Recurrent ETNK1 mutations in atypical chronic myeloid leukemia.

Posted by rob on March 13, 2015 under Uncategorized | Comments are off for this article

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Recurrent ETNK1 mutations in atypical chronic myeloid leukemia.

Blood. 2015 Jan 15;125(3):499-503

Authors: Gambacorti-Passerini CB, Donadoni C, Parmiani A, Pirola A, Redaelli S, Signore G, Piazza V, Malcovati L, Fontana D, Spinelli R, Magistroni V, Gaipa G, Peronaci M, Morotti A, Panuzzo C, Saglio G, Usala E, Kim DW, Rea D, Zervakis K, Viniou N, Symeonidis A, Becker H, Boultwood J, Campiotti L, Carrabba M, Elli E, Bignell GR, Papaemmanuil E, Campbell PJ, Cazzola M, Piazza R

Abstract

Despite the recent identification of recurrent SETBP1 mutations in atypical chronic myeloid leukemia (aCML), a complete description of the somatic lesions responsible for the onset of this disorder is still lacking. To find additional somatic abnormalities in aCML, we performed whole-exome sequencing on 15 aCML cases. In 2 cases (13.3%), we identified somatic missense mutations in the ETNK1 gene. Targeted resequencing on 515 hematological clonal disorders revealed the presence of ETNK1 variants in 6 (8.8%) of 68 aCML and 2 (2.6%) of 77 chronic myelomonocytic leukemia samples. These mutations clustered in a small region of the kinase domain, encoding for H243Y and N244S (1/8 H243Y; 7/8 N244S). They were all heterozygous and present in the dominant clone. The intracellular phosphoethanolamine/phosphocholine ratio was, on average, 5.2-fold lower in ETNK1-mutated samples (P < .05). Similar results were obtained using myeloid TF1 cells transduced with ETNK1 wild type, ETNK1-N244S, and ETNK1-H243Y, where the intracellular phosphoethanolamine/phosphocholine ratio was significantly lower in ETNK1-N244S (0.76 ± 0.07) and ETNK1-H243Y (0.37 ± 0.02) than in ETNK1-WT (1.37 ± 0.32; P = .01 and P = .0008, respectively), suggesting that ETNK1 mutations may inhibit the catalytic activity of the enzyme. In summary, our study shows for the first time the evidence of recurrent somatic ETNK1 mutations in the context of myeloproliferative/myelodysplastic disorders.

PMID: 25343957 [PubMed - indexed for MEDLINE]

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Inhibition of 32Dp210 cells harboring T315I mutation by a novel derivative of emodin correlates with down-regulation of BCR-ABL and its downstream signaling pathways.

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Inhibition of 32Dp210 cells harboring T315I mutation by a novel derivative of emodin correlates with down-regulation of BCR-ABL and its downstream signaling pathways.

J Cancer Res Clin Oncol. 2015 Feb;141(2):283-93

Authors: Li J, Chen Y, Chen B, Chen C, Qiu B, Zheng Z, Zheng J, Liu T, Wang W, Hu J

Abstract

PURPOSE: The clinical outcome of chronic myeloid leukemia (CML) patients has been changed dramatically due to the development of imatinib (IM). However, the emergence of IM resistance, commonly associated with point mutations within the BCR-ABL kinase domain, remains a major clinical problem. Here, we investigated the effects of E35, a novel derivative of emodin, on the IM-resistant 32Dp210-T315I cells.

METHODS: Cell proliferation was measured by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide and colony formation assay. Induction of apoptosis was confirmed by DNA fragmentation assay and annexin V/PI staining assay. Real-time quantitative PCR was used to access the BCR-ABL gene expression. Changes of related signaling molecules were detected through Western blot.

