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1
Özçeşmeci, İbrahim, Orhan Güney, Ali İhsan Okur, and Ahmet Gül. "New phthalocyanines containing bulky electron rich substituents." Journal of Porphyrins and Phthalocyanines 13, no. 06 (2009): 753–59. http://dx.doi.org/10.1142/s1088424609000838.
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Metal-free and metallophthalocyanines with four 9-anthroyl groups bound through ethylthio ester bridges on the periphery have been prepared. The new compounds were characterized by elemental analyses, 1 H NMR, IR, mass and UV-vis spectral data. The electronic spectra exhibit an intense π-π* transition of 9-anthroyl identity together with characteristic Q and B bands of the phthalocyanine core. Effect of metal ions on intensity of fluorescence spectra of phthalocyanine derivatives substituted with 9-anthroyl groups was investigated. The energy transfer to the phthalocyanine core and radiative decays of the 9-anthroyl emission and phthalocyanine core were examined.
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Pantoli, Leonardo, Giorgio Leuzzi, Francois Deborgies, Petar Jankovic, and Francesco Vitulli. "A Survey of MMIC Active Filters." Electronics 10, no. 14 (2021): 1680. http://dx.doi.org/10.3390/electronics10141680.
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High-Q filters are a critical component in many systems. However, high-Q filters require very low-loss passive elements that are not compatible with monolithic technology. Therefore, filters are often implemented as off-chip components. Tunable high-Q filters require even larger space and weight, and are usually quite bulky. Active filters have been proposed in the past for a monolithic implementation. However, it is not easy to fulfil such requirements as a high dynamic range, low power consumption, low noise, wide tunability, stability, etc. With this study, we propose a survey of the main solutions presented in the literature, investigating the fulfilment of all or most requirements and their potential applications and feasibility, to be used in practical applications.
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NONOMURA, TARO, NAGAO KOBAYASHI, and TATSUYA TOMURA. "Synthesis and some spectroscopic properties of tetra-2,3-pyridoporphyrazinatosilicon involving bulky axial ligands." Journal of Porphyrins and Phthalocyanines 04, no. 05 (2000): 538–43. http://dx.doi.org/10.1002/1099-1409(200008)4:5<538::aid-jpp268>3.0.co;2-g.
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Tetra-2,3-pyridoporphyrazinatosilicon ( SiPyD ) containing bis(tri-n-hexylsiloxy) (1) or bis(n-heptylcarbonyloxy) (2) axial ligands have been prepared and characterized by NMR, IR and electronic absorption spectroscopies and by thermogravimetric analysis (TGA) and differential thermal analysis (DTA). These SiPyDs are soluble in common organic solvents, and face-to-face-type stacking is prevented in solution and films. Accordingly, their NMR spectra could be reasonably assigned. Their electronic absorption spectra in solution appear to the blue and red compared with those of the corresponding Si phthalocyanines ( SiPcs ) and Si tetrapyrazinoporphyrazines ( SiPyZs ) respectively. These characteristics are reproduced by molecular orbital calculations in the framework of the Pariser-Parr-Pople approximation. On formation of films, the Q bands shift to the red of those in solution by ca 20 nm, suggesting that other similar tetravalent metallophthalocyanines with two long axial ligands can be used for shifting the Q band to the red. TGA and DTA experiments show that the thermal stability of the macrocycles is markedly influenced by the type of axial ligands.
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Ogata, Hiroshi, Ryuji Higashi, and Nagao Kobayashi. "Electronic absorption spectra of substituted phthalocyanines in solution and as films." Journal of Porphyrins and Phthalocyanines 07, no. 08 (2003): 551–57. http://dx.doi.org/10.1142/s1088424603000690.
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The electronic absorption spectra of several phthalocyanines substituted at the so-called α-, β- and α and β-positions of the macrocycle have been recorded in solution and as films (α = 1,4,8,11,15,18,22, and 25 positions or 1,8 (or 11),15 (or 18), and 22 (or 25) positions, and β = 2,3,9,10,16,17,23, and 24 positions or 2,9 (or 10),16 (or 17), and 23 (or 24) positions). Phthalocyanines substituted with bulky groups at the α-positions prevent cofacial aggregation so that their Q-absorption band remains at a similar wavelength both in solution and films, although the film spectra are generally broader. Phthalocyanines substituted at the β-positions are apt to aggregate cofacially in polar solvents but in films they may show broad Q-bands which spread out to both shorter and longer wavelengths of the solution Q-band, depending on the bulkiness of the substituents. The film spectra of hexadeca-substituted phthalocyanines exhibit Q-bands at a similar wavelength as in solution, with insignificant broadening of the Q-band on film formation. However, the Soret bands for most of the substituted phthalocyanines are shifted and broadened to longer wavelength in the films.
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Tsukruk, Vladimir. "Molecular packing and conformation of liquid crystalline polyesters with bulky side groups." Polymer 33, no. 12 (1992): 2605–10. http://dx.doi.org/10.1016/0032-3861(92)91144-q.
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Bloss, J. D., M. L. Berman, J. Mukhererjee, et al. "Bulky stage IB cervical carcinoma managed by primary radical hysterectomy followed by tailored radiotherapy." International Journal of Gynecology & Obstetrics 42, no. 1 (1993): 95. http://dx.doi.org/10.1016/0020-7292(93)90505-q.
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Blum, Marc-Michael, Annika Richter, Markus Siegert, Horst Thiermann, and Harald John. "Adduct of the blistering warfare agent sesquimustard with human serum albumin and its mass spectrometric identification for biomedical verification of exposure." Analytical and Bioanalytical Chemistry 412, no. 28 (2020): 7723–37. http://dx.doi.org/10.1007/s00216-020-02917-w.
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Abstract Apart from the well-known sulfur mustard (SM), additional sulfur-containing blistering chemical warfare agents exist. Sesquimustard (Q) is one of them and five times more blistering than SM. It is a common impurity in mustard mixtures and regularly found in old munitions but can also be used in pure form. Compared to the extensive literature on SM, very little experimental data is available on Q and no protein biomarkers of exposure have been reported. We herein report for the first time the adduct of Q with the nucleophilic Cys34 residue of human serum albumin (HSA) formed in vitro and introduce two novel bioanalytical procedures for detection. After proteolysis of this HSA adduct catalyzed either by pronase or by proteinase K, two biomarkers were identified by high-resolution tandem mass spectrometry (MS/HR MS), namely a dipeptide and a tripeptide, both alkylated at their Cys residue, which we refer to as HETETE-CP and HETETE-CPF. HETETE represents the Q-derived thio-alkyl moiety bearing a terminal hydroxyl group: “hydroxyethylthioethylthioethyl.” Targeting both peptide markers from plasma, a micro liquid chromatography–electrospray ionization tandem mass spectrometry method working in the selected reaction monitoring mode (μLC-ESI MS/MS SRM) was developed and validated as well suited for the verification of exposure to Q. Fulfilling the quality criteria defined by the Organisation for the Prohibition of Chemical Weapons, the novel methods enable the detection of exposure to Q alone or in mixtures with SM. We further report on the relative reactivity of Q compared to SM. Based on experiments making use of partially deuterated Q as the alkylating agent, we rule out a major role for six-membered ring sulfonium ions as relevant reactive species in the alkylation of Cys34. Furthermore, the results of molecular dynamics simulations are indicative that the protein environment around Cys34 allows adduct formation with elongated but not bulky molecules such as Q, and identify important hydrogen bonding interactions and hydrophobic contacts.
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Inaba, Yusuke, Kazuya Ogawa, and Yoshiaki Kobuke. "Syntheses and properties of acetylene-linked bis- and trisporphyrins toward two-photon photodynamic therapy." Journal of Porphyrins and Phthalocyanines 11, no. 06 (2007): 406–17. http://dx.doi.org/10.1142/s1088424607000461.
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Acetylene-bridged bisporphyrins and trisporphyrins having branched bulky bis(carboxylethyl)methyl meso-substituents were synthesized. These compounds showed large effective two-photon absorption cross-section values at 890 nm measured by using a nanosecond Z-scan method. Sodium salt of hydrolyzed trisporphyrins showed broad and red-shifted Q-bands over 900 nm. Two-photon absorption cross-section values of water-soluble dimers in water were similar to, or slightly larger than, those of ester forms evaluated in toluene. Furthermore, the generation of singlet oxygen upon one-photon irradiation for dimers in water was confirmed.
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An, Hyung Jun, Jong Min Park, Nazmul Abedin Khan, and Sung Hwa Jhung. "Adsorptive removal of bulky dye molecules from water with mesoporous polyaniline-derived carbon." Beilstein Journal of Nanotechnology 11 (April 8, 2020): 597–605. http://dx.doi.org/10.3762/bjnano.11.47.
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Polyaniline-derived carbon (PDC) was obtained via pyrolysis of polyaniline under different temperatures and applied for the purification of water contaminated with dye molecules of different sizes and charge by adsorption. With increasing pyrolysis temperature, it was found that the hydrophobicity, pore size and mesopore volume increased. A mesoporous PDC sample obtained via pyrolysis at 900 °C showed remarkable performance in the adsorption of dye molecules, irrespective of dye charge, especially in the removal of bulky dye molecules, such as acid red 1 (AR1) and Janus green B (JGB). For example, the most competitive PDC material showed a Q 0 value (maximum adsorption capacity) 8.1 times that of commercial, activated carbon for AR1. The remarkable adsorption of AR1 and JGB over KOH-900 could be explained by the combined mechanisms of hydrophobic, π–π, electrostatic and van der Waals interactions.
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Mösch-Zanetti, Nadia C., Manuel Hewitt, Thomas R. Schneider та Jörg Magull. "Titanium Complexes Containing Bulky η2-1,2,4-Triazolato Ligands". European Journal of Inorganic Chemistry 2002, № 5 (2002): 1181–85. http://dx.doi.org/10.1002/1099-0682(200205)2002:5<1181::aid-ejic1181>3.0.co;2-q.
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Ishikawa, Aya, Kazuchika Ohta, and Mikio Yasutake. "Flying-seed-like liquid crystals 5: Liquid crystals based on octakisphenylthiophthalocyanine and their optical properties." Journal of Porphyrins and Phthalocyanines 19, no. 05 (2015): 639–50. http://dx.doi.org/10.1142/s1088424615500479.
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We have synthesized three novel flying-seed-like liquid crystals based on phthalocyaninato copper(II) (abbreviated as PcCu ) substituted by bulky groups {(o- C1) PhS (i), (m- C1) PhS (j), [m, p-( C1)2] PhS (k)} instead of using long alkyl chains, in order to investigate their mesomorphism. Their phase transition behavior and the mesophase structures have been established by using a polarizing optical microscope, a differential scanning calorimeter, and a temperature-dependent small angle X-ray diffractometer. As the results, [(o-C1)PhS]8PcCu (8i), [(m-C1)PhS]8PcCu (8j) and {[m,p-(C1)2]PhS}8PcCu (8k) show a Coltet.omesophase at 314.9~362.9 °C, a Colro(P2m) mesophase at 287.4~334.2°C and a Colro(P2m) mesophase at 331.8~386.8°C, respectively. Very interestingly, each of the derivatives thus exhibits a columnar mesophase at very high temperatures. The mesomorphism is apparently originated from the novel bulky groups (i~k). It is also noteworthy that the Q-bands of the present PhS-containing Pc derivatives 8i~8k in THF significantly red-shift by about 35 nm in comparison with those of the corresponding PhO-containing derivatives in THF.
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Bai, Jing, Yang Shan Sun, and Feng Xue. "Microstructures and Creep Behaviour of Mg-4Al Alloy Containing Sr and Ca." Applied Mechanics and Materials 79 (July 2011): 134–39. http://dx.doi.org/10.4028/www.scientific.net/amm.79.134.
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Microstructures and creep property of the Mg-4Al based alloy with addition of 2% Sr and 1%Ca were investigated. The as-cast microstructures of the present alloy consist of dendritic α-Mg and two major intermetallics: lamellar eutectic C14-Mg2Ca and bulky type Mg-Al-Sr ternary phase. These intermetallics mainly distribute along grain or cell boundaries and form an almost continuous network. The alloy studied shows an excellent creep resistance under the experimental conditions. This is primarily attributed to formation of the thermostable intermetallics with addition of Sr and Ca to Mg-Al based alloy. The values of stress exponent, n, and creep activation energy, Q, imply that both dislocaiton motion and grain boundary sliding contribute to the creep deformation.
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Zimcik, Petr, Miroslav Miletin, Veronika Novakova, et al. "Effective Monofunctional Azaphthalocyanine Photosensitizers for Photodynamic Therapy." Australian Journal of Chemistry 62, no. 5 (2009): 425. http://dx.doi.org/10.1071/ch08392.
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In this work we present a rational design of the active part of third generation photosensitizers for photodynamic therapy based on phthalocyanine and an azaphthalocyanine core. The preferred zinc complexes of the AAAB type that contain bulky tert-butylsulfanyl substituents (A) and one carboxy group (B) have been synthesized by statistical condensation and fully characterized. The tetramerization was performed using magnesium(ii) butoxide followed by demetalation and insertion of ZnII. Compound 1 synthesized from 4,5-bis(tert-butylsulfanyl)phthalonitrile (A) and 2,3-dicyanoquinoxaline-6-carboxylic acid (B) exerted very promising photophysical properties (Q-band absorption at 726 nm, ϵ = 140000 M–1 cm–1), which allowed strong absorption of light at long wavelengths where the penetration of the light through human tissues is deeper. The very high singlet oxygen quantum yield of 1 (ΦΔ = 0.80) assures efficient photosensitization. As a result of bulky peripheral substituents, compound 1 shows good solubility in organic solvents with a low degree of aggregation, which makes it potentially viable for non-complicated modification. One carboxy group in the final structure of 1 allows simple binding to possible carriers. This compound is suitable for binding to targeting moieties to form the highly active part of a third-generation photosensitizer.
