Targeting of the Hedgehog pathway in myeloid malignancies: still a worthy chase?
Br J Haematol. 2015 Aug;170(3):323-35
Authors: Khan AA, Harrison CN, McLornan DP
Deregulated Hedgehog (Hh) signalling activity may be associated with a broad range of cancer types and hence has become an attractive target for therapeutic intervention. Although initial haematological interest focused on the therapeutic targeting of this pathway in chronic myeloid leukaemia), small molecule inhibitors targeting the Hh pathway are now being tested in a range of other myeloid disorders, including myelofibrosis, myelodysplasia and acute myeloid leukaemia. In this review we will evaluate the rationale for targeting of the Hh pathway in myeloid diseases and discuss the novel agents that have entered the clinical arena. We will discuss pre-clinical models, emerging clinical trial data, and suggest how these targeted therapies may address current unmet medical needs. Finally, we will explore potential limitations of these therapies due to the emergence of secondary resistance mechanisms and speculate on future developments within this arena.
PMID: 25892100 [PubMed - indexed for MEDLINE]
Long-term results of high-dose imatinib in children and adolescents with chronic myeloid leukaemia in chronic phase: the Italian experience.
Br J Haematol. 2015 Aug;170(3):398-407
Authors: Giona F, Putti MC, Micalizzi C, Menna G, Moleti ML, Santoro N, Iaria G, Ladogana S, Burnelli R, Consarino C, Varotto S, Tucci F, Messina C, Nanni M, Diverio D, Biondi A, Pession A, Locatelli F, Piciocchi A, Gottardi E, Saglio G, Foà R
Imatinib mesylate (IM) is used for the management of childhood chronic myeloid leukaemia (CML). The most effective dosage of IM and its long-term efficacy in children are not well defined. The purpose of this multicentre study is to report on the long-term results of high-dose IM (340 mg/m2 /d) in CML patients in chronic phase (CP-CML) aged <18 years at diagnosis. A total of 47 CP-CML patients with a median age at diagnosis of 11 years 9 months were enrolled in nine Italian centres. Complete cytogenetic response was achieved in 91.5% of the evaluable patients at a median time of 6 months. BCR-ABL1 International Scale ? 0.1% (major molecular response; MMR) and ?0.01% (molecular response; MR) at 12 months were 66.6% and 33%, respectively. During follow-up, MMR and MR were achieved in 78.6% and 61% of children, respectively. IM was safely discontinued in 3 long-term treated children with a durable MR. Twelve patients (eight cytogenetic/molecular responders) underwent stem cell transplantation. The progression-free survival probabilities at 96 months for responding patients who continued IM and for those transplanted were 60% and 50%, respectively. After a median follow-up of 52 months (range 3-146), all patients are alive. High-dose IM is a long-term effective therapy in children and adolescents with CP-CML.
PMID: 25891192 [PubMed - indexed for MEDLINE]
Red cell antigen loss in a patient with chronic myeloid leukemia: a case of ABO discrepancy.
Transfus Apher Sci. 2015 Feb;52(1):103-4
Authors: Shafiq M, Karim F
Change in ABO antigen expression on the surface of neoplastic cells have been seen for a variety of tumor types. This phenomenon has been linked with myeloid neoplasms as well but is reported infrequently. Here, we report a rare cause of ABO discrepancy in an elderly female having chronic myeloid leukemia.
PMID: 25481430 [PubMed - indexed for MEDLINE]
Allogeneic hematopoietic SCT in combination with tyrosine kinase inhibitor treatment compared with TKI treatment alone in CML blast crisis.
