[Research Advances on Anti-ANGPT2 Antibody in Acute Myeloid Leukemia].

Posted by rob on October 24, 2014 under Uncategorized | Comments are off for this article

[Research Advances on Anti-ANGPT2 Antibody in Acute Myeloid Leukemia].

Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2014 Sep;22(5):1459-62

Authors: Chen YW, Yang H, Mou H, Yang SL, Zhang Y

Abstract

Angiopoietin2( ANGPT2 ) plays an important role in tumor angiopoiesis. ANGPT2 antagonises ANGPT1 resulting in an effect on the stability of blood vessels, which promotes tumor growth, invasion, proliferation as well as relating to tumor vascular density. A lot of researches published papers about anti-ANGPT2 for the treatment of tumor, and have made some progresses. In this review, the role of ANGPT2 in the pathogenesis of acute myelogenous leukemia (AML), including its effects on proliferation of leukemia cells, bone marrow angiopoiesis, tumor invasion and metastasis are briefly summarised in order to provide the basis for targeted ANGPT2 in treatment of AML.

PMID: 25338607 [PubMed - in process]

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[Clinical Study on Role of CD34 in Patients with Biphenotypic Acute Leukemia].

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[Clinical Study on Role of CD34 in Patients with Biphenotypic Acute Leukemia].

Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2014 Sep;22(5):1226-9

Authors: Lu GJ, Song ZS, Zhang QM, Li PF

Abstract

This study was aimed to explore the expression of CD34 in patients with biphenotypic acute leukemia (BAL) and its relation with the prognosis of BAL. The flow cytometry was used to detect leukemia-associated antigen. The used monoclonal antibodys (McAb) included CD10, CD19 and CD34 for B lymphocyte lineage, CD2, CD3 and CD5 for T lymohocyte lineage, MPO, CD13 and CD33 for myeloid lineage. The finally results were respectively analyzed. The results indicated that 9 out of 216 cases of leukemia was diagnosed as BAL (4.2%). Among 9 cases of BAL, 6 cases showed the common expression of myeloid and T lymohocyte lineages (66.7%), 3 cases showed the common expression of myeloid and B lymohocyte lineages (33.3%). 4 cases of BAL displayed CD34 positive expression (44.4%). As compared with acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL), the BAL patients showed higher CD34 positive expression (P < 0.05). It is concluded that the BAL patients show a poor prognosis, as compared with AML or ALL patients. The therapeutic effect of BAL may negatively correlate with the CD34 positive expression.

PMID: 25338562 [PubMed - in process]

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[Expression of biomarkers related with bone marrow cells in patients with acute myelogenous leukemia].

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[Expression of biomarkers related with bone marrow cells in patients with acute myelogenous leukemia].

Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2014 Sep;22(5):1193-8

Authors: Huang X, Wang RH, Li DY, Lai ZL, Chu YT, Zhang Y, Chen XY

Abstract

This study was aimed to investigate the expression of biomarkers (PTEN, mTOR, NF-kB, CD44, PI3K) related with bone marrow cells in patients with acute myelogenous leukemia. The immunohistochemical method was used to detect the expression of PTEN, mTOR, NF-kB, CD44, PI3K in 20 patients. The AML patients were divided into remission group and non-remission group after calculating the percentage of leukemia cells in bone marrow. The results showed that by optical microscopy, the positive expression rates of PTEN, mTOR, NF-kB, CD44 and PI3K in remission group were 33.3%, 33.3%, 77.8%, 22.2%, 0, respectively; meanwhile, in non-remission group, the positive expression rates of above-menthioned biomarkers were 63.6%, 18.2, 90.9, 63.6%, 0, respectively. The percentage and mean OD for PTEN and CD44 were statistically different between the two groups (P < 0.05), but for mTOR, NF-kB and PI3K were not statistically differenly (P > 0.05). It is concluded that the high expression of PTEN and CD44 can be regarded as an important index for diagnosis and prognosis in acute myelogenous leukemia.

PMID: 25338556 [PubMed - in process]

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Endobronchial Valve Placement as Destination Therapy for Recurrent Pneumothorax in the Setting of Advanced Malignancy.

Posted by rob on October 23, 2014 under Uncategorized | Comments are off for this article

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Endobronchial Valve Placement as Destination Therapy for Recurrent Pneumothorax in the Setting of Advanced Malignancy.

