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1
Engelhardt, LM, PC Healy, JD Kildea, BW Skelton, and AH White. "Lewis-Base Adducts of Group 11 Metal(I) Compounds. LV. Synthesis and Structures of 1 : 1 Copper(I) Halide (Cl, Br, I)/2-Aminoquinoline Complexes." Australian Journal of Chemistry 42, no. 6 (1989): 933. http://dx.doi.org/10.1071/ch9890933.
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1 : 1 Adducts of the copper(I) halides, CuX (X=CI, Br, I), with 2-aminoquinoline (amq) have been synthesized by the crystallization of stoichiometric mixtures of these components from acetonitrile solution, and their structures determined by single-crystal X-ray methods; they are found to span a diverse array of structural types. The chloride crystallizes as a 'stair polymer' array [monoclinic, P21, a 7.487(6), b 3.771(7), c 15.506(2) � , 95.07(4)�, Z= 2]. The bromide is a centrosymmetric dimer , solvated by acetonitrile, [( amq )( MeCN )CuBr2Cu( MeCN )( amq )] [triclinic, PI, a 17.325(8), b 10.376(3), c 7.204(9) �, α 70.36(6), β 88.13(7), γ 77.52(3) �, Z= 2 dimers]; Cu-Br range from 2.551(2)-2.668(2); Cu-N( amq ) are 2.021(8), 2.010(6); Cu-N( MeCN ) are 1.986(8), 1.960(7) A (two independent dimers ). The iodide alone forms the expected single-strand 'split-stair' polymer [monoclinic, P21, a 12.090(5), b 9.971(5), c 4.132(2) � , P 98. 50(3) �, Z = 21, Cu-I, 2.527(3), 2. 567(3); Cu-N, 2.02(2) � . Residuals were 0.035, 0.050, 0.045 for 552, 2974, 608 independent 'observed' reflections respectively.
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Mautner, Franz A., Roland C. Fischer, Ana Torvisco, Nahed M. H. Salem, Amber R. Dugas, Shelby F. Aaron, Sushant P. Sahu, Febee R. Louka, and Salah S. Massoud. "Stereochemical Geometries and Photoluminescence in Pseudo-Halido-Zinc(II) Complexes. Structural Comparison between the Corresponding Cadmium(II) Analogs." Inorganics 9, no. 7 (July 9, 2021): 53. http://dx.doi.org/10.3390/inorganics9070053.
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Six pseudohalide zinc(II) containing a variety of N-donor auxiliary amines were structurally characterized. These include two mononuclear trigonal bipyramidal [Zn(NTB)(N3)]ClO4·½H2O (3) and [Zn(TPA)(NCS)]ClO4 (4), two distorted octahedral [Zn(1,8-damnph)2(dca)2] (5) and [Zn(8-amq)2(dca)2] (6a) as well as two 1D polymeric chains catena-[Zn(isq)2(μ1,5-dca)2] (7) and catena-[Zn(N,N-Me2en)2(μ1,5-dca)]dca (8), where NTB = tris(2-benzimidazolylmethyl)amine, TPA = tris(2-pyridylmethyl)amine, 1,8-damnph = 1,8-diaminonaphthalene, 8-amq = 8-amino-quinoline, isq = isoquinoline (isq) and N,N-Me2en = N,N-dimethylethylenediamine. In general, with the exception of 6 and 8, the complexes exhibited luminescence emission in MeOH associated with red shift of the emission maxima, and the strongest visible fluorescence peak was detected at 421 nm (λex = 330 nm) in the case of Complex 5.
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Maertens, Johan A., Hedy Teppler, Robert Lupinacci, Michael Bourque, Mark DiNubile, and Carole Sable. "Empirical Antifungal Therapy (Rx) with Caspofungin (CAS) vs Liposomal Amphotericin B (L-AmB) for Persistently Febrile Neutropenic Patients (Pts) with Acute Myeloid Leukemia (AML)." Blood 104, no. 11 (November 16, 2004): 1337. http://dx.doi.org/10.1182/blood.v104.11.1337.1337.
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Abstract Background: In a double-blind randomized trial of empirical antifungal Rx for persistently febrile neutropenic pts, CAS was as effective as and better tolerated than L-AmB. We now examine the results of this study in the subgroup of pts with AML. Methods: Randomization to CAS (70 mg x 1, then 50 mg/d) or L-AmB (3 mg/kg/d) was stratified by risk category [high risk = allogeneic hematopoietic stem cell transplant or relapsed acute leukemia] and use of antifungal prophylaxis. The primary efficacy endpoint was % of treated pts with documented fever and neutropenia who had a successful outcome defined by all the following: successful Rx of baseline (BL) invasive fungal infection (IFI) (if any), no breakthrough (BT) IFI to 7 d post-Rx, survival @7d post-Rx, no premature discontinuation (DC) due to lack of efficacy or study drug toxicity, and fever resolution x 48 hr during neutropenia. Results: 703/1095 (64%) of the treated pts had AML, including 364/556 (65%) and 339/539 (63%) in the CAS and L-AmB groups, respectively. Demographic characteristics were similar in AML pts in both Rx groups. 27% of CAS and 22% of L-AmB pts with AML were high risk. Median days of Rx were: CAS, 12; L-AmB, 11. The table shows % AML pts with a successful outcome by Rx group. % AML pts with a successful outcome by Rx group CAS (N=364) L-AmB (N=339) Difference (CAS - L-AmB) 95% CI for difference between treatment groups † 7/14 CAS and 5/16 L-AmB pts had successful Rx of BL IFI. Success Rx of BL IFI † 50 31 19 (−16, 53) No BT IFI 93 95 −2 (−5, 2) Suvival @ 7d post-Rx 92 88 4 (0, 8) No premature DC 87 86 2 (−3, 7) Fever resolution 48 46 2 (−5, 9) All of the above 40 38 2 (−5, 10) The composite success rates for the high risk AML pts were 46/99 (46%) for CAS and 31/76 (41%) for L-AmB. Conclusions: In this post hoc subgroup analysis, CAS provided an effective and generally well-tolerated option for the empirical Rx of persistently febrile neutropenic pts with AML.
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Erba, Harry Paul, Pamela S. Becker, Paul J. Shami, Michael Richard Grunwald, Donna L. Flesher, Yilong Zhang, Erik Rasmussen, Haby A. Henary, and Eunice S. Wang. "Dose escalation results of a phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in patients (Pts) with relapsed/refractory (r/r) acute myeloid leukemia (AML)." Journal of Clinical Oncology 35, no. 15_suppl (May 20, 2017): 7027. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.7027.
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7027 Background: The ubiquitin ligase MDM2 inhibits the tumor suppressor p53. In preclinical AML models, MDM2 inhibitors have antitumor activity as monotherapy that is synergistic when combined with MEK inhibitors. This open-label phase 1b study assessed the maximum tolerated dose (MTD), pharmacokinetics (PK), and preliminary antitumor activity of the investigational oral, selective MDM2 inhibitor AMG 232 as monotherapy or combined with the MEK kinase inhibitor trametinib in pts with r/r AML. Methods: Pts with r/r AML received AMG 232 for 7 days every 2 weeks (7 days on/7 days off) at 60, 120, 240, 480, and 960 mg PO QD as monotherapy (Arm 1) or combined with trametinib 2 mg PO QD (Arm 2). Primary endpoints were the incidence of adverse events (AEs), dose-limiting toxicities (DLTs), and PK. Additional endpoints included best response (revised IWG) and serum MIC-1 level (increased MIC-1 suggests p53 activation). p53 target gene ( P21, BAX, and PUMA) expression in bone marrow was assessed by microarray. Results: In total, 35 pts (Arm 1, n = 26; Arm 2, n = 9; median age, 68 y; range, 26–86) were treated. Arm 1 enrolled AMG 232 at 60 mg (n = 4), 90 mg (n = 4), 180 mg (n = 5), 240 mg (n = 3), and 360 (n = 10). Twenty-two (85%) pts in Arm 1 had treatment-related AEs; the most common were nausea (n = 14), diarrhea (n = 14), and vomiting (n = 6). No DLTs occurred; one pt is still on treatment. The MTD was determined as 360 mg based on tolerance of gastrointestinal toxicity. Arm 2 enrollment is ongoing at a fixed AMG 232 dose of 60 mg plus trametinib (n = 9). AMG 232 plasma exposure increased with dose escalation; PK was unaffected by trametinib. Trametinib PK was as expected. Increases from baseline (BL) to day 10 in serum MIC-1 were dose dependent. Evidence of increased P21, BAX, and PUMA expression (BL to day 7 or 8) was seen (n = 3). One pt (Arm 2) had complete remission (CR); three pts (Arm 1) achieved CRi/MLFS. Median response duration was 66 days [range, 21–377+]). Conclusions: AMG 232 monotherapy was tolerable in pts with r/r AML at doses up to 360 mg on a 7 days on/7 days off schedule with expected PK, on-target biological effects, and early evidence of antileukemia activity. Clinical trial information: NCT02016729.
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Pevnick, Joshua M., Caroline Nguyen, Cynthia A. Jackevicius, Katherine A. Palmer, Rita Shane, Galen Cook-Wiens, Andre Rogatko, et al. "Improving admission medication reconciliation with pharmacists or pharmacy technicians in the emergency department: a randomised controlled trial." BMJ Quality & Safety 27, no. 7 (October 6, 2017): 512–20. http://dx.doi.org/10.1136/bmjqs-2017-006761.
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BackgroundAdmission medication history (AMH) errors frequently cause medication order errors and patient harm.ObjectiveTo quantify AMH error reduction achieved when pharmacy staff obtain AMHs before admission medication orders (AMO) are placed.MethodsThis was a three-arm randomised controlled trial of 306 inpatients. In one intervention arm, pharmacists, and in the second intervention arm, pharmacy technicians, obtained initial AMHs prior to admission. They obtained and reconciled medication information from multiple sources. All arms, including the control arm, received usual AMH care, which included variation in several common processes. The primary outcome was severity-weighted mean AMH error score. To detect AMH errors, all patients received reference standard AMHs, which were compared with intervention and control group AMHs. AMH errors and resultant AMO errors were independently identified and rated by ≥2 investigators as significant, serious or life threatening. Each error was assigned 1, 4 or 9 points, respectively, to calculate severity-weighted AMH and AMO error scores for each patient.ResultsPatient characteristics were similar across arms (mean±SD age 72±16 years, number of medications 15±7). Analysis was limited to 278 patients (91%) with reference standard AMHs. Mean±SD AMH errors per patient in the usual care, pharmacist and technician arms were 8.0±5.6, 1.4±1.9 and 1.5±2.1, respectively (p<0.0001). Mean±SD severity-weighted AMH error scores were 23.0±16.1, 4.1±6.8 and 4.1±7.0 per patient, respectively (p<0.0001). These AMH errors led to a mean±SD of 3.2±2.9, 0.6±1.1 and 0.6±1.1 AMO errors per patient, and mean severity-weighted AMO error scores of 6.9±7.2, 1.5±2.9 and 1.2±2.5 per patient, respectively (both p<0.0001).ConclusionsPharmacists and technicians reduced AMH errors and resultant AMO errors by over 80%. Future research should examine other sites and patient-centred outcomes.Trial registration numberNCT02026453.
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Cheung, Kam, Gloria Juan, William Wayne, Kelly Hanestad, Kathleen Keegan, Justin Huard, Patricia McElroy, et al. "AMG 900, a Potent and Highly Selective Aurora Kinase Inhibitor Shows Promising Preclinical Activity Against Acute Myeloid Leukemia Cell Lines In Vitro and In Vivo." Blood 122, no. 21 (November 15, 2013): 3823. http://dx.doi.org/10.1182/blood.v122.21.3823.3823.
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Abstract Aurora kinases A and B play essential roles in multiple stages of mitosis and are frequently overexpressed in a subset of human cancers, including acute myeloid leukemia (AML) (Ikezoe T et al, 2007). AMG 900, a potent and highly selective small molecule inhibitor of aurora kinases, is currently in Phase 1 clinical testing in adult patients with AML. In this study, we report the preclinical effects of AMG 900 in AML cell lines. We show that AMG 900 inhibits the phosphorylation of Histone H3 on serine-10 (a proximal substrate of aurora-B) leading to aborted cell division, apoptosis and/or polyploidy. We evaluated the activity of AMG 900 and two other well-characterized aurora kinase inhibitors [AZD1152-hQPA (B-selective AKI) and MLN8054 (A-selective AKI)] in a panel of AML cell lines. AMG 900 inhibited proliferation in all 10 cell lines at single-digit nanomolar concentrations. At effective concentrations, AMG 900 and AZD1152-hQPA showed similar cellular phenotypes, indicating that the activity of AMG 900 may occur through inhibition of aurora-B. A subset of cell lines sensitive to AMG 900 and MLN8054 were insensitive to AZD1152-hQPA, suggesting that AMG 900 may be less susceptible to resistance mediated by drug-efflux (Grundy M et al, 2011). Two AMG 900 oral dosing schedules are being evaluated in the ongoing AML clinical trial; patients receive either 4 or 7 consecutive daily doses followed by a drug holiday in 14-day cycles. In this study, we evaluated the in vivo anti-proliferative effects of AMG 900 using the two dose schedules in the skeleton of NOD/SCID IL2γnull mice bearing MOLM-13 (AML) cells expressing luciferase. To assess tumor cell proliferation in vivo, we used 18FLT (radioactive thymidine analog) PET/CT imaging, a technique that has been used to monitor early treatment response in the bone marrow of AML patients (Vanderhoek M et al, 2011). Mice were imaged for luciferase activity and 18FLT uptake before treatment and at multiple time-points during the drug holiday phase within the 14-day cycle. While the two AMG 900 dosing schedules resulted in a similar decrease in tumor burden across study time points (as measured by luciferase activity), they differed in the timing of skeletal 18FLT responses. Mice administered AMG 900 showed an attenuated skeletal 18FLT uptake compared with the vehicle group, followed by an 18FLT flare. This 18FLT flare event is notably higher using the AMG 900 4-day schedule, although the cumulative dose is similar for both schedules. This difference in 18FLT flaring may indicate the schedules differ in the duration and/or level of target inhibition in the skeletal tumor and bone marrow cells. Mice treated with sunitinib (positive control agent) did not show a skeletal 18FLT flare during the drug holiday, suggesting its mode of action is distinct from that of AMG 900. At the end of the study, mouse bone marrow was assessed for tumor burden by flow cytometry. Mice treated with AMG 900 showed a significant decrease in tumor burden compared with the vehicle group. Interestingly, the mice administered AMG 900 7-day schedule showed the most suppression of tumor growth compared with either AMG 900 4-day schedule or sunitinib. Together, our preclinical studies demonstrate that AMG 900 is a potent inhibitor of aurora kinases that robustly suppresses the growth of AML cells in vitro and in vivo. Furthermore, we highlight the utility of in vivo imaging to monitor AMG 900 drug action, which may help to inform future dose scheduling and drug combination studies. Disclosures: Cheung: Amgen Inc: Employment, Equity Ownership. Juan:Amgen Inc.: Employment, Equity Ownership. Wayne:Amgen Inc.: Employment, Equity Ownership. Hanestad:Amgen Inc.: Employment, Equity Ownership. Keegan:Amgen Inc.: Employment, Equity Ownership. Huard:Amgen Inc.: Employment, Equity Ownership. McElroy:Amgen Inc.: Employment, Equity Ownership. Stanton:Amgen Inc.: Employment, Equity Ownership. Bush:Amgen Inc.: Employment, Equity Ownership. Kendall:Amgen Inc.: Employment, Equity Ownership. Radinsky:Amgen Inc.: Employment, Equity Ownership. Abella:Amgen Inc. : Employment, Equity Ownership. Pieslor:Amgen Inc.: Employment, Equity Ownership. Friberg:Amgen Inc.: Employment, Equity Ownership. Coxon:Amgen Inc.: Employment, Equity Ownership. Gamelin:Amgen Inc: Employment, Equity Ownership. Payton:Amgen Inc.: Employment, Equity Ownership. Off Label Use: AMG 900 is currently in phase 1 clinical development, there is no approved label.
