Zeitschriftenartikel: „WG 168.5“

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Abisror, N., Y. Nguyen, L. Marozio, E. Esteve-Valverde, S. Udry, D. E. Pleguezuelo, P. Billoir et al. „AB0457 OBSTETRICAL OUTCOME AND TREATMENTS DURING PREGNANCY IN SERONEGATIVE PRIMARY APS: DATA FROM EUROPEAN RETROSPECTIVE STUDY“. Annals of the Rheumatic Diseases 79, Suppl 1 (Juni 2020): 1527.1–1527. http://dx.doi.org/10.1136/annrheumdis-2020-eular.3537.

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Background:Objectives:To compare clinical characteristics, pregnancies, and treatments during pregnancies of seronegative and seropositive APS, and analyse factors associated with adverse obstetrical outcomes.Methods:Inclusion criteria were: (1) thrombotic arterial and/or venous; and /or obstetrical primary clinical APS (Sydney criteria); (2) absence of conventional antiphospholipid antibodies; (3) presence of at least one non-conventional APL among IgA ACL, IgA antiB2GPI, anti-vimentin G/M, anti-annexin V G/M, anti-PE G/M, anti-PS/PT G/M antibodies. The exclusion criteria were: (1) seropositive APS with conventional APS; (2) associated SLE or SLE like (SLE features and / or positive antinuclear autoantibodies); (3) other systemic connective tissue disease (Sjogren’s syndrome, systemic sclerosis, myositis).Results:187 women (mean 33±5 years) with seronegative APS were included from 12 centers in the world and compared to 285 patients with seropositive APS. Seronegative APS have mostly obstetrical phenotypes rather than venous thrombosis in comparison to seropositive APS. The maternal and fetal outcomes and the rates of live births were not significantly different in seronegative and seropositive APS, except for higher rates of intrauterine deaths (15% vs 5%; p=0.03) and lower live birth term (36±3 vs 38±3 weeks of gestation; p=0.04) in the seropositive APS group. The cumulative incidence of adverse obstetrical events was significantly improved in treated seronegative APS vs untreated ones (log rank<0.05), whereas there was no difference between patients who received aspirin or aspirin-LMWH combinationConclusion:Patients with clinical manifestations of APS without conventional APL should undergo testing for non-criteria APL. The diagnosis of seronegative APS could be important for a better care of these patients.Table 1.Characteristics of seronegative and seropositive APS women.Seronegative APSN=187Seropositive APSN=285APS featuresThrombotic APS Arterial APS (n;%)0105 (37)* Venous APS (n;%)9 (6)154 (54)*Obstetrical APS (n;%)168 (89)89 (31)*Mix APS (n;%)8 (4)16 (6)Non criteria features (n;%)16 (9)141 (49)*Obstetrical history Miscarriages (n;%)66 (35)18 (6)* Intrauterine deaths (n;%)60 (32)46 (16)* Prematurity <34 wg (n;%)43 (23)31 (11)*Table 2.Pregnancy outcome and treatment in seronegative and seropositive APS.Seronegative APS pregnanciesN=108Seropositive APS pregnanciesN=75Thrombotic APS Arterial APS (n;%)020 (27)* Venous APS (n;%)8 (7)42 (56)*Obstetrical APS (n;%)93 (86)36 (48)*Mix APS (n;%)6 (6)18 (24)Aspirin (n;%) / Aspirin alone95 (88) / 32 (30)57 (76)* / 2 (3)*LMWH isocoagulant amounts (n;%)63 (58)39 (52)Aspirin-LMWH (n;%)65 (60)55 (73)Preeclampsia/HELLP syndrome (n;%)7 (7)12 (16)*IUGR (n;%)5 (5)7 (10)Fetal loss (n;%)33 (31)22 (29)Miscarriage / Intrauterine deaths23 (21) / 5 (5)11 (15) / 11 (15)*Prematurity<34 weeks of gestation (n;%)6 (6)9 (12)Term of fetal loss (weeks gestation)10±813±7Live births (n;%)75 (69)53 (70)Term of live birth (weeks gestation)38±336±3*Disclosure of Interests: :None declared

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Jiang, J., A. Shaker und H. Zhang. „PREFACE: TECHNICAL COMMISSION III“. ISPRS Annals of the Photogrammetry, Remote Sensing and Spatial Information Sciences V-3-2021 (17.06.2021): 7. http://dx.doi.org/10.5194/isprs-annals-v-3-2021-7-2021.