RESULTS: E35 was found to potently inhibit proliferation of 32Dp210-T315I cells with an average IC50 of 2.4 µM at 48 h. Colony formation was almost fully suppressed in 1.0 ?M E35 group. DNA fragmentation and annexin V/PI staining assay exhibited the typical DNA fragmentation and the increased proportion of early apoptotic cells, respectively. The induction of apoptosis was associated with increase of Bax to Bcl-2 expression ratio and activation of caspase cascades involving decrease of pro-caspase 9 and pro-caspase 3 and increase of PARP cleavage. The protein expression of P210(BCR-ABL) and p-P210(BCR-ABL) was down-regulated in the presence of E35, although the mRNA levels remained almost unchanged. Moreover, the activation of the P210(BCR-ABL) downstream signaling pathways including CrkL, Akt/mTOR and MEK/ERK was fully suppressed by E35.

CONCLUSION: Our study indicated that E35 might be a potential antileukemia agent against IM resistance in CML.

PMID: 25217883 [PubMed - indexed for MEDLINE]

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Efficacy and pharmacologic data of second-generation tyrosine kinase inhibitor nilotinib in BCR-ABL-positive leukemia patients with central nervous system relapse after allogeneic stem cell transplantation.

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Efficacy and pharmacologic data of second-generation tyrosine kinase inhibitor nilotinib in BCR-ABL-positive leukemia patients with central nervous system relapse after allogeneic stem cell transplantation.

Biomed Res Int. 2014;2014:637059

Authors: Reinwald M, Schleyer E, Kiewe P, Blau IW, Burmeister T, Pursche S, Neumann M, Notter M, Thiel E, Hofmann WK, Kolb HJ, Burdach S, Bender HU

Abstract

Central nervous system (CNS) involvement is a severe complication of BCR-ABL-positive leukemia after allogenic stem cell transplantation (alloSCT) associated with fatal outcome. Although second-generation tyrosine-kinase inhibitors (TKI) such as nilotinib have shown activity in systemic BCR-ABL(+) disease, little data exists on their penetration and efficacy within the CNS. Four patients (3 male, 1 female; age 15-49) with meningeal relapse after alloSCT and subsequent treatment with nilotinib were identified. A total of 17 cerebrospinal fluid (csf) and serum samples were assessed for nilotinib concentration and patient outcome was recorded. Nilotinib concentrations showed a low median csf/plasma ratio of 0.53% (range 0.23-1.5%), yet pronounced clinical efficacy was observed with long-lasting responses (>1 year) in three patients. Comparison with historical data showed a trend towards superior efficacy of nilotinib versus imatinib. Despite poor csf penetration, nilotinib showed significant clinical activity in CNS relapse of BCR-ABL(+) leukemias. As nilotinib has a high protein-binding affinity, the low-protein concentration in csf could translate into a relatively higher amount of free and therefore active nilotinib in csf as compared to blood, possibly explaining the observed efficacy. Thus, treatment with a 2nd generation TKI warrants further investigation and should be considered in cases of CNS relapse of BCR-ABL-positive leukemia after alloSCT.

PMID: 25025064 [PubMed - indexed for MEDLINE]

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A case of childhood vitrectomy performed for dense vitreous hemorrhage secondary to leukemia therapy and tumor lysis syndrome.

Posted by rob on March 12, 2015 under Uncategorized | Comments are off for this article

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A case of childhood vitrectomy performed for dense vitreous hemorrhage secondary to leukemia therapy and tumor lysis syndrome.

Case Rep Ophthalmol. 2015 Jan-Apr;6(1):34-8

Authors: Kudo T, Suzuki Y, Metoki T, Nakazawa M

Abstract

PURPOSE: To report a case of vitrectomy performed in a child with dense massive vitreous hemorrhage due to secondary acute myelogenous leukemia (AML) and tumor lysis syndrome.

CASE: A 4-year-old boy with clear-cell renal cell carcinoma was successfully treated with chemotherapy in 2011. However, in May 2012, he developed secondary AML. Although he was treated with combined chemotherapy and radiation, tumor lysis syndrome occurred with renal and heart failure complications. After an ultrasound examination by pediatricians found bilateral subretinal protrusions, he was referred to our clinic. Fundus examinations confirmed that the protrusions were bilateral subretinal or choroidal hemorrhages. A few weeks later, dense vitreous hemorrhages occurred bilaterally, and he completely lost vision in both eyes. Electroretinograms were extinguished in both eyes. After improvement of his general condition, we performed a 25-gauge vitrectomy combined with lens extraction in his left eye in December 2012. After removal of the vitreous hemorrhage, we found the subretinal hemorrhage had already been absorbed, leaving a mottled fundus color. However, the optic disc was not pale. Nine months after the surgery, his best-corrected visual acuity finally improved to 0.1.