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Gemelli, E., S. Lourenci, M. V. Folgueras, and N. H. Almeida Camargo. "Assessment of industrial wastes in mortar layers deposited on stainless steel sheets of sinks." Cerâmica 50, no. 316 (December 2004): 336–44. http://dx.doi.org/10.1590/s0366-69132004000400009.
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This work deals with the properties of alternative mortars destined to strengthen metal sheets of sinks. The performance of these mortars was compared to that of a basic mortar made of cement, sand, and water, named standard mortar (SM). One of these mortars, named alternative mortar 2 (AM2), and composed of cement, textile residue, polyurethane, polypropylene fibers and water, was developed recently to replace the current one, named alternative mortar 1 (AM1), composed of cement, sand, polystyrene, polypropylene fibers and water. These mortars were manufactured and aged in a room in atmospheric environment for 7, 14, 28, 60 and 90 days, either with or without initial drying in a furnace. After cure of 90 days the flexion strength stress of the SM, AM1 and AM2 mortars was 5.21, 3.84, and 1.42 MPa, respectively. The SM and AM1 mortars were constituted of C-S-H phases, Ca(OH)2, SiO2, AFm and AFt (monossulphate/ettringite) phases. The AM2 mortar presented, apart from the compounds mentioned above, CaCO3. This compound is from the textile residue that is composed essentially of CaCO3 and Ca(OH)2. The reduction in flexion strength of AM1 mortar, compared to SM mortar, is caused by the polystyrene whereas the lowering mechanical strength of the AM2 is due to both polyurethane and textile residue. Even so, its mechanical strength is acceptable because the flexion strength stress required for the industrial application is 1.0 MPa.
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Longo, Flavio Alves, José Fernando Machado Menten, Adriana Ayres Pedroso, Adriana Nogueira Figueiredo, Aline M. Calil Racanicci, Juliano Benedito Gaiotto, and José Otávio Berti Sorbara. "Carboidratos na dieta pré-inicial de frangos de corte." Revista Brasileira de Zootecnia 34, no. 1 (February 2005): 123–33. http://dx.doi.org/10.1590/s1516-35982005000100016.
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Objetivou-se, com este estudo, determinar a energia metabolizável aparente corrigida (EMAn) de ingredientes como fonte de carboidrato para frangos de corte de 1 a 7 dias de idade, bem como avaliar a utilização destes diferentes ingredientes em dietas pré-iniciais sobre o desenvolvimento inicial de órgãos do trato gastrintestinal (TGI) e desempenho das aves. No Experimento 1, foi utilizado o método de coleta total das excretas com 220 pintos de 4 a 7 dias de idade, alojados em baterias em delineamento inteiramente casualizado com cinco tratamentos (uma dieta-referência e quatro dietas com inclusão de 20% do ingrediente-teste - amido de milho [AMI], amido de mandioca [AMA], glicose [GLI] e sacarose [SAC]) e quatro repetições de 11 aves. No Experimento 2, foram utilizados 520 pintos de corte machos de um dia de idade, distribuídos em delineamento inteiramente casualizado, com cinco tratamentos e quatro repetições de 26 aves. Os tratamentos foram aplicados de 1 a 7 dias e, no período subseqüente, as aves tiveram acesso a uma dieta basal padrão. Os tratamentos consistiram em: 1 - dieta de milho e farelo de soja, 2 - dieta de milho e farelo de soja + AMI, 3 - dieta de milho e farelo de soja + AMA, 4 - dieta de milho e farelo de soja + GLI, 5 - dieta de milho e farelo de soja + SAC. O valor da EMAn determinado para frangos de corte na fase pré-inicial foi de 3.269, 3.690, 3.427 e 3.524 kcal/kg para AMI, AMA, GLI e SAC, respectivamente. Observou-se que o desenvolvimento do TGI, de maneira geral, não foi influenciado pelos diferentes tratamentos, mas o consumo de ração das aves foi aumentado com o fornecimento de carboidrato de maior disponibilidade na dieta pré-inicial, contribuindo para aumento no peso vivo das aves.
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Erba, Harry P., Pamela S. Becker, Paul J. Shami, Michael R. Grunwald, Donna L. Flesher, Min Zhu, Erik Rasmussen, Haby A. Henary, Abraham A. Anderson, and Eunice S. Wang. "Phase 1b study of the MDM2 inhibitor AMG 232 with or without trametinib in relapsed/refractory acute myeloid leukemia." Blood Advances 3, no. 13 (June 28, 2019): 1939–49. http://dx.doi.org/10.1182/bloodadvances.2019030916.
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AbstractThis open-label, phase 1 study evaluated the safety, pharmacokinetics, and maximum tolerated dose of AMG 232, an investigational oral, selective mouse double minute 2 homolog inhibitor in relapsed/refractory acute myeloid leukemia (AML). AMG 232 was administered orally once daily for 7 days every 2 weeks (7 on/off) at 60, 120, 240, 360, 480, or 960 mg as monotherapy (arm 1) or at 60 mg with trametinib 2 mg (arm 2). Dose-limiting toxicities (DLTs), adverse events (AEs), pharmacokinetics, clinical and pharmacodynamic response, and expression of p53 target genes were assessed. All 36 patients received AMG 232. No DLTs occurred in arm 1, and 360 mg was the highest test dose; dose escalation was halted due to gastrointestinal AEs at higher doses. One of ten patients in arm 2 had a DLT (grade 3 fatigue); 60 mg was the highest dose tested with trametinib. Common treatment-related AEs (any grade) included nausea (58%), diarrhea (56%), vomiting (33%), and decreased appetite (25%). AMG 232 exhibited linear pharmacokinetics unaffected by coadministration with trametinib. Serum macrophage inhibitor cytokine-1 and bone marrow expression of BAX, PUMA, P21, and MDM2 increased during treatment. Of 30 evaluable patients, 1 achieved complete remission, 4 had morphologic leukemia-free state, and 1 had partial remission. Four of 13 (31%) TP53-wild-type patients and 0 of 3 (0%) TP53-mutant patients were responders. AMG 232 was associated with gastrointestinal AEs at higher doses but had acceptable pharmacokinetics, on-target effects, and promising clinical activity warranting further investigation in patients with relapsed/refractory AML. This trial was registered at www.clinicaltrials.gov as #NCT02016729.
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Jehn, U., R. Zittoun, and B. Löwenberg. "AML-6- und AML-7-Studie zur Behandlung der akuten myeloischen Leukämie." Oncology Research and Treatment 8, no. 3 (1985): 160–64. http://dx.doi.org/10.1159/000215646.
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Krupka, Christina, Peter Kufer, Roman Kischel, Gerhard Zugmaier, Thomas Köhnke, Felix S. Lichtenegger, Frauke M. Schnorfeil, et al. "PD-1/PD-L1 Blocking Enhances CD33/CD3-Bispecific BiTE® Antibody (AMG 330) Mediated Lysis of Primary AML Cells." Blood 124, no. 21 (December 6, 2014): 3738. http://dx.doi.org/10.1182/blood.v124.21.3738.3738.
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Abstract Antibody-based immunotherapy represents a promising strategy to target and eliminate chemoresistant leukemic cells in acute myeloid leukemia (AML). In our previous work, the potency of the CD33/CD3-bispecific BiTE® antibody AMG 330 to activate and redirect T-cells to AML cells was evaluated in a long-term culture system using unmanipulated peripheral blood (PB) or bone marrow (BM) samples from AML patients. We were able to show effective elimination of AML cells by AMG 330-activated and -expanded residual autologous T-cells (n=13, Krupka et. al, Blood 2014 123(3):356-65). The goal of the present study was to identify and manipulate factors that interfere with AMG 330-mediated lysis of primary AML cells. In our ex-vivo long-term culture system (n= 32 primary diagnosis, 3 relapse), we observed that successful elimination of primary AML cells was predominantly influenced by the initial effector:target (E:T) ratio. Reduced short-term lysis efficacy was observed for patient samples with low E:T ratios (median lysis: E:T ratio <1:10 23.5% vs >1:10 99.3%) after 4 days of culture. However, after 12 days of culture this effect was less prominent as effector T-cell numbers increased and lysis was observed even in cultures with very low initial E:T ratios (up to an E:T ratio of 1:80). Considering the ubiquitous expression pattern of CD33 within the myeloid compartment, the number of AMG 330 treatment days will be limited due to expected hematotoxicity. Therefore, AMG 330 efficacy might benefit by increasing the E:T ratio within a short time period. Programmed cell death-1 (PD-1) and its primary ligand PD-L1 are immune checkpoints that limit T-cell responses and may contribute to slower lysis kinetics during AMG 330 treatment. Therefore, we assessed PD-1 expression on T-cells and PD-L1 expression on primary AML cells. No constitutive expression of PD-1/PD-L1 on T-cells and corresponding AML cells was found at primary diagnosis (PD-1: n=23; PD-L1: n=193). Upon the addition of AMG 330 to our primary ex-vivo AML cultures, we observed a strong upregulation of PD-1 on activated T-cells, which correlated with the extent of T-cell proliferation (10/10). This was most prominent within the subpopulation of CD4+/CD45RA-/CCR7- effector memory T-cells. Furthermore, in response to AMG 330-mediated T-cell activation, we observed an upregulation of PD-L1 on primary AML cells (16/19). Data obtained from AML cell lines confirmed an upregulation of PD-L1 after co-cultivation with T-cells and AMG 330. This phenomenon was cytokine-mediated as the addition of IFNγ and TNFα also induced PD-L1 expression (n=6). Interestingly, we also observed a PD-L1 upregulation on T-cells upon activation with AMG 330, but to a much lower extent compared to primary AML cells (n=17; mean MFI ratio: T-cells: 4.7; AML cells: 12.1). Blockade of the PD-1/PD-L1 interaction through the addition of an inhibitory antibody induced an increase in T-cell proliferation in ex-vivocultures resulting in enhanced cytotoxicity against primary AML cells (lysis on day 18: with/without PD-1 blocking antibody: 75 vs 44%; fold change T-cell expansion: 6 vs 3). This was accompanied by a significant increase in IFNγ production (with/without PD-1 blocking antibody: 280 pg/ml vs 81 pg/ml). Complimentary experiments using primary AML cells and allogeneic T-cells at defined E:T ratios demonstrated that this effect is most prominent in co-cultures with a low percentage of T-cells within the primary sample (lysis on day 7 with/without PD-L1 blocking antibody: E:T ratio 1:1: 100% vs 94.5%; E:T ratio 1:5: 96.6% vs 82.7%; fold change T-cell expansion: E:T ratio 1:1: 3.1 vs 3.1; E:T ratio 1:5: 23.4 vs 9.8). Intriguingly, upon addition of lenalidomide to our primary AML cultures, we were also able to circumvent the immune inhibitory effect of the PD-1/PD-L1 interaction by a decrease in PD-L1 upregulation on primary AML cells. Our data show that AMG 330-mediated lysis of primary AML cells can be enhanced by inhibiting the PD-1/PD-L1 axis on T-cells and corresponding AML cells. The modulation of the PD-1/PD-L1 axis increased T-cell proliferation and accelerated attaining a beneficial E:T ratio. We hypothesize that PD-L1 upregulation on primary AML cells is a relevant immune escape mechanism employed by AML cells to escape cytokine-mediated immune responses. Prospective clinical trials will be needed to assess the relevance of our finding in AMG 330-treated AML patients. Disclosures Krupka: AMGEN Inc.: Research Funding. Kufer:AMGEN Inc.: Equity Ownership; AMGEN Research (Munich): Employment. Kischel:AMGEN Inc.: Equity Ownership; AMGEN Research (Munich): Employment. Zugmaier:AMGEN Research (Munich): Employment; AMGEN Inc.: Equity Ownership. Sinclair:AMGEN Inc.: Employment, Equity Ownership. Newhall:AMGEN Inc.: Employment, Equity Ownership. Frankel:AMGEN Inc.: Employment, Equity Ownership. Baeuerle:AMGEN Research (Munich): Employment; AMGEN Inc.: Equity Ownership. Riethmüller:AMGEN Inc.: Equity Ownership. Subklewe:AMGEN Inc.: Research Funding.
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Harrington, Kimberly H., Chelsea J. Gudgeon, George S. Laszlo, Kathryn J. Newhall, Angus M. Sinclair, Stanley R. Frankel, Roman Kischel, Guang Chen, and Roland B. Walter. "The Broad Activity of the CD33/CD3 Bispecific BiTE® Antibody AMG 330 in Primary Human AML Is Impacted By Disease Stage and Cytogenetic/Molecular Risk." Blood 124, no. 21 (December 6, 2014): 266. http://dx.doi.org/10.1182/blood.v124.21.266.266.