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Abstract. The work of ISPRS Technical Commission III is devoted to remote sensing. For the XXIVth ISPRS CONGRESS – 2021 Edition (Digital), Technical Commission III received total 201 submissions, including 72 full papers and 138 abstracts. Among these submissions 38 are accepted as peer-reviewed contributions for publication in the ISPRS Annals, 118 were accepted for publication in the ISPRS Archives.These papers are dedicated mostly to topics of the 10 TC III working groups and 4 inter-commission working groups as follows – WG III/1: Thematic Information Extraction; WG III/2: Microwave Remote Sensing; WG III/3: SAR-based Surface Generation and Deformation Monitoring; WG III/4: Hyperspectral Image Processing; WG III/5: Information Extraction from LiDAR Intensity Data; WG III/6: Remote Sensing Data Fusion; WG III/7: Landuse and Landcover Change Detection; WG III/8: Remote Sensing of Atmospheric Environment; WG III/9: Cryosphere and Hydrosphere; WG III/10: Agriculture and Natural Ecosystems Modelling and Monitoring; ICWG III/II: Planetary Remote Sensing and Mapping; ICWG III/Iva: Disaster Assessment, Monitoring and Management; ICWG III/IVb: Remote Sensing Data Quality; ICWG III/IVc: Environment and Health. The papers and abstracts were evaluated by the experts in the field and Working Group Chairs according to content, significance, originality, relevance, and clearness of presentation.We would like to thank the authors for their contributions, the reviewers for their reviewing, the working group officers for their efforts on calling for papers, and the organizers of the Congress for publishing this volume.

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Jiang, J., A. Shaker und H. Zhang. „PREFACE: TECHNICAL COMMISSION III“. International Archives of the Photogrammetry, Remote Sensing and Spatial Information Sciences XLIII-B3-2021 (28.06.2021): 7. http://dx.doi.org/10.5194/isprs-archives-xliii-b3-2021-7-2021.

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Abstract. The work of ISPRS Technical Commission III is devoted to remote sensing. For the XXIVth ISPRS CONGRESS – 2021 Edition (Digital), Technical Commission III received total 201 submissions, including 72 full papers and 138 abstracts. Among these submissions 38 are accepted as peer-reviewed contributions for publication in the ISPRS Annals, 118 were accepted for publication in the ISPRS Archives.These papers are dedicated mostly to topics of the 10 TC III working groups and 4 inter-commission working groups as follows – WG III/1: Thematic Information Extraction; WG III/2: Microwave Remote Sensing; WG III/3: SAR-based Surface Generation and Deformation Monitoring; WG III/4: Hyperspectral Image Processing; WG III/5: Information Extraction from LiDAR Intensity Data; WG III/6: Remote Sensing Data Fusion; WG III/7: Landuse and Landcover Change Detection; WG III/8: Remote Sensing of Atmospheric Environment; WG III/9: Cryosphere and Hydrosphere; WG III/10: Agriculture and Natural Ecosystems Modelling and Monitoring; ICWG III/II: Planetary Remote Sensing and Mapping; ICWG III/Iva: Disaster Assessment, Monitoring and Management; ICWG III/IVb: Remote Sensing Data Quality; ICWG III/IVc: Environment and Health. The papers and abstracts were evaluated by the experts in the field and Working Group Chairs according to content, significance, originality, relevance, and clearness of presentation.We would like to thank the authors for their contributions, the reviewers for their reviewing, the working group officers for their efforts on calling for papers, and the organizers of the Congress for publishing this volume.

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Peineau, Stéphane, Fabien Guimiot, Zsolt Csaba, Sandrine Jacquier, Assia Fafouri, Leslie Schwendimann, Nicolas de Roux et al. „Somatostatin Receptors Type 2 and 5 Expression and Localization During Human Pituitary Development“. Endocrinology 155, Nr. 1 (01.01.2014): 33–39. http://dx.doi.org/10.1210/en.2013-1683.

