frater, Talat Nasim, Daniel C Link, Michael H Tomasson, Peter Westervelt, John F DiPersio, Elaine R Mardis, Timothy J Ley, Richard K Wilson & Matthew J Walter Myelodysplastic syndromes (MDS) are hematopoietic stem cell disorders that often progress to chemotherapy-resistant secondary acute myeloid leukemia (sAML). We used whole-genome sequencing to perform an unbiased comprehensive screen to discover the somatic mutations in a sample from an ind...

ETV6 rearrangements are recurrent in myeloid malignancies and are frequently associated with other genetic events

Genes, Chromosomes and Cancer — Sat, 10 Dec 2011 01:42:03 +0100

AbstractETV6 (TEL) rearrangements are favorable in pediatric acute lymphoblastic leukemia but are less well characterized in myeloid malignancies. We investigated 9,550 patients with myeloid disorders for ETV6 rearrangements by chromosome banding analysis and interphase fluorescence in situ hybridization. ETV6 rearrangements were identified in 51 of 9,550 (0.5%) patients (range, 19.2–85.3 years). Frequencies were in detail: acute myeloid leukemia (AML): 40 of 3,798, 1.1%; myelodysplastic syndromes (MDS): 6 of 3,375, 0.2%; myeloproliferative neoplasms (MPNs): 5 of 1,720, 0.3%; MDS/MPN: 0 of 210; and chronic myelomonocytic leukemia: 0 of 447. Thirty‐three different partner bands of ETV6 were identified, and most were recurrent: 3q26 (n = 10), 5q33 (n = 4), 17q11 (n = 3), 22q12 (n = 3), 5...

Data and Safety Monitoring Board Recommends Continuation of Sunesis Pharmaceuticals' VALOR Trial Based on Periodic Safety Review

Medical News (via PRIMEZONE) — Fri, 09 Dec 2011 12:06:00 +0100

SOUTH SAN FRANCISCO, Calif., Dec. 9, 2011 (GLOBE NEWSWIRE) -- Sunesis Pharmaceuticals, Inc. (Nasdaq:SNSS) today announced that the independent Data and Safety Monitoring Board (DSMB) for the VALOR trial has completed a planned periodic safety review and recommended that the trial continue as planned without changes to study conduct. The VALOR trial is a Phase 3, randomized, double-blind, placebo-controlled, pivotal trial of vosaroxin, the Company's lead product candidate, in patients with first relapsed or refractory acute myeloid leukemia (AML). (Source: Medical News (via PRIMEZONE))

Prognostic factors for acute myeloid leukemia patients with t(6;9)(p23;q34) who underwent an allogeneic hematopoietic stem cell transplant

Leukemia — Fri, 09 Dec 2011 05:00:00 +0100

Authors: K Ishiyama, A Takami, Y Kanda, S Nakao, M Hidaka, T Maeda, T Naoe, S Taniguchi, K Kawa, T Nagamura, K Tabuchi, Y Atsuta & H Sakamaki (Source: Leukemia)

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The role of body mass index and other body composition parameters in early post-transplant complications in patients undergoing allogeneic stem cell transplantation with busulfan-cyclophosphamide conditioning.

International Journal of Hematology — Fri, 09 Dec 2011 05:00:00 +0100

This study was conducted to determine whether body mass index (BMI) and other body composition parameters, such as lean body mass index (LBMI) and body fat mass (BFM), are associated with early post-transplantation toxicity and mortality in allogeneic HSCT recipients. The records of 71 patients diagnosed with acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), or myelodysplastic leukemia (MDS) who had undergone allogeneic HSCT with a conditioning regimen of busulfan-cyclophosphamide (Bu-Cy), between September 2003 and January 2009 at the Stem Cell Transplantation Unit of Gazi University Hospital were retrospectively evaluated. BMI was found to be negatively correlated with the NCI grade of mucositis, cardiotoxicity, emesis, and hyperglycemia, a...