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Abstract Background: Recent studies have demonstrated that AMG 330, a novel CD33/CD3-directed bispecific T-cell engaging (BiTE¨) antibody, is highly active against CD33+ AML cell lines and can potently lyse leukemic blasts from AML patients. Here, we have investigated the preclinical determinants for AMG 330 activity in primary newly diagnosed and relapsed/refractory human AML samples to prospectively understand factors that might contribute to clinical response or resistance. Patients and Methods: Frozen aliquots of Ficoll-isolated mononuclear cells from peripheral blood or bone marrow specimens were obtained from adults with AML who consented to their use for research purposes. CD33 expression on myeloblasts (identified by appropriate CD45 and side-scatter properties) and the percentage of endogenous CD3+ T-cells were quantified by flow cytometry. To determine drug-induced cytotoxicity, AML cells were incubated in culture medium containing various concentrations of AMG 330; in some experiments, exogenous T-cells (isolated via magnetic cell sorting from a healthy adult volunteer who underwent leukapheresis) were labeled with CellVue Burgundy and added at different effector:target (E:T) cell ratios. After 48 hours, cell numbers and drug-induced cytotoxicity, using DAPI to detect non-viable cells, were determined by flow cytometry; AML cells were identified by forward/side scatter properties and negativity for CellVue Burgundy dye. Specific drug-induced cytotoxicity was calculated as: 100 x (1 – live target cellstreated/live target cellscontrol), and presented as mean±SEM. Results: Forty-one of the 49 studied specimens were included in our analyses as they had >40% myeloblasts upon thaw and were >50% and >30% viable at baseline and after 48 hours, respectively. Median age of the patients was 65.3 (range: 23.9-80.0) years. The median percentage of myeloid blasts and CD3+ T-cells in the studied specimens was 87.1% (range: 55.1-97.0%) and 2.0% (range: 0-27.3%), respectively, and median sample viability after 48 hours in culture was 76.7% (range: 31.1-93.5%). These characteristics were similar between the newly diagnosed (n=21) and relapsed/refractory (n=20) AML specimens. In the absence of healthy donor T-cells, AMG 330 resulted in modest cytotoxicity (at 500 pg/mL: 11.8±2.5%) that was correlated with the amount of autologous T-cells (at 500 pg/mL; r=0.566; p=0.0001; Spearman's rank correlation test). On the other hand, AMG 330 exerted marked cytotoxic activity in several specimens with very low CD33 expression, and there was no correlation between AMG 330 cytotoxicity and CD33 expression (at 500 pg/mL; r=-0.048; p=0.77). In the presence of healthy donor T-cells, AMG 330 cytotoxicity was strictly dependent on the drug dose (e.g. p<0.0001 at E:T=1:3) and E:T cell ratio (e.g. p<0.0001 at 500 pg/mL; Fig. 1). High cytotoxic activity of AMG 330 was observed in specimens with very low CD33 expression, and a correlation between AMG 330 cytotoxicity and CD33 expression was only observed at high E:T cell ratio (3:1) and higher AMG 330 doses (at 500 pg/mL: r=0.465, p=0.0022). In analyses of patient subsets, AMG 330 resulted in significantly higher cytotoxicity in specimens from patients with newly diagnosed AML (n=21) than those with relapsed/refractory disease (n=20) despite similar levels of CD33 on leukemic blasts (median of 837 [30-5,356] vs. 1,018 [7-2,567] arbitrary fluorescence units; Fig. 2A and B). Furthermore, AMG 330-induced cytotoxicity was higher in specimens from patients with cytogenetically/molecularly favorable-risk disease (n=5) as compared to those with intermediate- (n=26) or adverse risk disease (n=10; Fig. 2C and D). Conclusion: AMG 330 causes potent cytolysis of primary human AML cells in vitro in a dose- and E:T cell ratio-dependent manner across the entire spectrum of cytogenetic/molecular risk and disease stage, even in specimens with very low expression of CD33. Lower activity of AMG 330 was observed in relapsed/refractory AML specimens (relative to newly diagnosed AML specimens) and intermediate- or adverse-risk disease specimens (relative to favorable-risk specimens) suggesting the potential presence of yet undefined, CD33-independent, relative resistance mechanisms in defined patient subsets. Figure 1 Figure 1 Figure 1. Figure 2 Figure 2 Figure 2. Disclosures Off Label Use: Use of AMG 330 in AML (AMG 330 is investigational drug). Newhall:Amgen, Inc: Employment. Sinclair:Amgen, Inc: Employment. Frankel:Amgen, Inc: Employment. Kischel:Amgen, Inc: Employment. Chen:Amgen, Inc: Employment. Walter:Amgen, Inc: Research Funding; Seattle Genetics, Inc.: Research Funding; Amphivena Therapeutics, Inc.: Consultancy; Covagen AG: Consultancy.
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Rai, Manoj P., Heather Laird-Fick, Prabhjot Singh Bedi, Justin D. Kaner, Samanjit Kaur Kandola, Shilpa Kavuturu, Nishant Tageja, Marwan S. Abougergi, Stanley M. Marks, and James B. Bussel. "Differences in Predictors of Mortality and Resource Utilization Among Adult Patients with Acute Lymphocytic Leukemia and Acute Myeloid Leukemia." Blood 132, Supplement 1 (November 29, 2018): 4766. http://dx.doi.org/10.1182/blood-2018-99-111189.
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Abstract Introduction: Both acute lymphocytic leukemia (ALL) and acute myeloid leukemia (AML) require hospitalization for intensive chemotherapy, stem cell transplantation, and disease or treatment-related complications. There is a dearth of evidence in prediction of inpatient resource utilization and hospital outcomes among patients with these conditions. The goal of this study is to identify predictors of average length of stay in the hospital (ALOS) and inpatient mortality in adult ALL and AML patients. Methods: We performed a retrospective cohort analysis of the National Inpatient Sample 2014 Database (HCUP-NIS). Patients were included in the study if they had a principal diagnosis of ALL or AML and age 18 years or older. We used descriptive statistics to characterize the cohort in terms of personal demographic factors (age, race, sex, insurance type, community income level), hospital characteristics (size, geographical region, teaching status, and urban or rural location), and admission timing (weekend or weekday). We performed univariate and multivariate regression to analyze the association of these factors with mortality and ALOS. All analyses apply the HCUP-NIS weights. Results: The ALL cohort included 5,550 admissions. Most ALL patients were white (65%) males (60%), and approximately half were age 50 years or younger. The AML cohort included 18,930 admissions. Most AML patients were white (74%) males (54%), aged 60 years or older (59%). Nearly all (95%) of ALL patients had insurance coverage, either private (40%), Medicare (25.9%), Medicaid (25%), or another type (5%). In contrast, most AML patients had Medicare (46%), followed by private insurance (36%), Medicaid (11.0%), other insurance (3.8%) or no insurance (2.8%). Care for both cohorts occurred most often in large, urban, and teaching hospitals. While Charlson index was the only statistically significant predictor of mortality in the ALL cohort (AMD 1.34, 95% CI 1.11 to 1.63, p=0.002), age (OR 1.02; 95% CI 1.014 - 1.03), Charlson index (OR 1.24; 95% CI 1.16 - 1.34) and other type of insurance were associated with increased mortality for AML. ALOS was similar for both cohorts: ALL 18.5 days and AML 18.9 days. For ALL, multivariate analysis showed Charlson index (AMD 1.53, 95% CI 0.32 - 2.74, p=0.013), and hospital type (urban AMD 5.73; 95% CI 2.73 to 8.73, p<0.01 and teaching hospital AMD 6.86, 95% CI 4.36 to 9.36, p<0.01) to be independent predictors of ALOS. For AML, age (AMD -0.22, 95% CI -0.27 to -0.17), insurance type (Medicaid AMD 3.02, 95% CI 0.65 - 5.39, private insurance 4.10, 95% CI 2.60 - 5.60), Charlson index (AMD 0.63, 95% CI 0.25-1.01), and hospital type (urban AMD 6, 95% CI 2.65 to 8.72), and teaching AMD 7, 95% CI 6.06 to 9.09) predicted ALOS. Discussion: Care for ALL and AML occurs primarily in large, urban teaching centers. Although ALOS is similar for the two, age and insurance carrier (Medicaid and private) are associated with increased ALOS only for AML. The increased LOS with age is possibly because of increased complexities associated with it. LOS is longer in AML patients with Medicaid and a few private insurances possibly because the placement to health care facilities tends to be significantly more difficult and time-consuming than for Medicare. Similarly, age and other type of insurance are associated with increased mortality only in AML. No regional or racial/ethnic differences were seen for either cohort for ALOS or mortality. Understanding factors influencing ALOS may help institutions in planning health care resource allocation. Health policy decisions that negatively impact the financial health of large, urban teaching centers may influence their ability to provide the complex and expensive care for this group of patients. Table. Table. Disclosures Marks: UPMC: Employment; Odonate: Membership on an entity's Board of Directors or advisory committees; Heron: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Equity Ownership; Lilly: Membership on an entity's Board of Directors or advisory committees. Bussel:Uptodate: Honoraria; Momenta: Consultancy; Novartis: Consultancy, Research Funding; Prophylix: Consultancy, Research Funding; Amgen Inc.: Consultancy, Research Funding; Protalex: Consultancy; Rigel: Consultancy, Research Funding.
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Canaani, Jonathan. "Management of AML Beyond “3 + 7” in 2019." Clinical Hematology International 1, no. 1 (2019): 10. http://dx.doi.org/10.2991/chi.d.190316.001.
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Annino, Luciana, Anna Chierichini, Barbara Anaclerico, Erica Finolezzi, Marianna Norata, Stefania Cortese, Maria Iris Cassetta, Stefania Fallani, Andrea Novelli, and Corrado Girmenia. "Prospective Phase II Single-Center Study of the Safety of a Single Very High Dose of Liposomal Amphotericin B for Antifungal Prophylaxis in Patients with Acute Myeloid Leukemia." Antimicrobial Agents and Chemotherapy 57, no. 6 (March 25, 2013): 2596–602. http://dx.doi.org/10.1128/aac.00155-13.
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ABSTRACTSome preclinical and pharmacokinetic studies suggested the variable safety and the potential efficacy of an antifungal prophylaxis with a single high dose of liposomal amphotericin B (L-AmB) in high-risk patients. An open-label, prospective study was conducted with 48 adults receiving induction chemotherapy for acute myeloid leukemia (AML). Patients received a single infusion of 15 mg/kg of body weight L-AmB and, eventually, a second dose after 15 days of persistent neutropenia. The primary objective was tolerability and safety. Efficacy was also evaluated as a secondary endpoint. A pharmacokinetic study was performed with 34 patients in order to evaluate any association of plasma L-AmB levels with toxicity and efficacy. Overall, only 6 patients (12.5%) reported Common Toxicity Criteria (CTC) grade 3 hypokalemia, which was corrected with potassium supplementation in all cases, and no patient developed clinically relevant nephrotoxicity. Mild infusion-related adverse events occurred after 6 of 53 (11.3%) total infusions, with permanent drug discontinuation in only one case. Proven invasive fungal disease (IFD) was diagnosed in 4 (8.3%) patients. The mean AmB plasma levels at 6 h, 24 h, and 7 days after L-AmB administration were 160, 49.5, and 1 mg/liter, respectively. The plasma AmB levels were higher than the mean values of the overall population in 3 patients who developed CTC grade 3 hypokalemia and did not significantly differ from the mean values of the overall population in 3 patients who developed IFD. Our experience demonstrates the feasibility and safety of a single 15-mg/kg L-AmB dose as antifungal prophylaxis in AML patients undergoing induction chemotherapy.
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Ma, Wanlong, Francis Giles, Susan O’Brien, Iman Jilani, Xi Zhang, Zeev Estrov, Elihu Estey, Alessandra Ferrajoli, Michael Keating, and Maher Albitar. "Variations in Proteasome Enzymatic Activities in Plasma of Patients with Acute Myeloid Leukemia and Myelodysplastic Syndrome and Their Value in Predicting Clinical Behavior." Blood 108, no. 11 (November 16, 2006): 4497. http://dx.doi.org/10.1182/blood.v108.11.4497.4497.
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Abstract The ubiquitin-proteasome pathway is responsible for multiple pathways in cancer cells; proteasome inhibition causes rapid apoptosis of tumor cells. Three different types of peptidase activities have been reported for proteasomes: chymotrypsin-like (Ch-L), trypsin-like (Tr-L), and caspase-like (Cas-L) (postglutamyl peptide hydrolytic-like). Various proteasome inhibitors affect each of the 3 activities differently and at different concentrations. For example, NPI-0052 inhibits Ch-L and Tr-L activities at lower concentrations than does bortezomib, while bortezomib inhibits Cas-L at lower concentrations than does NPI-0052. These enzymatic activities are usually measured in normal or tumor cells to monitor therapy with proteasome inhibitors. Because rapidly proliferating leukemic cells pour their proteins, DNA, and RNA into the circulation, we developed fluorogenic kinetic assays using peripheral blood plasma. The assays used peptide-AMC (7-amino 4-methylcoumoran) substrates to measure Ch-L, Tr-L, and Cas-L activities. We measured proteasome activities in plasma from 188 patients with acute myeloid leukemia (AML) and 58 patients with myelodysplastic syndrome (MDS) and assessed their correlations with clinical behavior. Significantly (P < 0.001) higher Ch-L, Tr-L, and Cas-L activities were seen in AML patients (medians: 1.39, 1.51, and 2.40 pmol AMC/sec/mL, respectively) and MDS patients (medians: 1.16, 1.40, and 1.67 pmol AMC/sec/mL, respectively) than in healthy volunteers (n=42) (medians: 0.80, 0.74, and 0.81 pmol AMC/sec/mL, respectively). The difference in Cas-L activity between AML and MDS was significant (P <0.001). While there was no significant difference between Ch-L and Cas-L activities in healthy controls, there was a significant difference between the 2 activities in both AML and MDS. Cas-L and Ch-L, but not Tr-L, correlated with WBC count and lactic dehydrogenase in AML and MDS patients. In AML patients, higher levels of Ch-L and Cas-L were associated with poor response to a variety of therapies (P = 0.004 and P = 0.001, respectively). Cas-L correlated strongly with survival in AML patients when used as an activity-dependent variable (P <0.001) or when the median was used as a cut-off (P = 0.004). This was independent of cytogenetic abnormalities, age, and performance status. Patients with intermediate-risk cytogenetic abnormalities and Cas-L activity >3 pmol AMC/sec/mL had significantly shorter survival (P = 0.04). Ch-L activity was also predictive of survival in AML independent of age and cytogenetic and performance status, but not independent of Cas-L. In MDS, higher levels of Cas-L, but not Ch-L, correlated with shorter survival and this was independent of cytogenetic abnormalities. The increased cell-free circulating proteasome activities most likely reflect the leukemic cells and may be a marker not only for disease, but also potentially for monitoring therapy. These data also suggest that patients with AML may benefit differentially from proteasome inhibitors depending on the specific therapeutic effect of the inhibitor.
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Editorial, Equipo. "Editorial número 7." Arquitecno, no. 7 (May 11, 2015): 1. http://dx.doi.org/10.30972/arq.074276.
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Stamatoullas, A., A. Gouin, C. Bastard, M. P. Callat, and H. Tilly. "P096 AML/MDS with chromosome 5 and 7 abnormalities." Leukemia Research 31 (May 2007): S91—S92. http://dx.doi.org/10.1016/s0145-2126(07)70166-2.
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Septiantoro, Bayu Prio, and Indra Pradipta. "Erupsi Akneiformis Pada AML Dengan Regimen Kemoterapi “3 + 7”." Medica Hospitalia : Journal of Clinical Medicine 8, no. 2 (July 15, 2021): 248–51. http://dx.doi.org/10.36408/mhjcm.v8i2.609.
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Latar belakang: Kemoterapi bertanggung jawab terhadap sebagian besar manifestasi kulit dalam perawatan pasien kanker. Daunorubicin selama 3 hari ditambah sitarabin selama 7 hari untuk kemoterapi induksi pada pasien dengan AML dikenal sebagai regimen “3 + 7.” Walaupun erupsi akneiformis biasanya muncul pada pasien yang mendapatkan agen penghambat EGFR dan antibodi monoclonal, reaksi kulit ini juga dapat dialami pasien yang mendapatkan regime daunorubicin atau sitarabin.