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Tuhl, Ahmad, Saad Makhseed, Petr Zimcik, Nouria Al-Awadi, Veronika Novakova, and Jacob Samuel. "Heavy metal effects on physicochemical properties of non-aggregated azaphthalocyanine derivatives." Journal of Porphyrins and Phthalocyanines 16, no. 07n08 (2012): 817–25. http://dx.doi.org/10.1142/s1088424612500800.
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Two series of peripherally substituted azaphthalocyanines (AzaPcs) containing different transition metals ( Al(III), Zn(II), Ga(III), In(III) and Fe(II) ) were synthesized and studied for their photophysical properties. As confirmed by UV-vis and1H NMR analyses, the non-aggregation behavior was effectively induced by the applied bulky peripheral substituents which had no effect on the photophysical properties. Tuning the Q-band position was clearly achievable by using different central heavy metals which have considerable effects on the fluorescence quantum yield and singlet oxygen generation efficiency. This comparative study showed an interesting linear relationship between the former and atomic number of the central metal. The indium containing complexes exhibited the best result due to the heavy metal effect and therefore could be promoted as a potential photosensitizer in photodynamic therapy (PDT) application.
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Farnetti, Erica, Mauro Graziani, Antonio Mezzetti, and Alessandro Del Zotto. "Effect of bulky ligands on the hydrogenation of olefins catalyzed by cis-[MH2(dcpe)2] (M=Ru,Os; dcpe = 1,2-bis(dicyclohexylphosphino)ethane)." Journal of Molecular Catalysis 73, no. 2 (1992): 147–55. http://dx.doi.org/10.1016/0304-5102(92)80067-q.
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Yao, Qingkai, Yu Ding, Guodong Liu, and Lvming Zeng. "Low-cost photoacoustic imaging systems based on laser diode and light-emitting diode excitation." Journal of Innovative Optical Health Sciences 10, no. 04 (2017): 1730003. http://dx.doi.org/10.1142/s1793545817300038.
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Photoacoustic imaging, an emerging biomedical imaging modality, holds great promise for preclinical and clinical researches. It combines the high optical contrast and high ultrasound resolution by converting laser excitation into ultrasonic emission. In order to generate photoacoustic signal efficiently, bulky Q-switched solid-state laser systems are most commonly used as excitation sources and hence limit its commercialization. As an alternative, the miniaturized semiconductor laser system has the advantages of being inexpensive, compact, and robust, which makes a significant effect on production-forming design. It is also desirable to obtain a wavelength in a wide range from visible to near-infrared spectrum for multispectral applications. Focussing on practical aspect, this paper reviews the state-of-the-art developments of low-cost photoacoustic system with laser diode and light-emitting diode excitation source and highlights a few representative installations in the past decade.
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Dimopoulos, Meletios A., Christine Liakos, Hara G. Episkopou, et al. "A Polymerase Chain Reaction-Based Method to Detect Gene-Specific Adducts Induced by Anticancer Drugs. Clinical Application in Multiple Myeloma." Blood 114, no. 22 (2009): 1879. http://dx.doi.org/10.1182/blood.v114.22.1879.1879.
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Abstract Abstract 1879 Poster Board I-903 DNA repair plays an important role in the protection of cells and tissues after exposure to genotoxic agents including chemotherapeutics. We have previously shown that, in peripheral blood mononuclear cells (PBMC) of multiple myeloma (MM) patients treated with melphalan, accumulation of DNA adducts in the p53 gene correlates with better therapeutic response, and that repair in different genes correlated with the gene transcriptional activity and the degree of local chromatin condensation (Dimopoulos et al, J Clin Oncol 2005;23:4381–9; Souliotis et al, DNA Repair 2006;5:972–85; Dimopoulos et al, Haematologica 2007;92:1505–12). However, the assays used are fairly time-consuming, and require complex procedures such as Southern transfer and hybridization. Thus, we now present the development and clinical application in MM of a gene-specific, quantitative method for measuring DNA damage formation/repair following exposure to anticancer drugs inducing bulky adducts. Cell line (HepG2) as well as human whole blood and PBMC from eighteen patients (13M/5F) with MM were in vitro treated with melphalan. These patients underwent high dose melphalan with autologous stem cell support (ASCT) as part of their first line therapy and the whole blood was collected on the day of stem cell mobilization. Ten (55.5%) patients achieved further myeloma reduction after ASCT; 3 patients achieved a stringent complete response (CR), 2 a CR, 2 a very good partial response (vgPR) and 3 a PR. Among 8 non-responders post-ASCT, 6 had a stable disease while 2 experienced disease progression, according to the IMWG criteria. None of the patients had previously received alkylating agent therapy (melphalan-naive patients). Moreover, cell line (HepG2) and PBMC from five healthy volunteers (all females) were treated with platinum-based drugs (cisplatin, carboplatin). Following DNA isolation, gene-specific damage formation/repair was examined using Southern blot as well as a multiplex long quantitative PCR (Q-PCR). The extent of PCR amplification was conversely proportional to the treatment concentrations of all anticancer drugs examined, implying dose-related inhibition by the DNA adducts formed. In the case of melphalan, the adduct levels measured by Q-PCR were identical to the levels of interstrand cross-links (ICL) measured by Southern blot analysis. In addition, monoadducts induced by monofunctional melphalan could not be measured by Q-PCR, suggesting that this assay measures only melphalan-induced ICLs. Application of the Q-PCR assay to in vitro-treated human blood samples from MM patients taken prior to ASCT showed that the levels of DNA damage varied up to 12-fold, which probably reflects inter-individual DNA repair differences. Interestingly, significantly greater gene-specific damage was found in the responders group compared to non-responders [176.8±67.3 adducts/106 nucleotides (range 41.0 to 273.0) for responders and 65.1±39.4 adducts/106 nucleotides (range 22.0 to 135.0) for non-responders, p=0.002]. Similar results were obtained using whole blood from the same MM patients, but differences did not reach statistical significance [84.3±63.0 adducts/106 nucleotides (range 15.0 to 165.0) for responders and 46.5±2.1 adducts/106 nucleotides (range 45.0 to 48.0) for non-responders, p=0.5]. As for the platinum-based drugs, cisplatin-induced intrastrand cross-links levels measured by Southern blot analysis, reached a plateau within ∼3h of treatment, while peak interstrand cross-links was obtained at ∼24h of exposure. Carboplatin-induced maximal levels of both intra- and interstrand cross-links were obtained within 24h of drug incubation. Parallel analysis of the same samples using both Southern blot and Q-PCR showed that the DNA adducts measured by Q-PCR correspond to total platinum-induced lesions. In conclusion, our study suggest that by using the current Q-PCR methodology, it is feasible to measure gene-specific damage formation/repair in a readily accessible biological material such as PBMC from humans exposed to anticancer drugs inducing bulky adducts and to examine, at the level of individual patient, the relationship between the induction/repair of cytotoxic DNA damage and the clinical outcome. Patient accrual is ongoing and updated results will be presented during the meeting. Disclosures: No relevant conflicts of interest to declare.
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Toogood, H. S., M. Prescott, and R. M. Daniel. "A pepstatin-insensitive aspartic proteinase from a thermophilic Bacillus sp." Biochemical Journal 307, no. 3 (1995): 783–89. http://dx.doi.org/10.1042/bj3070783.
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Bacillus sp. strain Wp22.A1 produced a cell-associated aspartic proteinase which was purified to homogeneity using phenyl-Sepharose (hydrophobic and affinity chromatography) and Mono Q. The proteinase has a molecular mass of 45 kDa by SDS/PAGE and a pI of 3.8. It is insensitive to pepstatin, but is sensitive to the other aspartic proteinase-specific inhibitors diazoacetyl-DL-norleucine methyl ester (DAN) and 1,2-epoxy-3-(p-nitrophenoxy)propane. Inactivation by DAN was only partial, suggesting that it had non-specifically modified an aspartate residue at a site other than the active site. The enzyme was not inhibited by any of the serine or cysteine proteinase inhibitors tested. Maximum proteolytic activity was observed at pH 3.5. The proteinase had a higher activity with haemoglobin, but was more specific (Vmax./Km) for cytochrome c. Substrate inhibition was observed with both these substrates. The cleavage of oxidized insulin B chain tended to occur at sites where the P1 amino acid was bulky and non-polar, and the P1′ amino acid was bulky and polar, such as its primary cleavage site of Val2-Asn3. The proteinase was stable in the pH range 2.5-5.5. Thermostability was increased in the presence of Ca2+, although to a lesser extent at higher temperatures. The thermostabilities at 60, 70, 80 and 90 degrees C were 45 h, 102, 21 and 3 min respectively in the presence of Ca2+.
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Ikeue, Takahisa, Naoko Sawada, Naomi Matsumoto, et al. "Synthesis and magnetic properties of an annulated dinuclear copper(II) phthalocyanine peripherally having 2,6-dimethylphenoxy substituents." Journal of Porphyrins and Phthalocyanines 18, no. 08n09 (2014): 708–14. http://dx.doi.org/10.1142/s1088424614500485.
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A dinuclear copper(II) phthalocyanine complex with 12 2,6-dimethylphenoxyl groups at the peripheral positions of the [ CuPc ]2 framework, where [ CuPc ] units are linked by a common annulated benzene ring to give the planar dinuclear structure, was prepared and characterized. The introduced bulky 2,6-dimethylphenoxyl groups were revealed to effectively suppress the aggregation of the dinuclear complex in the toluene solution, showing a considerably red-shifted Q-band at 838 nm. The EPR spectrum (measured in the frozen toluene solution at 15 K) and temperature-dependent magnetic moment indicated the existence of antiferromagnetic interaction between the copper(II) ions. The exchange integral J was estimated to be -1.8 cm-1 using Bleaney Bowers equation for the S1 = S2 = 1/2 system. The long-range interaction ( Cu – Cu distance = 10.7 Å) through the common annulated benzene ring between two [ CuPc ] units was confirmed by the DFT calculation result.
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Giri, Tilak, Ram Prasad Pandey, Sabin Bhandari, Sujan Moktan, and Lagat Karki. "Design and Simulation of three Phase three Wire Shunt Active Filter using Instantaneous PQ Theory." Journal of the Institute of Engineering 15, no. 1 (2020): 181–86. http://dx.doi.org/10.3126/jie.v15i1.27728.
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Due to intensive use of power converters and other non-linear loads, power quality is degrading. The presence of harmonics in the power lines result in greater power losses in distribution, interference problems in communication systems. Non linearity reduces the efficiency and power factor of the system. As the power factor reduces, the reactive power demanded from the supply increases which have no any contribution in energy transfer, so compensation is required. For this, shunt passive filter has been developed but it is bulky and frequency dependent and has many drawbacks. In contrast to passive filter, shunt active filter (SAF) has been developed which is smaller and has wide range of applications. In this paper, shunt active filter based on p-q theory is demonstrated for compensating reactive power and current harmonics. Simulation has been done with and without SAF and results are presented and ended with recommendation and conclusion. An effort is made to reduce the THD of the source current below 5% (specified by IEEE).
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Biswas, Dipon K., Melissa Sinclair, Tien Le, Salvatore Andrea Pullano, Antonino S. Fiorillo, and Ifana Mahbub. "Modeling and Characterization of Scaling Factor of Flexible Spiral Coils for Wirelessly Powered Wearable Sensors." Sensors 20, no. 8 (2020): 2282. http://dx.doi.org/10.3390/s20082282.
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Wearable sensors are a topic of interest in medical healthcare monitoring due to their compact size and portability. However, providing power to the wearable sensors for continuous health monitoring applications is a great challenge. As the batteries are bulky and require frequent charging, the integration of the wireless power transfer (WPT) module into wearable and implantable sensors is a popular alternative. The flexible sensors benefit by being wirelessly powered, as it not only expands an individual’s range of motion, but also reduces the overall size and the energy needs. This paper presents the design, modeling, and experimental characterization of flexible square-shaped spiral coils with different scaling factors for WPT systems. The effects of coil scaling factor on inductance, capacitance, resistance, and the quality factor (Q-factor) are modeled, simulated, and experimentally validated for the case of flexible planar coils. The proposed analytical modeling is helpful to estimate the coil parameters without using the time-consuming Finite Element Method (FEM) simulation. The analytical modeling is presented in terms of the scaling factor to find the best-optimized coil dimensions with the maximum Q-factor. This paper also presents the effect of skin contact with the flexible coil in terms of the power transfer efficiency (PTE) to validate the suitability as a wearable sensor. The measurement results at 405 MHz show that when in contact with the skin, the 20 mm× 20 mm receiver (RX) coil achieves a 42% efficiency through the air media for a 10 mm distance between the transmitter (TX) and RX coils.
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Advani, Ranjana, Fangxin Hong, Leo I. Gordon, et al. "Patterns of Failure in Patients with Stage I/II Bulky Mediastinal Hodgkin Lymphoma (HL) Treated with ABVD + Radiotherapy or the Stanford V Regimen in the Randomized Phase III North American Intergroup Trial: E2496." Blood 118, no. 21 (2011): 1603. http://dx.doi.org/10.1182/blood.v118.21.1603.1603.