Respir Care. 2014 Oct 21;

Authors: Gilbert CR, Toth JW, Osman U, Reed MF

Abstract

The development of a persistent air leak after pneumothorax can be encountered in patients with underlying structural lung disease. In those with advanced malignancy or other comorbidities, the ability to tolerate general anesthesia and thoracoscopic procedures may limit definitive management. We describe the case of a 68-y-old male with refractory acute myelogenous leukemia presenting with recurrent secondary spontaneous pneumothorax and persistent air leak related to an underlying fungal pneumonia. Endobronchial valve placement allowed for timely chest tube removal and discharge from the hospital, as well as avoidance of a thoracoscopic procedure and pleurodesis.

PMID: 25336533 [PubMed - as supplied by publisher]

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Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia.

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Results of phase 2 randomized study of low-dose decitabine with or without valproic acid in patients with myelodysplastic syndrome and acute myelogenous leukemia.

Cancer. 2014 Oct 21;

Authors: Issa JP, Garcia-Manero G, Huang X, Cortes J, Ravandi F, Jabbour E, Borthakur G, Brandt M, Pierce S, Kantarjian HM

Abstract

BACKGROUND: Hypomethylating agents have demonstrated activity in patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Preclinical and single-arm trials have suggested that adding histone deacetylase (HDAC) inhibitors may synergize the epigenetic modulation of hypomethylating agents and improve treatment results.

METHODS: The objective of this study was to evaluate the possible benefit of adding valproic acid, an HDAC inhibitor, to decitabine in the treatment of MDS and AML.

RESULTS: Patients with higher risk MDS or with AML aged ?60 years were eligible. Patients were randomized in a Bayesian response-adaptive design to receive intravenous decitabine 20 mg/m(2) daily for 5 days or decitabine plus oral valproic acid 50 mg/kg daily for 7 days. Courses were repeated every 4 to 6 weeks. A maximum of 150 patients were to be treated. In total, 149 patients were treated on study, including 87 patients with MDS and 62 patients with AML. The median patient age was 69 years (range, 20-89 years; 42% of patients were aged ?70 years). Overall, 34% of patients achieved complete remission, and 55% had an objective response. The median survival was 11.9 months, and the estimated 2-year survival rate was 27%. Outcome was not different with the addition of valproic acid to decitabine versus decitabine alone in relation to the rates of complete remission, overall response, or survival. Subset analyses did not demonstrate a benefit within the MDS or AML categories. Toxicities-particularly neurotoxicities-were higher with the combination arm.

CONCLUSIONS: Adding valproic acid to decitabine was not associated with improved outcome in the treatment of patients with MDS or elderly patients with AML. Future therapies may consider combining hypomethylating agents with better HDAC inhibitors and using different schedules. Cancer 2014. © 2014 American Cancer Society.

PMID: 25336333 [PubMed - as supplied by publisher]

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Allosteric inhibitors of Bcr-Abl: towards novel myristate-pocket binders.

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Allosteric inhibitors of Bcr-Abl: towards novel myristate-pocket binders.

Curr Pharm Biotechnol. 2013;14(5):477-87

Authors: Radi M, Schenone S, Botta M

Abstract

Among the currently available options for the treatment of chronic myeloid leukemia (CML), ATP-competitive tyrosine kinases inhibitors (Gleevec(®), Dasatinib(®) and Nilotinib(®)) represent one of the most promising therapeutic approaches developed in the last 10-15 years. However, the initial enthusiasm generated by the high response rate to these drugs has been dampened by the development of resistance. The T315I mutation at the gatekeeper residue is very frequent in advanced phases of the disease and is one of the main causes of resistance, disrupting important contact points between the inhibitors and the enzyme. Different strategies have been implemented to overcome this resistance, such as the recent development of more selective non-ATP competitive inhibitors targeting sites outside the ATP-binding cleft. Some of these allosteric inhibitors alter the kinase conformation, while others directly compete with the protein substrates. Another interesting family of allosteric inhibitors is represented by those compounds targeting the myristate-pocket of Bcr-Abl (myristate-pocket binders). The binding of these inhibitors blocks the Bcr-Abl kinase in the inactive conformation and provides an advantage in overcoming drug resistance due to kinase mutations. This review reports the last findings in the development of novel myristate-pocket binders of Bcr-Abl as promising anti-leukemia agents.

PMID: 22429131 [PubMed - indexed for MEDLINE]

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Secondary Leukemia in Primary Mediastinal Large B Cell Lymphoma (PMBL) Presenting as Myeloid Sarcoma in the Paraspinal Area.

Posted by rob on October 22, 2014 under Uncategorized | Comments are off for this article

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Secondary Leukemia in Primary Mediastinal Large B Cell Lymphoma (PMBL) Presenting as Myeloid Sarcoma in the Paraspinal Area.