Laporan kasus: Seorang wanita berusia 19 tahun dengan diagnosa AML masuk rumah sakit untuk menjalani kemoterapi dengan regimen 3+7 (daunorubicin 45mg/m2 selama 3 hari dan sitarabin 100mg/m2 selama 7 hari). Setelah hari pertama kemoterapi diberikan, muncul akne berupa bintik merah di wajah dan bertambah berat setelah sesi kemoterapi selesai dimana meluas hingga ke leher, dada dan punggung bahkan ke daerah kulit kepala, dengan adanya rasa gatal, papul dan eritema. Ia terdiagnosa erupsi akneiformis.
Tujuan: Untuk melaporkan kasus reaksi kulit berupa erupsi aneiformis pada pasien dengan diagnose AML yang menjalani kemoterapi dengan regime 3+7.
Pembahasan: Lesi erupsi akneiformis biasanya muncul sebagai papula dan pustula inflamasi monomorfik yang biasanya melibatkan wajah, leher, dada, punggung atas dan dapat diperluas hingga selain daerah seboroik. Beberapa karakteristik dapat membantu untuk mendukung hubungan potensial antara obat dengan munculnya akne. Diantaranya yang teridentifikasi pada pasien ini yaitu timbulnya akne secara tiba-tiba tanpa adanya riwayat akne vulgaris sebelumnya, lesi monomorfik dengan inflamasi, serta sedikit komedo dan kista. Terdapat empat tingkatan yang dapat digunakan dalam mengklasifikasikan keparahan efek samping kulit ini dimana tingkat III (berat) dapat diberikan antibiotik secara oral seperti klindamisin 300mg/12 jam.
Kesimpulan: Reaksi kulit berupa erupsi akneiformis dapat muncul pada pasien yang mendapatkan obat selain EGFR inhibitor dan antibodi monoclonal yaitu daunorubisin dan atau sitarabin. Perlu dilakukan penelitian lebih lanjut untuk mengetahui agen spesifik yang menjadi penyebab, serta mekanisme terjadinya reaksi tersebut.
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Marcinek, Anetta, Bettina Brauchle, Dragica Udiljak, Roman Kischel, Peter Kufer, Karsten Spiekermann, Michael von Bergwelt, Felix S. Lichtenegger, and Marion Subklewe. "The Ratio of Costimulatory Vs Coinhibitory Molecules on AML Cells Determines the CD33-BiTE® Mediated T-Cell Response." Blood 132, Supplement 1 (November 29, 2018): 1349. http://dx.doi.org/10.1182/blood-2018-99-116297.
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Abstract Bispecific T-cell engagers (BiTE® antibody constructs) represent a novel immunotherapeutic strategy relying on the recruitment of T cells against tumor cells independent of TCR specificity. In Acute Myeloid Leukemia (AML), CD33 represents a suitable target antigen with high expression levels in >90 % of primary AML samples (Krupka et al, 2014). A CD33-BiTE® antibody construct (AMG 330) was developed mediating cytotoxicity against primary AML in vitro although to a variable degree (Krupka et al, 2016). Several parameters have been identified which modulate AMG 330-mediated cytotoxicity, including CD33 expression level as well as effector to target cell (E:T) ratio. However, the exact mechanism of T-cell activation through BiTE® antibody constructs is only partly understood. Physiological T-cell activation is based on engagement of the T-cell receptor complex together with costimulatory molecules whereas the absence of positive costimulation leads to T-cell anergy. In line with this concept, we hypothesized that BiTE®-mediated cytotoxicity requires positive costimulatory signals on the target cells for T-cell activation. We hypothesize that the ratio of costimulatory and coinhibitory molecules on AML cells determines the susceptibility to AMG 330-mediated cytotoxicity independent of target antigen expression level. A stable expression system was established utilizing murine Ba/F3 cells expressing human CD33 ± CD80 ± CD86 ± PD-L1. Co-cultures of Ba/F3 constructs and T cells were performed in presence of AMG 330 or a control BiTE® (cBiTE®) (5 ng/ml). For some experiments, T cells were separated into naive (CD45RA+/CCR7+) vs memory (CD45RADIM) cells using fluorescence-activated cell sorting. After 3 days, specific lysis was determined by flow cytometry and calculated as % specific lysis = 100 × (1 - live CD33+ cellsAMG 330 / live CD33+ cellscBiTE). T-cell proliferation was defined as number of CD2+ cells on day 3 compared to day 0. The expression pattern of CD33, CD80, CD86 and PD-L1 on primary AML cells was evaluated by specific fluorescence intensity (SFI) using multiparameter flow cytometry. A sample was considered positive at an SFI of > 1.5. Characterized primary AML patient samples were used in a long-term culture assay to determine the influence of the checkpoint molecule expression profile on AMG 330-mediated cytotoxicity. CD33 single positive Ba/F3 cells were not lysed upon the addition of AMG 330 and allogeneic T cells. Cytotoxicity could be restored by expression of CD80, CD86 and CD80+CD86 with following tendency: CD80+CD86 >> CD80 > CD86 (see table 1). There was a direct correlation of T-cell proliferation to AMG 330 mediated cytotoxicity. Memory T cells showed increased cytotoxicity compared to naive T cells against the different Ba/F3 cell lines. The influence of co-inhibition was investigated by additionally transducing PD-L1 into the different Ba/F3 cells. This led to a reduced AMG 330-mediated cytotoxicity in all PD-L1 expressing Ba/F3 cells (Table 1). This was accompanied by a reduction in T-cell proliferation. Looking at the expression profile of CD80 and CD86 in primary AML samples, we observed expression of CD80 in 7/123 and of CD86 in 188/226 of cases (respectively 5.7 % and 83.2 %). When comparing AMG 330-mediated cytotoxicity against primary AML cells for patient pairs with similar CD33 expression levels, a higher CD86/PD-L1 ratio led to an increased AMG 330-mediated cytotoxicity compared to patient samples with a lower CD86/PD-L1 ratio (exemplary data: SFI CD33+: 81.7; SFI-ratio CD86/PD-L1: 4; specific cytotoxicity: 64.2 % vs. SFI CD33+: 89.5; SFI-ratio CD86/PD-L1: 15.9; specific cytotoxicity: 96.4 %). In summary, this data supports the hypothesis that AMG 330-mediated cytotoxicity and T-cell proliferation are influenced by the ratio of costimulatory and coinhibitory molecules on AML cells. Our data supports the notion that the checkpoint profile on AML, rather than one molecule by itself, determines T-cell response to AMG 330. Prospective analyses in clinical trials are needed to validate the relevance of checkpoint molecules on target cells as a predictive biomarker for response. Disclosures Marcinek: AMGEN Research Munich: Research Funding. Brauchle:AMGEN Inc.: Research Funding. Kischel:AMGEN: Employment. Kufer:AMGEN Research Munich: Employment. Subklewe:Pfizer: Membership on an entity's Board of Directors or advisory committees; Roche AG: Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Research Funding.
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Roos, Martina M., Michelle Li, Pang Amara, and John P. Chute. "Pharmacologic Targeting of LIN28/Let-7 in Acute Myeloid Leukemia." Blood 132, Supplement 1 (November 29, 2018): 4072. http://dx.doi.org/10.1182/blood-2018-99-119982.
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Abstract Acute myeloid leukemia (AML) is a genetically heterogeneous malignancy with high relapse rates and mortality due to the outgrowth of chemotherapy-resistant leukemic stem cells (LSCs). Thus, the development of novel therapeutic strategies capable of eradicating human AML represents a major area of unmet medical need. The RNA binding protein, LIN28, is a known driver of many cancer stem cells, AML included, wherein overexpression of LIN28 correlates with reduced patient survival. LIN28 blocks the function of the let-7 microRNA family, which exert tumor suppressive effects by repressing oncogenes and cell cycle regulators including MYC, RAS and CyclinD. Thus, LIN28 is an attractive mechanistic target for the purpose of inhibiting AML LSCs. Using a targeted high-throughput screen, we identified a class of small molecules which selectively block the LIN28/let-7 interaction (Roos et al., ACS Chem Biol, 2016). Preliminary studies demonstrate that a lead small molecule markedly impairs the proliferation and clonogenic capacity of human AML cell lines and primary patient AML samples. In vivo, systemic administration of a lead small molecule LIN28/let-7 inhibitor decreases leukemic tumor burden, reduces LSC numbers and significantly improves animal survival. Mechanistic studies revealed that targeted inhibition of the LIN28/let-7 axis restores let-7 microRNA levels in AML LSCs and subsequently inhibits a panoply of key oncogenic driver genes, including the NF-ĸB pathway, a hallmark for LSC proliferation. Furthermore, AML cell lines and primary patient cells treated with the LIN28/let-7 small molecule inhibitor showed a block at the G1/S phase interface and significantly decreased cell cycle progression. Consequently, LIN28/let-7 inhibition leads to LSC differentiation and ultimately leukemic cell death. In summary, we demonstrate for the first time the drugability of the LIN28/let-7 axis in vivo and reveal a novel pharmacological means to suppress a multitude of oncogenic driver genes in human AML. These results suggest that small molecule inhibition of LIN28/let-7 has high therapeutic potential as a new class of targeted therapies for AML. Disclosures No relevant conflicts of interest to declare.
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Krupka, Christina, Bettina Lindl, Thomas Köhnke, Julia Platzer, Lavinia Pachzelt, Felix S. Lichtenegger, Torben Altmann, et al. "Steroids Abrogate BiTE® Antibody Construct-Mediated Cytotoxicity in Primary AML Cells." Blood 128, no. 22 (December 2, 2016): 3940. http://dx.doi.org/10.1182/blood.v128.22.3940.3940.
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Abstract Antibody based immunotherapy represents a promising strategy to eliminate chemoresistant cells in acute myeloid leukemia (AML). Clinical experience in acute lymphoblastic leukemia (ALL) has shown a clear correlation of leukemic burden and the occurrence of a cytokine release syndrome (CRS) during treatment with blinatumomab (CD19/CD3 BiTE®). A cytoreductive phase prior to or in combination with antibody therapy might be beneficial to reduce the severity of adverse events like CRS. The latter is often treated with steroids (dexamethasone, DEX) or less commonly, with the IL-6R antibody tocilizumab (TOC). As T-cell proliferation and function are of crucial importance for BiTE® activity (Zugmaier 2015), the effect of the drugs on effector cell function will dictate clinical response to therapy. In this study, we evaluated the influence of cytoreductive- (azacythidine, AZA; decitabine, DEC), and immunmodulatory (DEX and TOC) drugs on antibody-mediated cytotoxicity and T-cell proliferation. A CD33/CD3 BiTE® antibody construct (AMG 330) served as model T-cell recruiting antibody in this study. To address this question we set up the following experimental approaches: AML cells were cocultured with healthy donor (HD) T cells for up to 14 days ex vivo. T cells were either incubated with the specific drug for 3 days prior to coculture or the drugs were simultaneously added to AML-T cell cultures. Drug concentrations were chosen based on published serum concentrations in AML patients and their ex vivo stability in culture, validated by mass spectrometry. BiTE® mediated cytotoxicity and T-cell proliferation were assessed by flow cytometry. Preincubation of T cells with AZA and DEC impaired antibody mediated cytotoxicity of HL60 cells in a concentration dependent manner (% lysis control (ctrl) vs AZA at 1, 5, 10 µM: 99.9 vs 99.2 vs 52.1 vs 28.7, n=7; ctrl vs DEC at 0.2, 2, 5 µM: 98.4 vs 71.3 vs 60.0 vs 50.0, n=3). Similarly, T-cell proliferation was also markedly decreased (fold change (FC) T cells ctrl vs AZA at 1, 5, 10 µM: 2.9 vs 2.8 vs 1.5 vs 0.7; ctrl vs DEC at 0.2, 2, 5 µM: 3.8 vs 3.0 vs 2.3 vs 1.2). For DEX it was shown that incubation of T cells with steroids prior to cocultures had no negative effect on BiTE® mediated cytotoxicity (Brandl 2007). However, as steroids are often used simultaneously with T-cell recruiting immunotherapies, we tested the influence of DEX in combination with AMG 330. The addition of DEX to primary AML-T cell cultures (75 ng/ml) significantly impaired AMG 330 mediated cytotoxicity (% lysis AMG 330 vs AMG 330+DEX day (d) 6: 95.9 vs 47.5, n=9). This correlated to a markedly reduced T-cell proliferation (FC T cells AMG 330 vs AMG 330+DEX d6: 11.2 vs 1.2, n=9). Correspondingly, secretion of IFNγ was also decreased (n=3). Upon discontinuation of DEX an increase in AMG 330 mediated cytotoxicity was observed. Nevertheless, cytotoxicity was still considerably lower compared to control cultures (%lysis AMG 330 vs AMG 330+DEX d9: 95.6 vs 77.0). In contrast to DEX, TOC (110 µg/ml) had no negative effect on T-cell proliferation (FC T cells d6: AMG 330 vs AMG 330+TOC: 42.3 vs 36.9, n=4). Similarly, secretion of IFNγ was not affected through the simultaneous addition of TOC to primary AMG 330 cultures (pg/ml AMG 330 vs AMG 330+TOC d6: 543.9 vs 345.8 n=2). Importantly, drugs might not only interfere with effector cell function but also modulate target antigen expression. As we have previously demonstrated that antigen expression levels influence BiTE® mediated cytotoxicity (Krupka 2016), we analysed the effect of the drugs on CD33 expression. None of the drugs induced a significant up- or downregulation of CD33 on AML celllines as detected by flow cytometry. Hence our data support the notion that these drugs do not modulate antigen expression dependent lysis kinectics. We conclude, that drugs given prior or concomitant to BiTE® therapy have the potential to reduce T-cell proliferation and cytotoxicity. In particular, we observed a negative impact of AZA and DEC when given prior to AML-T cell cocultures. Importantly, even short exposure to DEX led to a significanly reduced T-cell responsiveness. Our data suggest the careful evaluation of concomitant drugs in T-cell recruiting antibody therapies and support the restrictive use of steroids in patients receiving BiTE® antibody therapy. For management of severe CRS, TOC could be considered as a targeted biologic therapy that preserves BiTE®-dependent T cell function. Disclosures Krupka: AMGEN Research Munich: Research Funding. Kufer:AMGEN Research Munich: Employment, Equity Ownership, Patents & Royalties. Kischel:AMGEN Research Munich: Employment, Equity Ownership, Patents & Royalties. Subklewe:AMGEN Research Munich: Research Funding.
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Cardoso, Mariana Nadal, Herberto José Chong Neto, Lêda Maria Rabelo, Carlos Antônio Riedi, and Nelson Augusto Rosário. "Utility of Asthma Control Questionnaire 7 in the assessment of asthma control." Jornal Brasileiro de Pneumologia 40, no. 2 (April 2014): 171–74. http://dx.doi.org/10.1590/s1806-37132014000200011.