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Abstract Abstract 1603 Background: We have previously reported similar outcomes for patients with bulky stage I or II mediastinal HL treated with combined modality therapy either with ABVD + radiotherapy or the Stanford V regimen in the North American Intergroup trial E2496 (Advani et al, ASH 2010 abstract 416). In the current analysis, we compare the patterns of failure between the two groups. Methods: Patients with stage I/II bulky mediastinal HL (maximum mediastinal mass width > 1/3 of intrathoracic diameter) were randomized to receive chemotherapy (CT) on either Arm A (ABVD x 6–8 cycles administered q 28 days) or Arm B (12 weeks of Stanford V administered weekly). Two-3 weeks after completion of chemotherapy all patients received modified involved field radiotherapy (RT) (36 Gy) delivered to the mediastinum, hila, and supraclavicular regions. Patients on Stanford V arm also received involved field RT to any other sites ≥ 5 cm at diagnosis. Patients were assessed 3, 6 and 12 months after completing RT with computed tomography scanning and then every 6 months for 5 years. The primary end points were failure free survival (FFS) and overall survival (OS). Disease progression was defined as 'in-field', 'distant' or both relative to the radiation fields prescribed in the E2496 protocol. Distant sites of failure were further characterized as intra-thoracic, intra-abdominal or other (bone, bone marrow and axillae, if not previously irradiated). Results: Two hundred and sixty-seven patients were randomized: 136 on the ABVD arm and 131 on the Stanford V arm. Patient characteristics were well matched with no differences between two arms in overall response rates (ORR), FFS and OS. (Advani et al ASH 2010 abstract 416). At a median follow up of 5.5 years 40 patients have relapsed with no difference in ABVD (n=18, 13%) versus Stanford V (n=22, 17%) (p=0.49). Central review of RT fields available in 37/40 patients found major violations with under treatment of tumor noted in 7/37 (19%). Patterns of failure are shown in Table 1. There were no differences in patterns of relapse for the two study arms. In-field relapses occurred in <10% in both study arms. Conclusion: For patients with stage I/II bulky mediastinal HL, combined modality therapy with either ABVD +RT or the Stanford V regimen results in excellent disease control. In-field relapse was uncommon. These results set a benchmark for assessing ongoing trials omitting RT in patients with stage I/II bulky mediastinal HL. Future research efforts should focus on risk stratification to identify the small subset of patients who are likely to fail standard upfront therapy. US cooperative group efforts in this subset of patients are ongoing that use interim PET-CT imaging based risk-adapted strategies. Disclosures: Horning: Genentech: Employment, Equity Ownership.
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Rossi, Davide, Silvia Rasi, Alberto Fabbri, et al. "The Host Genetic Background of DNA Repair Mechanisms Represents An Independent Predictor of Progression and Survival in Diffuse Large B-Cell Lymphoma Treated with R-CHOP." Blood 114, no. 22 (2009): 442. http://dx.doi.org/10.1182/blood.v114.22.442.442.
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Abstract Abstract 442 Scant information is availabel on the impact of the host genetic background in predicting outcome of diffuse large B cell lymphoma (DLBCL). We recently documented that host single nucleotide polymorphisms (SNPs) affecting doxorubicin pharmacodynamics and alkylator detoxification may predict outcome in R-CHOP-treated DLBCL (Rossi et al, Leukemia 2009; 23:118-26). Several DNA repair mechanisms are involved in resistance to R-CHOP drugs. We verified whether SNPs of DNA repair genes may further refine prognostic stratification and toxicity prediction in DLBCL treated with R-CHOP. The study was based on 163 consecutive DLBCL treated with R-CHOP and provided with a prospectively collected dataset. At diagnosis, age >60 years was observed in 104/163 (63.8%) cases, ECOG PS >1 in 21/163 (12.9%), extranodal sites >1 in 41/163 (25.2%), Ann Arbor stage III-IV in 85/163 (52.1%), bulky disease in 46/163 (28.2%), B symptoms in 38/163 (23.3%), LDH elevation in 75/163 (46.0%), IPI >2 in 55/163 (33.7%). Median follow up was 40 months. Candidate SNPs selected for the analysis belonged to genes involved in repairing DNA damage produced by R-CHOP drugs, and included SNPs affecting the following DNA repair mechanisms: i) base excision repair (OGG1 rs1052133); ii) nucleotide excision repair (ERCC2 rs1799793, ERCC2 rs13181, ERCC6 rs3793784, ERCC6 rs2228528, ERCC6 rs2228529, XPA rs1800975, XPC rs2227999, XPC rs2228000); iii) mismatch repair (MLH1 rs1799977); iv) double strand break repair (LIG4 rs1805388, XRCC6 rs132788, XRCC6 rs55751129, BRCA1 rs799917). Genotyping was performed by SNP-minisequencing on DNA extracted from granulocytes. Clinical endpoints considered in the study were overall survival (OS), progression free survival (PFS) and toxicity. Associations of SNPs with clinical endpoints were controlled for multiple testing by FDR analysis. Among the SNPs included in the study, univariate log-rank analysis controlled for multiple comparisons by FDR testing identified MLH1 rs1799977 as a predictor of both PFS and OS in DLBCL treated with R-CHOP. MLH1 encodes a DNA mismatch repair gene involved in alkylating agents and doxorubicin resistance. DLBCL patients carrying the MLH1 rs1799977 AG/GG genotypes displayed a poorer PFS (Events/N: 23/52; 3-year PFS: 51.9%) compared to DLBCL patients carrying the MLH1 rs1799977 AA genotype (Events/N: 33/111; 3-year PFS: 72.0%) (p=.020; q=.240) (Fig. 1). Other variables predicting PFS were ECOG PS (p=.042), Ann Arbor stage (p=.035), bulky disease (p=.001), number of extranodal sites (p=.009), LDH (p=.007), and IPI (p=.002). Multivariate analysis selected MLH1 rs1799977 AG/GG (HR: 1.17; p=.034) as an independent predictor of PFS, along with IPI (HR: 1.44; p=.002) and bulky disease (HR: 2.20, p=.004). The MLH1 rs1799977 genotype was also relevant for predicting DLBCL survival, since DLBCL patients carrying the MLH1 rs1799977 AG/GG genotypes displayed a poorer OS (Events/N: 19/52; 3-year OS: 61.8%) compared to DLBCL patients carrying the MLH1 rs1799977 AA genotype (Events/N: 18/111; 3-year OS: 83.3%) (p=.001; q=.013) (Fig. 2). Other variables predicting OS were age (p=.026), ECOG PS (p=.002), bulky disease (p<.001), number of extranodal sites (p=.027), IPI (p=.020), relative dose intensity of doxorubicin (p=.017), and comorbidity score (p=.003). Multivariate analysis selected MLH1 rs1799977 AG/GG (HR: 2.84; p=.002) as an independent predictor of OS, along with IPI (HR: 1.40; p=.013) and bulky disease (HR: 3.20; p=.001). The impact of SNPs was also evaluated for toxicity in 803 R-CHOP courses. A multivariate model for toxicity was built by generalized estimating equations (GEE), which adjust for the clustering of treatment courses within a patient. After correcting for multiple comparisons and adjusting for potentially confounding variables, none of the DNA repair SNPs analysed was found to be associated with R-CHOP toxicity. Overall, MLH1 rs1799977 SNP is an independent predictor of progression and survival in DLBCL treated with R-CHOP. The biologic plausibility of this association is supported by two lines evidence: i) MLH1 rs1799977 G variant allele is known to reduce MLH1 protein expression and function; ii) loss of MLH1 DNA mismatch repair function is known to result in in vitro resistance to doxorubicin and alkylating agents. Consistently, DLBCL carriers of the MLH1 rs1799977 AG/GG genotypes displayed poor PFS and OS possibly due to altered MLH1 function. Disclosures: No relevant conflicts of interest to declare.
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Pfreundschuh, Michael, Konstantinos Christofyllakis, Bettina Altmann, et al. "Radiotherapy to bulky disease PET-negative after immunochemotherapy in elderly DLBCL patients: Results of a planned interim analysis of the first 187 patients with bulky disease treated in the OPTIMAL>60 study of the DSHNHL." Journal of Clinical Oncology 35, no. 15_suppl (2017): 7506. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.7506.
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7506 Background: RT to bulky sites improves outcome of elderly DLBCL patients [Lancet Oncol 2008; 9: 105-116; J Clin Oncol 2014; 32:112-1118]. Whether RT can be spared in PET-negative pts. after R-CHOP was prospectively addressed in OPTIMAL >60. Methods: 61 to 80 y-old pts. were randomized in a 2x2 factorial design to 6xCHOP-14 or 6xCHLIP-14 (liposomal instead of conventional vincristine) plus 8 x rituximab 375 mg/m2(R) q 2 wks. or 12xR (days -4,-1,1,4,14,28,42,56,91,126,175, 238). Pts. with bulk (>=7.5 cm) PET-positive after 6 cycles chemotherapy were assigned to RT (39.6 Gy), while PET-negative bulks were observed. Results: 187/505 (37%) had bulky disease and were compared to 117/306 (38%) RICOVER-60 pts. (38%) who had received 6xCHOP-14+8R. OPTIMAL>60 pts. were older (70 vs. 68 years) and had more IPI=3 (33% vs. 29%) and IPI=4,5 (34% vs. 23%) compared to RICOVER-60. PET was performed in 166/187 OPTIMAL>60 bulk pts. (reasons for no PET: early death: 5; excessive toxicity: 3; protocol violation: 1, non-compliance: 4, change of diagnosis: 6, others: 2). 80/166 (48%) bulks remained PET-positive after 6 cycles of chemotherapy and 62/80 (78%) were irradiated (reasons for no RT: progression: 8; medical reasons: 9; negative biopsy: 1), reducing RT from 67/117 (57%) in RICOVER-60 by 42% to 62/187 (33%) in OPTIMAL>60. Despite the unfavorable demographics, outcome of the 187 bulk pts. in OPTIMAL>60 was non-inferior to RICOVER-60, not even in the least intensive of the 4 OPTIMAL>60 treatment arms consisting of 47 pts. who received 6xCHOP-14+8R as in RICOVER-60. 2-year PFS and OS in OPTIMAL>60 was 79% and 88%, respectively, compared to 75% and 78% of the 117 RICOVER-60 pts. In a multivariable analysis adjusting for the IPI risk factors, the hazard ratio of the OPTIMAL>60 compared to the RICOVER-60 bulk pts. was 0.7 (95% CI: 03.; 1.5; p=0.345) for PFS and 0.5 (95% CI: 02.; 1.3; p=0.154) for OS. Conclusions: RT can be spared in bulky disease PET-negative after chemotherapy. This strategy results in a 42% reduction of RT without compromising the outcome of these patients. Supported by Amgen, Roche, Spectrum. Clinical trial information: NCT01478542.
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Holm, Sonja, Mads Bertelsen, Anar Singh, Jürg Schefer, Kim Lefmann, and Mogens Christensen. "HEIMDAL: A novel materials science neutron powder diffractometer at ESS." Acta Crystallographica Section A Foundations and Advances 70, a1 (2014): C1754. http://dx.doi.org/10.1107/s205327331408245x.
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Developing new materials is the most challenging task for the future demands due to limitations in energy, resources but also environmental damage. Improvements in material performances are reached for example by the incorporation of advanced ceramics and polymers into heterogeneous systems. Their performances usually depend on the interplay between properties defined by the atomic, nano/mesoscopic and microscopic structure. In-situ and in-operandi investigations will be in the focus of such investigations. The instrument HEIMDAL proposed for the European spallation neutron source ESS will offer here perfect prospects, as the instrumental resolution of this powder diffractometer can widely be adapted taking either full advantage of the broad pulse of ESS (2.86ms) offering highest intensity, or using a fraction of the pulse for highest resolution. A thermal and a cold guides pointing to the same virtual source extend the spatial window of the instrumental from an atomic scale (0.3Å-1≤Q≤50Å-1) to a nano/meso scale, 0.002Å-1≤Q≤0.1Å-1 by adding a narrow-band SANS instrument behind. Our chopper system allows switching the different operation modes electronically. Traditionally such structural information has been collected in separated experiments such as powder diffraction (PD), wide angle diffraction scale, small angle diffraction and direct space imaging techniques (sub-micronic to millimeter scale), whereas HEIMDAL can offer these options in its final stage at the same time at therefore for absolutely identical experimental conditions. The top-loading geometry foreseen not only accepts auxiliary from the ESS pool (cryogenics, pressure cells, magnets) but also allows implementing bulky brought-in user equipment. It can be pretested off-line at the instrument, but already fully connected to the HEIMDAL electronics. Figure 1: a) Operation modes of the HEIMDAL b) Layout of the instrument HEIMDAL
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Ding, Fei, Yiting Chen, and Sergey I. Bozhevolnyi. "Focused vortex-beam generation using gap-surface plasmon metasurfaces." Nanophotonics 9, no. 2 (2020): 371–78. http://dx.doi.org/10.1515/nanoph-2019-0235.