Chest. 2014 Oct 1;146(4_MeetingAbstracts):666A

Authors: Arumugam Raajasekar AK, Belur A, Chandra A

Abstract

SESSION TITLE: Cancer Student/Resident Case Report Posters IIISESSION TYPE: Medical Student/Resident Case ReportPRESENTED ON: Tuesday, October 28, 2014 at 01:30 PM – 02:30 PMINTRODUCTION: Myeloid sarcoma is a localized extramedullary tumor composed of immature myeloid cells. It can occur in a patient with no prior history of acute myeloid leukemia[1]. It is usually seen in association with acute leukemia, myeloproliferative neoplasm, and myelodysplastic syndromes. They have a predilection for the skin, lymph nodes, small intestine, spine, and the mean time between the diagnosis and development of AML 10.5 months [2]. In addition MS may be the initial manifestation of relapse of AML following chemotherapy or hematopoietic stem-cell transplantation [3].CASE PRESENTATION: A 28 year old male ppresented 4 years with chest pain to the ED. He had completed 6 cycles of R-CHOP for B-Cell lymphoma of the anterior mediastinum with subsequent follow up PET scans negative for reccurence. Initial investigations including Echocardiogram, CT chest with contrast, MRI spine failed to reveal any evidence of disease. A repeat PET/CT showed increased uptake in anterior mediastinal soft tissue and pasraspinal area compared with the prior imaging. He underwent paraspinal mass biopsy which showed myeloid sarcoma. Bone marrow biopsy and aspirate was consistent with nonpromyelocytic acute myeloid leukemia. FISH analysis was positive for a RUNX1T1/RUNX1 (ETO/AML1) rearrangement and negative for a rearrangement or loss/gain of MLL. Trisomy 11/11q, was observed in 3.8% of cells. No PML/RARA translocation were found. Karyotype showed 45,X,-Y,t(8;21)(q22;q22)(19)/46,XY(1). Patient was referred for an allogenic transplant.DISCUSSION: Therapy-related myelodysplasia (tMDS) and secondary acute myelogenous leukemia (sAML) are late complications of high-dose therapy for lymphoid malignancies (incidence 5% to 15%). tMDS and sAML are clinically and cytogenetically distinct from de novo cases and the observed cytogenetic changes are often characteristic of chemotherapy-induced chromosomal damage . Alkylating agents are associated with complete or partial deletions of chromosome 5 and/or 7. Topoisomerase II inhibitors are typically associated with balanced translocations involving chromosome bands 11q23 and 21q22. Trisomy 11 has also been reported in myeloid sarcoma.The presence of translocation t(8;21) is associated with a relatively good prognosis when treated with standard induction and intensive consolidation chemotherapy.

CONCLUSIONS: We describe a rarely reported t(8,21) translocation in a patient with tMDS secondary to Topoisomerase II inbitor.Reference #1: Brunning RD et al Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues. Vol. 3. Lyon, France: IARC Press; 2001. pp. 104-105. Reference #2: Breccia M et al. Granulocytic sarcoma with breast and skin presentation: a report of a case successfully treated by local radiation and systemic chemotherapy. Acta Haematologica. 2000;104(1):34-37Reference #3: Armitage JO et al. Treatment-related myelodysplasia and acute leukemia in non-Hodgkin’s lymphoma patients. Journal of Clinical Oncology. 2003;21(5):897-906.DISCLOSURE: The following authors have nothing to disclose: Arun Kumar Arumugam Raajasekar, Anuradha Belur, Abhinav ChandraNo Product/Research Disclosure Information.

PMID: 25334719 [PubMed - as supplied by publisher]

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Malnutrition Effects on Critically Ill Patients With Acute Myelogenous Leukemia.

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Malnutrition Effects on Critically Ill Patients With Acute Myelogenous Leukemia.