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Our objective was to evaluate the reproducibility of Asthma Control Questionnaire 7 (ACQ-7) in asthma patients, comparing our results against those obtained with the Global Initiative for Asthma (GINA) criteria. We evaluated 52 patients. Patients completed the ACQ-7, underwent spirometry, and were clinically assessed to determine the level of asthma control according to the GINA criteria, in two visits, 15 days apart. The ACQ-7 cutoff for uncontrolled asthma was a score of 1.5. The ACQ-7 showed good reproducibility, with a correlation coefficient of 0.73. The ACQ-7 identified a greater number of patients with uncontrolled asthma than did the GINA criteria; according to the GINA criteria, 47 patients (90.4%) presented with partially controlled asthma.
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Kanafani-Zahar, Aïda. "Le “7 épices” libanais." Anthropology of the Middle East 15, no. 2 (December 1, 2020): 34–46. http://dx.doi.org/10.3167/ame.2020.150204.
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Résumé : Le piment de Jamaïque, une épice peu connue en France, est au coeur de la cuisine libanaise, du littoral comme de l’intérieur des terres, domestique et professionnelle. Elle est indispensable dans les mets carnés et, par affection et attachement, dans des préparations non carnées de légumes, de légumes secs et de plantes potagères. Son ampleur aromatique est telle qu’avec d’autres épices, elle est jugée la plus performante pour débarrasser les viandes et les abats de la zankha, miasme honni des Libanais, et pour les parfumer. Pour les jeunes générations, le mélange « 7 épices » partage des prérogatives similaires. Après avoir analysé le lien entre carné, zankha, et épice, ce texte s’interroge sur la pertinence d’un mélange aromatique dans la composition culinaire.Abstract: Little known in France, allspice is at the heart of the Lebanese cuisine, of the littoral and inland, among home and restaurant cooks. It is imperative for meat preparations, and, by affection and attachment, in vegetable and pulse dishes. Its aromatic scope is such that, with other spices, it is deemed most efficient to invalidate meats and offal from zankha, an abhorred miasma, and to bestow fragrance to them. For younger generations, the “7 spice mixture” shares similar prerogatives. After analysing the correlation between meat, zankha and spice, this study ponders on the pertinence of an aromatic mixture in the elaboration of culinary compositions in Lebanon.
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Choi, Dae-Hee, Seung-Joon Lee, and Jun Yeon Won. "Efficiency ofChlamydia PneumoniaeCulture in the Upper Airway Epithelial Cell Lines: AMC-HN-4, AMC-HN-7, and AMC-HN-8." Korean Journal of Otorhinolaryngology-Head and Neck Surgery 56, no. 2 (2013): 90. http://dx.doi.org/10.3342/kjorl-hns.2013.56.2.90.
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Bhatt, Anant Narayan, Yogesh Rai, Amit Verma, Sanjay Pandey, Kumar Kaushik, Virinder S. Parmar, Anu Arya, Ashok K. Prasad, and Bilikere S. Dwarakanath. "Non-Enzymatic Protein Acetylation by 7-Acetoxy-4-Methylcoumarin: Implications in Protein Biochemistry." Protein & Peptide Letters 27, no. 8 (September 24, 2020): 736–43. http://dx.doi.org/10.2174/0929866527666200305143016.
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Background: The semi-synthetic acetoxycoumarins are known to acetylate proteins using novel enzymatic Calreticulin Transacetylase (CRTAase) system in cells. However, the nonenzymatic protein acetylation by polyphenolic acetates is not known. Objective: To investigate the ability of 7-acetoxy-4-methyl coumarin (7-AMC) to acetylate proteins non-enzymatically in the test tube. Methods: We incubated 7-AMC with BSA and analyzed the protein acetylation using Western blot technique. Further, BSA induced biophysical changes in the spectroscopic properties of 7-AMC was analyzed using Fluorescence spectroscopy. Results: Using pan anti-acetyl lysine antibody, herein we demonstrate that 7-AMC acetylates Bovine Serum Albumin (BSA) in time and concentration dependent manner in the absence of any enzyme. 7-AMC is a relatively less fluorescent molecule compared to the parental compound, 7- hydroxy-4-methylcoumarin (7-HMC), however the fluorescence of 7-AMC increased by two fold on incubation with BSA, depending on the time of incubation and concentration of BSA. Analysis of the reaction mixture of 7-AMC and BSA after filtration revealed that the increased fluorescence is associated with the compound of lower molecular weight in the filtrate and not residual BSA, suggesting that the less fluorescent 7-AMC undergoes self-hydrolysis in the presence of protein to give highly fluorescent parental molecule 7-HMC and acetate ion in polar solvent (phosphate buffered saline, PBS). The protein augmented conversion of 7-AMC to 7-HMC was found to be linearly related to the protein concentration. Conclusion: Thus protein acetylation induced by 7-AMC could also be non-enzymatic in nature and this molecule can be exploited for quantification of proteins.
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Bansal, Pratima (Tima), and Kevin Corley. "Publishing in AMJ—Part 7: What's Different about Qualitative Research?" Academy of Management Journal 55, no. 3 (June 2012): 509–13. http://dx.doi.org/10.5465/amj.2012.4003.
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Kota, Vamsi, Rima M. Saliba, Ulas D. Bayraktar, Amer Beitinjaneh, Julianne J. Chen, Simrit Parmar, Sergio A. Giralt, et al. "Chromosome 7 Abnormalities in Allogeneic Transplantation for AML and MDS." Blood 118, no. 21 (November 18, 2011): 2037. http://dx.doi.org/10.1182/blood.v118.21.2037.2037.
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Abstract Abstract 2037 Introduction: Monosomy 7 and deletion 7q (‘del 7’) are associated with poorer prognosis in Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS). Less is known, however, of the influence of chromosome 7 deletions with additional chromosomal abnormalities on the outcomes of allogeneic stem cell transplantation (SCT). We hypothesized that multiple abnormalities in addition to ‘del 7’ lead to worse transplant results, and investigated this hypothesis in a cohort of AML (n=101) and MDS (n=100) patients transplanted between year 1990 and 2011 in our institution. Methods: Patient and disease characteristics are shown in the table. Year 2002 marks the year in which allele level HLA class I typing was incorporated, and also when most patients received the preparative regimen of busulfan 130 mg/m2 and fludarabine × 4 days +/− clofarabine. Covariates considered in the statistical analysis were age, ‘del 7’ alone versus multiple, conditioning (busulfan-fludarabine-based versus others), disease status, donor type, stem cell source, treatment-related disease, year of treatment (before and after 2002), and IPSS (MDS only). Results: AML: 60% had active disease at transplant. Median follow-up of AML survivors was 36 months (range, 0.7 – 237). ‘Del 7’ alone was present in 27 patients, while 74 had ‘del 7’ with complex cytogenetics. Preparative regimen was busulfan/fludarabine-based (n=42) or others (n=59). Donors were related (n=47) or unrelated (n=54). Grafts were bone marrow (n=35), peripheral blood (n=60), or cord blood (n=6). 39 patients were transplanted before 2002. Multivariate analysis showed that survival was independently influenced by age (>50 years) (HR=2; 95% CI 1.2–3.3; p=0.006), use of busulfan/fludarabine-based preparative regimen (HR=0.6; 95%CI 0.3–0.9; p=0.04), and remission at transplant (HR=0.4; 95%CI 0.2–0.7; p=0.001). Same factors influenced PFS. MDS patients: median follow-up in survivors was 17 months (range, 0.8– 197); 32 patients had ‘del 7’ and 68 had ‘del 7’ with complex abnormalities. 54 patients had treatment-related MDS. IPSS score was <= 1.5 in 60 patients and >1.5 in 38 patients, and 92 patients had active disease at transplant. Preparative regimens were Flu/Bu based (n=51), and others (n=49). Donor type was related (n=52) and unrelated (n=48). Grafts were bone marrow (n=37), peripheral blood (n=58) and cord blood (n=5); 35 patients were transplanted before 2002. Multivariate analysis showed that survival was influenced by absence of other chromosomal abnormalities in addition to ‘del 7’ (HR=0.5; 95% CI 0.3–0.8; p=0.01), transplant after year 2002 (HR=0.6; 95%CI 0.3–0.9; p=0.03), and IPSS >= 1.5 (HR=2; 95%CI 1.2–3.4; p=0.006). Same factors influenced PFS. Conclusions: Presence of complex chromosomal abnormalities in addition to monosomy 7 or deletion 7q did not independently influence outcomes of AML patients, but was an independent predictor of survival and PFS in MDS patients undergoing allogeneic transplantation. Disclosures: No relevant conflicts of interest to declare.
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Smith, Owen P., Brian R. Reeves, Helena M. Kempski, and Jane P. Evans. "Kostmann's disease, recombinant HuG-CSF, monosomy 7 and MDS/AML." British Journal of Haematology 91, no. 1 (September 1995): 150–53. http://dx.doi.org/10.1111/j.1365-2141.1995.tb05260.x.
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Schuster, Michael W., Mikkael A. Sekeres, Erick Gamelin, Erik Rasmussen, Gloria Juan, Abraham Anderson, Vincent Chow, Greg Friberg, Florian D. Vogl, and Hagop Kantarjian. "Phase 1 Study of AMG 900, an Orally Administered Pan-Aurora Kinase Inhibitor, in Adult Patients (Pts) with Acute Myeloid Leukemia (AML)." Blood 126, no. 23 (December 3, 2015): 4929. http://dx.doi.org/10.1182/blood.v126.23.4929.4929.
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Abstract Background: Aurora kinases form a family of highly conserved serine/threonine protein kinases that regulate key steps in mitosis. Aurora kinases A and B are amplified and/or overexpressed in many malignancies, including various types of leukemia, and are associated with high proliferation rates, poor prognosis, and therapeutic resistance. AMG 900 is an investigational, orally administered, highly potent, selective, small-molecule pan-aurora kinase inhibitor that has shown single-agent activity in heavily pretreated pts with chemotherapy-resistant/refractory solid tumors. This open-label, multicenter, sequential dose escalation study (NCT01380756) assessed AMG 900 in adult pts with AML. Methods: The primary objectives of this study were to evaluate the safety and tolerability of AMG 900, to evaluate pharmacokinetics after multiple oral administrations, to determine the optimal dose schedule, and to determine the maximum tolerated dose (MTD). A secondary objective was to evaluate antitumor activity in pts with AML. Key inclusion criteria included definitively diagnosed AML that had failed standard treatments or for which no standard therapy was available, Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, and life expectancy > 3 months. Dose escalation included parallel evaluation of 2 schedules in separate groups. In group 1, AMG 900 was administered daily 4 days on/10 days off at doses of 15, 25, 40, 60, 80, 100, 125, and 150 mg. In group 2, AMG 900 was administered daily 7 days on/7 days off at doses of 30, 40, 50, 60, and 75 mg. Dose escalation was conducted using a 3+3+3 design; intrapatient dose escalation was not allowed. The relationship between gene expression at baseline and clinical response was an exploratory objective. RNA levels for preselected genes were measured by microarray in mononuclear cells obtained from bone marrow (BM) aspirates. Results: A total of 35 pts were enrolled: 22 in group 1 and 13 in group 2. Twenty-three pts (65.7%) were male, 27 (77.1%) were white, and mean (SD) age was 66.1 (12.2) years. ECOG status was 0 in 7 pts (20.0%), 1 in 22 pts (62.9%), and 2 in 6 pts (17.1%). Pts received a median (min, max) of 14 (4, 49) doses of AMG 900. Mean maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) increased with increasing dose. Thirty pts (85.7%) had treatment-related adverse events (AEs). The most common AEs (in ≥ 10% of pts overall) were nausea (31.4%), diarrhea (28.6%), febrile neutropenia (28.6%), fatigue (22.9%), vomiting (17.1%), alopecia (14.3%), dyspnea (11.4%), epistaxis (11.4%), mucosal inflammation (11.4%), and rash (11.4%). Nine pts (25.7%) died during the study from lung infection and respiratory failure (2 pts each) and acute respiratory failure, cardiorespiratory arrest, respiratory distress, sepsis, and septic shock (1 pt each). Only respiratory failure and septic shock (1 pt each) were considered potentially related to AMG 900 by the investigators. All 35 pts discontinued treatment. Reasons for discontinuation were disease progression (65.7%), AEs (11.4%), death (8.6%), withdrawal of consent (5.7%), other reasons (5.7%), and requirement for alternative therapy (2.9%). Two pts (5.7%) experienced dose-limiting toxicities: 1 pt from group 1 (40 mg) had grade 3 pancytopenia, and 1 pt from group 2 (50 mg) had febrile neutropenia and grade 3 abdominal pain. The MTD of AMG 900 was not formally reached in either dose schedule. Three pts (8.6%) from group 1 (40 mg [2 pts] and 60 mg [1 pt]) had a best response of complete response with incomplete count recovery (CRi). Overall, the objective response rate for CRi was 8.6% (80% confidence interval: 3%, 18%). Higher gene expression of BIRC5, AURKB, AURKA, TTK, and CCNB1 was associated with objective response in univariate logistic regression models (P < .02), and was still significant after adjusting for average dose and percentage of blasts in the BM in a multivariate model (P < .01). Expression profiles of responders were clustered together in a principal component analysis. Conclusions: AMG 900 had an acceptable safety profile in this grievously ill population of adult pts with recurrent/refractory AML. Prolonged cytopenias hampered further dose escalation in this single-agent treatment setting. Combination of low doses of AMG 900 with other anticancer agents should be evaluated in future studies. Disclosures Schuster: Amgen Inc.: Equity Ownership, Honoraria, Speakers Bureau. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Gamelin:Amgen Inc.: Employment, Equity Ownership. Rasmussen:Amgen Inc.: Employment, Equity Ownership. Juan:Amgen Inc.: Employment, Equity Ownership. Anderson:Amgen Inc.: Employment, Equity Ownership. Chow:Amgen Inc.: Employment, Equity Ownership. Friberg:Amgen Inc.: Employment, Equity Ownership. Vogl:Amgen Inc.: Employment, Equity Ownership.
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Blom, N. A. "Kindercardiologie AMC." Tijdschrift voor Kindergeneeskunde 81, S1 (February 2013): 124–26. http://dx.doi.org/10.1007/s12456-013-0118-7.
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Groothoff, J. W. "Kindernefrologie AMC." Tijdschrift voor Kindergeneeskunde 81, S1 (February 2013): 142–43. http://dx.doi.org/10.1007/s12456-013-0126-7.
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Arana Yi, Cecilia Y., Hagop M. Kantarjian, Guillermo Garcia-Manero, William G. Wierda, Gautam Borthakur, Alfonso Quintas-Cardama, Marina Konopleva, et al. "Comparing Outcomes of Patients with Secondary AML: Treatment-Related MDS/AML, AML Secondary to Myeloproliferative Neoplasms (t-MPN), and AML with Prior Malignancies." Blood 120, no. 21 (November 16, 2012): 3557. http://dx.doi.org/10.1182/blood.v120.21.3557.3557.