CONCLUSION: We successfully treated a case of severe vitreous hemorrhage secondary to leukemia therapy and tumor lysis syndrome using 25-gauge vitrectomy. This procedure may be safe and effective to perform, even in children with complications.

PMID: 25759668 [PubMed]

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Barriers to Physician Adherence to Evidence-Based Monitoring Guidelines in Chronic Myelogenous Leukemia.

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Barriers to Physician Adherence to Evidence-Based Monitoring Guidelines in Chronic Myelogenous Leukemia.

J Oncol Pract. 2015 Mar 10;

Authors: Goldberg SL, Akard LP, Dugan MJ, Faderl S, Pecora AL

Abstract

PURPOSE: Although monitoring of cytogenetic/molecular responses to therapy in chronic myelogenous leukemia (CML) facilitates superior outcomes, less than one half of CML patients are monitored using published evidence-based guidelines. Barriers to physician adherence with guidelines are unknown.

METHODS: An anonymous survey was mailed to 515 hematologist-oncologists in New Jersey and Indiana exploring attitudes toward monitoring guidelines.

RESULTS: Ninety-six physicians (19%) responded-89% in community practice, 83% with more than 10 years of experience, and 92% caring for CML patients. Eighty-four percent self-reported using CML monitoring guidelines, 14% were familiar with but did not adopt guidelines and 2% were unfamiliar. Eighty-four percent performed molecular monitoring quarterly as recommended; 6% did not perform molecular monitoring at all during the first year. Guidelines were considered evidence based by 98%, but only 54% strongly considered them easy to find; only 51% strongly felt they addressed all aspects of disease management. Patient resource barriers were a significant deterrent toward implementation with 30% citing high costs. Physician resources, including lack of time to search guidelines, limited use in one fifth. Despite 90% believing an online database helpful, between one third and one half did not feel that additional training, professional society endorsements, or availability of expert consultations would encourage use.

CONCLUSIONS: Significant barriers to adherence with evidence-based CML guidelines exist. Resource barriers, lack of familiarity and lack of agreement restrict adoption, but efforts to facilitate use are not desired. Multifaceted educational strategies, including automated computerized reminders at point of care, are needed to improve quality outcomes in CML.

PMID: 25758446 [PubMed - as supplied by publisher]

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The role of Beclin 1 in SDT induced apoptosis and autophagy in human leukemia cells.

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The role of Beclin 1 in SDT induced apoptosis and autophagy in human leukemia cells.

Int J Radiat Biol. 2015 Mar 11;:1-32

Authors: Su X, Wang X, Liu Q, Wang P, Xu C, Leung AW

Abstract

PURPOSE: To prove the occurrence of autophagy after treatment by protoporphyrin IX (PpIX)- mediated sonodynamic therapy (SDT) of human chronic myelogenous leukemia K562 cells as well as its relationship with apoptosis.

MATERIALS AND METHODS: The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenylter-trazolium bromide tetrazolium (MTT) assay was adopted to examine cytotoxicity of different treatments. Nuclear morphology changes were observed under a fluorescence microscopy with 4′-6-Diamidino-2-Phenylindole (DAPI) staining. Western blotting was used to analyze the expression of caspase-3, Beclin 1 (BECN 1) and the conversion of LC3-phosphatidylethanolamine conjugate / a cytosolic form of LC3 (LC3 II / I). Fluorescence microscope was used to identify the formation of autophagic vacuoles (AVO) during autophagy.

RESULTS: Under optimal conditions, SDT was shown to induce autophagy in K562 cells, which caused the up-regulation of Beclin-1 and the formation of AVO. In addition, pre-treatment of cancer cells with beclin 1-targeted short hairpin RNA (Beclin 1 shRNA) was shown to reduce the level of LC3-II accumulation and staining with punctate spots of monodansylcadaverine (MDC) staining. Besides, the cytotoxic effect of SDT was significantly increased by Beclin 1 shRNA. Furthermore, studies showed a marked effect on the apoptosis of cells by Beclin 1 shRNA to sonodamage with increased DAPI staining and caspase-3 cleavage.