Bone Marrow Transplant. 2014 Sep;49(9):1146-54
Authors: Jiang H, Xu LP, Liu DH, Liu KY, Chen SS, Jiang B, Jiang Q, Chen H, Chen YH, Han W, Zhang XH, Wang Y, Wang JZ, Wang FR, Qin YZ, Lai YY, Huang XJ
CML treatment with tyrosine kinase inhibitors (TKIs) has improved many patients’ prognosis, but during the disease’s terminal phase, the blast crisis (CML-BC), has been disappointing. Allo-HSCT is another treatment, but survival rates are still disappointing. Currently, a combination of these two is suggested but with little evidence. This retrospective comparison reports on this combination and TKI alone for treatment of CML-BC. Of the 83 CML-BC patients, 45 received TKIs (imatinib; nilotinib or dasatinib after imatinib resistance; TKIs group) and 38 were treated with allo-HSCT after TKI (TKIs+allo-HSCT group). Treatment success was measured in terms of the hematologic, cytogenic and molecular responses, and subject outcome. Follow-up was 30-126 months or until death. Univariate and multivariate analyses determined EFS and OS predictors. Allo-HSCT significantly improved the 4-year OS (46.7 vs 9.7%, P<0.001) and EFS (47.1 vs 6.7%, P<0.001) compared to TKI treatment alone. Hemoglobin <100 g/L, non-return to chronic phase after TKI therapy and TKI treatment alone are independent adverse predictors of OS and EFS. Allo-HSCT with individualized intervention after TKI therapy is superior to TKI alone for CML-BC.
PMID: 25046218 [PubMed - indexed for MEDLINE]
Adiponectin enhances Imatinib anti-tumour activity in human chronic myeloid leukaemia cells with serum levels associated with Imatinib efficacy in early chronic phase patients.
Cell Prolif. 2015 Aug;48(4):486-96
Authors: Tan G, Shi L, Li Q, Wang M
OBJECTIVES: Adiponectin, a functional ligand of adiponectin receptor-1 (AdipoR1) and adiponectin receptor-2 (AdipoR2), has been found to be linked to risk of development of chronic myeloid leukaemia (CML). Imatinib, as its first-line therapy, exhibits striking activity in both chronic and accelerated phases of the condition. However, numerous clinical trials have shown that many patients become refractory or experience relapses. Thus, development of new, hopefully effective Imatinib-based treatment strategies, are still needed.
MATERIALS AND METHODS: Effects of recombinant adiponectin protein, in enhancing Imatinib anti-tumour activities, in K562 and MEG-01 CML cells, were examined in vitro and in vivo. Forty-eight consecutive newly diagnosed adult patients with Bcr-Abl-positive CML, in the early chronic phase (ECP), were enrolled in the study. Imatinib efficacy, plasma adiponectin levels and their correlations were analysed.
RESULTS: Data presented here indicate that adiponectin enhanced Imatinib efficacy in vitro and in vivo. Furthermore, this augmented effect was due to inhibition of Bcr-Abl tyrosine kinase activity in an AdipoR1-dependent way, while AdipoR2 was not involved. Most importantly, additional clinical data revealed that adiponectin plasma levels in CML ECP patients, correlated with Imatinib efficacy.
CONCLUSIONS: Adiponectin enhanced Imatinib anti-tumour activity in human chronic myeloid leukaemia cells and its serum levels were associated with Imatinib efficacy, in early chronic phase patients.
PMID: 26147296 [PubMed - indexed for MEDLINE]
Functional activity of CD34-positive cells in chronic myeloid leukemia patients with different response to imatinib therapy.
Exp Oncol. 2015 Mar;37(1):70-2
Authors: Sviezhentseva IO, Perekhrestenko TP, Bilko DI, Gordienko AI, Diachenko MV, Dyagil IS
INTRODUCTION: It is believed that the reason of the leukemic clone cell resistance to treatment with tyrosine kinase inhibitors during chronic myeloid leukemia (CML) is mutations in the genome of an early bone marrow progenitor cells that are CD34-positive. Such cells, regardless of treatment, acquire ability to proliferation and differentiation. This leads to the re-expansion of the CD34(+) cells.
AIM: to determine the CD34 antigen expression in bone marrow and peripheral blood cells in CML patients with different response to imatinib therapy using the results of hematopoietic cells culturing and the data of flow cytometry.
METHODS: Bone marrow aspirate from 39 patients who were treated with imatinib was studied with cytogenetic, flow cytometry and culture methods in vitro.