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AbstractIn spite of a wide range of applications ranging from particle trapping to optical communication, conventional methods to generate vortex beams suffer from bulky configurations and limited performance. Here, we design, fabricate, and experimentally demonstrate orthogonal linear-polarization conversion and focused vortex-beam generation simultaneously by using gap-surface plasmon metasurfaces that enable high-performance linear-polarization conversion along with the complete phase control over reflected fields, reproducing thereby the combined functionalities of traditional half-wave plates, lenses, and q-plates. The fabricated metasurface sample features the excellent capability of orthogonal linear-polarization conversion and focused vortex-beam generation within the wavelength range of 800–950 nm with an averaged polarization conversion ratio of ~80% and absolute focusing efficiency exceeding 27% under normal illumination with the x-polarized beam. We further show that this approach can be extended to realize a dual-focal metasurface with distinctly engineered intensity profiles by using segmented metasurfaces, where an orthogonal-polarized beam with Gaussian-distributed intensity and a vortex beam with intensity singularity have been experimentally implemented. The proposed multifunctional metasurfaces pave the way for advanced research and applications targeting photonics integration of diversified functionalities.
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Advani, Ranjana, Fangxin Hong, Richard I. Fisher, et al. "Randomized Phase III Trial Comparing ABVD + Radiotherapy and the Stanford V Regimen In Patients with Stage I/II Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the US Intergroup Trial E2496." Blood 116, no. 21 (2010): 416. http://dx.doi.org/10.1182/blood.v116.21.416.416.
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Abstract Abstract 416 Background: Standard therapy for locally extensive Hodgkin Lymphoma (HL) defined as stage I/II with bulky mediastinal disease [mediastinal mass ratio (MMR) > than 1/3 of the chest diameter on standing postero-anterior chest x-ray or 10 cm on computerized tomography] is combined modality therapy (CMT). E2496 was a North American intergroup, randomized phase III study comparing ABVD versus the Stanford V regimen for patients with locally extensive and advanced stage HL. In this subgroup analysis we compare two CMT approaches, ABVD + radiotherapy (RT) and the Stanford V regimen, in patients with stage I/II bulky mediastinal HL. Methods: Patients with stage I/II HL bulky mediastinal disease were randomized to receive chemotherapy (CT) on either Arm A (ABVD × 6–8 cycles administered q 28 days) or Arm B (12 weeks of Stanford V, administered weekly). Two-3 weeks after completion of chemotherapy, modified involved field RT was delivered at 36 Gy to the mediastinum to patients on ABVD as well as Stanford V. Patients on Stanford V also received involved field RT to any other sites >5 cm at diagnosis. The primary endpoint was failure free survival (FFS) defined as the time to either progression/relapse or death. The log-rank test was used to compare FFS and OS (overall survival) for all eligible patients. Results: Of the 812 eligible patients with advanced HL enrolled on the study 267 had locally advanced bulky mediastinal disease: 136 on ABVD and 131 on Stanford V. Patient characteristics between the two randomized groups were well matched with a median age of 30 years and 86% had stage II disease. On ABVD 61% of patients received 6 cycles, 29% 8 cycles of CT and 77% required some dose modification. In Stanford V 97% completed the assigned 12 weeks of CT and 76% required some dose modification. 82% received RT per protocol in ABVD versus 88% in Stanford V. The overall response (CR+PR) was 82% in ABVD and 86% in Stanford V. At a median follow-up of 5.47 years, there are 19 failures and 6 deaths in the ABVD group and 25 failures with 9 deaths in the Stanford V group. We failed to detect statistically significant differences between ABVD +RT and Stanford V for FFS (5y 85% versus 77% p=0.13, HR=1.56 95% CI (0.87, 2.88) and OS (5y 95% versus 92% p=0.31, HR=1.69 95% CI (0.60, 4.75). No difference in hematologic toxicity was observed between the two arms. Evaluation of pulmonary function and patterns of failure are pending. Conclusions: For stage I/II patients with bulky mediastinal disease, CMT with either ABVD +RT or the Stanford V regimen results in high cure rates and is highly effective. ABVD for 6–8 cycles plus 36 Gy RT remains the US standard of care. Longer follow up is required to assess RT related late effects. Future research efforts should focus on risk stratification to identify; a) the 15–20% of patients destined to relapse after standard therapy and evaluate treatment intensification strategies and b) the 80–85% of patients who are cured with standard therapy and determine whether a subset can achieve the same excellent outcomes with a reduction or elimination of radiation. Planned US cooperative group trials will address these questions, using ABVD as the chemotherapy backbone in conjunction with interim PET imaging for risk stratification. Disclosures: Blum: Seattle Genetics: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Horning:Genentech: Employment.
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Jain, Preetesh, Long Xuan Trinh, Ohad Benjamini, et al. "Deletion 11q Abnormality in Patients with Chronic Lymphocytic Leukemia (CLL) May Not Have Poor Clinical Outcomes and Bulky Disease (clinical and radiological) At Presentation – Clinical Characteristics of (n=172) Previously Untreated Patients with CLL and del11q Cytogenetic Abnormality." Blood 120, no. 21 (2012): 2890. http://dx.doi.org/10.1182/blood.v120.21.2890.2890.
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Abstract Abstract 2890 Introduction: Del11q aberration is universally considered as an adverse prognostic marker in patients with CLL. However, large studies describing the clinical characteristics of del11q in CLL patients (pts) have never been reported. We studied the clinical features, outcomes and treatment responses among (172) previously untreated pts with CLL and del11q. Methods: This is a retrospective analysis of CLL pts (n=172) with del11q, who presented at our institution between 2003–2012. All pts signed an informed consent as per the declaration of Helsinki and IRB approval. Del11q was determined from bone marrow (BM) aspirate or blood samples by FISH (Fluorescent in-situ hybridization) technique. Detection of the 11q22.3 (ATM gene) on chromosome 11 used a multi-color FISH technique. Pts were divided into five categories – One – 57; del11q alone, Two – 105; del11q and del13q, others – 10 (4; del11q with +12, 1; del11q with del17p and 5; del11q, del13q with +12). Baseline bulky lymphadenopathy by CT scan or physical exam (PE) was also analysed. The probabilities of OS, PFS and TTFT (time to first treatment) were estimated using KM plots (log rank). PFS was assessed in 121 treated pts, from date of starting therapy to date of progression or death on therapy. The Cox proportional hazards regression model was used to assess the association between pt characteristics and OS, PFS or TTFT. Results: At the baseline, majority of pts with del11q were young (median age <60 years), males (81.4%) without very high white cell count (median 33.8 K/UL), absolute lymphocyte count – (median 27.1 K/UL) and β2 microglobulin (3 mg/L). Only 16.7% (n=28) patients had advanced Rai stage (3, 4). Majority were IGHV unmutated (n=112; 89.6%), CD38 high (n=88; 51.8%), Zap-70 high (n=100; 75.8%). Status of bulky disease was assessed by PE and baseline CT scans. Bulky disease by PE was observed in n=11 (6.4%) only. Baseline CT scans were performed for 108 patients out of whom only 16 patients (14.8%) had bulky disease. Thus, majority of del11q pts did not have bulky disease by PE or by CT scanning. Analysis of time dependent variables was performed. Among the total 172 pts, 19 (11%) have died. and median time to death has not been reached (NR) - OS. 48/125 (38%) pts who were treated died or progressed and median PFS time was 49.2 months. Overall, 123 (71%) patients received therapy after initial presentation at MDACC. The median TTFT was 10.6 months. FCR based therapies were given in (91; 73 %) pts. Median PFS on FCR based therapy was 32 mo (Figure -1). CR was achieved in (70%; n=64) and overall response was 89%. Pts who received fludarabine based therapy had a significantly shorter TTFT as compared to non fludarabine based therapy (P<0.0001). Other pts (32) were treated with single agent rituximab and lenalidomide protocols. To address whether del11q has any influence over presence of deletion 13 q abnormality we compared (del11q alone; n=57) vs (del11 and del13q; n=105) patients. Patients with sole del11q had significant proportions of younger patients, lesser WBC count, and ALC and β2 microglobulin. Furthermore, there was no significant difference in OS, PFS and TTFT among the two categories. In the multivariate analysis for OS and PFS among the two categories, β2 microglobulin was significantly predictive of increased risk of death or progression among the two categories and FISH categories were not significantly predictive of OS or PFS or TTFT. Bulky disease by PE (and not by CT scan) was significantly associated with a shorter TTFT (HR=2.93; 95%CI -1.5–5.69 and P=0.002). Furthermore, a separate cohort of (n=500) patients with sole del13q was compared with del11q alone (n=57) and del11q with del13q (n=105). There was no significant difference in OS but the TTFT was significantly shorter in del11q alone (data not shown). Conclusions: We describe the clinical features of del11q in CLL patients. This study suggests that occurrence of del11q is frequent with del13q abnormality. The majority of patients with del11q did not have bulky disease as assessed by PE or by CT scan. Presence of bulky disease by PE predicted for a shorter TTFT. β2 microglobulin level significantly predicted for OS and PFS. FCR based therapy has good responses. Del11q is similar to del13q in terms of OS, PFS and TTFT. Del11q may not have very poor adverse outcomes in patients with CLL inspite of a shorter TTFT. Disclosures: Burger: Pharmacyclics: Consultancy, Research Funding. Wierda:Abbott: Research Funding; Genentech: Consultancy, Research Funding; GlaxoSmithKline: Consultancy, Research Funding; AmGen: Research Funding; Merck: Consultancy; Celgene: Consultancy; Pharmacyclics: Consultancy; Genzyme: Consultancy. Kantarjian:Genzyme: Research Funding.
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Swarup, Sriman, Donald P. Quick, Anita Sultan, et al. "Efficacy of Ibrutinib in Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma: A Combined Analysis of Three Phase III Randomized Controlled Trials." Blood 134, Supplement_1 (2019): 5479. http://dx.doi.org/10.1182/blood-2019-123172.
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Introduction: The B-cell receptor signaling pathway involves in the pathogenesis of chronic lymphocytic leukemia/ small lymphocytic lymphoma (CLL/ SLL), the most common adult lymphoproliferative disorder in western countries. Ibrutinib, a novel Bruton's tyrosine kinase (BTK) inhibitor, has shown great efficacy in the treatment of hematological malignancies via inhibition of BTK, a kinase involved in cellular signaling downstream of the B-cell receptor. However, treatment becomes more challenging upon progression after initial treatment. We performed a combined analysis of currently available randomized controlled trials (RCTs) to evaluate the efficacy of ibrutinib in relapsed or refractory CLL/SLL. Methods: We systematically conducted a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts from inception through June 2019. Phase III RCTs utilizing ibrutinib in patients with previously treated, relapsed or refractory CLL/SLL were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled hazard ratio (HR) for progression-free survival (PFS) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q -statistic. Random effects model was applied. Results: Three phase III RCTs (HELIOS, RESONATE and Huang et al. studies) with a total of 1,129 patients with relapsed or refractory CLL/SLL were eligible. Studies compared ibrutinib vs ofatumumab, ibrutinib vs rituximab, and ibrutinib+ bendamustine+ rituximab vs bendamustine+ rituximab were included in the analysis. The randomization ratio was 2:1 in Huang et al. study and 1:1 in other studies. The I2 statistic for heterogeneity was 49, suggesting some heterogeneity among RCT. The pooled HR for PFS was statistically significant at 0.17 (95% CI: 0.12-0.22; P < 0.0001). The PFS benefit was observed in all Rai stages, either del11q or del17p status and bulky disease (≥ 5cm); Rai stage ≤ 2 cohort (HR, 0.14; 95% CI: 0.09- 0.22; P < 0.0001), Rai stage >2 cohort (HR, 0.26; 95% CI: 0.19- 0.36; P < 0.0001), del11q group (HR, 0.10; 95% CI: 0.06- 0.17; P < 0.0001), del17p group (HR, 0.24; 95% CI: 0.14- 0.39; P < 0.0001), and bulky disease cohort (HR, 0.19; 95% CI: 0.15- 0.25; P < 0.0001). Conclusions: Our study depicted that ibrutinib maintains activity in previously treated, relapsed or refractory CLL/SLL, across all Rai stages, in bulky disease and in del11q or del17p. Thus, the use of ibrutinib is likely beneficial to patients with relapsed or refractory CLL/SLL, regardless of disease stage, bulkiness or del11q/del 17p status. Disclosures No relevant conflicts of interest to declare.
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Orfanakis, Michalis, George J. Tserevelakis, and Giannis Zacharakis. "A Cost-Efficient Multiwavelength LED-Based System for Quantitative Photoacoustic Measurements." Sensors 21, no. 14 (2021): 4888. http://dx.doi.org/10.3390/s21144888.
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The unique ability of photoacoustic (PA) sensing to provide optical absorption information of biomolecules deep inside turbid tissues with high sensitivity has recently enabled the development of various novel diagnostic systems for biomedical applications. In many cases, PA setups can be bulky, complex, and costly, as they typically require the integration of expensive Q-switched nanosecond lasers, and also presents limited wavelength availability. This article presents a compact, cost-efficient, multiwavelength PA sensing system for quantitative measurements, by utilizing two high-power LED sources emitting at central wavelengths of 444 and 628 nm, respectively, and a single-element ultrasonic transducer at 3.5 MHz for signal detection. We investigate the performance of LEDs in pulsed mode and explore the dependence of PA responses on absorber’s concentration and applied energy fluence using tissue-mimicking phantoms demonstrating both optical absorption and scattering properties. Finally, we apply the developed system on the spectral unmixing of two absorbers contained at various relative concentrations in the phantoms, to provide accurate estimations with absolute deviations ranging between 0.4 and 12.3%. An upgraded version of the PA system may provide valuable in-vivo multiparametric measurements of important biomarkers, such as hemoglobin oxygenation, melanin concentration, local lipid content, and glucose levels.