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Somatostatin (SRIF), by acting mainly through sst2 and sst5 receptors, is a potent inhibitor of hormonal secretion by the human anterior pituitary gland. However, the pattern of protein expression of these SRIF receptors remains unknown during pituitary development. To get further insights into the physiological role of SRIF receptors in human development and pituitary function, the present study examined the developmental expression of the sst2 and sst5 receptors in the individual cell types of the anterior human pituitary. Thirteen fetal human pituitaries were investigated between 13 to 38 weeks of gestation (WG) by double-labeling immunofluorescence with antibodies raised against sst2 or sst5 receptors and GH, LH, FSH, TSH, or pro-opiomelanocortin proteins. SRIF immunoreactivity in the hypothalamus and median eminence was investigated at the same developmental ages. Immunoreactivity for the sst2 receptor was evident as early as 13 to 15 WG and onward mainly in TSH-, LH-, and FSH-expressing cells, whereas sst5 immunoreactivity was apparent at the late development stages (35–38 WG). GH-expressing cells mainly expressed sst5 immunoreactivity. SRIF-positive fibers and cells were detected as soon as 13 to 16 WG in the hypothalamus and median eminence and their densities increased with gestational age. The early appearance of hypothalamic SRIF cells and fibers suggests a physiological link between SRIF and its receptors during pituitary development. Whereas sst2 receptors might play a primary role in the differentiation and regulation of TSH, LH, and FSH cells, sst5 receptors appear to be mainly involved in GH regulation from birth onward.

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Buzatu, Mihaela Alina, Gicuța Sbîrciog, Stelica Cristea und Costache Marcel. „ACTIVE INGREDIENTS COMBINATIONS FOR PATHOGENS AND PESTS CONTROL ON EGGPLANT CROPS IN THE FIELD“. Romanian journal of Horticulture 1, Nr. 1 (12.12.2020): 37–42. http://dx.doi.org/10.51258/rjh.2020.05.

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The present study aims to identify combinations of active substances for the complex control of pathogens and pests on eggplant crops in the field. The experiments were conducted between 2016 - 2017, in field conditions, using the variety of eggplant Luiza and the following experimental variants: V 1 - Acrobat MZ 69 WG 0.2% + Mospilan 20 SG 0.04%; V 2 - Acrobat MZ 69 WG 0.2% + Vertimec 1.8 EC 0.1%; V 3 - Acrobat MZ 69 WG 0.2% + Laser 240 SC 0.05%; V 4 - Melody Compact 49 WG 0.2% + Mospilan 20 SG 0.04%; V 5 - Melody Compact 49 WG 0.2% + Vertimec 1.8 EC 0.1%; V 6 - Melody Compact 49 WG 0.2% + Laser 240 SC 0.05%; V 7 - Ortiva Top 0.1% + Mospilan 20 SG 0.04%; V 8 - Ortiva Top 0.1% + Vertimec 1.8 EC 0.1%; V 9 - Ortiva Top 0.1% + Laser 240 SC 0.05%; V 10 - untreated control. The average efficacy of the treatment variants experienced in 2016 and 2017 varied between 83.2% (V4) and 85.0% (V8) depending on the combinations of products pathogens and pests control. Analyzing the yields obtained (34.6 -44.0 t / ha in 2016 and 33.5 - 43.1 t / ha in 2017), compared to the untreated control variant (30.4 t / ha in 2016 and 31.1 t / ha in 2017), it is found that the yield differences obtained in addition to the untreated control variants were in all cases, very significant.

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Putman, Charles T., Karen J. B. Martins, Maria E. Gallo, Gary D. Lopaschuk, Jean A. Pearcey, Ian M. MacLean, Ryan J. Saranchuk und Dirk Pette. „α-Catalytic subunits of 5′AMP-activated protein kinase display fiber-specific expression and are upregulated by chronic low-frequency stimulation in rat muscle“. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 293, Nr. 3 (September 2007): R1325—R1334. http://dx.doi.org/10.1152/ajpregu.00609.2006.

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5′-AMP-activated protein kinase (AMPK) signaling initiates adaptive changes in skeletal muscle fibers that restore homeostatic energy balance. The purpose of this investigation was to examine, in rats, the fiber-type protein expression patterns of the α-catalytic subunit isoforms in various skeletal muscles, and changes in their respective contents within the tibialis anterior (TA) after chronic low-frequency electrical stimulation (CLFS; 10 Hz, 10 h daily), applied for 4 ± 1.2 or 25 ± 4.8 days. Immunocytochemical staining of soleus (SOL) and medial gastrocnemius (MG) showed that 86 ± 4.1 to 97 ± 1.4% of type IIA fibers stained for both the α1- and α2-isoforms progressively decreased to 63 ± 12.2% of type IID/X and 9 ± 2.4% of IIB fibers. 39 ± 11.4% of IID/X and 83 ± 7.9% of IIB fibers expressed only the α2 isoform in the MG, much of which was localized within nuclei. α1 and α2 contents, assessed by immunoblot, were lowest in the white gastrocnemius [WG; 80% myosin heavy chain (MHC) IIb; 20% MHCIId/x]. Compared with the WG, α1 content was 1.6 ± 0.08 ( P < 0.001) and 1.8 ± 0.04 ( P < 0.0001)-fold greater in the red gastrocnemius (RG: 13%, MHCIIa) and SOL (21%, MHCIIa), respectively, and increased in proportion to MHCIIa content. Similarly, α2 content was 1.4 ± 0.10 ( P < 0.02) and 1.5 ± 0.07 ( P < 0.001)-fold greater in RG and SOL compared with WG. CLFS induced 1.43 ± 0.13 ( P < 0.007) and 1.33 ± 0.08 ( P < 0.009)-fold increases in the α1 and α2 contents of the TA and coincided with the transition of faster type IIB and IID/X fibers toward IIA fibers. These findings indicate that fiber types differ with regard to their capacity for AMPK signaling and that this potential is increased by CLFS.