CONCLUSIONS: These results demonstrated that SDT significantly induced autophagy of K562 cells, probably to protect the K562 cells from sonodamage.

PMID: 25758178 [PubMed - as supplied by publisher]

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Three hematologic malignancies in the same patient: chronic lymphocytic leukemia, followed by chronic myeloid leukemia and acute myeloid leukemia.

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Three hematologic malignancies in the same patient: chronic lymphocytic leukemia, followed by chronic myeloid leukemia and acute myeloid leukemia.

Clin Lab. 2014;60(11):1929-32

Authors: Fattizzo B, Radice T, Cattaneo D, Pomati M, Barcellini W, Iurlo A

Abstract

The co-existence of both chronic myeloid leukemia (CML) and chronic lymphocytic leukemia (CLL) have been described in a few cases, either simultaneously or subsequently presenting. We report an unusual case of three he-matological malignancies in the same patient: CLL, CML, and acute myeloid leukemia (AML). None of the three malignancies shared the same origin, since the marrow sample was negative for BCR-ABL1 transcript at the time of CLL diagnosis, CLL was in remission at CML diagnosis, and CML was in complete cytogenetic response at AML onset, indicating that this was not a blast crisis. Background: Chronic lymphocytic leukemia (CLL) and chronic myeloid leukemia (CML) are the most common proliferative disorders in Western countries, with an incidence of 4.2/100,000/year and 1-1.5/100,000/year, respectively. The co-existence of both CML and CLL is an extremely rare event, even if it has been described in a few cases, either simultaneously or subsequently presenting. Above all, the presence of more than two different hematologic neoplasms has not been described in literature so far. In the present study we report a particular case of a CLL patient, who first developed CML and then acute myeloid leukemia (AML).

PMID: 25648037 [PubMed - indexed for MEDLINE]

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Outcome of pregnancy in chronic myeloid leukaemia patients treated with tyrosine kinase inhibitors: short report from a single centre.

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Outcome of pregnancy in chronic myeloid leukaemia patients treated with tyrosine kinase inhibitors: short report from a single centre.

Leuk Res. 2015 Jan;39(1):47-51

Authors: Alizadeh H, Jaafar H, Rajnics P, Khan MI, Kajtár B

Abstract

BACKGROUND: The aim of this work was to report on the outcome of pregnancy in patients with chronic myeloid leukaemia who were on tyrosine kinase inhibitor treatment.

PATIENTS AND METHODS: We report the result of 22 pregnancies in 14 patients (9 female and 5 male) who conceived or their partner conceived while being on tyrosine kinase inhibitors for their CML.

RESULTS: All pregnancies except one were uneventful. 25 newborns were born and except in one case where small atrial septal defect was diagnosed, all infants were healthy and showed normal development after birth.

CONCLUSION: This small series does indicate that parents can most likely expect an uneventful outcome to a pregnancy despite exposure of either partner to TKIs. There is no consensus or guideline regarding the best practice in case of pregnancy. More reports of similar nature would certainly be beneficial to practitioners and patients alike. As such it is still recommended to practice effective contraception during the period of TKI treatment.

PMID: 25455655 [PubMed - indexed for MEDLINE]

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Molecular-defined clonal evolution in patients with chronic myeloid leukemia independent of the BCR-ABL status.

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Molecular-defined clonal evolution in patients with chronic myeloid leukemia independent of the BCR-ABL status.