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Maruyama, Yosh, John R. Van Nagell, Justine Yoneda, et al. "Dose-response and failure pattern for bulky or barrel-shaped stage ib cervical cancer treated by combined photon irradiation and extrafascial hysterectomy." Cancer 63, no. 1 (1989): 70–76. http://dx.doi.org/10.1002/1097-0142(19890101)63:1<70::aid-cncr2820630112>3.0.co;2-q.
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Cidlina, Antonin, Zuzana Pausimova, Miroslav Miletin, Petr Zimcik, and Veronika Novakova. "The effect of substitutents at alkylsulfanyl/arylsulfanyl non-peripherally substituted phthalocyanines: Spectral and photophysical properties, basicity and photostability." Journal of Porphyrins and Phthalocyanines 19, no. 10 (2015): 1095–106. http://dx.doi.org/10.1142/s1088424615500832.
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A series of magnesium, zinc and metal-free derivatives of non-peripherally substituted phthalocyanines (Pcs) bearing alkylsulfanyl or arylsulfanyl groups of different bulkiness was synthesized. Their spectral and photophysical properties including also the basicity of azomethine nitrogens and photostability were compared within the series as well as with similar peripherally substituted Pcs. Non-peripheral position of substituents led to the 70[Formula: see text]nm red-shift of Q-band in comparison to the peripherally substituted Pcs. However, unexpected blue-shift of approximately 50[Formula: see text]nm was observed in the series of non-peripherally substituted Pcs for the most bulky tert-butylsulfanyl derivative caused probably by extreme distortion of the macrocycle. The substitution had no effect on photophysical properties and compounds reached [Formula: see text] values 0.74–0.76 and [Formula: see text] 0.053–0.080 for zinc complexes, and [Formula: see text] 0.47–0.51 and [Formula: see text] 0.10–0.17 for magnesium complexes following the rule of heavy atom effect. Generally, non-peripherally substituted Pcs possessed improved singlet oxygen production in comparison to peripherally substituted ones. The photostability of the target compounds decreased with the red-shift of their absorption maxima with the arylsulfanyl derivatives being less photostable. The basicity of azomethine nitrogens was clearly dependent on the position and the character of substituent. Thus, non-peripherally substituted Pcs showed extraordinary increased basicity over the peripherally substituted ones with the most pronounced effect at alkylsulfanyl derivatives.
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Omomo, Satoshi, Ko Furukawa, Haruyuki Nakano та Yoshihiro Matano. "Comparison of electronic effects of β-aryl substituents on optical and electrochemical properties of 5,15-diazaporphyrin π-systems". Journal of Porphyrins and Phthalocyanines 19, № 06 (2015): 775–85. http://dx.doi.org/10.1142/s1088424615500509.
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The syntheses and optical/electrochemical properties of 3-aryl-10,20-dimesityl-5,15-diazaporphyrin-metal complexes (MDAPs; mesityl = 2,4,6-trimethylphenyl; M = Ni , Zn ) are reported. Treatment of 3-bromo-MDAPs with arylboronic acids in the presence of a Pd catalyst and a bulky phosphine ligand in a dioxane-water mixed solvent afforded the corresponding 3-aryl-MDAPs in moderate to good yields. X-ray crystallographic analysis of p- EtO 2 CC 6 H 4- NiDAP showed that the β-aryl group was tilted toward the NiDAP ring, with a dihedral angle of 21.7°. In the UV-visible absorption spectra, all the Ar-MDAPs showed intense Q-bands attributable to HOMO-to-LUMO transitions. The para substituents were found to influence the HOMO energies, which eventually resulted in fine tuning of the HOMO–LUMO gaps of the diazaporphyrin chromophores. It is worth noting that the p- Ph 2 NC 6 H 4- ZnDAP showed broad absorption and emission bands in the visible-near-infrared regions. The large Stokes shifts and their linear solvation energy relationships vs. orientation polarizability show that this Ph 2 N -substituted derivative has intrinsically high charge transfer from the triphenylamine (donor) to the ZnDAP (acceptor) unit. These experimental observations were supported by theoretical calculations for model Ar-ZnDAP compounds. These results confirm that the introduction of a highly electron-donating aryl group at the peripheral β-carbon is a promising strategy for enhancing the light-harvesting and light-emitting abilities of diazaporphyrin-based π-systems in the visible-near-infrared regions.
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Fukuda, Takamitsu, Keita Yamamoto, and Nagao Kobayashi. "Synthesis and properties of non-planar octaphenyl-substituted phthalocyaninato manganese(III)." Journal of Porphyrins and Phthalocyanines 17, no. 08n09 (2013): 756–62. http://dx.doi.org/10.1142/s1088424613500272.
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A trivalent manganese complex of a non-planar 1,4,8,11,15,18,22,25-octaphenylphthalocyanine derivative, 3, has been synthesized by treating metal-free 1,4,8,11,15,18,22,25-octaphenylphthalocyanine, 2, with manganese(II) chloride in refluxing DMF. X-ray crystallography has revealed that the complex adopts a highly-deformed skeletal conformation due to steric congestions between the substituted bulky phenyl groups. Although mass spectrometry results provide no indication of the presence of axial ligands, the crystal data clearly show that the manganese ion is coordinated axially by a chloride ion in addition to the four equatorial isoindole nitrogen atoms. The oxidation state of the manganese center of 3, therefore, has been assigned to 3+. Electronic absorption spectra revealed that the Q-band of 3 shows a significant bathochromic shift compared to that of the planar Mn ( III ) phthalocyanine 4 and non-planar metal-free phthalocyanine 2. The analysis of MCD and UV-vis spectra suggests that the absorption band observed at 555 nm for 3 is LMCT in origin. Electrochemical investigations indicate that the first oxidation couple is ligand-centered. Since the HOMO of 2 is destabilized due to the synergetic effects of the electron-donating phenyl groups at the non-peripheral positions and the deformed π-electronic skeleton, the resulting manganese complex 3, is anticipated to also have a ligand-centered HOMO. The results of spectroelectrochemistry confirm that the first oxidation process of 3 is indeed ligand-centered. DFT calculations indicate that the MO amplitudes of the HOMO and LUMO localize mainly on the Pc ligand and the manganese ion, respectively, also supporting the assignments of the cyclic voltammograms. By combining the manganese ion and non-planar Pc ligand, a novel, stable near-infrared (NIR)-absorbing material has been achieved in the present study.
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Knecht, Hans, Narisorn Kongruttanachok, Bassem Sawan, Zelda Lichtensztejn, Daniel Lichtensztejn, and Sabine Mai. "3D Telomere Dynamics In Hodgkin's Lymphoma." Blood 116, no. 21 (2010): 745. http://dx.doi.org/10.1182/blood.v116.21.745.745.
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Abstract Abstract 745 Introduction: Innovative 3D telomere q-FISH allows a mechanistic understanding of the transition from the mononuclear Hodgkin (H) to the multinuclear Reed-Sternberg (RS) cell in in Hodgkin's lymphoma (HL) derived cell lines and diagnostic patient biopsies (Leukemia. 2009; 23:565-573). In RS-cells the telomere protecting shelterin complex appears to be disrupted and deregulation of DNA repair mechanisms is observed. These changes occur in both, classical EBV negative and EBV-associated, LMP1 expressing HL (Lab Invest. 2010; 90:611-619). However, it is not known whether the 3D telomere profile at diagnostic biopsy is different in patients entering rapid remission after initiation of standard chemotherapy (ABVD) compared to that-one of patients with relapsing or refractory disease. In order to answer this question we analyzed by 3D telomere q-FISH diagnostic biopsies of HL patients entering rapid complete remission and compared them to diagnostic biopsies of patients with relapsing or refractory disease. Patients and methods: Rapid remission group (after 1–4 cycles of ABVD): 7 diagnostic biopsies of 7 patients, 19–57 years old, 5 male, 3 LMP1 expressing, 4 nodular sclerosis subtype, 3 mixed cellularity subtype, stages IA, IIA, IIIA × 2, IIIB x2, IVA. Relapse group: 7 diagnostic biopsies of 4 patients, 40–77 years old, 2 male, 1 LMP1 expressing, 3 nodular sclerosis subtype, 1 mixed cellularity subtype, stages IIA bulky, IIIB × 2, IVB; first remission after 6–8 cycles of ABVD in 3 patients, 1 patient died from progressive disease after 11 months. 3D telomere q-FISH was performed as described (Lab Invest. 2010; 90:611-619) and statistical analysis was performed using nested or two-way analysis of variance. Results: Bi- or multinuclear RS-cells of all patients from both groups showed a significant increase of very short telomeres and telomere aggregates when compared to the mononuclear precursor H-cells. However, most importantly, all diagnostic biopsies of the relapse group contained a very high percentage of very small telomeres, including so-called “t-stumps”, in both, H-cells (76,8 ± 11,8%) and RS-cells (87,9 ± 7,3%). Compared to the percentage of very small telomeres identified in both, H-cells (33,7 ± 9,4%) and RS-cells (54,6 ± 15,0%) of the rapid remission group, this increase is highly significant (p <0.001). Moreover, analogous findings are observed for the number of telomere aggregates. In the relapse group the average numbers of telomere aggregates per cell were 4,3 ± 2,4 aggregates per H-cell and 5,4 ± 3.0 aggregates per RS-cell, compared to 1,2 ± 0,7 aggregates per H-cell and 3,3 ± 1,1 aggregates per RS-cell in the rapid remission group. Discussion: The 3D nuclear telomere organization of H- and RS- cells in diagnostic biopsies of relapsing or refractory HL is characterized by both, H- and RS-cells with abundant “t-stumps” and numerous telomere aggregates. Very short telomeres, including t-stumps, and telomere aggregates, both, are characteristics of aggressiveness in cancer biology (Mol Cell. 2007;28:315-327; J Cell Biochem. 2010; 109:1095-1102). Thus, H- and RS-cells of refractory or relapsing HL show significant differences in the 3D telomere dynamics already at first, diagnostic biopsy when compared to H- and RS-cells of HL entering rapid remissions. Disclosures: No relevant conflicts of interest to declare.
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Reardon, David A., James J. Vredenburgh, Annick Desjardins, et al. "REACT: A phase II study of rindopepimut (CDX-110) plus bevacizumab (BV) in relapsed glioblastoma (GB)." Journal of Clinical Oncology 30, no. 15_suppl (2012): TPS2103. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.tps2103.
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TPS2103 Background: EGFRvIII is a constitutively active tumorigenic deletion mutation of EGFR. It is expressed in ~30% of primary GB where it is linked to poor long-term survival (Pelloski 2007). The investigational vaccine rindopepimut consists of the unique EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin (KLH), delivered intradermally (500ug with 150ug GM-CSF as an adjuvant). Remarkably consistent and promising results across 3 phase II studies in newly diagnosed, resected EGFRvIII+ GB (Lai 2011) represent a statistically significant improvement over a historical control cohort matched for major eligibility criteria (median overall survival [OS] = 24.4 - 24.6 vs. 15.2 months from diagnosis [m] and median progression-free survival [PFS] = 12.3 - 15.3 vs. 6.4 m). ACT IV, a phase III trial in this population, is ongoing. The immunosuppressive influence of residual/advanced GB presents a challenge to activation of efficacious antitumor immune responses. Anecdotal evidence (compassionate use cases, Sampson 2008) suggests that rindopepimut may induce specific immune responses and regression in multifocal and bulky residual tumors. Rindopepimut with BV, which inhibits VEGF and its immunosuppressive properties (including impaired maturation of dendritic cells and disruption of tumoral T cell infiltration [Johnson 2007, Shrimali 2010]) may further optimize EGFRvIII-specific immune response and antitumor activity. Methods: ReACT is a Phase II study of rindopepimut plus BV in patients (pts) with 1st or 2nd relapse of EGFRvIII+ GB. BV-naïve pts will be enrolled to Group 1 (n=70: randomized 1:1 to BV plus either rindopepimut/GM-CSF or control injection [low-dose KLH]) while BV-refractory patients will enter Group 2 (n=25: to receive BV plus open-label rindopepimut/GM-CSF). Concurrent with BV (10 mg/kg, q 2 wks), blinded treatment or open-label vaccine is given in priming phase (days 1, 15 and 29), then monthly until PD. Tumor response is assessed every 8 weeks, and patients are followed for survival after PD. Objectives are PFS at 6 months (primary), objective response rate, PFS, OS, safety, immunogenicity and elimination of EGFRvIII. ReACT opened to accrual in December 2011 (NCT01498328).
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Murawski, Niels, Josif Amam, Bettina Altmann, et al. "Anti-infective prophylaxis with aciclovir and cotrimoxazole to reduce the rate of infections and therapy-associated deaths in elderly patients with DLBCL undergoing R-CHOP immunochemotherapy." Journal of Clinical Oncology 35, no. 15_suppl (2017): 7539. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.7539.