Chest. 2014 Oct 1;146(4_MeetingAbstracts):246A

Authors: Abdelfatah M, Nijim A, Nayfe R, Elkhanany A

Abstract

SESSION TITLE: Critical Care PostersSESSION TYPE: Original Investigation PosterPRESENTED ON: Wednesday, October 29, 2014 at 01:30 PM – 02:30 PMPURPOSE: Malnutrition is a common complication in critically ill patients. Recovery from this critical illness is characterized when the rate of anabolism exceeds that of catabolism. Adequate nutrition provide substrate for anabolic state1, recent evidence suggests that starting feeding early in those patients can markedly affect the outcome1. Acute myelogenous leukemia [AML], one of the most debilitating diseases in critically ill patients. The purpose of the study is to evaluate the effect of malnutrition on the outcome of critically ill AML patientsMETHODS: A total of 188 adult patients with Acute AML between 2002-2012 were enrolled. Retrospective data obtained included: demographic information, labs, bone marrow (BM) biopsy, cytogenetics, outcome, and overall survival (OS) were obtained. Low serum prealbumin was defined as &lt;18mg/dl.RESULTS: The median age was 70 years, 98 were men. 46 patients had moderate to sever BM fibrosis, 45 patients had complex cytogenetics, 10 patients (5%) were underweight, 34 (18%) had normal BMI, 59 (32%) were overweight, and 84 (45%) were obese. 149 patients (80%) were not diabetic, 12 patients (6%) had high risk for DM, and 26 patients (14%) uncontrolled DM. Overall median OS was 23 weeks, in univariate line regression a definitive correlation exists between survival in weeks and age (r=-0.34, P&lt;0.0001). In univariate OS, when compared across groups, significant correlation was found with low Prealbumin (p&lt; 0.0001), where median survivals for low versus normal levels were 21 and 352 weeks respectively, and complex Cytogenetics (p=0.03) with median survival 126 versus 150 weeks. However, other parameters of the cohort were mostly non-significant, including DM control (p=0.39), BMI subcategories (p=0.4), GFR status (p=0.1), and concomitant diagnosis of BM Fibrosis (p=0.71). In multivariate analysis using Cox regression, adjusting for age, sex, BMI, Prealbumin, cytogenetics, there were significant impact of both age (P &lt;0.0001) and Prealbumin level (OR=3.86 compared with normal level, P=0.0004) on survival.CONCLUSIONS: Low Prealbumin has all been shown to have a statistically significant effect on survival in critically ill AML patients.

CLINICAL IMPLICATIONS: According to our data we recommend that intensivists monitor nutritional status and correct malnutrition early as it is crucial in critically ill patients especially leukemia patients.

DISCLOSURE: The following authors have nothing to disclose: Mohamed Abdelfatah, Ala Nijim, Rabih Nayfe, Ahmed ElkhananyNo Product/Research Disclosure Information.

PMID: 25334255 [PubMed - as supplied by publisher]

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Aspergillus Tracheobronchitis With Endobronchial Obstruction: A Rare but Deadly Complication After Bone Marrow Transplant.

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Aspergillus Tracheobronchitis With Endobronchial Obstruction: A Rare but Deadly Complication After Bone Marrow Transplant.

Chest. 2014 Oct 1;146(4_MeetingAbstracts):161A

Authors: Sentana D, Gui J, Sharif M

Abstract

SESSION TITLE: Infectious Disease Student/Resident Case Report Posters ISESSION TYPE: Medical Student/Resident Case ReportPRESENTED ON: Tuesday, October 28, 2014 at 01:30 PM – 02:30 PMINTRODUCTION: Invasive Aspergillosis most commonly occurs in the setting of immunosuppression, and usually involves lung parenchyma. Here we report a rare case of Aspergillus infection causing severe endobronchial obstruction, also known as Aspergillus tracheobronchitis.CASE PRESENTATION: A 40 year old male with acute myelogenous leukemia (AML) presented with dyspnea and wheezing. He was on immunosuppression after an allogeneic bone marrow transplant (BMT) and steroids for graft-versus-host disease (GVHD) of the skin. CT chest was done, which was suggestive of GVHD. Patient continued to have dyspnea, eventually requiring endotracheal intubation. Bronchoscopy showed significant endobronchial lesions causing severe circumferential narrowing of distal bronchi (see image). Endobronchial biopsy showed inflammatory cells with fungal hyphae consistent with Aspergillus. Endobronchial culture revealed presence of Aspergillus fumigatus. Based on these findings, the diagnosis of endobronchial obstructive Aspergillus tracheobronchitis was made. Patient was started on systemic antifungal therapy, and later received endobronchial amphotericin B injections. However, his condition continued to decline, and eventually withdrawal of care was done.DISCUSSION: Invasive Aspergillosis commonly affects the immunocompromised population. About 7-10% of invasive Aspergillosis manifest as Aspergillus tracheobronchitis, which is a rare complication after BMT. Aspergillus tracheobronchitis involves the tracheobronchial tree, and causes respiratory failure either by endobronchial obstruction or hemorrhage due to the invasion of the pulmonary vessels. First clinical symptoms present as fever, cough, dyspnea, and wheezing, followed by respiratory failure. Chest radiograph and CT may not reveal pulmonary lesions, and diagnosis requires bronchoscopy with biopsy and cultures. Several risk factors associated with Aspergillus tracheobronchitis include underlying airway disease, prolonged use of endotracheal tube, and decreased mucociliary production. The uses of steroids have been reported as possible risk factor for Aspergillus tracheobronchitis in BMT patients. Our patient was on steroids prior to admission, which may contribute to his risk factor for this disease. Despite the early diagnosis and initiation of antifungal therapy, our patient succumbed to progressive respiratory failure.CONCLUSIONS: Aspergillus tracheobronchitis with endobronchial obstruction carries poor prognosis. This diagnosis should be considered in BMT patients presenting with respiratory symptoms, and when suspected, bronchoscopy should be done immediately despite normal chest imaging to ensure early diagnosis.Reference #1: Krenke R, Grabczak E. Tracheobronchial Manifestations of Aspergillus Infections. TheScientificWorldJOURNAL. 2011;11:2310-2329.Reference #2: Machida U, Kami M, et al. Aspergillus tracheobronchitis after allogeneic bone marrow transplantation. Bone Marrow Transplantation. 1999; 24:1145-1149.DISCLOSURE: The following authors have nothing to disclose: Debby Sentana, Junhong Gui, Mohammed SharifNo Product/Research Disclosure Information.