RESULTS: In patients with an optimal response to imatinib therapy the number of colonies was 1.8 times lower than the number of those in the group of patients with a suboptimal response to therapy. In turn, in patients with failure of imatinib therapy the number of colonies was the highest and was 2.1 times higher than the patients with optimal response. The results of cytometric studies have shown that the number of CD34(+) cells in bone marrow was significantly higher compared to the number of CD34(+) cells in peripheral blood cells and increased with the acquisition of leukemic cells the resistance to imatinib. There was a direct correlation between the number of colonies and clusters in semisolid agar in vitro and the number of CD34(+) cells in the bone marrow of patients.
CONCLUSIONS: The correlation between the number of CD34(+) cells and the number of cell aggregates in semisolid agar in vitro indicates the prognostic value of the method for determining CD34(+) cells in the patient bone marrow. The parallel increase of their number in the peripheral blood will allow developing express methods for the detection of individual patient response to imatinib therapy.
PMID: 25804236 [PubMed - indexed for MEDLINE]
Regulation of myelopoiesis by the transcription factor IRF8.
Int J Hematol. 2015 Apr;101(4):342-51
Authors: Tamura T, Kurotaki D, Koizumi S
Interferon regulatory factor-8 (IRF8) is a transcription factor expressed in hematopoietic cells, particularly in mononuclear phagocytes [monocytes/macrophages and dendritic cells (DCs)] and their progenitors. Various studies have demonstrated that IRF8 is essential for the development of monocytes, DCs, eosinophils, and basophils. Conversely, IRF8 suppresses the generation of neutrophils. Accordingly, Irf8 (-/-) mice develop immunodeficiency and a chronic myeloid leukemia (CML)-like disease. Mutations and loss of expression of the human IRF8 gene are also associated with immunodeficiency and CML, respectively. Recent findings have begun to reveal the transcription factor network and epigenetic changes governed by IRF8. For example, in mononuclear phagocyte progenitors, IRF8 cooperates with PU.1 to promote the formation of promoter-distal enhancers to induce monocyte-related genes including the critical downstream transcription factor gene Klf4. On the other hand, IRF8 blocks C/EBP? activity to suppress the neutrophil differentiation program. Indeed, Irf8 (-/-) mononuclear phagocyte progenitors fail to efficiently generate monocytes and DCs and, instead, aberrantly give rise to neutrophils. This article provides an overview of recent advances in our understanding of the role of IRF8 in myelopoiesis and related diseases.
PMID: 25749660 [PubMed - indexed for MEDLINE]
PDQ Cancer Information Summaries
This PDQ cancer information summary has current information about the treatment of childhood acute myeloid leukemia and other myeloid malignancies. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care. Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Date Last Modified”) is the date of the most recent change. The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Pediatric Treatment Editorial Board.
Src family kinases interfere with dimerization of STAT5A through a phosphotyrosine-SH2 domain interaction.
Cell Commun Signal. 2015;13:10
Authors: Fahrenkamp D, de Leur HS, Küster A, Chatain N, Müller-Newen G
BACKGROUND: Chronic myeloid leukemia (CML) is driven by the expression of the BCR-ABL oncoprotein. STAT5 is a BCR-ABL substrate and persistently activated by tyrosine phosphorylation in CML cells. Activated STAT5 (pSTAT5) drives proliferation and survival of leukemic cells and contributes to initial transformation and maintenance of the disease. In cytokine-induced STAT5 signaling, phosphorylation of STAT5A on Y694 leads to nuclear accumulation of the transcription factor, followed by DNA-binding and gene induction. However, Src-family kinases (SFK) mediate cytoplasmic retention of pSTAT5A leading to attenuated target gene expression and colony formation in CML cells.
RESULTS: In this study we show that autophosphorylation of Y416 in the highly conserved activation loop of SFK generates a potent recruitment site for the SH2 domain of STAT5A. Binding of the SH2 domain to the activation loop is required for STAT5A(Y694) phosphorylation by SFK, but at the same time promotes the persistent cytoplasmic localization of the transcription factor as found in BCR-ABL(+) leukemia. As a consequence of the complex formation between tyrosine-phosphorylated SFK and the SH2 domain of STAT5A, the dimerization of STAT5A is impaired. We further demonstrate that constitutively active STAT5A(S710F) escapes from SFK-mediated cytoplasmic retention by enhancing STAT5A dimer stability.