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BOURGEOIS, P. Y., M. OXBORROW, M. E. TOBAR, N. BAZIN, Y. KERSALÉ und V. GIORDANO. „MASER OSCILLATION FROM ELECTRONIC SPIN RESONANCE IN A CRYOGENIC SAPPHIRE FREQUENCY STANDARD“. International Journal of Modern Physics B 20, Nr. 11n13 (20.05.2006): 1606–12. http://dx.doi.org/10.1142/s0217979206034157.

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We report the first observation of an Fe3+ maser oscillation at zero magnetic field inside a whispering gallery (WG) sapphire resonator. The described maser is new in that it operates at zero-field and with low ion concentration. At zero-field, the Fe3+ ion shows a 3-level structure related to the electron spin resonance (ESR). By applying a 31 GHz pump (|1/2〉 → |5/2〉), the ion operates as a maser at 12 GHz (|5/2〉 → |3/2〉). The maser effect is made possible by the high Q-factor (several 108) of the cryogenic whispering gallery resonator. Additionnaly, the sharp cavity resonance provides short term stability. Preliminary measurements indicate a frequency stability of parts in 10-14 (Allan deviation at 100 s), still limited by the instrument. The ultimate maser stability is still unknown.

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Amrein, Philip C., Xin Kai, Yasuyuki Iuchi, Jon Arnason, Jennifer R. Brown, Karen K. Ballen, Eyal C. Attar et al. „Inhibition of Phosphorylation of ERK in CLL Cells Pre-Treatment Correlates Best with Response to Dasatinib, Fludarabine, and Rituximab for Patients with Relapsed CLL“. Blood 124, Nr. 21 (06.12.2014): 3636. http://dx.doi.org/10.1182/blood.v124.21.3636.3636.