PMID: 25334162 [PubMed - as supplied by publisher]

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Acute Myeloid Leukemia with BCR/ABL Fusion Chimera.

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Acute Myeloid Leukemia with BCR/ABL Fusion Chimera.

Indian J Hematol Blood Transfus. 2014 Sep;30(Suppl 1):280-2

Authors: Madashira Gopal M, Kotwal J, Kapoor R

Abstract

Philadelphia (Ph) chromosome is most commonly associated with chronic myelogenous leukemia (CML), a subset of precursor B-cell acute lymphoblastic leukemia and acute biphenotypic leukemia. In contrast only 1 % of acute myeloid leukemia (AML) show a consistent association with the Ph Chromosome. Before making a diagnosis of Ph + AML stringent criteria need to be applied in order to differentiate it from blast crisis stage of CML. It is important to identify this rare entity as patients who otherwise carry a poor prognosis with standard chemotherapy regimen, would benefit from therapy with imatinib mesylate. This article discusses the morphological, immunophenotype and clinical characteristics of a rare case of Ph + AML.

PMID: 25332597 [PubMed]

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Chronic neutrophilic leukemia: a rare case report.

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Chronic neutrophilic leukemia: a rare case report.

Indian J Hematol Blood Transfus. 2014 Sep;30(Suppl 1):77-9

Authors: Rane SR, Kulkarni MM, Puranik SC

Abstract

Chronic neutrophilic leukemia (CNL) is a rare chronic myeloproliferative disorder characterized by splenomegaly, sustained neutrophilic leukocytosis, raised serum vitamin B12 level and absence of the Philadelphia chromosome and BCR/ABL1 fusion gene. CNL can be distinguished from chronic myelogenous leukemia, leukemoid reaction and myelodysplastic syndrome. We report a case of 45 year old male patient with CNL.

PMID: 25332542 [PubMed]

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Chaetocin antileukemia activity against chronic myelogenous leukemia cells is potentiated by bone marrow stromal factors and overcomes innate imatinib resistance.

Posted by rob on October 21, 2014 under Uncategorized | Comments are off for this article

Chaetocin antileukemia activity against chronic myelogenous leukemia cells is potentiated by bone marrow stromal factors and overcomes innate imatinib resistance.

Oncogenesis. 2014;3:e122

Authors: Truitt L, Hutchinson C, DeCoteau JF, Geyer CR

Abstract

Chronic myelogenous leukemia (CML) is maintained by a minor population of leukemic stem cells (LSCs) that exhibit innate resistance to tyrosine kinase inhibitors (TKIs) targeting BCR-ABL. Innate resistance can be induced by secreted bone marrow stromal cytokines and growth factors (BMSFs) that protect CML-LSCs from TKIs, resulting in minimal residual disease. Developing strategies to eradicate innate TKI resistance in LSCs is critical for preventing disease relapse. Cancer cells balance reactive oxygen species (ROS) at higher than normal levels, promoting their proliferation and survival, but also making them susceptible to damage by ROS-generating agents. Bcr-Abl increases cellular ROS levels, which can be reduced with TKI inhibitors, whereas, BMSFs increase ROS levels. We hypothesized that BMSF-mediated increases in ROS would trigger ROS damage in TKI-treated CML-LSCs when exposed to chaetocin, a mycotoxin that imposes oxidative stress by inhibiting thioredoxin reductase-1. Here, we showed that chaetocin suppressed viability and colony formation, and induced apoptosis of the murine hematopoietic cell line TonB210 with and without Bcr-Abl expression, and these effects were potentiated by BMSFs. In contrast, imatinib activities in Bcr-Abl-positive TonB210 cells were inhibited by BMSFs. Further, BMSFs did not inhibit imatinib activities when TonB210 cells expressing Bcr-Abl were cotreated with chaetocin. Chaetocin showed similar activities against LSC-enriched CML cell populations isolated from a murine transplant model of CML blast crisis that were phenotypically negative for lineage markers and positive for Sca-1 and c-Kit (CML-LSK). BMSFs and chaetocin increased ROS in CML-LSK cells and addition of BMSFs and chaetocin resulted in higher levels compared with chaetocin or BMSF treatment alone. Pretreatment of CML-LSKs with the antioxidant N-acetylcysteine blocked chaetocin cytotoxicity, even in the presence of BMSFs, demonstrating the importance ROS for chaetocin activities. Chaetocin effects on self-renewal of CML-LSKs were assessed by transplanting CML-LSKs into secondary recipients following ex vivo exposure to chaetocin, in the presence or absence of BMSFs. Disease latency in mice transplanted with CML-LSKs following chaetocin treatment more than doubled compared with untreated CML-LSKs or BMSFs-treated CML-LSKs. Mice transplanted with CML-LSKs following chaetocin treatment in the presence of BMSFs had significantly extended survival time compared with mice transplanted with CML-LSKs treated with chaetocin alone. Our findings indicate that chaetocin activity against CML-LSKs is significantly enhanced in the presence of BMSFs and suggest that chaetocin may be effective as a codrug to complement TKIs in CML treatment by disrupting the innate resistance of CML-LSKs through an ROS dependent mechanism.