CONCLUSION: Our results reveal important structural aspects of cytoplasmic pSTAT5A found in myeloid leukemias and will contribute to the understanding of STAT5A mediated cytoplasmic signaling.
PMID: 25885255 [PubMed - indexed for MEDLINE]
Chronic myeloid leukemia-derived exosomes promote tumor growth through an autocrine mechanism.
Cell Commun Signal. 2015;13:8
Authors: Raimondo S, Saieva L, Corrado C, Fontana S, Flugy A, Rizzo A, De Leo G, Alessandro R
BACKGROUND: Chronic myeloid leukemia (CML) is a clonal hematopoietic stem cell disorder in which leukemic cells display a reciprocal t(9:22) chromosomal translocation that results in the formation of the chimeric BCR-ABL oncoprotein, with a constitutive tyrosine kinase activity. Consequently, BCR-ABL causes increased proliferation, inhibition of apoptosis, and altered adhesion of leukemic blasts to the bone marrow (BM) microenvironment. It has been well documented that cancer cells can generate their own signals in order to sustain their growth and survival, and recent studies have revealed the role of cancer-derived exosomes in activating signal transduction pathways involved in cancer cell proliferation. Exosomes are small vesicles of 40-100 nm in diameter that are initially formed within the endosomal compartment, and are secreted when a multivesicular body (MVB) fuses with the plasma membrane. These vesicles are released by many cell types including cancer cells, and are considered messengers in intercellular communication. We have previously shown that CML cells released exosomes able to affect the tumor microenvironment.
RESULTS: CML cells, exposed up to one week, to exosomes showed a dose-dependent increased proliferation compared with controls. Moreover, exosome treatment promotes the formation of LAMA84 colonies in methylcellulose. In a CML xenograft model, treatment of mice with exosomes caused a greater increase in tumor size compared with controls (PBS-treated mice). Real time PCR and Western Blot analysis showed, in both in vitro and in vivo samples, an increase in mRNA and protein levels of anti-apoptotic molecules, such as BCL-w, BCL-xl, and survivin, and a reduction of the pro-apoptotic molecules BAD, BAX and PUMA. We also found that TGF- ?1 was enriched in CML-exosomes. Our investigations showed that exosome-stimulated proliferation of leukemia cells, as well as the exosome-mediated activation of an anti-apoptotic phenotype, can be inhibited by blocking TGF-?1 signaling.
CONCLUSIONS: CML-derived exosomes promote, through an autocrine mechanism, the proliferation and survival of tumor cells, both in vitro and in vivo, by activating anti-apoptotic pathways. We propose that this mechanism is activated by a ligand-receptor interaction between TGF-?1, found in CML-derived exosomes, and the TGF- ?1 receptor in CML cells.
PMID: 25644060 [PubMed - indexed for MEDLINE]
PDQ Cancer Information Summaries
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of chronic myelogenous leukemia. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
PDQ Cancer Information Summaries
This PDQ cancer information summary has current information about the treatment of chronic myelogenous leukemia. It is meant to inform and help patients, families, and caregivers. It does not give formal guidelines or recommendations for making decisions about health care. Editorial Boards write the PDQ cancer information summaries and keep them up to date. These Boards are made up of experts in cancer treatment and other specialties related to cancer. The summaries are reviewed regularly and changes are made when there is new information. The date on each summary (“Date Last Modified”) is the date of the most recent change. The information in this patient summary was taken from the health professional version, which is reviewed regularly and updated as needed, by the PDQ Adult Treatment Editorial Board.
Inclusion body myositis in a patient with chronic myeloid leukemia treated with dasatinib: a case report.
J Med Case Rep. 2015;9:214
Authors: AlJohani NI, Carette S, Lipton JH
INTRODUCTION: Chronic myelogenous leukemia is often treated using tyrosine kinase inhibitors such as dasatinib. Here we describe a rare case of inflammatory myopathy in a patient with chronic myelogenous leukemia treated with the tyrosine kinase inhibitor dasatinib.