Leukemia. 2014 Dec;28(12):2292-9

Authors: Schmidt M, Rinke J, Schäfer V, Schnittger S, Kohlmann A, Obstfelder E, Kunert C, Ziermann J, Winkelmann N, Eigendorff E, Haferlach T, Haferlach C, Hochhaus A, Ernst T

Abstract

To study clonal evolution in chronic myeloid leukemia (CML), we searched for BCR-ABL-independent gene mutations in both Philadelphia chromosome (Ph)-negative and Ph-positive clones in 29 chronic-phase CML patients by targeted deep sequencing of 25 genes frequently mutated in myeloid disorders. Ph-negative clones were analyzed in 14 patients who developed clonal cytogenetic abnormalities in Ph-negative cells during treatment with tyrosine kinase inhibitors (TKI). Mutations were detected in 6/14 patients (43%) affecting the genes DNMT3A, EZH2, RUNX1, TET2, TP53, U2AF1 and ZRSR2. In two patients, the mutations were also found in corresponding Ph-positive diagnostic samples. To further investigate Ph-positive clones, 15 randomly selected CML patients at diagnosis were analyzed. Somatic mutations additional to BCR-ABL were found in 5/15 patients (33%) affecting ASXL1, DNMT3A, RUNX1 and TET2. Analysis of individual hematopoietic colonies at diagnosis revealed that most mutations were part of the Ph-positive clone. In contrast, deep sequencing of subsequent samples during TKI treatment revealed one DNMT3A mutation in Ph-negative cells that was also present in Ph-positive cells at diagnosis, implying that the mutation preceded the BCR-ABL rearrangement. In summary, BCR-ABL-independent gene mutations were frequently found in Ph-negative and Ph-positive clones of CML patients and may be considered as important cofactors in the clonal evolution of CML.

PMID: 25212276 [PubMed - indexed for MEDLINE]

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AKT-induced reactive oxygen species generate imatinib-resistant clones emerging from chronic myeloid leukemia progenitor cells.

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AKT-induced reactive oxygen species generate imatinib-resistant clones emerging from chronic myeloid leukemia progenitor cells.

Leukemia. 2014 Dec;28(12):2416-8

Authors: Nieborowska-Skorska M, Flis S, Skorski T

PMID: 25151958 [PubMed - indexed for MEDLINE]

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Adiponectin signals through Adiponectin Receptor 1 to reverse imatinib resistance in K562 human chronic myeloid leukemia cells.

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Adiponectin signals through Adiponectin Receptor 1 to reverse imatinib resistance in K562 human chronic myeloid leukemia cells.

Biochem Biophys Res Commun. 2015 Jan 2;456(1):367-72

Authors: Wu S, Zheng C, Chen S, Lin B, Chen Y, Zhou W, Li Z

Abstract

Adiponectin, a member of adipokines, is a functional ligand for Adiponectin Receptor-1 (AdipoR1) and Adiponectin Receptor-2 (AdipoR2), and has been found to be linked to the risk of CML. Imatinib has undoubtedly revolutionised the management and outcome of chronic myeloid leukemia (CML), however imatinib resistance has been recognized as a major problem in CML therapy. In this study, we first established imatinib-resistant K562 CML cells, and then evaluated the effect of Adiponectin in reversing imatinib resistance. The data presented here demonstrated that Adiponectin was able to reverse K562 resistance to imatinib in vitro and in vivo. Additional data with molecular approaches suggested that the reversion of Adiponectin in imatinib resistance signals through AdipoR1 but not AdipoR2 to downregulate Bcr-Abl expression and effect in imatinib-resistant K562 CML cells. Taken together, our data showed that Adiponectin can reverse imatinib resistance in CML, and to a certain extent elucidate the mechanism of Adiponectin reversing imatinib resistance that may provide a new and promising approach in imatinib resistance management in CML therapy.

PMID: 25475722 [PubMed - indexed for MEDLINE]

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Development of chronic myelogenous leukemia during treatment with TPO receptor agonist for ITP.

Posted by rob on March 7, 2015 under Uncategorized | Comments are off for this article

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Development of chronic myelogenous leukemia during treatment with TPO receptor agonist for ITP.