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Abstract Survival, proliferation, and resistance to chemotherapy in CLL cells have been consistently shown to be associated with the activity of the B-cell receptor (BCR) and the associated downstream pathways activated by it. Key molecules in this pathway are Lyn and Syk (Spleen tyrosine kinase), as well as PI3K, Btk (Bruton’s tyrosine kinase), and ERK. Dasatinib, given at standard doses, allows for serum levels well above 11 nM, the IC50 for the direct suppression of Lyn kinase and Btk. We have previously shown that dasatinib used as a single agent in patients with relapsed CLL results in lymph node responses in 60% of patients and partial responses in 20% of patients as defined by NCI-WG criteria. In the current study, patients with relapsed CLL were treated with a regimen combining dasatinib at 140 mg/day, days 1-14, with fludarabine (F) 25 mg/m2/day, days 1-3, and rituximab (R) 375 mg/m2 per cycle, repeated every 28 days, for up to 6 cycles. Patients were followed closely for response with CT scans every 2 months initially. Among the first 10 patients treated, the schedule of treatment was altered to determine signal transduction effects and resultant apoptosis of the CLL cells due to the different components of the regimen. Hence, only dasatinib was given on Day 1, only fludarabine and rituximab on Day 3, and all 3 drugs on Day 4. Blood samples were obtained from the patients before dosing and at 6 hours after treatment to measure effects on the CLL cells, which were isolated by standard Ficoll separation and frozen until the assays could be performed. For these 10 patients the median time to progression (TTP) was 21 months, and the initial clinical response was as follows: Site CR CRi PR SD PD ORR 95% CI Blood 4 2 4 0 0 100% 74%, 100% Nodes 6 1 1 1 1 80% 49%, 96% CT 2 0 2 6 0 40% 15%, 70% IWCLL 2 0 2 5 1 40% 15%, 70% Key: CR=complete response in blood = < 4,000/ul lymphocytes, CR in nodes = no nodes palpable by PE, CRi = complete response with incomplete blood recovery, PR=partial response, SD=stable disease, PD=progressive disease, ORR=overall response rate, CI=confidence interval. IWCLL = International Workshop on CLL criteria. The patterns of signal transduction in response to the various drugs at 6 hours are shown in aggregate for the patients below. The numbers represent the ratio of phosphorylated protein to total protein at the times indicated with respect to their baseline levels set as 100%. The phosphorylation sites tested were p-Lyn (Y416), p-Syk (Y352), p-ERK1/2 (T202/Y204). Phosphorylation at 6 h after indicated treatment – % of baseline ± SE (N=7): Day 1 (D) Day 3 (F+R, no D) Day 4 (D+F+R) p-Lyn/Lyn: 42% ± 3% 207% ± 63% 58% ± 13% p-Syk/Syk: 34% ± 15% 122% ± 67% 36% ± 15% p-ERK/ERK : 64% ± 22% 168% ± 40% 56% ± 22% The patterns of signal transduction for the 3 patients with the most favorable outcome (TTP and OS) were compared to that for the 4 patients with the poorest clinical outcome. The baseline ratios of phospho-ERK1/2 to ERK1/2 (pre-treatment) correlated most strongly with outcome. Those with a good outcome exhibited low basal p-ERK/ERK (mean 1.0, range 0.1 to 1.8 percent), while patients with a poor outcome exhibited high basal p-ERK/ERK (mean 22.1, range 2.2 to 65.6 percent). Conclusions: For most patients, dasatinib inhibits (directly or indirectly) phosphorylation of Lyn kinase, Syk kinase, and ERK1/2 in the first 6 hours. The degree of apoptosis (to be presented, but not shown here) resulting from this is variable and is probably affected by activation of the PI3K/Akt pathway and other pathways. The long-term clinical outcome of our patients correlated strongly with the baseline phosphorylation of ERK1/2, suggesting that future treatments of patients with CLL might benefit from targeting ERK directly, or by targeting other molecules in the MAPK pathway. Disclosures Off Label Use: Dasatinib for treatment of CLL is off-label use. We present a rationale for its use in CLL patients.. Brown:Sanofi, Onyx, Vertex, Novartis, Boehringer, GSK, Roche/Genentech, Emergent, Morphosys, Celgene, Janssen, Pharmacyclics, Gilead: Consultancy. Attar:Agios: Employment. Fathi:Seattle Genetics, Inc.: Consultancy, Research Funding; Takeda pharmaceuticals International Co.: Research Funding; Exelixis: Research Funding; Ariad: Consultancy.

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Delp, Michael D. „Myogenic and vasoconstrictor responsiveness of skeletal muscle arterioles is diminished by hindlimb unloading“. Journal of Applied Physiology 86, Nr. 4 (01.04.1999): 1178–84. http://dx.doi.org/10.1152/jappl.1999.86.4.1178.

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The purpose of the present study was to determine whether hindlimb unloading of rats alters vasoconstrictor and myogenic responsiveness of skeletal muscle arterioles. After either 2 wk of hindlimb unloading (HU) or cage control (C), second-order arterioles were isolated from the white portion of gastrocnemius (WG; C: n = 9, HU: n = 10) or soleus (Sol; C: n = 9, HU: n = 10) muscles and cannulated with two micropipettes connected to reservoir systems for in vitro study. Intraluminal pressure was set at 60 cmH2O. The arterioles were exposed to step changes in intraluminal pressure ranging from 20 to 140 cmH2O to determine myogenic responsiveness and to KCl (10–100 mM) and norepinephrine (10−9–10−4M) to determine vasoconstrictor responsiveness. Although maximal diameter of WG arterioles was not different between C (185 ± 12 μm) and HU (191 ± 14 μm) rats, WG arterioles from HU rats developed less spontaneous tone (C: 33 ± 5%, HU 20 ±3%), were unable to maintain myogenic tone at pressures from 140 to 100 cmH2O, and were less sensitive to the vasoconstrictor effects of KCl and norepinephrine (as indicated by a higher agonist concentration that produced 50% of maximal vasoconstrictor response). In contrast, maximal diameter of Sol arterioles from HU rats (117 ± 12 μm) was smaller than that in C rats (148 ± 14 μm). However, the development of spontaneous tone (C: 30 ± 4%, HU: 36 ± 5%), myogenic activity, and the responsiveness to vasoconstrictor agonists were not different between Sol arterioles from C and HU rats. These results indicate that hindlimb unloading diminishes the myogenic autoregulatory and contractile responsiveness of arterioles from muscle composed of type IIB fibers and suggest that the compromised ability to elevate vascular resistance after exposure to microgravity may be related to these vascular alterations. In addition, hindlimb unloading appears to induce vascular remodeling of arterioles from muscle composed of type I fibers, as indicated by the decrease in maximal diameter of arterioles from Sol muscle.