CASE PRESENTATION: A 69-year-old Caucasian man with imatinib-resistant chronic myelogenous leukemia achieved complete molecular remission in response to dasatinib therapy. However, from a normal initial serum creatine kinase level, he developed elevated serum creatine kinase levels and gradual-onset progressive muscle weakness after dasatinib therapy was initiated. Our patient was eventually diagnosed with inclusion body myositis. However, we were unable to determine the mechanism underlying the dasatinib-associated muscle weakness. Given the efficacy of dasatinib in the treatment of chronic myelogenous leukemia and our patient’s mild symptoms of inclusion body myositis, he continued to receive dasatinib under close clinical and laboratory observation.
CONCLUSION: Despite the wide use of dasatinib and its documented safety, we report a case of severe muscle injury of unknown etiology. Therefore, patients with chronic myelogenous leukemia receiving dasatinib and perhaps all tyrosine kinase inhibitors should be carefully monitored for signs of muscle injury, especially if this is associated with significant elevations in serum creatine kinase levels.
PMID: 26376827 [PubMed - in process]
Chronic myeloid leukemia and chronic lymphocytic leukemia.
JAAPA. 2014 Feb;27(2):45-6; quiz 45-6
Authors: Gore JM
PMID: 24463751 [PubMed - indexed for MEDLINE]
Chronic Myelogenous Leukemia After Therapy for Langerhans Cell Histiocytosis in an Adolescent.
J Pediatr Hematol Oncol. 2015 Oct;37(7):572-573
Authors: Yoon HS, Choi YS, Park TS
PMID: 26376235 [PubMed - as supplied by publisher]
Fertility after treatment with high dose melphalan in women with acute myelogenous leukemia.
Pediatr Blood Cancer. 2015 Sep 16;
Authors: Even-Or E, Ben-Haroush A, Yahel A, Yaniv I, Stein J
BACKGROUND: High-dose melphalan (HDM) is an integral component of conditioning regimens for autologous and allogeneic hematopoietic stem cell transplantation for patients with malignant and non-malignant diseases. The gonadotoxic effects of HDM are often obscured by previous or concurrent administration of alkylating agents. From April 1996 to January 2006 our acute myeloid leukemia treatment regimen included induction and consolidation therapy with cytosine arabinoside, anthracyclines and etoposide, followed by HDM and autologous stem cell infusion. We explored gonadal function in surviving female patients so treated, who represent a unique group of patients exposed to HDM as a single gonadotoxic agent.
PROCEDURE: The fertility assessment included a questionnaire, blood tests for luteinizing hormone, follicle stimulating hormone and anti mullerian hormone (AMH), and a gynecological ultrasound exam for antral follicular count (AFC).
RESULTS: Eight female survivors participated. Although fertility assessment showed considerable damage to ovarian reserve in all participants, four of the eight female survivors conceived and bore children without medical intervention.
CONCLUSION: In this cohort, HDM treatment reduced fertility potential but did not preclude fecundity. Early referral to a fertility clinic and long term follow-up including serial measurements of AMH levels and AFC for female patients receiving HDM are recommended. Pediatr Blood Cancer 2015. © 2015 Wiley Periodicals, Inc.
PMID: 26375177 [PubMed - as supplied by publisher]
Modeling chronic myeloid leukemia in immunodeficient mice reveals expansion of aberrant mast cells and accumulation of pre-B cells.
Blood Cancer J. 2014;4:e269
Authors: Askmyr M, Ågerstam H, Lilljebjörn H, Hansen N, Karlsson C, von Palffy S, Landberg N, Högberg C, Lassen C, Rissler M, Richter J, Ehinger M, Järås M, Fioretos T
Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm that, if not treated, will progress into blast crisis (BC) of either myeloid or B lymphoid phenotype. The BCR-ABL1 fusion gene, encoding a constitutively active tyrosine kinase, is thought to be sufficient to cause chronic phase (CP) CML, whereas additional genetic lesions are needed for progression into CML BC. To generate a humanized CML model, we retrovirally expressed BCR-ABL1 in the cord blood CD34(+) cells and transplanted these into NOD-SCID (non-obese diabetic/severe-combined immunodeficient) interleukin-2-receptor ?-deficient mice. In primary mice, BCR-ABL1 expression induced an inflammatory-like state in the bone marrow and spleen, and mast cells were the only myeloid lineage specifically expanded by BCR-ABL1. Upon secondary transplantation, the pronounced inflammatory phenotype was lost and mainly human mast cells and macrophages were found in the bone marrow. Moreover, a striking block at the pre-B-cell stage was observed in primary mice, resulting in an accumulation of pre-B cells. A similar block in B-cell differentiation could be confirmed in primary cells from CML patients. Hence, this humanized mouse model of CML reveals previously unexplored features of CP CML and should be useful for further studies to understand the disease pathogenesis of CML.