Rinsho Ketsueki. 2014 Dec;55(12):2429-32

Authors: Hattori H, Kuwayama M, Takamori H, Nishiura N, Karasuno T

Abstract

We report a 77-year-old Japanese man with idiopathic thrombocytopenic purpura (ITP) which developed into chronic myelogenous leukemia (CML) during treatment with eltrombopag, a thrombopoetin (TPO) receptor agonist, because the disease was refractory to prednisolone. Eltrombopag can induce a good reaction in terms of the platelet count. However, CML in the chronic phase developed in about 19 months in our present case. Dasatinib was administered because he had diabetes. However, a blastic crisis immediately occurred. He died despite switching to Nilotinib. Recently, the occurrence of myelofibrosis and hematological malignancies due to long-term use of TPO receptor agonists has become a concern. This is the first report of a TPO receptor agonist possibly contributing to CML onset and crisis.

PMID: 25744045 [PubMed - in process]

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Osteoblast ablation reduces normal long-term hematopoietic stem cell self-renewal but accelerates leukemia development.

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Osteoblast ablation reduces normal long-term hematopoietic stem cell self-renewal but accelerates leukemia development.

Blood. 2015 Mar 5;

Authors: Bowers M, Zhang B, Ho Y, Agarwal P, Chen CC, Bhatia R

Abstract

Hematopoietic stem cells (HSCs) reside in regulatory niches in the bone marrow (BM). Although HSC niches have been extensively characterized, the role of endosteal osteoblasts (OBs) in HSC regulation requires further clarification, and the role of OBs in regulating leukemic stem cells (LSC) is not well studied. We used an OB visualization and ablation mouse model to study the role of OBs in regulating normal HSC and chronic myelogenous leukemia (CML) LSC. OB ablation resulted in increase in cells with a LSK Flt3-CD150+CD48- long-term HSC (LTHSC) phenotype, but reduction of a more highly selected LSK Flt3-CD34-CD49b-CD229- LTHSC subpopulation. LTHSCs from OB-ablated mice demonstrated loss of quiescence, and reduced long-term engraftment and self-renewal capacity. Ablation of OB in a transgenic CML mouse model resulted in accelerated leukemia development with reduced survival compared to control mice. The notch ligand Jagged-1 was overexpressed on CML OB. Normal and CML LTHSC cultured with Jagged-1 demonstrated reduced cell cycling, consistent with a possible role for loss of Jagged-1 signals in altered HSC and LSC function after OB ablation. These studies support an important role for OBs in regulating quiescence and self-renewal of LTHSCs, and a previously unrecognized role in modulating leukemia development in CML.

PMID: 25742698 [PubMed - as supplied by publisher]

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Hemoperitoneum: an unusual presentation of chronic granulocytic leukemia in a pediatric patient.

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Hemoperitoneum: an unusual presentation of chronic granulocytic leukemia in a pediatric patient.

Pediatr Emerg Care. 2014 Jun;30(6):418-20

Authors: Ramirez EC, Bastidas MA, Santiago NC, Machorro RD, Del Mazo Ruiz P, Shalkow-Klincovstein J

Abstract

Chronic granulocytic leukemia (CGL) is a rare hematologic disease in pediatric patients. It usually presents with insidious symptoms. However, some cases may have an atypical presentation. We report herein the case of a 13-year-old female admitted to the emergency department with acute abdomen. She had hyperleukocytosis of 500.0 × 1000 cells/mm suggestive of CGL. A paracentesis was performed due to abdominal compartment syndrome that demonstrated hemoperitoneum. At laparotomy, a ruptured ovarian mass was found with multiple tumor implants in the serosal surface. Pathology revealed a CGL-infiltrated ovary. The patient is currently stable, has finished adjuvant chemotherapy, and is at 24 months of follow-up. To our knowledge, this is the first report of such a case.

PMID: 24892682 [PubMed - indexed for MEDLINE]

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Current Role of Radiation Therapy for Multiple Myeloma.

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Current Role of Radiation Therapy for Multiple Myeloma.