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7539 Background: To study if anti-infective prophylaxis with aciclovir and cotrimoxazole is effective in preventing infections in pts. receiving R-CHOP, we compared infections and treatment-related deaths in two prospective DSHNHL trials with different anti-infective strategies. Methods: 61-80-yo. pts. in RICOVER-60 study [Lancet Oncol 2008; 9:105-116] received 6 or 8 cycles of CHOP-14 with or without 8 applications of rituximab. Anti-infective prophylaxis consisted of ciprofloxazine (500 mg/d) during days of severe leukocytopenia ( < 1000 / mm3). In OPTIMAL > 60, pts. were randomized to 6xCHOP-14 or 6xCHLIP-14 (conventional substituted by liposomal vincristine) in combination with rituximab, 8 applications q 2 wks. or 12 applications between days -4 and 238 /2x2 factorial design). In OPTIMAL > 60, anti-infective prophylaxis consisted of cotrimoxazole (2 double strength doses twice every week p. o.) and aciclovir (4 x 400 mg/d p.o.) in addition to ciprofloxazine. Results: In RICOVER-60, grade 3&4 infections in 232 patients (IPI = 1 and bulky disease or IPI > 1) receiving 6xCHOP-14+8R were 6% (76/1200) per cycle and 28% (60/218) per patient. With intensified anti-infective prophylaxis in OPTIMAL > 60 there were no differences with respect to infections between the 4 treatment arms. Grade 3&4 infections were 4% (83/1987) per cycle (p = 0.007) and 18% (64/365 pts. with toxicity documentation) per patient (p = 0.004). Treatment-related deaths (defined as all non-lymphoma associated deaths during and within 2 months after the end of chemotherapy) went down from 15/232 (7%) in RICOVER-60 to 7/385 (2%; p = 0.003) in OPTIMAL > 60. Conclusions: Anti-infective prophylaxis with cotrimoxazole and aciclovir in addition to ciprofloxazine significantly reduced the rates of severe infections and treatment-related deaths in elderly patients receiving R-CHOP supporting the use of this anti-infective strategy in all DLBCL patients receiving R-CHOP. Clinical trial information: NCT01478542.
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Chauhan, Aman, Arun Kumar Arumugam Raajasekar, Zin Myint, Leaundra Murray, and Lowell Brian Anthony. "Capecitabine and temozolomide (CAPTEM) in neuroendocrine tumor of unknown primary." Journal of Clinical Oncology 35, no. 15_suppl (2017): e15691-e15691. http://dx.doi.org/10.1200/jco.2017.35.15_suppl.e15691.
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e15691 Background: Better diagnostics, recognition and knowledge of neuroendocrine tumors (NETs) have led to consistent growth in incidence and prevalence of the disease. Being an orphan disease, therapeutic options are limited. Scarce data exists regarding use of Capecitabine and Temozolomide (CAPTEM) in neuroendocrine tumors. There are no published data on use of CAPTEM in neuroendocrine tumors of unknown primary. NETs of unknown primary accounts for 10-15 % of NETs. Historically NETs with unknown primary are thought to be relatively aggressive, conferring a poorer prognosis. Methods: Patients with neuroendocrine tumor with unknown primary were identified from Markey Cancer Center database over a five-year period (2012-2016). Patients treated with CAPTEM regimen were analyzed for radiological response in first scan, time to progression on treatment and toxicity. IRB approval was obtained. Results: 56 patients with neuroendocrine tumors of unknown primary were identified. 12 patients were treated with CAPTEM. Median age of study cohort was 62 years. 6/12 were females. Seven patients were grade II, 4 were grade III and only one was grade I NET. CAPTEM was used as front line systemic therapy in 9 patients. Mean duration of treatment before progression was 10.8 months. 6 patients showed reduction in metastatic tumor volume at first q 3 monthly CT scan. 3 patients had stable disease and 3 patients showed disease progression at first surveillance scan. Following were the rates of common side-effects. Grade 2 thrombocytopenia (n = 4), Grade 1 lymphocytopenia (n = 3), hand/foot syndrome Grade 1 (n = 1), Grade 3(n = 1), Fatigue, Grade 1 (n = 6) Conclusions: CAPTEM shows activity in neuroendocrine tumor of unknown primary. Currently FDA approved treatment options for grade I and grade II GI NETs includes somatostatin analogs and everolimus. Both of which are cytostatic and of limited use in case of visceral crisis or bulky disease where disease shrinkage is required. CAPTEM should be considered for grade II NETS of unknown primary.
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Smolej, Lukas, Martin Spacek, Yvona Brychtova, et al. "Low-Dose Fludarabine and Cyclophosphamide Combined with Rituximab In the Treatment of Elderly/Comorbid Patients with chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL): Preliminary Results of Project Q-Lite by Czech CLL Study Group." Blood 116, no. 21 (2010): 2466. http://dx.doi.org/10.1182/blood.v116.21.2466.2466.
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Abstract Abstract 2466 Background: Combination of fludarabine, cyclophosphamide and rituximab (FCR) is currently considered the treatment of choice in physically fit patients (pts) with chronic lymphocytic leukemia (CLL). However, many patients cannot tolerate this aggresive treatment because of advanced age and/or serious comorbid conditions. For these patients, chlorambucil has remained so far the standard of treatment. Low-dose fludarabine-based regimens have recently demonstrated promising results in small studies. Aims: to assess efficacy and safety of low-dose FC or FCR regimen used in elderly/comorbid patients with CLL. Patients and Methods: Between March 2009 and June 2010, we treated 74 pts with active disease (CLL, n=70, SLL, n=4, 57% males, median age, 70 years [range, 58–83], median Cumulative Illness Rating Score 4 [range, 0–10]) by low-dose FC/FCR at fourteen centers cooperating within Czech CLL Study Group. Dose reduction of chemotherapy was as follows: fludarabine to 50% (12 mg/m2 i.v. or 20 mg/m2 orally on Days 1–3), cyclophosphamide to 60% (150mg/m2 i.v./p.o. D1-3). The dose of rituximab was standard (375mg/m2 in 1st cycle, 500mg/m2 from 2nd cycle). The choice of regimen (FC vs FCR) was at the discretion of the attending physician. Treatment was repeated every 4 weeks. Antimicrobial prophylaxis with cotrimoxazole and aciclovir or equivalents was recommended. Fifty per cent of pts were treated in first line, the remaining half had relapsed/refractory CLL. Rai stage III/IV was present in 57% pts; 39% had bulky disease. IgVH genes were unmutated in 74%; according to hierarchical model, del 11q was present in 32% and del 17p in 8%. Results: FCR was used in 72 pts, FC in 2. Based on intention-to-treat principle, the overall response/complete response rate (including clinical CR and CR with incomplete blood count recovery) was 70/35%; 34 pts are still on treatment. No data on PFS/OS are available yet. Serious (CTC grade III/IV) neutropenia occurred in 51%, thrombocytopenia in 13% and anemia in 10% of pts. Serious infections were diagnosed in 13% of pts. Three pts (4%) died, all of them after failure of treatment (pneumonia, n=2, pulmonary embolism, n=1). Conclusions: Treatment of elderly/comorbid CLL patients with low-dose FC/FCR demonstrated very promising results. Toxicity was acceptable and manageable. Longer follow-up is needed for the assessment of PFS and OS. Supported by research project MZO 00179906 from Ministry of Health, Czech Republic. Disclosures: Smolej: Roche: Honoraria; Bayer-Schering: Honoraria; Genzyme: Honoraria. Off Label Use: Low-dose FCR in elderly/comorbid patients with CLL. Belada: Roche: Consultancy, Honoraria. Motyckova: Roche: Honoraria.
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Smolej, Lukas, Yvona Brychtova, Michael Doubek, et al. "Low-Dose FCR Is a Safe and Effective Treatment Option for Elderly/Comorbid Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. Updated Results of Project Q-Lite By Czech CLL Study Group." Blood 124, no. 21 (2014): 4670. http://dx.doi.org/10.1182/blood.v124.21.4670.4670.
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Abstract Background: Combination of fludarabine, cyclophosphamide and rituximab (FCR) is the current gold standard for physically fit patients (pts) with chronic lymphocytic leukemia (CLL). Nevertheless, many CLL patients cannot tolerate this intensive regimen owing to advanced age and/or serious comorbidities. Combination protocols based on dose-reduced fludarabine demonstrated promising results in pilot studies. Therefore, the Czech CLL Study Group initiated Project Q-lite, an observational study to assess efficacy and safety of low-dose FCR regimen used in elderly/comorbid patients with CLL/SLL. Updated results including progression-free survival (PFS), overall survival (OS) and multivariate analysis are presented. Patients and Methods: Between March 2009 and July 2012, a total of 207 pts with active disease (CLL, n=196, SLL, n=11) were treated by low-dose FCR at 16 centers cooperating within Czech CLL Study Group. Dose reductions of chemotherapy compared to full-dose FCR were: 50% of fludarabine (12 mg/m2 i.v. or 20 mg/m2 orally on days 1-3) and 60% of cyclophosphamide (150 mg/m2 i.v./p.o. on days 1-3). Rituximab was administered in standard schedule (375mg/m2 i.v. day 1 in 1st cycle, 500mg/m2 i.v. day 1 from 2nd cycle). Treatment was repeated every 4 weeks; antimicrobial prophylaxis with sulfamethoxazol/trimethoprim and aciclovir or equivalents was recommended. The basic characteristics are summarized in Table 1. Results: Based on intention-to-treat principle, the overall response rate / complete responses including clinical CR (without bone marrow biopsy) and CRi were 81/37% in 1st line and 63/30% in relapsed/refractory (R/R) disease. Serious (CTCAE grade III/IV) neutropenia was frequent (56 and 50%) but grade III/IV infections were only 15 and 18%. The most common causes of death were CLL progression and infections. At the median follow-up of 25 months, median progression-free survival (PFS) for previously untreated and R/R patients was 28 and 15 months; median overall survival (OS) has not been reached in previously untreated pts (75 % at 30 months) and was 30 months in R/R pts. Multivariate analysis identified del 11q, del 17p, bulky lymphadenopathy (1st line) and del 17p (R/R) as independent predictors of shorter PFS; absence of therapeutic response was the only factor associated with shorter OS (both in 1st line and R/R pts). Conclusions: Low-dose FCR appears to be an effective treatment for elderly/comorbid patients with CLL/SLL in first-line as well as R/R setting. Toxicity was acceptable and manageable. In historical comparison, efficacy of low-dose FCR compares favourably with chlorambucil monotherapy and is similar to obinutuzumab-chlorambucil combination from German CLL11 study. Interestingly, neither CIRS score nor creatinine clearance were predictive of PFS/OS. The study is registered at www.clinicaltrials.gov (NCT02156726). Fig 1. Fig 1. Disclosures Smolej: Janssen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Travel grants, Travel grants Other; GlaxoSmithKline: Consultancy, Honoraria, Travel grants, Travel grants Other; Roche: Consultancy, Honoraria, Research Funding, Travel grants Other. Brychtova:Roche: Travel grants Other. Doubek:Roche: Consultancy; GlaxoSmithKline: Research Funding; Janssen: Consultancy. Spacek:Roche: Consultancy, Travel grants Other. Belada:Celgene: Research Funding; Roche: Consultancy, Research Funding, Travel grants, Travel grants Other; GlaxoSmithKline: Research Funding. Motyckova:Roche: Travel grants Other. Prochazka:Roche: Honoraria, Travel grants Other; Takeda: Speakers Bureau. Kozak:Roche: Honoraria, Travel grants Other.
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Rossi, Davide, Silvia Rasi, Alice Di Rocco, et al. "The Genotype of MLH1 Is An Independent Predictor of Outcome In Diffuse Large B-Cell Lymphoma Treated with R-CHOP: a Training-Validation Study." Blood 116, no. 21 (2010): 992. http://dx.doi.org/10.1182/blood.v116.21.992.992.