PMID: 25501026 [PubMed - indexed for MEDLINE]
Chronic myeloid leukemia drug evaluation using a multisignal amplified photoelectrochemical sensing platform.
Anal Chem. 2014 Dec 2;86(23):11680-9
Authors: Zhou S, Kong Y, Shen Q, Ren X, Zhang JR, Zhu JJ
Chronic myeloid leukemia (CML) is a malignant clone disease of hematopoietic stem cells. At present, the most effective therapy for CML is bone marrow transplantation, but this procedure is expensive, and it is often difficult to find appropriately matched bone marrow donors. As an alternative to marrow transplantation, a more effective anticancer drug should be developed to cure the disease; in addition, an effective system to evaluate the activity of the drug needs to be developed. Herein, we present a novel antileukemia drug evaluation method based on a multisignal amplified photoelectrochemical sensing platform that monitors the activity of caspase-3, a known marker of cell apoptosis. Manganese-doped CdS@ZnS core-shell nanoparticles (Mn:CdS@ZnS) were synthesized via a simple wet chemical method, which provided a stable photocurrent signal. A DEVD-biotin peptide and streptavidin-labeled alkaline phosphatise (SA-ALP) were immobilized successively at these nanoparticles through amide bonding and through specific interaction between biotin and streptavidin, respectively. The photocurrent of this sensing platform improved as the ALP hydrolyzed the substrate 2-phospho-l-ascorbic acid (AAP) to ascorbic acid (AA), a more efficient electron donor. The activity of caspase-3 was detected using this sensing platform, and thus, the efficacy of nilotinib for targeting K562 CML cells could be evaluated. The results indicate that nilotinib can effectively induce apoptosis of the K562 cells. This sensing platform exhibited sensitive, reproductive, and stable performance in studying the nilotinib-induced apoptosis of K562 CML cells, and the platform could be utilized to evaluate other anticancer drugs.
PMID: 25372503 [PubMed - indexed for MEDLINE]
Rapid clinical improvement of peripheral artery occlusive disease symptoms after nilotinib discontinuation despite persisting vascular occlusion.
Blood Cancer J. 2014;4:e247
Authors: Maurizot A, Beressi JP, Manéglier B, de la Marre NH, Spentchian M, Soury P, Solvet-Sebire P, Collet-Gaudillat C, Baud JM, Livarek B, Guilhot F, Rousselot P
PMID: 25238138 [PubMed - indexed for MEDLINE]
Development of chronic myeloid leukaemia in patients treated with anti-VEGF therapies for clear cell renal cell cancer.
Future Oncol. 2015;11(1):17-26
Authors: Czarnecka AM, Oborska S, Rzepecki P, Szczylik C
Tyrosine kinase inhibitors are novel therapies targeting specific cellular signalling pathways. Sunitinib and sorafenib primarily block tyrosine kinase receptors involved in the progression of many tumours, including clear cell renal cell cancer (ccRCC). Although developed to target selected receptors, it is becoming apparent that they inhibit other kinases; this may result in the development of unexpected side effects. This is potentially dangerous as kinases on noncancerous cells are also inhibited. TKI off-target effects contributing to cardiotoxicity, hypothyroidism, hypertension, fatigue, hair depigmentation, hand-foot syndrome and gastrointestinal perforation have been described. We report three patients (3/412) treated with sunitinib and sorafenib who developed chronic myeloid leukaemia (CML) during treatment for ccRCC, proposing a molecular mechanism of tyrosine kinase inhibitors action on bone marrow cells that might be co-responsible for CML development.
PMID: 24953672 [PubMed - indexed for MEDLINE]