Adverse Prognostic Impact of Abnormal Lesions Detected by Genome-Wide Single Nucleotide Polymorphism Array-Based Karyotyping Analysis in Acute Myeloid Leukemia With Normal Karyotype [Hematologic Malignancies]

Journal of Clinical Oncology — Thu, 08 Dec 2011 05:00:00 +0100

Conclusion Our data demonstrated that abnormal SNP lesions detected by SNP-A karyotyping might indicate an adverse prognosis in patients with AML-NK, thus requiring a more sophisticated treatment strategy for improvement of treatment outcomes. (Source: Journal of Clinical Oncology)

De Novo polycythaemia vera arising 5 years following acute myeloid leukemia remission: suggestion of a chemotherapy resistant JAK2 clone

British Journal of Haematology — Thu, 08 Dec 2011 05:00:00 +0100

(Source: British Journal of Haematology)

Clinical significance of SF3B1 mutations in myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms

Blood — Thu, 08 Dec 2011 05:00:00 +0100

In a previous study, we identified somatic mutations of SF3B1, a gene encoding a core component of RNA splicing machinery, in patients with myelodysplastic syndrome (MDS). Here, we define the clinical significance of these mutations in MDS and myelodysplastic/myeloproliferative neoplasms (MDS/MPN). The coding exons of SF3B1 were screened using massively parallel pyrosequencing in patients with MDS, MDS/MPN, or acute myeloid leukemia (AML) evolving from MDS. Somatic mutations of SF3B1 were found in 150 of 533 (28.1%) patients with MDS, 16 of 83 (19.3%) with MDS/MPN, and 2 of 38 (5.3%) with AML. There was a significant association of SF3B1 mutations with the presence of ring sideroblasts (P < .001) and of mutant allele burden with their proportion (P = .002). The mutant gene had a positiv...

NUP98 gene fusions and hematopoietic malignancies: common themes and new biologic insights

Blood — Thu, 08 Dec 2011 05:00:00 +0100

Structural chromosomal rearrangements of the Nucleoporin 98 gene (NUP98), primarily balanced translocations and inversions, are associated with a wide array of hematopoietic malignancies. NUP98 is known to be fused to at least 28 different partner genes in patients with hematopoietic malignancies, including acute myeloid leukemia, chronic myeloid leukemia in blast crisis, myelodysplastic syndrome, acute lymphoblastic leukemia, and bilineage/biphenotypic leukemia. NUP98 gene fusions typically encode a fusion protein that retains the amino terminus of NUP98; in this context, it is important to note that several recent studies have demonstrated that the amino-terminal portion of NUP98 exhibits transcription activation potential. Approximately half of the NUP98 fusion partners encode homeodoma...

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Down-regulation of the RUNX1-target gene NR4A3 contributes to hematopoiesis deregulation in familial platelet disorder/acute myelogenous leukemia

Blood — Thu, 08 Dec 2011 05:00:00 +0100

RUNX1 encodes a DNA-binding α subunit of the core-binding factor, a heterodimeric transcription factor. RUNX1 is a master regulatory gene in hematopoiesis and its disruption is one of the most common aberrations in acute leukemia. Inactivating or dominant-negative mutations in the RUNX1 gene have been also identified in pedigrees of familial platelet disorders with a variable propensity to develop acute myeloid leukemia (FPD/AML). We performed analysis of hematopoiesis from 2 FPD/AML pedigrees with 2 distinct RUNX1 germline mutations, that is, the R139X in a pedigree without AML and the R174Q mutation in a pedigree with AML. Both mutations induced a marked increase in the clonogenic potential of immature CD34+CD38– progenitors, with some self-renewal capacities observed only fo...

Early implementation of antifungal therapy in the management of febrile neutropenia is associated with favourable outcome during induction chemotherapy for acute leukaemias

Internal Medicine Journal — Thu, 08 Dec 2011 05:00:00 +0100

ABSTRACTMortality related to induction chemotherapy during the treatment of acute leukaemias (AL) has been estimated at 5‐20%, and this increases with age. Fungal infection remains one of the major causes of morbidity and mortality and is considered an obstacle to the successful management of acute leukaemias.We retrospectively analysed all patients treated for acute leukaemias at a single institution between July 2006 and January 2009, to assess the impact of early antifungal therapy on outcome during induction chemotherapy. There were 44 episodes of induction chemotherapy, with a median age of patients of 61 years (range 18‐81), including 29 patients with acute myeloid leukaemia, 9 with acute lymphoblastic leukaemia, and 6 with relapsed AL. The median age was 61 years (range 18‐81)...