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Abstract Abstract 992 Several drugs utilized in diffuse large B cell lymphoma (DLBCL) rely on DNA damage for tumor killing. This study aimed at verifying whether single nucleotide polymorphisms (SNPs) of genes involved in DNA repair may contribute to prognostication of DLBCL treated with R-CHOP. The study utilized a training-validation design. The training cohort (n=163) was a mono-institutional, prospectively collected, consecutive series of DLBCL homogeneously treated with the same chemotherapeutic regimen both at diagnosis (R-CHOP21) and at relapse/progression (R-DHAP ± BEAM conditioned autologous stem cell transplant, ASCT). The validation cohort (n=156) was a multi-institutional retrospective series of DLBCL treated with R-CHOP at diagnosis. Candidate SNPs (n=35) were selected by an educated guess approach, and included SNPs belonging to genes involved in: i) mismatch repair (MLH1); ii) base excision repair (XRCC1, OGG1); iii) nucleotide excision repair (ERCC1, ERCC2, ERCC4, ERCC5, ERCC6, XPA, XPC); iv) double strand break repair (BRCA1, BRCA2, LIG4, XRCC2, XRCC3, XRCC4, XRCC6); and v) direct reversal (MGMT). Clinical endpoints were progression free survival (PFS) after R-CHOP, overall survival (OS) from diagnosis, and OS from salvage treatment. Univariate analysis controlled for multiple comparisons identified MLH1 rs1799977 as the sole SNP predicting DLBCL OS in the training series (AG/GG genotype: HR: 3.23; 4-year OS: 55.5% vs AA genotype: 4-year OS: 80.9%; p<.001; q=.009) (Fig. 1A). Multivariate analysis identified the MLH1 rs1799977 AG/GG genotype (HR: 3.14; p<.001) as an independent predictor of OS, along with IPI score (HR: 1.38; p=.037) and bulky disease (HR: 2.56; p=.004). The prognostic relevance of MLH1 rs1799977 in the DLBCL training series was due to the impact on risk of failing both R-CHOP21 (AG/GG genotype; HR: 2.02; 4-year PFS: 47.5%; AA genotype: 4-year PFS: 65.6%; p=.007) (Fig. 1B) and second line treatment (AG/GG genotype: HR: 3.04; 2-year OS from salvage: 16.0%; AA genotype: 2-year OS from salvage: 57.3%; p=.007) (Fig. 1C). Multivariate analysis identified the MLH1 rs1799977 AG/GG genotype (HR: 1.96; p=.010) as an independent predictor of PFS after R-CHOP21, along with IPI score (HR: 1.41; p=.002) and bulky disease (HR: 1.96; p=.012). By bivariate analysis, MLH1 predicted OS from salvage treatment independent of having (p=.002) or having not (p=.049) consolidated with ASCT. The DLBCL validation series did not differ from the training series in terms of clinical features at presentation, median follow-up (p=.429), OS (p=.331), PFS (p=.416), OS from salvage (p=.987), and prevalence of MLH1 rs1799977 genotypes (p=.378). The MLH1 rs1799977 AG/GG genotype was confirmed as a predictor of poor outcome in the DLBCL validation series when considering all clinical endpoints, including: i) OS (unadjusted HR: 3.22, p=.001; adjusted HR: 3.15; p=.001); ii) PFS (unadjusted HR: 1.98, p=.017; adjusted HR: 1.86, p=.018); and iii) OS from salvage treatment (unadjusted HR: 2.95, p=.027). Pooling of the training and validation series (n=319) revealed that MLH1 AG/GG predicts DLBCL OS within subgroups defined by IPI. The biologic plausibility of the association between MLH1rs1799977 genotype and DLBCL outcome is supported by four lines evidence: i) MLH1rs1799977 is a nonsynonymous SNP causing the I219V amino acidic substitution in MLH1, a gene of the mismatch repair pathway; ii) in silico, MLH1rs1799977 is predicted to have deleterious consequences; iii) in vitro, the G variant allele of MLH1rs1799977 associates with reduced MLH1 protein expression; iv) loss of MLH1 expression in tumor cells is known to induce refractoriness to doxorubicin and platinum compounds. Disclosures: No relevant conflicts of interest to declare.
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Galili, Naomi, Vladimir Trifonov, Mark Ewalt, Siddhartha Mukherjee, Raul Rabadan, and Azra Raza. "Identification of Dido1 Mutation Associated with Familial Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML)." Blood 120, no. 21 (2012): 169. http://dx.doi.org/10.1182/blood.v120.21.169.169.
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Abstract Abstract 169 Introduction Approximately half of all patients with sporadic MDS will present with one of the known recurrent genetic alterations including additions/deletions of large chromosomal segments or mutations in single genes. Familial cases of MDS are rare, however, and the mutations that have been identified are not unique to MDS. Here we describe a family in which three of nine siblings were affected with early-onset MDS and a del(20) karyotype (Table 1). One of the brothers progressed to AML and died while the remaining 2 brothers are stable. Methods and Results We performed whole exome sequencing on 2 affected brothers and 2 normal male family members followed by Sanger sequencing. Comparison of non-synonymous mutations common to the 2 brothers with MDS but not found in the normal controls revealed a mutated gene, Dido1, which is located at 20q13.33 upstream of the deleted region in the MDS brothers. The G to A mutation leads to substitution of a bulky basic, polar arginine in place of a small neutral non-polar glycine at amino acid 956 of the protein. This mutation, confirmed by PCR, was present in one allele in both the marrow and T-cells (not part of the MDS clone) of both brothers with MDS (Figure 1) showing that the mutation is not somatic but is, rather, a germline mutation. Since all three affected brothers harbored a del(20), it was of interest to investigate whether other patients with MDS or MDS/MPD and del(20)(q11.2) may also have this specific mutation. DNA from bone marrow mononuclear cells (BMMNC) of 10 del(20q) patients with either MDS or MDS/MPD was examined by PCR and Sanger sequencing. No mutation was found in any of the samples, suggesting that the mutation is unique to the affected family. BMMNC were available for 16 additional members of this extensive family. PCR followed by sequencing showed that 7/16 members of generation III have the identical heterozygous mutation. Interestingly, while no DNA was available from the brother who died of AML, analysis of his children revealed that 2 sons (III- Q and III-R) carry the mutation, confirming that the father also carried this mutation. Similarly, while DNA from sister II-G was not available for analysis, one of her daughters carries the mutation confirming the presence of mutation in the mother. Discussion Death inducer-obliterator 1 (Dido1) is a putative transcription factor originally identified in a screen for apoptosis related genes in a murine pre-B cell line. The gene encodes three alternate isoforms and gene targeting of all three isoforms in a murine model leads to development of a transplantable myeloid disorder with features similar to MDS/MPN. These studies also showed variable decreased Dido1 expression in a subset of patients with myeloid disorders when compared to healthy controls. Our results support the hypothesis that Dido1 aberrations in hematopoietic stem cells may contribute to MDS evolution. The fact that deletions in the long arm of chromosome 20 are one of the most frequent aberrations found in MDS and clearly was a secondary event in the 3 affected brothers of this family suggests that Dido1 may ontribute to this specific genomic instability. Generation III are still young, but those with the mutation may have an increased susceptibility to myeloid disease and should be clinically followed. Conclusion The identification of the Dido1 mutation in this family suggests a novel pathogenic mechanism for the development of familial MDS. Disclosures: No relevant conflicts of interest to declare.
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Mariotti, Jacopo, Anna Guidetti, Michele Magni, et al. "High Cure Rates of the Short-Term GITIL Chemotherapy Programme for Adult Patients with Burkitt Lymphoma." Blood 124, no. 21 (2014): 1734. http://dx.doi.org/10.1182/blood.v124.21.1734.1734.
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Abstract Burkitt lymphoma (BL) is a rare disease that account for 2% of all cases of non-Hodgkin lymphoma in adults. Several treatments have been published so far with improving response rates obtained after augmentation with Rituximab of the original protocols. We have previously published the results of a short and intensive chemotherapy regimen translated from the pediatric patients to adults. Here we update and extend our previous results to a cohort of 51 patients with confirmed diagnosis of BL. From December 1991 to January 2014, we enrolled 51 patients with Burkitt lymphoma. The original regimen was applied to the first 22 patients who were treated at the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan. The treatment consisted of and induction phase comprising CTX (500 mg/mq, day 1-2) and VCR (1,4 mg/mq day 1); MTX (150 mg/kg day 8), VP-16 (250 mg/mq q 12 hs, day 14); MTX (250 mg/kg day 21), ADM (50 mg/mq, day 28), VCR (1,4 mg/mq, day 35), and a consolidation phase with HD ARA-C (1000 mg/mq continuos infusion for 4 days with a daily extra dose of 750 mg/mq) plus CDDP (20 mg/mq 4 day continuos infusion). Weekly intratechal chemotherapy for 6 doses was administered. Patients not achieving complete remission (CR) before consolidation, were shifted to sequential high-dose chemotherapy (HDS) comprising HD-CTX and stem cell harvest, HD-ARAC, Dexa-BEAM and BEAM followed by infusion of autologous stem cell transplant (ASCT). Rituximab was included in R-HDS only for in-vivo purging of collected stem cells. An updated version of the protocol was introduced from year 2003 and was applied to a set of 39 patients enrolled by the Gruppo Italiano Terapie Innovative nei Linfomi (GITIL) in four different centers. The new regimen was augmented with rituximab both in the induction (on day 15, day 29, day 36) and after consolidation (two weekly administrations) phases. Also for R-HDS salvage regimen, more rituximab infusions were added to the original schema for a total of 6 administrations. Patients characteristics were as follow: M/F 33/18, median age 46 years (range 18-90 years), stage I-II/III-IV 22/29, IPI H or HI 24 patients, bulky disease 20 patients, CNS involvement in 4 subjects, high LDH levels in 25 patients, ECOG performance status (PS) 0-1 vs 2-3 33/18, BM involvement in 7 subjects. Of 49 patients evaluable for response (2 died of early regimen-related toxicity), CR was obtained after consolidation in 80% of the subjects and was improved to 94% by the R-HDS salvage regimen. In details, of the 4 subjects with PD and the 3 with PR after the induction phase, only one and all three were rescued by R-HDS treatment, respectively. Three patients relapsed after the short-intensive regimen: of them one was saved with R-HDS. With a median follow-up of 1994 days, Kaplan-meier estimates of 5-year OS and PFS were 78% (Figure 1) and 69% respectively, and cumulative incidence of relapse, with Gray test, was 15% (95% CI, 6.5-27; Figure 2). We did not observe any difference in terms OS (p=0.6) and DFS (p=0.7) between patients treated before 2003 by a single center or after 2003 when other hospitals participated to the study. In this study we extended our previous finding and confirmed that the short intensive chemotherapy program achieves high percentages of complete response in patients with BL, while those with primary refractory disease can effectively be saved by the R-HDS regimen. In addition, we demonstrated that our program is easily exportable to other hospitals with reproducible results in a multicenter setting. Figure 1: 5-year OS of patients with Burkitt lymphoma treated with a short-intensive chemotherapy regimen. Figure 1:. 5-year OS of patients with Burkitt lymphoma treated with a short-intensive chemotherapy regimen. Figure 2: 5-year Cumulative Incidence of relapse (with 95% confidential interval) of patients with Burkitt lymphoma treated with a short-intensive chemotherapy regimen Figure 2:. 5-year Cumulative Incidence of relapse (with 95% confidential interval) of patients with Burkitt lymphoma treated with a short-intensive chemotherapy regimen Disclosures No relevant conflicts of interest to declare.
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Tedeschi, Alessandra, Richard Greil, Fatih Demirkan, et al. "Single-Agent Ibrutinib Versus Chlorambucil-Obinutuzumab As First-Line Treatment in Patients with Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma (CLL/SLL): Results of a Cross-Trial Comparison." Blood 132, Supplement 1 (2018): 5565. http://dx.doi.org/10.1182/blood-2018-99-111369.