PMID: 25329721 [PubMed - as supplied by publisher]

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Second-generation tyrosine kinase inhibitors in first-line treatment of chronic myeloid leukaemia (CML).

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Second-generation tyrosine kinase inhibitors in first-line treatment of chronic myeloid leukaemia (CML).

BioDrugs. 2014 Feb;28(1):17-26

Authors: Abruzzese E, Breccia M, Latagliata R

Abstract

Tyrosine kinase inhibitors (TKIs) have contributed to marked improvements in survival in patients with chronic myeloid leukaemia (CML). This article discusses the place of the second-generation TKIs dasatinib and nilotinib in the first-line treatment of CML and is based on published literature. The new agents are more potent and effective than imatinib. Data from pivotal clinical trials indicate that response to dasatinib and nilotinib is greater and more rapid than that to imatinib, resulting in a higher probability of patients achieving an optimal response to treatment. Differences between the newer agents with respect to patient groups for whom caution is advised, drug interaction potential, haematological toxicity, pulmonary toxicity, changes in the immune system and effects on laboratory parameters are discussed. With similar levels of efficacy, the choice of second-generation agents should be guided by the characteristics of the individual patient and the most suitable dosing regimen.

PMID: 24043361 [PubMed - indexed for MEDLINE]

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Development of NK cell expansion methods using feeder cells from human myelogenous leukemia cell line.

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Development of NK cell expansion methods using feeder cells from human myelogenous leukemia cell line.

Blood Res. 2014 Sep;49(3):154-61

Authors: Bae DS, Lee JK

Abstract

BACKGROUND: Natural killer (NK) cells constantly survey surrounding tissues and remove newly generated cancer cells, independent of cancer antigen recognition. Although there have been a number of attempts to apply NK cells for cancer therapy, clinical application has been somewhat limited because of the difficulty in preparing a sufficient number of NK cells. Therefore, ex vivo NK cell expansion is one of the important steps for developing NK cell therapeutics.

METHODS: CD3(+) depleted lymphocytes were cocultured with IL-2 and with feeder cells (peripheral blood mononuclear cells [PBMCs], K562, and Jurkat) for 15 days. Expanded NK cells were tested for cytotoxicity against cancer cell lines.

RESULTS: We compared feeder activities of three different cells-PBMC, K562, and Jurkat. K562 expanded NK cells by almost 20 fold and also showed powerful cytotoxic activity against cancer cells. K562-NK cells remarkably expressed the NK cell activation receptors, NKG2D, and DNAM-1. K562-NK cells exhibited more than two-fold production of cytotoxic granules compared with Jurkat-NK cells, producing more perforin and granzyme B than naïve NK cells.

CONCLUSION: Our findings suggest that K562 are more efficient feeder cells than Jurkat or PBMCs. K562 feeder cells expanded NK cells by almost 20 fold and showed powerful cytotoxic activity against cancer cells. We herein propose an intriguing approach for a design of NK cell expansion.

PMID: 25325034 [PubMed]

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New Strategies in Acute Myelogenous Leukemia: Leukemogenesis and Personalized Medicine.

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New Strategies in Acute Myelogenous Leukemia: Leukemogenesis and Personalized Medicine.