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Wierda, William G., Susan O'Brien, Alessandra Ferrajoli, Charles Asa Koller, Jan A. Burger, Stefan Faderl, Guillermo Garcia-Manero, Tapan Kadia, Susan Lerner und Michael J. Keating. „Pretreatment Patient Characteristics Associated with Achieving Bone Marrow Minimal Residual Disease-Free Status with Frontline Fludarabine, Cyclosphosphamide, Rituximab (FCR) Chemoimmunotherapy for CLL“,. Blood 118, Nr. 21 (18.11.2011): 3902. http://dx.doi.org/10.1182/blood.v118.21.3902.3902.

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Abstract Abstract 3902 Chemoimmunotherapy (CIT) is highly effective treatment and standard of care for patients (pts) with CLL. Response to treatment by NCI-WG/IWCLL criteria correlates with outcome; pts who achieve complete remission (CR) have superior progression-free and overall survival compared to pts who achieve partial remission (PR); and pts who fail therapy have the poorest outcome. Emerging data indicate improved outcomes for pts who achieve minimal residual disease (MRD)-free status in blood or bone marrow (BM) by end of treatment. We are conducting a clinical trial to prospectively evaluate pretreatment pt characteristics and prognostic factors and correlations with NCI-WG response, MRD-free status, and time to event outcomes with standard frontline fludarabine, cyclophosphamide, and rituximab (FCR) CIT. A total of 197 pts have been registered, 160 have completed treatment and are evaluable for response by NCI-WG criteria, and 127 have BM MRD status evaluated by standard 4-color flow cytometry at Course 3 and/or end of treatment. We report on pretreatment characteristics associated with MRD-free status at end of treatment. For the 160 pts evaluable for response by NCI-WG criteria, 63% were male; the median (range) age, β2M, and absolute lymphocyte count (ALC) were 58 yrs (38–84), 3.6 mg/l (1.3–14.1), and 78.7 K/μl (.8–394), respectively. The percent pts with Rai high-risk disease, unmutated IGHV status, ZAP70+ by immunohistochemistry (IHC) and CD38+ (30% cutoff) was 35%, 60%, 63%, and 37%, respectively. According to the hierarchical categorization, FISH demonstrated 17p del in 9%, 11q del in 18%, +12 in 17%, 13q del in 36%, and no abnormality in 20% of pts. The median number of FCR courses given was 6; 57% received all intended 6, 21% received 4–5, and 23% received ≤3. Of the 160 pts, 63% achieved CR, 12% nodular PR (nPR), 23% PR and 3% did not respond. Of 127 pts with BM evaluated by 4-color flow cytometry at end of treatment, 56% were MRD-free. Of 71 MRD-free pts, 27 were negative at end of course 3, 33 converted to negative after course 3, and 11 were negative at end of treatment but did not have a course 3 evaluation. Univariable Chi-square analyses demonstrated pretreatment β2M, IGHV mutation status, 17p del, and +12 correlated with MRD-free status at end of treatment (Table). The following did not correlate: age, Rai stage, WBC, ALC, HGB, PLT, ZAP70, CD38, or number of FCR courses received. Multivariable logistic regression model identified β2M≥4 mg/l (odds ratio=.78; p=.007) and unmutated IGHV (odds ratio=.77; p=.006) as independently associated with lower likelihood to achieve MRD-free status. In conclusion, mutated IGHV and β2M <4 mg/l are independently associated with increased likelihood of achieving MRD-free status with frontline FCR CIT; further follow up is needed to correlate MRD-free status with improved survival outcomes for patients treated on this trial.TableNCI-WG Responsen% MRD-NegativeCR8071nPR150PR3047*NR20Pretreatment Characteristicn% MRD-Negativep-valueAge (yrs) <65100600.07≥652741Rai Stage Low & Int-risk82610.12High-risk4347b2M (mg/l) <473640.02≥44942ALC (K/ml) <5040560.86≥508755IGHV Mutated47700.006Unmutated6244ZAP70 IHC Negative41610.28Positive7351CD38+ ≤7%4863Ref**8–29%27480.23≥30%42550.46FISH 13q del4556RefNone22680.32+1220800.0611q del20400.2417p del10200.04*All MRD-free are PR due to cytopenia, with no evidence of CLL**Used as reference or comparison group Disclosures: No relevant conflicts of interest to declare.