Front Oncol. 2015;5:40

Authors: Talamo G, Dimaio C, Abbi KK, Pandey MK, Malysz J, Creer MH, Zhu J, Mir MA, Varlotto JM

Abstract

Background: Radiation therapy (RT) is a treatment modality traditionally used in patients with multiple myeloma (MM), but little is known regarding the role and effectiveness of RT in the era of novel agents, i.e., immunomodulatory drugs and proteasome inhibitors. Methods: We retrospectively reviewed data from 449 consecutive MM patients seen at our institute in 2010-2012 to assess indications for RT as well as its effectiveness. Pain response was scored similarly to RTOG 0631 and used the Numerical Rating Pain Scale. Results: Among 442 evaluable patients, 149 (34%) patients and 262 sites received RT. The most common indication for RT was palliation of bone pain (n?=?109, 42%), followed by prevention/treatment of pathological fractures (n?=?73, 28%), spinal cord compression (n?=?26, 10%), and involvement of vital organs/extramedullary disease (n?=?25, 10%). Of the 55 patients evaluable for pain relief, complete and partial responses were obtained in 76.4 and 7.2%, respectively. Prior RT did not significantly decrease the median number of peripheral blood stem cells collected for autologous transplant, even when prior RT was given to both the spine and pelvis. Inadequacy of stem cell collection for autologous stem cell transplant (ASCT) was not significantly different and it occurred in 9 and 15% of patients receiving no RT and spine/pelvic RT, respectively. None of the three cases of therapy-induced acute myelogenous leukemia/MDS occurred in the RT group. Conclusion: Despite the introduction of novel effective agents in the treatment of MM, RT remains a major therapeutic component for the management in 34% of patients, and it effectively provides pain relief while not interfering with successful peripheral blood stem cell collection for ASCT.

PMID: 25741475 [PubMed - as supplied by publisher]

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Low-dose Arsenic trioxide combined with aclacinomycin A synergistically enhance the cytotoxic effect on human acute myelogenous leukemia cell line by induction of apoptosis.

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Low-dose Arsenic trioxide combined with aclacinomycin A synergistically enhance the cytotoxic effect on human acute myelogenous leukemia cell line by induction of apoptosis.

Leuk Lymphoma. 2015 Mar 5;:1-26

Authors: Ye Y, Xu X, Zhang M, Qiu D, Bai X, Wang J, Weng G, Zhou R, Guo Z, He H, Yi W, He X, Guo K

Abstract

ABSTRACT Acute myeloid leukemia (AML) is a common disorder in the elderly. Although remarkable progress has been made over the past decades, the outcome remains poor. Thus, the development of a more effective method to overcome this problem is necessary. In this study, we aim to investigate the synergistic cytotoxic effect of low-dose arsenic trioxide (As2O3) combined with aclacinomycin A (ACM) on the human AML cell lines KG-1a and HL-60, and to clarify the underlying mechanism. The results showed that As2O3 combined ACM exerting synergistical cytotoxic effect by activation of apoptosis pathway. additionally, we found that the combination treatment decreased Bcl-2, c-IAP, and XIAP expression but increased SMAC and caspase-3 expression more significantly than the single drug treatments. Furthermore, the combination index (CI) values were < 1 in all matched combination groups. Additional evaluation of As2O3 combined with ACM as a potential benefit for AML seems warranted.

PMID: 25739941 [PubMed - as supplied by publisher]

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Ponatinib-Induced Pityriasiform, Folliculocentric and Ichthyosiform Cutaneous Toxicities.

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Ponatinib-Induced Pityriasiform, Folliculocentric and Ichthyosiform Cutaneous Toxicities.

Br J Dermatol. 2015 Mar 4;

Authors: Alloo A, Sheu J, Butrynski JE, DeAngelo DJ, George S, Murphy GF, LeBoeuf NR

Abstract

Ponatinib, a potent third-generation tyrosine kinase inhibitor (TKI), has demonstrated significant efficacy in chronic myelogenous leukaemia (CML), Philadelphia-chromosome positive acute lymphocytic leukaemia (ALL) and is currently being employed in solid organ tumor trials. Among the most common side effects reported are a non-specific “rash” or “dry skin”.(1-2) We report five patients, treated with ponatinib, who developed prominent pityriasis rubra pilaris (PRP)-like, hyperkeratotic, folliculocentric and ichthyosiform eruptions. This article is protected by copyright. All rights reserved.