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Abstract Abstract 3557 Background: Secondary Acute Myeloid Leukemia (AML) accounts for approximately 10% of AML's and are often associated with adverse outcomes compared to de novo AML. In addition to cytogenetics, multiple gene mutations have been incorporated in the de novo AML risk stratification as independent prognostic and predictive factors. Little is known about these molecular markers in secondary AML. We analyzed the characteristics and outcomes of AML patients arising from myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), treatment-related AML (t-AML), or with prior history of cancer not treated with chemotherapy or radiation compared to de novo AML, and investigated the frequency and prognostic relevance of molecular markers among those groups. Patients and Methods: We analyzed the outcomes of adult patients with AML receiving induction chemotherapy at MDACC (n= 248) from 2010 to 2012. Median age was 67 years (range 17–82) and 142 (57.2 %) patients were >60 yrs. 108 (44%) were female. 146 (59 %) had de novo AML, 43 (17%) had t-AML, 23 (9%) had post-MDS, 16 (7%) post-MPN, and 20 (8%) AML with antecedent cancer not treated with chemotherapy and/or radiation therapy. Median white blood cell count (WBC) at diagnosis was 4.45 × 109/L (r: 0.4–186.5), and 82 (33%) pts had WBC >10 x109/L. Cytogenetics were diploid in 91 (37%), inv 16 in 16 (7%), t(8;21) in 12 (5%), trisomy 8 in 10 (4%), chromosome −5 and/or −7 in 60 (24%), 11q in 11 (4%), miscellaneous in 30 (12%), and insufficient metaphases on 18 (7%). 43(17%) had FLT3 mutations including 26 (10%) with FLT3-ITD, 14 (6%) FLT3-D835, and 3 (1%) double mutant. 32 (13 %) had NPM 1, 15 (6%) CBFb-MYH1, 10 (4%) ABL1/ETO, 6 (2%) JAK2, 34 (14 %) RAS, 1 (0.4%) cKIT, 18 (7%) CEBPA, 10 (4%) IDH1, and 8 (3.2%) IDH2. The pts were treated with several different induction chemotherapies. Idarubicin and cytarabine (IA)-based were more frequent in de novo and in 2nd cancer groups, while hypomethylating agents were more common in post-MDS and post-MPN groups. CR rates were higher in de novo AML than the rest of the groups, and early deaths were more common in the post-MPN group. The frequency of mutations was similar among groups with the exception of JAK 2 mutation, which was more frequent in post-MPN (Table 1). In pts with secondary AML, FLT3 mutations do not seem to further worsen their outcome (median survival 6.2 months for FLT3 wt and 6.4 for FLT3 ITD in 2nd AML; corresponding values for de novo AML are not reached and 13.3 months, respectively). (Figure 1) EFS and OS was worse in the post-MDS and post-MPN groups compared to de novo AML and second cancer group (p>0.001). Conclusion: In patients with secondary AML, antecedent of MDS or MPN are associated with unique molecular signatures (eg, rare FLT3-ITD in post MDS, frequent JAK2 in post-MPN) and have an inferior outcome. In contrast AML in pts with history of previous cancers not previously exposed to chemotherapy or radiation therapy survival outcomes are similar to de novo AML. Mutational status may not be as predictive of outcome among patients with secondary AML as it is for de novo AML. Disclosures: No relevant conflicts of interest to declare.
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Stamm, Hauke, Felix Klingler, Daniela Pende, Eik Vettorazzi, Michael Heuser, Ulrike Mock, Carsten Bokemeyer, et al. "Expression of Novel Immune Checkpoint Molecules PVR and PVRL2 Confers a Negative Prognosis to Patients with Acute Myeloid Leukemia and Their Blockade Augments T-Cell Mediated Lysis of AML Cells Alone or in Combination with the BiTE® Antibody Construct AMG 330." Blood 126, no. 23 (December 3, 2015): 789. http://dx.doi.org/10.1182/blood.v126.23.789.789.
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Abstract Background: T-cell activity is regulated by immune checkpoints to maintain the sensitive balance of co-stimulatory and inhibitory immune signals. Therapeutic blockade of checkpoint molecules on tumor or T cells such as CTLA-4 or PD-L1 has shown clinical success in several tumor types including Hodgkin´s disease. Furthermore, Blinatumomab, a bispecific T-cell engager (BiTE antibody construct) directing cytotoxic T cells to CD19 positive leukemic cells has been approved for treatment of acute lymphoblastic leukemia. The CD33 specific BiTE antibody construct AMG 330 has been developed for the therapy of acute myeloid leukemia (AML) and will be evaluated in phase I studies shortly. In our current study, we investigated the therapeutic utility of blockade of the novel checkpoint proteins PVR (poliovirus receptor) and PVRL2 (poliovirus receptor-related 2) alone and in combination with AMG 330 in AML. Methods and results: Samples from 140 treatment naive patients with newly diagnosed AML (AMLSG 07-04, NCT00151242) were analyzed by RT-qPCR for expression of the immune checkpoint molecules PVR, PVRL2 and Galectin-9 (Gal-9). Expression was correlated with patient demographics (age, karyotype, FLT3 mutation status) and clinical survival data by multivariate cox regression. The majority of patients showed mRNA expression of PVR (94%), PVRL2 (95%) and Gal-9 (92%). In a multivariate stepwise cox regression for overall survival, an unfavorable karyotype, high PVR and high Gal-9 expression were identified as independent prognostic markers (p<0.001, HR: 2.10, CI 1.39-3.15 for the karyotype; p=0.001, HR: 1.64, CI 1.21-2.21 for PVR and p<0.001, HR: 0.67, CI 0.54-0.84 for Gal-9). Due to a high correlation between PVR and PVRL2 (Pearson's rho=0.827, p<0.001), PVRL2 was removed during the stepwise process. Nevertheless, if PVR was excluded from the multivariate cox regression, PVRL2 remained as significant term in the stepwise procedure in addition to the karyotype and Gal-9 (p=0.003, HR: 1.58, CI 1.17-2.13 for PVRL2). In a second, independent patient cohort containing microarray-based gene expression and clinical data of 291 AML patients (Verhaak et.al., Haematologica 2009;94) a high PVR and PVRL2 expression in contrast to expression of CD80, CD86 or PD-L1 was associated with poor overall survival (log-rank test p=0.003 and p=0.032, respectively). In in vitro killing assays the therapeutic effect of PVR and PVRL2 blockade was studied by FACS using 7-AAD staining. AML cell lines MV4-11, Kasumi-1 and Molm-13 were preincubated with blocking antibodies against PVR, PVRL2 or both and co-cultured for 24h with peripheral blood mononuclear cells (PBMCs) of healthy donors in the presence or absence of AMG 330. In the absence of AMG 330, the cell kill of MV4-11 increased from 12.6±4.7% (control) to 33.0±8.8% (PVR), to 40.4±10.4% (PVRL2) and to 56.0±12.0% (both PVR + PVRL2). In the presence of suboptimal concentration of AMG 330 (0.1 ng/ml) MV4-11 cell lysis was 29.4±9.0% (AMG 330 alone), 49.7±12.6% (AMG 330 + PVR), 57.9±11.3% (AMG 330 + PVRL2) and 70.0±9.8% (AMG 330 + PVR + PVRL2; n=4, p<0.05 for all comparisons). Comparable results were found for Kasumi-1 and Molm-13 with blockade of both checkpoint inhibitors being the most effective treatment, although additive effects of antibodies against PVR and PVRL2 could not be verified in all cases (data not shown). To confirm specificity of the approach and to exclude effects caused by antibody dependent cellular cytotoxicity (ADCC), PVR and PVRL2 double knockouts of the cell line MV4-11 were generated by CRISPR/Cas-9. Significantly increased killing was observed in PVR and PVRL2 double knockout cells compared to wild-type cells (40.5±8.1 % vs. 25.9±9.1; n=3, p<0.001). Further experiments using an irrelevant antibody against CD117 or Fcγ receptor blockade by purified IgG antibodies excluded ADCC confirming the functional relevance of PVR/PVRL2 blockade. Conclusion: The expression of immune checkpoint ligands PVR and PVRL2 confers a negative prognosis to AML patients possibly due to immune evasion. We could further show that the killing of AML cells by PBMCs could be augmented by blockade of these novel checkpoint inhibitors. Furthermore, addition of PVR and/or PVRL2 blocking antibodies to AMG 330 could enhance cytotoxicity. Therefore, blockade of PVR and PVRL2 represents a promising target for the treatment of AML. Disclosures Kischel: Amgen Research (Munich) GmbH: Employment. Stienen:Amgen Research (Munich) GmbH: Employment. Friedrich:Amgen Research (Munich) GmbH: Employment. Lutteropp:Amgen Research (Munich) GmbH: Employment. Nagorsen:Amgen: Employment, Equity Ownership, Patents & Royalties: Inventor on blinatumomab-related patent.
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Subklewe, Marion, Anthony Stein, Roland B. Walter, Ravi Bhatia, Andrew H. Wei, David Ritchie, Veit Bücklein, et al. "Preliminary Results from a Phase 1 First-in-Human Study of AMG 673, a Novel Half-Life Extended (HLE) Anti-CD33/CD3 BiTE® (Bispecific T-Cell Engager) in Patients with Relapsed/Refractory (R/R) Acute Myeloid Leukemia (AML)." Blood 134, Supplement_1 (November 13, 2019): 833. http://dx.doi.org/10.1182/blood-2019-127977.
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Background: AMG 673 is a novel half-life extended (HLE) BiTE® (bispecific T-cell engager) construct that binds both CD33 and CD3 and is genetically fused to the N-terminus of a single-chain IgG Fc region, thereby potentially increasing the half-life of the molecule. AMG 673 redirects T cells toward CD33+ cells, with the induced proximity leading to T-cell‒mediated cytotoxicity against acute myeloid leukemia (AML) blasts. Anti-AML activity of other CD33/CD3 bispecific T-cell engager molecules has been previously reported (Blood, 2018, 132, 25; Blood, 2018, 132, 1455). The objectives of this ongoing study are to evaluate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of AMG 673 in adult patients aged ≥18 years with relapsed/refractory (R/R) AML. Methods: This is an ongoing first-in-human, open-label, phase 1, sequential dose escalation study (NCT03224819). AMG 673 was administered as two, short, and intermittent intravenous (IV) infusions during a 14-day cycle in adult patients with R/R AML. Patients received treatment cycles of AMG 673 until disease progression or unacceptable toxicities. T-cell activation, cytokine, and AMG 673 levels in patients' blood were evaluated by validated assays. Results were summarized descriptively by the dosing cohorts and potential associations between PK, PD, safety, and preliminary efficacy were evaluated. Results: As of June 14, 2019, 30 patients had enrolled in 10 cohorts and were treated with AMG 673 (dose range, 0.05-72 μg IV per dose). The median age was 67.5 (range: 25.0-84.0) years; 20/30 (67%) patients had received ≥4 prior anti-AML treatments, baseline myelosuppression at study entry was common (grade ≥3 neutropenia 21/30 [70%], thrombocytopenia 25/30 [83%], leukopenia 14/30 [47%]), and 7/30 (23%) patients had undergone hematopoietic stem cell transplant (HSCT) before enrolling in the study. Patients received a median of 1.5 (range: 1.0-6.0) cycles of AMG 673; 27/30 (90%) patients discontinued treatment due to disease progression (n=21), patient request (n=2), protocol-specified criteria (n=2), or adverse events (AEs; n=2). A total of 3 patients were still receiving AMG 673 at the time of data analysis. The most common treatment-related AE was cytokine release syndrome (CRS) reported in 15/30 (50%) patients (grade 1, n=6; grade 2, n=5; grade 3, n=4; no grade 4 CRS). Treatment-related serious AEs were reported in 11/30 (37%) patients, and 15/30 (50%) patients experienced treatment-related AEs of grade ≥3, with the most common being abnormal hepatic enzymes (n=5, 17%), CRS (n=4, 13%), leukopenia (n=4, 13%), thrombocytopenia (n=2, 7%), and febrile neutropenia (n=2, 7%). Two deaths, unrelated to AMG 673, were reported on days 19 and 28 after the last dose. Assessment of bone marrow in treated patients showed a decrease in blasts in 12/27 (44%) evaluable patients, of which 6 experienced ≥50% reduction in blasts compared with baseline (Figure 1). One patient achieved complete remission with incomplete hematologic recovery (CRi) with 85% reduction in bone marrow blasts at a dose of 36 µg. Dose-related increases in Cmax and AUC were observed following AMG 673 infusions. Preliminary half-life estimates for AMG 673 were longer than those observed for canonical CD33-specific BiTE® molecule with short half-lives. Upregulation of T-cell activation markers CD25 and CD69 on T-cell subsets and cytokine release post-infusion were observed at higher doses. Preliminary associations between AMG 673 exposures, T-cell activation, safety, and clinical response have been evaluated. Conclusions: Preliminary data of AMG 673 dosed up to 72 µg provide early evidence of the molecule's acceptable safety profile, drug tolerability, and anti-leukemic activity. An association was observed between PK/PD relationships that were consistent with the biological activity of AMG 673. These preliminary results support further dose escalation of the AMG 673 HLE BiTE® molecule in patients with R/R AML. Disclosures Subklewe: AMGEN: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Morphosys: Research Funding; Janssen: Consultancy; Celgene: Consultancy, Honoraria; Miltenyi: Research Funding; Oxford Biotherapeutics: Research Funding; Pfizer: Consultancy, Honoraria. Stein:Celgene: Speakers Bureau; Stemline: Speakers Bureau; Amgen: Consultancy, Speakers Bureau. Walter:Amgen: Consultancy; Amphivena Therapeutics: Consultancy, Equity Ownership; Aptevo Therapeutics: Consultancy, Research Funding; Argenx BVBA: Consultancy; Astellas: Consultancy; BioLineRx: Consultancy; BiVictriX: Consultancy; Seattle Genetics: Research Funding; Boehringer Ingelheim: Consultancy; Boston Biomedical: Consultancy; Covagen: Consultancy; Daiichi Sankyo: Consultancy; Agios: Consultancy; Race Oncology: Consultancy; Jazz Pharmaceuticals: Consultancy; Kite Pharma: Consultancy; Pfizer: Consultancy, Research Funding; New Link Genetics: Consultancy. Wei:Astellas: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Macrogenics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Honoraria, Research Funding; Janssen: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties: AHW is a former employee of the Walter and Eliza Hall Institute and receives a fraction of its royalty stream related to venetoclax, Research Funding, Speakers Bureau. Ritchie:Amgen: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; BMS: Research Funding; Takeda: Research Funding; Beigene: Research Funding; Imago: Research Funding; Novartis: Honoraria; Sanofi: Honoraria. Vachhani:AbbVie: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Astellas: Speakers Bureau. Dai:Amgen: Employment, Equity Ownership. Hindoyan:Amgen Inc.: Employment, Other: stock ownership. Agarwal:Amgen: Employment, Equity Ownership; AbbVie: Equity Ownership. Anderson:Amgen Inc.: Employment, Equity Ownership. Khaldoyanidi:Amgen: Employment, Equity Ownership; BMS: Equity Ownership. Ravandi:Macrogenix: Consultancy, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Consultancy, Research Funding; Menarini Ricerche: Research Funding; Selvita: Research Funding; Cyclacel LTD: Research Funding.