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Sukarman, Sukarman, Siti Murniasih, Rendy Gynanjar, Rina Hirnawati, Mochammad Zamroni, Lili Solichah, Nina Meilisza, Megarizka Aulia und Ratna Komala. „SAND CRAB (Emerita sp.) MEAL AS A NOVEL FEED INGREDIENT FOR KOI CARP (Cyprinus carpio)“. Indonesian Aquaculture Journal 18, Nr. 2 (19.12.2023): 155. http://dx.doi.org/10.15578/iaj.18.2.2023.155-167.

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Sand crab (Emerita sp.) is a marine biodiversity, but it has not been used as a fish feed ingredient. This study aimed to evaluate the nutritional value of sand crabs and to understand its effect when used as feed ingredient on the performance of Koi carp. The study was conducted in two steps, which is evaluation of the nutritional value of sand crab and its effect on fish performance. The proximate composition, amino acids, and fatty acids were measured using AOAC methods, and then the carotenoid content was determined by spectrophotometry. In the second step, the sand crab was added to fish feed at doses of 0, 5, 10, and 15 percent, and fed to koi fish for 42 days. The parameters observed were length gain (LG), weight gain (WG), and feed efficiency (FE). Nutritional data were analyzed by description and compared with fish feed ingredients from previous studies. Fish performance were analyzed by one-way ANOVA. When significant, Tukey’s significant mean test was applied. The result showed that the nutritional value of sand crab was comparable to other feed ingredients with a protein content of 37.88%, while carotenoid content was superior. The best performance of Koi carp was obtained with a dose of 15% sand crab in the diet, with LG, WG, and FE values of 0.93 ± 0.05 cm, 0.48 ± 0.06 g, and 63.50 ± 7.05 %, respectively. Based on this result, it can be concluded that sand crab has a high nutritional value and can be used up to 15% in Koi carp diet.

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Hoque, MZ, AM Akanda, MIH Miah, MKA Bhuiyan, MG Miah und F. Begum. „In vitro screening of fungicides and tannins against fungal pathogens of jujube fruits“. Progressive Agriculture 27, Nr. 2 (17.08.2016): 154–61. http://dx.doi.org/10.3329/pa.v27i2.29325.

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The aim of this study to identify the effective fungicides for controlling major leaf and fruit diseases of Jujube caused by different fungal pathogens. An in vitro experiment was undertaken to screen ten fungicides and two Tannins against six important fungal pathogens of Jujube fruits which were Alternaria alternata, Colletotrichum gloeosporioides, Curvularia lunata, Lasiodiplodia theobromae, Fusarium semitectum and Pestalotiopsis palmarum. Fungicides were Conza 5 EC (Hexaconazole), Folicur 250 EC (Tebuconazole) and Potent 250 EC (Propiconazole), Bavistin DF (Carbendazim), Kasumin 2% liquid (Kasugamycin), Rovral 50 WP (Iprodine), Matco 72 WP (Mancozeb 64% + Metalaxyl 8%), Geneb 80 WP (Mancozeb), Emivit 50 WP (Copper oxychloride) and Evavit 80 WG (Sulphur 80 WG). And two tannins were Chestnut Tannin and Quabracho Tannin. Plain water was used as control. Poison food technique was followed to conduct the experiment. Both Tannins did not show satisfactory inhibition of mycelial growth of any of the six fungal pathogens. The effectiveness of fungicides varied greatly with fungal species. The most effective fungicides were Folicur 250 EC followed by Potent 250 EC, Rovral 50 WP, Conza 5 WP and Bavistin DF. Folicur 250 EC caused 89.52% inhibition of mycelium growth of A. alternata and 100% growth inhibition in other five fungi. In addition, Potent 250 EC inhibited growth of L. theobromae, C. lunata, F. semitectum and P. palmarum by 100% and that of C. gloeosporioides by 91.79%. Complete growth inhibition of F. semitectum and P. palmarum was achieved with Bavistin DF. Furthermore, Conza 5 EC caused 100% growth inhibition in C. lunata and more than 90% in L. theobromae and F. semitectum.Progressive Agriculture 27 (2): 154-161, 2016

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Diana, Thiago Ferreira, Luiz Fernando Teixeira Albino, Horácio Santiago Rostagno, Bruno Figueiredo de Almeida, Maurílio de Lucas Xavier Júnior, Pedro Eleutério Aleixo, Samuel Oliveira Borges und Arele Arlindo Calderano. „Xylanase and β-glucanase in maize- and soybean meal-based diets for broilers“. Semina: Ciências Agrárias 41, Nr. 6supl2 (06.11.2020): 3259–74. http://dx.doi.org/10.5433/1679-0359.2020v41n6supl2p3259.