Synergism between arsenite and proteasome inhibitor MG132 over cell death in myeloid leukaemic cells U937 and the induction of low levels of intracellular superoxide anion.

Toxicology and Applied Pharmacology — Thu, 08 Dec 2011 05:00:00 +0100

Authors: Lombardo T, Cavaliere V, Costantino SN, Kornblihtt L, Alvarez EM, Blanco GA Abstract Increased oxygen species production has often been cited as a mechanism determining synergism on cell death and growth inhibition effects of arsenic-combined drugs. However the net effect of drug combination may not be easily anticipated solely from available knowledge of drug-induced death mechanisms. We evaluated the combined effect of sodium arsenite with the proteasome inhibitor MG132, and the anti-leukaemic agent CAPE, on growth-inhibition and cell death effect in acute myeloid leukaemic cells U937 and Burkitt's lymphoma-derived Raji cells, by the Chou-Talalay method. In addition we explored the association of cytotoxic effect of drugs with changes in intracellular superoxide anion (O...

Deletion of the long arm but not the 5q31 region of chromosome 5 in myeloid malignancies

Leukemia Research — Thu, 08 Dec 2011 05:00:00 +0100

Deletion of the long arm of chromosome 5 is a recurrent cytogenetic abnormality that is frequently found in myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). The commonly deleted region (CDR) has been identified by various investigators (review in ). The proximal CDR in the 5q31.2 region has been detected in MDS, AML and therapy-related MDS/AML. The distal CDR in the 5q32-q33 region is involved in the pathogenesis of MDS with isolated deletion 5q . Mutational analyses of the residual intact allele have not identified tumor suppressor genes. Haploinsufficiency of multiple genes in the proximal and distal CDRs may cooperate in MDS initiation and/or progression . (Source: Leukemia Research)

An acquired CSF3R mutation in an adult chronic idiopathic neutropenia patient who developed acute myeloid leukaemia

British Journal of Haematology — Wed, 07 Dec 2011 05:00:00 +0100

(Source: British Journal of Haematology)

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Proteasome inhibitor bortezomib overcomes P‐gp‐mediated multidrug resistance in resistant leukemic cell lines

Clinical and Laboratory Haematology — Wed, 07 Dec 2011 05:00:00 +0100

Conclusion: Bortezomib is a promising potential therapy for acute leukemia, especially mdr1 drug‐resistant leukemia. (Source: Clinical and Laboratory Haematology)

Proteasome inhibitor bortezomib overcomes P-gp-mediated multidrug resistance in resistant leukemic cell lines.

International Journal of Laboratory Hematology — Wed, 07 Dec 2011 05:00:00 +0100

Conclusion: Bortezomib is a promising potential therapy for acute leukemia, especially mdr1 drug-resistant leukemia. PMID: 22145750 [PubMed - as supplied by publisher] (Source: International Journal of Laboratory Hematology)

Absence of mutations in the activation loop and juxtamembrane domains of VEGFR-1 and VEGFR-2 gene in chronic myelomonocytic leukemia (CMML)

Leukemia Research — Wed, 07 Dec 2011 05:00:00 +0100

Angiogenesis is recognized as a main feature of many human neoplasms. Vascular endothelial growth factor (VEGF) is a potent angiogenic peptide with exerts its biologic effects by interaction with either of 2 high-affinity tyrosine kinase receptors, VEGFR-1 (FLT1) and VEGFR-2 (KDR). Several studies have shown that both monocytes and myeloid precursors are able to produce and secreted VEGF and, commonly, co-express one or both VEGF receptors. On the other hand, overexpression and secretion of VEGF have been observed in 72% of patients with acute myeloid leukemia (AML), with the corresponding mRNA of the genes FLT1 or KDR being expressed in 60% and 19% of AML patients, respectively . (Source: Leukemia Research)

The dual mTORC1 and mTORC2 inhibitor AZD8055 has anti-tumor activity in acute myeloid leukemia

Leukemia — Tue, 06 Dec 2011 05:00:00 +0100

Authors: L Willems, N Chapuis, A Puissant, T T Maciel, A S Green, N Jacque, C Vignon, S Park, S Guichard, O Herault, A Fricot, O Hermine, I C Moura, P Auberger, N Ifrah, F Dreyfus, D Bonnet, C Lacombe, P Mayeux, D Bouscary & J Tamburini (Source: Leukemia)