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Oyake, Tatsuo, Yuka Fujisawa, Norifumi Sugawara, Ryousei Sasaki, Wataru Izumita, Takahiro Mine, Maki Asahi, et al. "Comparison of Micafungin and Liposomal Amphotericin B for Empirical Antifungal Therapy in Febrile Neutropenic Patients with Acute Myeloid Leukemia: A Randomized Controlled Trial." Blood 128, no. 22 (December 2, 2016): 1607. http://dx.doi.org/10.1182/blood.v128.22.1607.1607.
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Abstract Background: Invasive fungal infections (IFIs) incur significant morbidity and mortality in neutropenic patients with hematological malignancies (HEM) after chemotherapy. The risk for these infections is related to the intensity and duration of neutropenia, and varies from 2% to 40%. Mortality rates associated with documented IFIs are considerable, reportedly ranging from 30% to 60%. Empirical antifungal therapy is the standard care for neutropenic patients with HEM, who remain febrile despite broad-spectrum antibacterial treatment. Several antifungal agents including voriconazole (VRCZ) or liposomal amphotericin B (L-AMB) have been studied as empirical therapy for febrile neutropenia (FN). However, limited data are available concerning the efficacy of micafungin (MCFG) in FN patients with acute myeloid leukemia (AML). Methods: We conducted a randomized, cooperative group, open-label trial comparing MCFG (150 mg once daily) with L-AMB (2.5 mg/kg once daily) as a first-line empirical antifungal treatment for 102 hospitalized FN patients with AML (MCFG, 53; L-AMB, 49). The efficacy end point was a favorable overall response, as determined by a five-component end point according to the criteria of Walsh et al (N Engl J Med 2004; 351: 1391). Results: At the time of enrolment, there were no significant differences in the demographics or baseline characteristics between the two groups. The mean treatment duration for MCFG and L-AMB was 14.8 and 17.1 days, respectively. The efficacy rates of MCFG and L-AMB were not significantly different (58.5% vs. 44.9%, p = 0.1698*), evaluated based on: (1) successful treatment of baseline fungal infection (3/5cases (5.7%) vs. 0/1case (0%), p = 0.170*), (2) absence of breakthrough fungal infection (90.6% vs. 98.0%, p = 0.112*), (3) survival for ≥7 days after study completion (88.7% vs. 89.8%, p = 0.855*), (4) absence of premature study drug discontinuation due to poor efficacy or drug-related adverse events (67.9% vs. 75.5%, p = 0.396*), and (5) resolution of fever during neutropenia (66.0% vs. 55.1%, p = 0.258*). However, discontinuation due to drug-related adverse events occurred less frequently in the MCFG group (1.9% vs. 12.2%, p = 0.038*). In safety evaluation, adverse events of creatinine increase and hypokalemia were less often in the MCFG group than in the L-AMB group (9.4% vs. 26.5%, P=0.023*, 22.6% vs. 57.1%, P=0.0004*). *: Chi square test. Conclusions: MCFG was as effective as L-AMB, and better tolerated than L-AMB as an empirical antifungal therapy in FN patients with AML. Disclosures Ishida: Kyowa Hakko Kirin Co: Research Funding; Nippon Shinyaku Co: Research Funding; CHUGAI PHARMACEUTICAL CO: Research Funding; Astellas Pharma Inc.: Other: Astellas Pharma Inc. (Tokyo, Japan) supported this clinical study with a grant; the sponsor was not involved in the design of study, the enrollment of patients, the collection, analysis, interpretation of the data., Research Funding.
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Batten, Alex, Cassie Jaeger, David Griffen, Paula Harwood, and Karen Baur. "See You in 7: improving acute myocardial infarction follow-up care." BMJ Open Quality 7, no. 2 (June 2018): e000296. http://dx.doi.org/10.1136/bmjoq-2017-000296.
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Acute myocardial infarction (AMI) follow-up care is a crucial part of the AMI recovery process. The American College of Cardiology’s ‘See You in 7 Challenge’ advocates that all patients discharged with a diagnosis of AMI have a cardiac rehabilitation referral made and outpatient cardiac rehabilitation appointment scheduled to occur within 7 days of hospital discharge. A streamlined AMI cardiac rehabilitation referral and appointment scheduling process was not in place at this urban academic medical centre. To develop the streamlined processes, a Six Sigma project was initiated. Four months before the intervention, 1/38 patients with AMI (2.6%) were scheduled to have the initial outpatient cardiac rehabilitation appointment occur within 7 days of hospital discharge, with an average 18.7 days from hospital discharge to the scheduled initial outpatient cardiac rehabilitation appointment. To reduce the time to this initial appointment, availability of outpatient cardiac rehabilitation appointments was increased, additional staff were trained in appointment scheduling and insurance verification processes and appointments were scheduled prior to hospital discharge. After intervention, the number of patients scheduled to attend an outpatient cardiac rehabilitation appointment within 7 days of hospital discharge improved to 72/79 (91.1%) (two-proportion test, p<0.001). Days from hospital discharge to first scheduled outpatient cardiac rehabilitation appointment were reduced from 18.7 days to 6.3 days (a 66.3% reduction) (Mann-Whitney U test, p<0.01). Initial outpatient cardiac rehabilitation attendance within 7 days of hospital discharge increased from 1/38 (2.6%) to 42/79 (53.2%) (a 50.6% increase) (two-proportion test, p<0.001).
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Wu, Wenjing, Hui Wang, Changan Yu, Jiahui Li, Yanxiang Gao, Yuannan Ke, Yong Wang, Yifeng Zhou, and Jingang Zheng. "Association of ADAMTS-7 Levels with Cardiac Function in a Rat Model of Acute Myocardial Infarction." Cellular Physiology and Biochemistry 38, no. 3 (2016): 950–58. http://dx.doi.org/10.1159/000443047.
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Background/Aims: High ADAMTS-7 levels are associated with acute myocardial infarction (AMI), although its involvement in ventricular remodeling is unclear. In this study, we investigated the association between ADAMTS-7 expression and cardiac function in a rat AMI model. Methods: Sprague-Dawley rats were randomized into AMI (n = 40) and sham (n = 20) groups. The left anterior descending artery was sutured to model AMI. Before surgery and 7, 14, 28, and 42 days post-surgery, ADAMTS-7 and brain natriuretic peptide (BNP), and cartilage oligomeric matrix protein (COMP) were assessed by ELISA, western blot, real-time RT-PCR, and/or immunohistochemistry. Cardiac functional and structural parameters were assessed by M-mode echocardiography. Results: After AMI, plasma ADAMTS-7 levels increased, peaking on day 28 (AMI: 13.2 ± 6.3 vs. sham: 3.4 ± 1.3 ng/ml, P < 0.05). Compared with the sham group, ADAMTS-7 expression was higher in the infarct zone at day 28. COMP present in normal myocardium was degraded by day 28 post-AMI. Plasma ADAMTS-7 correlated positively with BNP (r = 0.642, P = 0.025), left ventricular end-diastolic diameter (r = 0.695, P = 0.041), left ventricular end-systolic diameter (r = 0.710, P = 0.039), left ventricular ejection fraction (r = 0.695, P = 0.036), and left ventricular short-axis fractional shortening (r = 0.721, P = 0.024). Conclusions: ADAMTS-7 levels may reflect the degree of ventricular remodeling after AMI.
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ROSEN, JOSHUA E., LYNDON JONES, and FRANK X. GU. "LIGHT-INDUCED AGGREGATION OF NANOPARTICLES FUNCTIONALIZED WITH 7-AMINO-4-METHYLCOUMARIN." Nano LIFE 02, no. 03 (September 2012): 1241007. http://dx.doi.org/10.1142/s1793984412410073.
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Herein, we report on the modification of silica nanoparticles with the molecule 7-amino-4-methylcoumarin (AMC) via a hydrophilic dextran linker using reductive amination chemistry. The AMC-functionalized nanoparticles were shown to aggregate in response to irradiation by 350 nm UV light. The aggregation of the particles was studied using dynamic light scattering, UV-VIS spectroscopy, and transmission electron microscopy. The synthesis method described herein utilizes a classic reductive amination reaction, which can potentially be transferred to a variety of different types of nanoparticles. Particles displaying this behavior have many potential applications in the field of nanomedicine, as they can potentially allow one to modulate the particle size of a nanoparticle formulation after administration to the body. The AMC-functionalized particles studied in this report serve as a convincing proof-of-concept for synthesizing light-responsive nanoparticles.
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Ivanoff, Sarah, Emilie Lemasle, Berengere Gruson, Lavinia Merlusca, Amandine Charbonnier, Anne Parcelier, Gandhi Damaj, Bruno Royer, and Jean Pierre Marolleau. "Azacitidine in Relapsed and Refractory AML: Efficacy for Patients Relapsing As MDS Post AML." Blood 120, no. 21 (November 16, 2012): 4332. http://dx.doi.org/10.1182/blood.v120.21.4332.4332.
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Abstract Abstract 4332 Background: Azacitidine (Aza), inhibitor of DNA methyltransferases, plays an important role in epigenetic regulation of gene expression and tumorogenesis, and is active in myeloid neoplasia such as myelodysplasia (MDS) and de novo acute myeloid leukemia (AML). Efficacy of Aza for relapsed and refractory AML has not been so far reported. Methods: We report in 2 french centers (Amiens, Rouen) retrospective study, the results of Aza for relapsed or refractory patients. All patients received Aza (75 mg/m2 per day over 7 days for 4 weeks cycles), until progression, and at least one cycle. Leukocyte blood count was < 10109/l. The primary endpoint was overall response rate (ORR), according to IWG 2006: complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD), hematological improvement (HI). Secondary endpoints were duration of response and overall survival (OS). Results: 41 patients (26 males and 15 females) with a median age of 59 years (range 28–78) were studied from August, 2007 and November, 2011 (Table): 15 had refractory and 26 relapsed AML. At relapse 11/26 had MDS, defined by blast count <20% and cytological morphology of MDS in bone marrow aspirate, and 15/26 AML. Patients received in average 6 cycles (1–30): 4 (1–7) for refractory; 7 (1–30) for relapsed (11 (3–30) for MDS post AML; 3 (3–5) for relapsed AML). Overall, the ORR was 34% (7 CR, 5 RP, and 9 HI). For patients with MDS post AML OR was 82% (7 CR, 2 RP, 7 HI), 13% (1 RP, 1 HI) for relapsed AML, and 13% (2 PR and 1HI) for refractory AML. The average duration of response was 4 months (0–39) for the 41 patients: 14 months (0–39) for MDS post AML, 0.3 for relapsed AML, and 0.5 for refractory. Overall survival from diagnosis was 29 months (6.9–87): 38.2 (12–57) for MDS post AML, 30.1 (6.9–87) for relapsed AML and 13.3 (6.9–35.5) for refractory (no significant differences). Overall survival from initiation of Aza was 9.4 months (1.1–39.2): 22.6 (4.8–39.2) for MDS post relapsed and 3.9 (0.3–11.3) for relapsed AML and 6.2 (1.1–13.3) for refractory patients. The differences are not statically significant probably due to small effective of our study. Contrarily to the others 2 groups, 6 patients (55%) with MDS post AML are alive in CR at the latest report; moreover three of them underwent an allogeneic transplantation. Conclusion: Aza seems to efficient for relapsed AML patient, especially for MDS post AML, but inappropriate for refractory patients. Disclosures: No relevant conflicts of interest to declare.
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Schiffer, C. A. "OP07 3&7 remains the standard induction therapy for AML." Leukemia Research 31 (September 2007): S34. http://dx.doi.org/10.1016/s0145-2126(07)70287-4.
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Cardoso, Mariana N., Herberto J. Chong Neto, Carlos Antonio Riedi, and Nelson A. Rosario. "Reproducibility of Acq-7 Questionnaire in the Assessment of Asthma Control." Journal of Allergy and Clinical Immunology 131, no. 2 (February 2013): AB207. http://dx.doi.org/10.1016/j.jaci.2012.12.1409.
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Borchers, Moritz. "Zauberkugeln gegen AML." InFo Onkologie 21, no. 2 (March 2018): 56–57. http://dx.doi.org/10.1007/s15004-018-6030-7.
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Gruber. "AMA und Gemeinschaftsrecht." Wirtschaftsrechtliche Blätter 21, no. 9 (September 2007): 455. http://dx.doi.org/10.1007/s00718-007-1014-7.
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Choi, Yunsuk, Je-Hwan Lee, Jung-Hee Lee, Dae-Young Kim, Sung-Doo Kim, Sung-Nam Lim, Eun-Hye Hur, et al. "Genetic Alterations of Wilms' Tumor 1 (WT1) Gene In Korean Patients with Normal Karyotype Acute Myeloid Leukemia." Blood 116, no. 21 (November 19, 2010): 4852. http://dx.doi.org/10.1182/blood.v116.21.4852.4852.
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Abstract Abstract 4852 Introduction: Acquired mutations of the WT1 gene have been reported in 5–10% of normal karyotype AML (NK-AML) patients. Poor prognostic impact of the mutations has been reported, but some studied found no such correlation. Recent report from Germany showed the association of single nucleotide polymorphism (SNP) rs16754 status with clinical outcomes in NK-AML (J Clin Oncol 2009; 28:578). We assessed clinical implication of WT1 gene alterations in Korean patients with NK-AML. Patients and Methods: This study included a total of 75 patients with NK-AML. All patients received standard induction chemotherapy (‘7+3’ regimen) at the Asan Medical Center, Seoul, Korea between May 1999 and Dec 2006. WT1 exons 7 and 9 were amplified using polymerase chain reaction (PCR) and purified PCR fragments were directly sequenced. The clinico-laboratory data were retrieved from the AMC Leukemia Registry. Results: WT1 mutations were found in four patients (5.3%): two duplication mutations and two insertion mutations. All mutations were in exon 7 and none in exon 9. Two of four patients harboring WT1 mutation failed to achieve complete remission (CR) and died at 3.9 and 7.0 months after diagnosis of AML. One of two patients attaining CR was alive without relapse at 44.0 month and another died in CR at 4.7 months. WT1 SNP rs16754 was AA genotype (WT1AA) in 5 (3.7%), AG (WT1AG) in 29 (38.2%), and GG (WT1GG) in 41 (54.7%). The findings are significantly different from those of German report (WT1AA in 74.3%, WT1AG in 24.1%, and WT1GG in 1.6%) (P<0.0001). No significant difference of baseline clinico-laboratory findings was observed between different genotypes of WT1 SNP rs16754 (WT1AA/AG vs. WT1GG). The CR rates were similar between two SNP groups (WT1AA/AG vs. WT1GG, 85.3% vs. 80.5%, P=0.78). The five-year probabilities of overall (OS) and relapse-free (RFS) survival appeared to be lower in patients with WT1GG genotype, but the differences were not statistically significant (WT1AA/AG vs. WT1GG; OS, 49.3% vs. 36.9%, P=0.43; RFS, 56.3% vs. 42.5%, P=0.64). Conclusion: The prognostic impact of WT1 mutation in NK-AML could not be assessed in this study due to low number of patients harboring the mutation, but three of four patients died with relatively short survival duration, suggesting poor prognosis of the patients with WT1 mutation. The frequency of WT1 SNPs rs16754 in our patients was different from that of German report and survivals were not significantly different according to the SNP genotypes. Disclosures: No relevant conflicts of interest to declare.