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Abstract Background : Ibrutinib (ibr), a first-in-class, once-daily inhibitor of Bruton's tyrosine kinase, is approved in the US and EU for patients (pts) with CLL and allows for treatment without chemotherapy. Standard of care for first-line CLL in older pts or those with comorbidities includes single-agent ibr or chemoimmunotherapy (CIT) with chlorambucil (clb) plus anti-CD20 therapy. As no data were available from phase 3 studies directly comparing single-agent ibr with CIT, we performed a cross-trial analysis using data from two phase 3 studies to assess single-agent ibr vs clb plus obinutuzumab (G) in first-line CLL. Methods : In the ongoing PCYC-1115/1116 (RESONATE-2), pts with previously untreated CLL/SLL aged ≥65 years without del(17p) were randomized to receive ibr (420 mg once daily continuously) or clb. In PCYC-1130 (iLLUMINATE), pts with untreated CLL/SLL aged ≥65 years or <65 years with coexisting conditions or del17p/TP53 mutation were randomized to receive ibr plus 6 cycles of G or 6 cycles of clb-G. As pts with del(17p) were ineligible for RESONATE-2, pts with del(17p) in iLLUMINATE were excluded from cross-trial analyses. Primary analysis was investigator (INV)-assessed progression-free survival (PFS) with single-agent ibr in RESONATE-2 vs clb-G in iLLUMINATE; secondary analyses were PFS in the high-risk population (del(11)q, TP53 mutation, or unmutated IGHV), medical resource utilization in the first 6 mo, and safety (including time-matched analysis at 6 mo to account for different treatment durations). Additional exploratory analyses compared single-agent ibr in RESONATE-2 vs ibr-G in iLLUMINATE to evaluate lymphocytosis (≥50% increase in absolute lymphocyte count from baseline and ≥5 × 109/L), and overall response rate (ORR). Results : Primary analysis included 136 pts treated with single-agent ibr and 98 pts treated with clb-G. Median age was 73 years in both groups. High-risk genomic features were generally well balanced (54% and 58% of pts, respectively), including del(11q) (21% and 22%), TP53 mutations (9% and 5%), and unmutated IGHV (43% and 46%). Bulky disease (≥5 cm) was present in 40% and 37% of pts, respectively. Median follow-up was 48.8 mo for ibr and 31.3 mo for clb-G. Single-agent ibr significantly prolonged PFS compared with clb-G (median not reached [NR] vs 22.2 mo), with an 82% reduction in risk of progression or death (HR 0.184; P<0.0001; Figure 1). PFS rates at 30 mo were 85% vs 40% for ibr vs clb-G. Superior PFS with ibr vs clb-G was also seen in the high-risk population (median NR vs 18.3 mo; HR 0.072; P<0.0001), with a 93% reduction in risk of progression or death. PFS consistently favored ibr over clb-G across all subgroups examined. Median treatment duration was 46.9 mo for ibr and 5.1 mo for clb-G, resulting in an AE collection period that was 9 times longer for ibr. Hospitalizations were similar for ibr vs clb-G (26% vs 28% of pts), while use of blood supportive products (16% vs 20%) or growth factors (6% vs 41%) was lower for ibr. Most common grade ≥3 adverse events (AEs) are in Table 1. During the first 6 mo, AEs led to discontinuation (DC) of ibr in 7% and DC of clb-G in 18% of pts; over the entire AE reporting period, AEs led to DC of ibr in 26%, and DC of clb-G in 18% of pts; (Table 1). With ibr, AEs leading to ibr DC in ≥2 pts were atrial fibrillation (n = 4), palpitations, pneumonia, death, and CLL (n = 2 each). With clb-G, AEs leading to DC of either clb or G in ≥2 pts were infusion-related reaction (n = 6) and neutropenia (n = 4). Exploratory analyses included 136 pts treated with single-agent ibr and 99 pts treated with ibr-G. Median follow-up was 31.3 mo for ibr-G. ORR by INV was similar with ibr vs ibr-G (91% vs 92%), but complete response (CR/CRi) was higher for ibr-G (44% vs 27%; P=0.006). Lymphocytosis occurred in 57% vs 8% of pts with ibr vs ibr-G and resolved in 95% vs 100%; median duration of lymphocytosis was 12.4 vs 3.1 weeks, respectively. Conclusions : Despite limitations of this cross-trial analysis, results suggest that PFS with single-agent ibr was superior to clb-G, including, importantly, in patients with high-risk genomic characteristics or bulky disease. In a time-matched analysis, AE profile with single-agent ibr appeared favorable to clb-G. In comparing ibr and ibr-G, lymphocytosis was more common with ibr than ibr-G but resolved in almost all pts, and ORR was similar for ibr and ibr-G. While CR rate was higher for ibr-G vs ibr, CR was not needed to achieve long-term PFS benefit with single-agent ibr. Disclosures Tedeschi: AbbVie: Consultancy; Gilead: Consultancy; Janssen: Consultancy, Speakers Bureau. Greil:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sandoz: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Honoraria, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; MSD: Honoraria, Research Funding. Demirkan:AbbVie: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding. Robak:Janssen: Consultancy, Honoraria; AbbVie, Inc: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria; Gilead: Consultancy. Moreno:AbbVie: Consultancy; Janssen: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy. Barr:AbbVie, Gilead: Consultancy. Simpson:Acerta: Research Funding; Merck: Honoraria, Research Funding; BeiGene: Research Funding; Sanofi: Research Funding; Bristol-Myers Squibb: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Novartis: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; MSD: Honoraria; Pharmacyclics LLC, an AbbVie Company: Research Funding; Roche: Honoraria, Research Funding; Abbvie: Honoraria, Research Funding; Amgen: Research Funding, TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen: Honoraria, Research Funding. Gaidano:Morphosys: Honoraria; Amgen: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Bairey:Jansen: Research Funding; AbbVie: Consultancy; ROCHE: Research Funding. Stevens:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gill:Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau. Flinn:Takeda: Research Funding; Calithera: Research Funding; Agios: Research Funding; Forma: Research Funding; Trillium: Research Funding; Infinity: Research Funding; ArQule: Research Funding; Gilead: Research Funding; TG Therapeutics: Research Funding; Incyte: Research Funding; Pharmacyclics: Research Funding; Janssen: Research Funding; Verastem: Research Funding; Genentech: Research Funding; Kite: Research Funding; Curis: Research Funding; Portola: Research Funding; Novartis: Research Funding; Verastem: Consultancy, Research Funding; Merck: Research Funding; BeiGene: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Forty Seven: Research Funding; Constellation: Research Funding; Seattle Genetics: Research Funding. Kipps:Verastem: Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; F. Hoffmann-La Roche Ltd: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech Inc: Consultancy, Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lin:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Webb:Janssen: Employment; Johnson & Johnson: Equity Ownership. Fedorov:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Styles:Pharmacyclics LLC, an AbbVie Company: Employment; AbbVie: Equity Ownership. Gribben:TG Therapeutics: Honoraria; Pharmacyclics: Honoraria; NIH: Research Funding; Novartis: Honoraria; Acerta Pharma: Honoraria, Research Funding; Abbvie: Honoraria; Kite: Honoraria; Roche: Honoraria; Unum: Equity Ownership; Wellcome Trust: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Cancer Research UK: Research Funding; Medical Research Council: Research Funding.
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Widman, Adam, Cole Khamnei, Jake Bass, et al. "33 Dynamic monitoring of response to immune checkpoint blockade through deep-learning empowered ultra-sensitive liquid biopsy in melanoma." Journal for ImmunoTherapy of Cancer 8, Suppl 3 (2020): A32—A34. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0033.
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BackgroundClearance of circulating tumor DNA (ctDNA) following checkpoint blockade (CB) can precede radiographic response,1 2 though current state of the art ctDNA detection via targeted panels faces limited sensitivity in low burden disease (figure 1). We previously showed that whole genome sequencing (WGS) of plasma can overcome low input of ctDNA to dynamically track low volume malignancy using matched tumor tissue.3 We therefore sought to evaluate ctDNA for tracking early response to checkpoint blockade (CB) in melanoma, and developed a novel classifier that allows us to track disease without matched tumor tissue for expanded applicability in immunotherapy.MethodsTo identify ctDNA sparsely diluted in noncancerous plasma cell free DNA (cfDNA), we developed Phoenix, a deep-learning classifier that uses genomic and epigenomic features to distinguish single nucleotide variants (SNVs) in melanoma from sequencing noise. We evaluated Phoenix on a retrospective cohort of serially sampled plasma from patients with advanced cutaneous melanoma on CB (nivolumab alone or with ipilimumab). Plasma was collected at 0, 3, 6 and 12 weeks after first dose of immunotherapy. ctDNA dynamics were compared to radiographic imaging results at 12 weeks.ResultsWe trained Phoenix on tumor-confirmed SNVs in plasma from a single patient with high tumor mutational burden (TMB) melanoma and cfDNA from age-matched patients without known cancer. Overall ctDNA signal-to-noise enrichment ranged from 100 - 260x in validation patients (n=2) with bulky disease. Phoenix learned key features of melanoma ctDNA including the UV mutational signature and short fragment size (figure 2), and sensitively tracked persistent low burden disease seen on imaging (figure 3). To validate these findings, we expanded our cohort (n= 15) of serially tracked tumors. In our preliminary analysis of 12 patients, Phoenix detected pretreatment ctDNA in 92% of patients at a specificity of 97% (figure 4), compared with only 17% with the benchmark in the field (iChorCNA, a plasma-based WGS liquid biopsy tool; table 1). Phoenix detected a decrease in ctDNA 3 weeks after initiation of CB in 80% of patients (figure 5) with an objective response on imaging. No change in ctDNA was seen in patients who did not respond to treatment.ConclusionsPhoenix successfully identified pretreatment melanoma ctDNA without matched tumor tissue and identified response to CB as early as 3 weeks after treatment. Our ongoing studies aim to optimize this technology for early identification of CB response in clinical practice.Abstract 33 Figure 1WGS of plasma increases sensitivity in low-burden diseaseLikelihood of ctDNA SNV detection is a function of tumor fraction, depth, and breadth (number of candidate sites). Because the limited number of genomic equivalents exhausts depth in targeted sequencing, detection sensitivity is limited by the relatively small number of sites in a clinical panel. In contrast, WGS at modest depth (35x) can detect low tumor fraction by integrating signal from thousands of SNVs across the genome.Abstract 33 Figure 2Phoenix learns key covariates for melanoma ctDNAPhoenix was trained on tumor-confirmed SNVs in plasma from patients with high burden melanoma and cfDNA from age-matched patients without known cancer. We aggregated Phoenix positive (ctDNA, blue) and negative (cfDNA, red) predictions on SNVs from a held out validation melanoma plasma sample. Phoenix ctDNA predictions correctly reflect important melanoma SNV attributes including UV-signature (C>T trinucleotide context, a), low DNase accessibility (b), late replication timing (c), and short fragment length (d).Abstract 33 Figure 3Phoenix sensitively tracks response to nivolumabPlasma samples were collected to monitor treatment response to nivolumab. Treatment monitoring by computed tomography (CT) shows response to therapy but residual disease after 3 months of therapy (a). Phoenix quantifies tumor response, matching radiographic changes, in higher temporal resolution than what is feasible with imaging (b). IchorCNA sensitivity captures initial treatment response dynamics but does not detect residual disease after 3 months of treatment (c). Log z score is calculated from a single plasma sample for each timepoint compared to a panel of control samples (n = 37).Abstract 33 Table 1Characteristics of patients at baseline and ctDNA dynamicsBaseline characteristics for preliminary validation cohort (n=12)Abstract 33 Figure 4Phoenix detects pre- and intratreatment melanoma ctDNAWe evaluated Phoenix post-filter sample-level detection rate. Phoenix detects ctDNA in 92% of pretreatment melanoma plasma samples (green, n=12) at a specificity of 97% relative to held-out noncancerous controls (blue, n=38). Phoenix detected ctDNA in 84% of postreatment plasma samples (n=38, yellow), indicating full ctDNA clearance in 7/38 samples.Abstract 33 Figure 5ctDNA response to checkpoint blockade after 3 weeksSerial plasma samples were taken from patients on checkpoint blockade (nivolumab alone or with ipilimumab). ctDNA burden was measured as detection rate among post-filter candidate SNVs and compared to a 97% specificity boundary among a panel of healthy controls. Phoenix detects a response to checkpoint blockade, measured as a decrease in ctDNA detection rate, as early as 3 weeks as shown in 3 patients (MSK-38, MSK-40, MSK 42).AcknowledgementsThanks to support from the Conquer Cancer FoundationEthics ApprovalUse of human data in this study was approved by Memorial Sloan Kettering’s IRB, Assurance Number FWA0000499ReferencesZhang Q, Luo J, et al. Prognostic and predictive impact of circulating tumor DNA in patients with advanced cancers treated with immune checkpoint blockade. Cancer Discov 2020 pp: CD-20-0047. doi:10.1158/2159-8290.CD-20-0047Bratman SV, Yang SYC., Iafolla MAJ, et al. Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab. Nat Cancer (2020). https://doi.org/10.1038/s43018-020-0096-53.Zviran A, Schulman RC, Shah M, et al. Genome-wide cell-free DNA mutational integration enables ultra-sensitive cancer monitoring. Nat Med 2020;26(7):1114–1124. doi:10.1038/s41591-020-0915-3Adalsteinsson VA, Ha G, Freeman SS, et al. Scalable whole-exome sequencing of cell-free DNA reveals high concordance with metastatic tumors. Nat Commun2017;8(1):1324. Published 2017 Nov 6. doi:10.1038/s41467-017-00965-y
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Lin, Pao, Vivek Singh, Yan Cai, et al. "Mid-infrared silicon waveguide resonators with Q∼105 by using photonic crystal cavities." MRS Proceedings 1510 (2013). http://dx.doi.org/10.1557/opl.2013.353.
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ABSTRACTOne dimensional photonic crystal 1D-PhC silicon waveguide resonators with quality factor, Q∼105, are demonstrated at mid-infrared wavelengths between 2 um to 5 um. Silicon has several advantages for mid-infrared applications including its broad mid-infrared transmission spectrum which extends out to 9 um, CMOS compatible fabrication processing, and ease of electronic-photonic integration. The proposed resonators are composed of photonic crystal cavities with optimized (i) lattice parameter a, (ii) cavity width w and (iii) hole radius r. Finite difference time domain (FDTD) simulations are used to adjust these three parameters, a, w, and r, to select a resonant frequency of interest within the mid-infrared spectral range. Due to the high quality factor Q, these PhC silicon waveguide resonators have much higher sensitivity as chemical sensors and have the potential to replace bulky instruments such as an FTIR.
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Dionne, Gerald F. "Ferrites for Tunable RF and Microwave Devices." MRS Proceedings 603 (1999). http://dx.doi.org/10.1557/proc-603-71.
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AbstractMicrowave systems for communications and radar require control of propagation of the rf signal. Devices that accomplish this function include phase shifters, isolators and circulators, and tunable filters. In many instances, these devices are magnetic and are based on the variable permeability of electrically insulating ferrimagnetic oxides (ferrites). Recent advances in microwave ferrite devices have featured superconductor circuitry that promises to virtually eliminate insertion losses due to rf surface resistance. Lower conduction losses allow the use of small lightweight microstrip configurations in place of traditional bulky waveguide structures. For operation at cryogenic temperatures ferrimagnetic spinels and garnets will require chemical alteration to realize the full potential of these devices. Challenges include the reduction of magnetocrystalline anisotropy to optimize switching energies and speeds, and the elimination of fast-relaxing impurities in the magnetic garnets that can increase magnetic losses and degrade resonator Q factors at low temperatures.
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Dionne, Gerald F., and Daniel E. Oates. "Ferrite Properties and Technology Issues for Improved Microwave Systems." MRS Proceedings 833 (2004). http://dx.doi.org/10.1557/proc-833-g4.6.
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ABSTRACTMicrowave device engineers continually seek materials advances to improve performance of magnetic components at reduced size and cost. Wherever possible, microstrip or stripline device configurations are adopted in preference to bulky waveguide structures. In radar and communications applications, the nonreciprocal propagation properties of ferrites are essential for realizing phase shifters, circulators, isolators, and power limiters. The introduction of superconductor circuits has led to the development of very low-loss phase shifters and circulators. Recent demonstrations of tuning reciprocal rf permeability by varying the state of magnetization at very low magnetic fields has led to the development of high-speed, high-Q tunable filters. In this paper, design issues of four classes of microwave device are reviewed from the standpoint of their ferrite material requirements: (1) low-loss microstrip phase shifters (2) microstrip tunable resonators, (3) self-biased microstrip circulators with normal or in-plane uniaxial anisotropy, and (4) high-power quasi-optical circulators.