Clin Cancer Res. 2014 Oct 16;

Authors: Gojo I, Karp JE

Abstract

Recent advances in molecular technology have unraveled the complexity of leukemogenesis and provided the opportunity to design more personalized and pathophysiology-targeted therapeutic strategies. Despite the use of intensive chemotherapy, relapse remains the most common cause for therapeutic failure in acute myelogenous leukemia (AML). The interactions between leukemia stem cells (LSC) and marrow microenvironment appear to be critical in promoting therapeutic resistance through progressive acquisition of genetic and epigenetic changes within leukemia cells and immune evasion, resulting in leukemia cell survival. With advances in genomic sequencing efforts, epigenetic and phenotypic characterization, personalized therapeutic strategies aimed at critical leukemia survival mechanisms may be feasible in the near future. Here, we review select novel approaches to therapy of AML such as targeting LSC, altering leukemia/marrow microenvironment interactions, inhibiting DNA repair or cell cycle checkpoints, and augmenting immune-based anti-leukemia activity.

PMID: 25324141 [PubMed - as supplied by publisher]

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Targeted therapies: Imatinib prior to allogeneic HSCT therapy improves both relapse and nonrelapse survival in patients with Ph+ ALL.

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Targeted therapies: Imatinib prior to allogeneic HSCT therapy improves both relapse and nonrelapse survival in patients with Ph+ ALL.

Nat Rev Clin Oncol. 2014 May;11(5):241

Authors: Killock D

PMID: 24642681 [PubMed - indexed for MEDLINE]

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NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia.

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NRASG12V oncogene facilitates self-renewal in a murine model of acute myelogenous leukemia.

Blood. 2014 Oct 14;

Authors: Sachs Z, LaRue RS, Nguyen HT, Sachs K, Noble KE, Mohd Hassan NA, Diaz-Flores E, Rathe SK, Sarver AL, Bendall SC, Ha NA, Diers MD, Nolan GP, Shannon KM, Largaespada DA

Abstract

Mutant RAS oncoproteins activate signaling molecules that drive oncogenesis in multiple human tumors including acute myelogenous leukemia (AML). However, the specific functions of these pathways in AML are unclear, thwarting the rational application of targeted therapeutics. To elucidate the downstream functions of activated NRAS in AML, we employed a murine model that harbors Mll-AF9 and a tetracycline repressible, activated NRAS (NRAS(G12V)). By employing computational approaches to explore our gene expression datasets, we found that NRAS(G12V) enforced the leukemia self-renewal gene expression signature and was required to maintain an MLL-AF9 and MYB-dependent leukemia self-renewal gene expression program. NRAS(G12V) was required for leukemia self-renewal independently of its effects on growth and survival. Analysis of the gene expression patterns of leukemic subpopulations revealed the NRAS(G12V)-mediated leukemia self-renewal signature is preferentially expressed in the leukemia stem cell-enriched subpopulation. In a multiplexed analysis of RAS-dependent signaling, Mac-1(Low) cells, which harbor leukemia stem cells, were preferentially sensitive to NRAS(G12V) withdrawal. NRAS(G12V) maintained leukemia self-renewal through mTOR and MEK pathway activation, implicating these pathways as potential targets for cancer stem cell-specific therapies. Together, these experimental results define a RAS oncogene-driven function that is critical for leukemia maintenance and represents a novel mechanism of oncogene addiction.

PMID: 25316678 [PubMed - as supplied by publisher]

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Enlarged memory T-cell pool and enhanced Th1-type responses in chronic myeloid leukemia patients who have successfully discontinued IFN-? monotherapy.

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Enlarged memory T-cell pool and enhanced Th1-type responses in chronic myeloid leukemia patients who have successfully discontinued IFN-? monotherapy.

PLoS One. 2014;9(1):e87794

Authors: Ilander M, Kreutzman A, Rohon P, Melo T, Faber E, Porkka K, Vakkila J, Mustjoki S