PMID: 25736577 [PubMed - as supplied by publisher]

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Successful maintenance of molecular remission in chronic myelogenous leukaemia during pregnancy with transition from imatinib to pegylated interferon.

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Successful maintenance of molecular remission in chronic myelogenous leukaemia during pregnancy with transition from imatinib to pegylated interferon.

Intern Med J. 2015 Mar;45(3):358-9

Authors: Ellis M, Mills AK

PMID: 25735582 [PubMed - in process]

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Myeloid derived suppressor cells (MDSCs) are increased and exert immunosuppressive activity together with polymorphonuclear leukocytes (PMNs) in chronic myeloid leukemia patients.

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Myeloid derived suppressor cells (MDSCs) are increased and exert immunosuppressive activity together with polymorphonuclear leukocytes (PMNs) in chronic myeloid leukemia patients.

PLoS One. 2014;9(7):e101848

Authors: Giallongo C, Parrinello N, Tibullo D, La Cava P, Romano A, Chiarenza A, Barbagallo I, Palumbo GA, Stagno F, Vigneri P, Di Raimondo F

Abstract

Tumor immune tolerance can derive from the recruitment of suppressor cell population, including myeloid derived suppressor cells (MDSCs), able to inhibit T cells activity. We identified a significantly expanded MDSCs population in chronic myeloid leukemia (CML) patients at diagnosis that decreased to normal levels after imatinib therapy. In addition, expression of arginase 1 (Arg1) that depletes microenvironment of arginine, an essential aminoacid for T cell function, resulted in an increase in patients at diagnosis. Purified CML CD11b+CD33+CD14-HLADR- cells markedly suppressed normal donor T cell proliferation in vitro. Comparing CML Gr-MDSCs to autologous polymorphonuclear leukocytes (PMNs) we observed a higher Arg1 expression and activity in PMNs, together with an inhibitory effect on T cells in vitro. Our data indicate that CML cells create an immuno-tolerant environment associated to MDSCs expansion with immunosuppressive capacity mediated by Arg1. In addition, we demonstrated for the first time also an immunosuppressive activity of CML PMNs, suggesting a strong potential immune escape mechanism created by CML cells, which control the anti-tumor reactive T cells. MDSCs should be monitored in imatinib discontinuation trials to understand their importance in relapsing patients.

PMID: 25014230 [PubMed - indexed for MEDLINE]

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Rich Spectroscopic and Molecular Dynamic Studies on the Interaction of Cytotoxic Pt(II) and Pd(II) Complexes of Glycine derivatives with Calf Thymus DNA.

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Rich Spectroscopic and Molecular Dynamic Studies on the Interaction of Cytotoxic Pt(II) and Pd(II) Complexes of Glycine derivatives with Calf Thymus DNA.

J Biomol Struct Dyn. 2015 Mar 3;:1-42

Authors: Eslami Moghadam M, Saidifar M, Divsalar A, Mansouri-Torshizi H, Saboury AA, Farhangian H, Ghadamgahi M

Abstract

Some amino acid derivatives, such as R-glycine, have been synthesized together with their full spectroscopic characterization. The sodium salts of these bidentate amino acid ligands have been interacted with [M(bpy)(H2O)2](NO3)2 giving the corresponding some new complexes with formula [M(bpy)(R-gly)]NO3 (where M is Pt(II) or Pd(II), bpy is 2,2′-bipyridine and R-gly is butyl-, hexyl- and octyl-glycine). Due to less solubility of octyl derivatives, the biological activities of butyl and hexyl derivatives have been tested against chronic myelogenous leukemia cell line, K562. The interaction of these complexes with highly polymerized calf thymus DNA has been extensively studied by means of electronic absorption, fluorescence and other measurements. The experimental results suggest that these complexes positive cooperatively bind to DNA presumably via groove binding. Molecular dynamic results show that the DNA structure is largely maintained its native structure in hexylglycine derivative-water mixtures and at lower temperatures. The simulation data indicates that the more destabilizing effect of butylglycine is induced by preferential accumulation of these molecules around the DNA and due to their more negative free energy of binding via groove binding.

PMID: 25734364 [PubMed - as supplied by publisher]

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