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Zuba-Surma, Ewa K., Magda Kucia, Yiru Guo, Buddhadeb Dawn, Roberto Bolli, and Mariusz Z. Ratajczak. "An In Vivo Evidence That Murine Very Small Embryonic Like (VSEL) Stem Cells Are Mobilized into Peripheral Blood after Acute Myocardial Infarction (AMI) and Contribute to Myocardiac Regeneration." Blood 110, no. 11 (November 16, 2007): 3694. http://dx.doi.org/10.1182/blood.v110.11.3694.3694.
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Abstract We have recently identified a population of SSEA-1+/Oct-4+/Sca-1+/lin−/CD45− pluripotent, very small embryonic-like stem cells (VSEL) in adult murine bone marrow (BM). We found that VSEL possess the ability to differentiate in vitro into all three germ layers including cardiac lineage. However, the input of these cells in regeneration of injured tissues including infarcted myocardium was uncertain. Therefore, the aim of this study was to establish if VSEL are mobilized into peripheral blood (PB) after acute heart infarction and could play a potential role in myocardiac regeneration. To address this question C57BL/6 mice (6- or 15-wk-old) underwent a 30-min coronary occlusion followed by reperfusion and were euthanized at 24 h, 48 h, or 7 days after AMI. PB samples were collected for flow cytometric, confocal microscopic, and RQ-PCR analysis. Sham controls underwent sham surgery (1-h open-chest state without AMI) while controls did not. In flow cytometric analysis, VSEL were detectable in PB on low level under baseline conditions but increased significantly after AMI, peaking at 48 h post AMI both in younger (6-wk-old) and older (15-wk-old) mice (3.33±0.37 and 7.73±1.02 cells/μl of PB, respectively) (Figure 1). By confocal microscopy, sorted PB-derived VSEL were positive for Oct-4 and negative for CD45 in contrast to hematopoietic stem cells (HSC). Furthermore, RQ-PCR analysis revealed increased level of mRNA for markers of pluripotency, such as Oct-4, Nanog, Rex-1, Dppa1, and Rif1, in total PB cells of both age groups of mice at 48 h after AMI. We observed 10.01±1.98, 6.02±1.66, 5.28±1.68, 2.07±0.99 and 3.18±0.49 -fold increase in mRNA level of these genes, respectively, as compared with sham control in 6-wk-old mice. HSCs were also mobilized after AMI and were detected on higher level up to 7 days post AMI (Figure 1A). We also investigated regenerative potential of VSEL injected into infarcted myocardium in vivo. Mice underwent a 30-min coronary occlusion followed by reperfusion and, 48 h later, received intramyocardial injection of vehicle (group I), freshly sorted VSEL (group II) or VSEL predifferentiated in cardiomyogenic medium (group III). At 35 day of follow up, the heart function was investigated by echocardiography. Mice in group III exhibited improved function of infarcted left ventricle (LV) showing higher LV ejection fraction (54.5±3.3% vs. 41.5±3.3% in group I) (Figure 1B). The other parameters including infarct wall thickening fraction and end-diastolic volume also indicated improvement of heart function. This report is the first showing that the pluripotent stem cells (VSEL) are not only mobilized from the bone marrow into the peripheral blood after AMI, but also participate in regenerative processes of infarcted myocardium. Figure 1 A. Levels of circulating VSELs and HSCs in peripheral blood of 6- and 15- weeks old mice after AMI (# P <0,0025 vs. II: Sham control ). Figure 1B. Heart function after treatment of infarcted mycocardium with VSELs evaluated with echocardiography (*P < 0,05 vs. Group 1). BSL - baseline test, 96h and 35d – test performed after 96h and 35 days post AML. Figure 1. A. Levels of circulating VSELs and HSCs in peripheral blood of 6- and 15- weeks old mice after AMI (# P <0,0025 vs. II: Sham control). . / Figure 1B. Heart function after treatment of infarcted mycocardium with VSELs evaluated with echocardiography (*P < 0,05 vs. Group 1). BSL - baseline test, 96h and 35d – test performed after 96h and 35 days post AML.
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Maserati, Emanuela, Antonella Minelli, Carla Olivieri, Livia Bonvini, Antonietta Marchi, Mauro Bozzola, Cesare Danesino, Susi Scappaticci, and Francesco Pasquali. "Isochromosome (7)(q10) in Shwachman Syndrome Without MDS/AML and Role of Chromosome 7 Anomalies in Myeloproliferative Disorders." Cancer Genetics and Cytogenetics 121, no. 2 (September 2000): 167–71. http://dx.doi.org/10.1016/s0165-4608(00)00246-6.
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Hildebrandt, D. A., and R. O. Banks. "Effect of atrial natriuretic factor on renal function in rats with nephrotic syndrome." American Journal of Physiology-Renal Physiology 254, no. 2 (February 1, 1988): F210—F216. http://dx.doi.org/10.1152/ajprenal.1988.254.2.f210.
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This study was designed to evaluate the renal effects of atrial natriuretic factor [ANF(8-33)] in rats with aminonucleoside (AMN)-induced nephrotic syndrome. AMN (100 mg/kg iv) was administered to adult female rats either 2 (AMN 2, n = 7), 4 (AMN 4, n = 7), 6 (AMN 6, n = 7), or 14 (AMN 14, n = 6) days before clearance experiments; untreated (UNT, n = 7) animals served as controls. During clearance experiments, rats were anesthetized with pentobarbital sodium. Protein excretion rates were similar between UNT and AMN 2 but increased stepwise in AMN 4, AMN 6, and AMN 14 rats. The glomerular filtration rate (GFR) was similar in UNT and AMN 2, lower in AMN 4 and AMN 14, and lowest in AMN 6 rats. Basal sodium excretion (UNaV) was not different among the five groups. An ANF primer (1.0 micrograms/kg iv) plus a constant infusion (0.1 micrograms.kg-1.min-1) for 1 h produced a significantly lower increase in UNaV in AMN 2 and AMN 14 than in UNT and was not natriuretic or diuretic in AMN 4 or AMN 6 rats. The ANF-induced increase in UNaV was similar between AMN 2 and AMN 14 rats. ANF had no effect on the GFR in any group. A higher ANF bolus (5.0 micrograms/kg iv) was then infused. This ANF bolus increased UNaV only in UNT and AMN 2 rats. Finally, a bolus of furosemide (4.0 mg/kg iv) was given; UNaV increased similarly in UNT, AMN 2, and AMN 14, and to a lesser extent in AMN 4 and AMN 6 rats. Thus, there is an attenuated natriuretic and diuretic response to ANF in rats with AMN-induced nephrotic syndrome. This altered responsiveness to ANF may contribute to the sodium and water retention characteristic of this disorder.
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Dicker, Frank, Claudia Haferlach, Wolfgang Kern, Torsten Haferlach, and Susanne Schnittger. "High Frequency of AML1/RUNX1 Mutations in Specific Cytogenetic Subgroups in De Novo Acute Myeloid Leukemia." Blood 110, no. 11 (November 16, 2007): 986. http://dx.doi.org/10.1182/blood.v110.11.986.986.
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Somatic mutations in the DNA-binding domain, the socalled Runt homology domain, of the AML1/RUNX1 gene have been identified to occur in acute myeloid leukaemia (AML) with the highest incidence in AML M0, in therapy-related myelodysplastic syndrome (t-MDS), in therapy-related AML (t-AML) and AML after MDS (s-AML). Cytogenetic aberrations that are associated with RUNX1 mutations (RUNX1mut) have been reported to be trisomy 13 in AML and trisomy 21 in myeloid malignancies, but also loss of chromosome 7q, mainly in t-MDS but rarely in t-AML. So far the majority of RUNX1mut have been described in secondary or therapy-related cases. Thus, we characterized a cohort of 119 patients (pts) with de novo AML and compared these results to 19 MDS and s-AML, 2 t-MDS (n=2) and 8 t-AML. The cohort was selected for specific cytogenetics with high reported frequencies of RUNX1mut: trisomy 13 (n=17), trisomy 21 (n=9), −7/7q- (n=34). In addition pts with normal karyotype (NK) (n=42), inv(3)/t(3;3) (n=12), trisomy 8 (n=11), complex karyotype (n=13) and 10 pts with various other cytogenetic aberrations (other) were analyzed. The incidence of RUNX1mut in the different cytogenetic subgroups was: 94% (16/17) in +13, 56% (5/9) in +21, 29% (10/34) in −7/7q-, 10% (4/42) in NK, 17% (2/12) in inv(3)/t(3;3), 18% (2/11) in +8, 0% (0/13) in complex karyotype and 20% (2/10) in other, respectively. Based on clinical history we observed RUNX1 mutations in: 6/19 (32%) in MDS/s-AML, 1/10 (10%) in t-MDS/t-AML and 34/119 (29%) in de novo AML. Of the 6 RUNXmut cases with MDS/s-AML the karyotypes were heterogeneous NK (n=1), −7 (n=2) +13 (n=1), +21 (n=1), and inv(3) (n=1). The only recurrent cytogenetic aberration in MDS/s-AML was −7, thus the frequency of RUNXmut in the MDS/s-AML group with −7 was 2/8 (25%). Also the only RUNX1mut case with t-AML revealed a −7. These data correspond to those reported in the literature. We further focussed on the analyses of RUNX1 in de novo AML which is rarely reported so far. In the de novo AML group only we detected RUNX1mut with the highest frequency in +13 (16/16; 100%) followed by +21 (4/8; 50%) −7 (7/21; 33%), + 8 (2/10, 20%), inv(3) (1/8; 12.5%), and NK (3/33; 9.1%). In addition, in the group with “other” aberration 2/8 were mutated. Interestingly, these 2 mutated cases displayed a high number of trisomies including +8 and +13. No RUNX1mut were detected in AML with complex karyotype (n=10). These data for the first time show that RUNX1mut are not strongly correlated to MDS, s-AML or t-AML. With almost the same frequency they can be observed in de novo AML if specific cytogenetic groups are considered. Thus the RUNXmut seem to be more related to these cytogenetic subgroups than to the MDS, s-AML or t-AML.
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Van Gils, Noortje, Han J. M. P. Verhagen, Arjo Rutten, Renee X. Menezes, Mei-Ling Tsui, Esmee Dekens, Fedor Denkers, et al. "Insulin-like Growth Factor Binding Protein 7 Activates the Retinoid Acid Differentiation Pathway in Acute Myeloid Leukemia Cells." Blood 132, Supplement 1 (November 29, 2018): 3937. http://dx.doi.org/10.1182/blood-2018-99-115858.
Full textAbstract:
Abstract Acute myeloid leukemia (AML) is characterized by the accumulation of malignant blasts with impaired transcriptional differentiation programs. Despite important advances in AML therapy, the five-year overall survival rate of AML patients remains a disappointing 30-40%. This poor prognosis is mainly caused by survival of chemotherapy resistant leukemic cells, named leukemic stem cells (LSC), re-initiating relapse. However, for AML patients with PML-RARA positive acute promyelocytic leukemia (APL), treatment with all trans retinoic acid (ATRA) results in cure rates of >90%. Upon ATRA treatment, APL cells can restore transcription leading to granulocytic differentiation, and in combination with arsenic trioxide APL cells go into apoptosis. While the success of ATRA treatment has been demonstrated for APL patients, so far it has not proved effective for non-APL AML patients. Previously, we demonstrated that insulin-like growth factor binding protein 7 (IGFBP7), a negative regulator of IGF1 receptor (IGF1R) activity, induces apoptosis of AML cells and sensitizes AML cells to chemotherapy-induced cell death. Since it has been shown that IGF1R inhibitors can eliminate therapy-resistant cells by modifying their chromatin state, we hypothesized that IGFBP7 may also have the capacity to modify an epigenetic state and unlock the ATRA-driven differentiation response. To this end, we generated APL cell lines with down- or upregulated IGFBP7 levels and demonstrated that knockdown of IGFBP7 in NB4 cells blocked ATRA-induced differentiation, whereas overexpression of IGFBP7 led to an 8-fold increase in differentiation in the presence of low concentrations of ATRA, together suggesting a role for IGFBP7 in ATRA-induced differentiation in APL cells. Strategies to increase efficacy of ATRA-based therapy might also improve treatment outcomes for non-APL AML, and therefore we investigated the potential of IGFBP7 to induce susceptibility for ATRA-driven differentiation in this group. ATRA and IGFBP7 treatment of non-APL AML cell lines and primary AML cells derived from patients at diagnosis demonstrated an enhanced efficiency of the combination therapy to induce differentiation of myeloid CD45dimCD33+ AML cells (2.5-fold increase in CD11b-expression) and/or to reduce viability of AML CD45dim cells as compared to single treatments (from 30-39% to 70% reduction upon IGFBP7, ATRA or combination therapy, respectively), in 50% of tested primary AML samples, while this combination therapy did not influence normal hematopoietic cell survival. Remarkably, ATRA-IGFBP7 treatment diminished the in vivo engraftment potential of primary AML cells as compared to treatment with either drug alone in NSG mice (from 28% and 52% to 17% engraftment upon ATRA, IGFBP7 or combination therapy, respectively). Re-transplantation of human AML derived from first transplanted mice into secondary recipients demonstrated that the ATRA-IGFBP7 combination treatment also eliminated LSC more effectively (1.4-fold reduction). Together these data suggest that IGFBP7 enhances sensitivity of AML (stem) cells to ATRA, and is able to induce a transcriptional program sensitizing AML cells for ATRA-induced differentiation and cell death. To identify factors responsible for IGFBP7-induced ATRA sensitivity, we performed gene expression profiling of primary AML samples treated with IGFBP7, and identified growth factor independent protein 1 (GFI1) as one of the top down-regulated genes upon IGFBP7 stimulation. As overexpression of GFI1 in non-APL AML patient samples resulted in a >2.5-fold reduction in IGFBP7-induced susceptibility to ATRA-driven differentiation, low GFI1 expression is suggested to be associated with susceptibility to ATRA in AML cells. In conclusion, our results indicate that treatment of AML patient with a combination of ATRA and IGFBP7 might be successful in preventing relapse and improving AML patient survival, which has to be confirmed in further clinical studies. Disclosures Ossenkoppele: Karyopharm: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Jazz: Consultancy, Honoraria; Genentech: Consultancy, Honoraria; Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Genmab: Research Funding; Celgene: Honoraria, Research Funding; Johnson & Johnson: Consultancy, Honoraria, Research Funding.