Abstract

A small proportion of chronic myeloid leukemia patients treated with interferon-? (IFN-?) monotherapy are able to discontinue the treatment without disease relapse although residual leukemia cells are present. Recently, we showed that these patients have increased amount of NK-cells and a distinct blood cytokine profile. We now aimed to study the function of NK- and T-cells in order to understand the role of the immune system in maintaining the treatment response after IFN-? discontinuation. The study included 13 patients: 5 patients were still treated with IFN-? monotherapy (IFN-ON, median treatment time 163 months) and 8 had stopped the treatment successfully (IFN-OFF, median time without therapy 42 months). Detailed immunophenotype and cytokine production of NK- and T-cells was analyzed with flow cytometry. In addition, the cytotoxicity of NK-cells was studied using K562 as target cells and both the degranulation and direct killing was measured. Compared to healthy controls, IFN-OFF patients had increased proportion of CD4(+) effector memory (CCR7(-)CD45RA(-); median 23% vs. healthy 16%, p = 0.009) and CD8(+) central memory T-cells (CCR7(+)CD45RA(-); median 26% vs. healthy 14%, p = 0.004). Further, upon stimulation the IFN-?/TNF-? cytokine secretion by CD4(+) T-cells was significantly enhanced in IFN-OFF patients (median 13.7% vs. healthy 7.8%, p = 0.01), and CD4+ effector and central memory cells were the main cytokine producers. No similar increase was observed in IFN-ON group (6.5%). In addition, the proportion of NK-cells was significantly increased in IFN-OFF patients (median IFN-OFF 24%, healthy 13%, p = 0.04), but their direct killing of K562 cells was impaired. The cytotoxicity of NK-cells was also diminished in IFN-ON patients. To conclude, in addition to elevated NK-cell count, IFN-OFF patients have increased amount of memory T-cells, which are able to induce strong cytokine response upon stimulation. This activity may contribute to the maintenance of prolonged remission after successful IFN-? discontinuation.

PMID: 24498197 [PubMed - indexed for MEDLINE]

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Functional characterization of a novel FGFR1OP-RET rearrangement in hematopoietic malignancies.

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Functional characterization of a novel FGFR1OP-RET rearrangement in hematopoietic malignancies.

Mol Oncol. 2014 Mar;8(2):221-31

Authors: Bossi D, Carlomagno F, Pallavicini I, Pruneri G, Trubia M, Raviele PR, Marinelli A, Anaganti S, Cox MC, Viale G, Santoro M, Di Fiore PP, Minucci S

Abstract

The RET (REarranged during Transfection) receptor tyrosine kinase is targeted by oncogenic rearrangements in thyroid and lung adenocarcinoma. Recently, a RET (exon 12) rearrangement with FGFR1OP [fibroblast growth factor receptor 1 (FGFR1) oncogene partner] (exon 12) was identified in one chronic myelomonocytic leukemia (CMML) patient. We report the molecular cloning and functional characterization of a novel FGFR1OP (exon 11)-RET (exon 11) gene fusion event (named FGFR1OP-RET), mediated by a reciprocal translocation t(6; 10)(q27; q11), in a patient affected by primary myelofibrosis (PMF) with secondary acute myeloid leukemia (AML). The FGFR1OP-RET fusion protein displayed constitutive tyrosine kinase and transforming activity in NIH3T3 fibroblasts, and induced IL3-independent growth and activation of PI3K/STAT signaling in hematopoietic Ba/F3 cells. FGFR1OP-RET supported cytokine-independent growth, protection from stress and enhanced self-renewal of primary murine hematopoietic progenitor and stem cells in vitro. In vivo, FGFR1OP-RET caused a spectrum of disease phenotypes, with >50% of mice showing a fatal myeloproliferative disorder (MPD). Other phenotypes were leukemia transplantable in secondary recipients, dramatic expansion of the mast cell lineage, and reduction of repopulating activity upon lethal irradiation. In conclusion, FGFR1OP-RET chimeric oncogenes are endowed with leukemogenic potential and associated to myeloid neoplasms (CMML and PMF/AML).

PMID: 24315414 [PubMed - indexed for MEDLINE]

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Ever-advancing chronic myeloid leukemia treatment.

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Ever-advancing chronic myeloid leukemia treatment.

Int J Clin Oncol. 2014 Feb;19(1):3-9

Authors: Kimura S, Ando T, Kojima K

Abstract

Treatment of chronic myeloid leukemia (CML) has been drastically changed by the emergence of the ABL tyrosine kinase inhibitor (TKI), imatinib mesylate. However, resistance and intolerance have frequently been reported, particularly in patients with advanced-stage disease. Point mutations within the ABL kinase domain that interfere with imatinib binding are the most critical cause of imatinib resistance. To overcome this resistance, four second-generation ATP competitive ABL TKIs, dasatinib, nilotinib, bosutinib and bafetinib, have been developed. Dasatinib and nilotinib also demonstrated higher efficacy than imatinib in previously untreated CML patients in chronic phase. Despite promising clinical results, the frequently observed mutant T315I is not effectively targeted by any of the second-generation ABL TKIs. Thus, a third-generation ABL TKI, ponatinib, was developed to inhibit all mutated BCR-ABL and showed clinical efficacy in CML cells harbouring T315I. CML treatment is rapidly progressing and further evolution is surely expected. Moreover, it was recently reported that some CML patients who achieved sustained complete molecular response could stop TKI. CML may become the first human cancer to be conquered solely with oral medicines.

PMID: 24258348 [PubMed - indexed for MEDLINE]

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