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The objective of this study was to evaluate the effect of adding different xylanase and ?-glucanase enzyme blends to maize- and soybean meal-based diets on performance and energy metabolizability in broilers. Two experiments were carried out with broilers of the COBB 500 strain. In the first experiment, 1960 chicks were assigned to a completely randomized design with a 2 × 3 + 1 factorial arrangement, totaling seven treatments, namely, T1- Positive control (PC); T2 - Negative control 1 (NC1; PC minus 200 kcal kg-1 ME); T3 - NC1 + Blend A; T4 - NC1 + Blend B; T5 - Negative control 2 (NC2; PC minus 167 kcal kg-1 ME and 5% amino acids); T6 - NC2 + Blend A; and T7 - NC2 + Blend B. Fourteen replicates were used per treatment and 20 birds per experimental unit. The parameters evaluated at 21 and 42 days of age were weight gain (WG), feed intake (FI) and feed conversion (FC). At 42 days, production efficiency index (PEI), viability and the yields of cuts were also calculated. Birds that received diets with a reduced nutritional value showed a reduction in WG and PEI and worsened FC as compared those of PC treatment (p < 0.05). However, the birds that consumed the NC2 diet with Blend B exhibited a similar WG to those in PC group (p > 0.05) from 1 to 21 days of life. For the yield of thigh + drumstick, the factors were statistically similar (p > 0.05) to those observed in the PC birds. In the second experiment, 432 fourteen-day-old chicks were distributed in a completely randomized design with seven treatments, with eight replicates per treatment and six birds per experimental unit. The apparent metabolizable energy (AME) and nitrogen-corrected AME (AMEn) values were determined. Overall, the NC2 diet with Blend B provided the highest AME and AMEn values; however, NC1 with the same enzyme blend was the treatment which provided the lowest values. The addition of xylanase and ?-glucanase enzyme blends to maize- and soybean meal-based diets improves WG at 21 days as well as PEI in broilers; however, it does not influence the yield of cuts. Enzymes (Blend B) improve the energy metabolization of broiler diets with reduced energy and amino acid levels.

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Jansson, R. K., S. H. Lecrone und R. Lance. „Management of Lepidopterous Pests on Cabbage, 1991“. Insecticide and Acaricide Tests 18, Nr. 1 (01.01.1993): 104–5. http://dx.doi.org/10.1093/iat/18.1.104.

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Abstract ‘Rio Verde’ cabbage seeds were incorporated into a germination mix (Pro-Mix) and direct seeded into a Rockdale soil at the University of Florida’s Tropical Research and Education Center on 13 Feb 1991. The soil was fumigated with Terr-O-Gas (75% methyl bromide, 25% chloropicrin; 246 kg/ha) and covered with white on black plastic mulch on 6 Feb. Plants were spaced 0.3 m apart within rows and 0.76 m apart between rows on 1.8 m-center beds. Fertilizer (1680 kg/ha of granular 6:12:12) was applied and incorporated into the soil on 5 Feb. Goal 2 EC was applied (0.56 kg (AI)/ha) between the beds on 15 Feb for weed control. Plants were irrigated 4 h/day using a turbo T-tape drip irrigation system (model 40) which delivered 5.0 liters of water/m of dripline/h. All treatments, with the exception of the chemical insecticide standard, Phosdrin (0.56 Kg (AI)/ha), in combination with Cutlass WP (1.1 kg/ha), were biological insecticides consisting of Bacillus thuringienis var. kurstaki. X-77R (0.3 ml/liter) was added to three of the treatments, Cutlass WP (2.2 kg/ha), Javelin WG (1.1 kg/ha) and Phosdrin EC (0.56 kg (AI)/ha) in combination with Cutlass WP (1.1 kg/ha). Treatments were replicated 4 times in a randomized complete block design. Treatment plots were 4 rows (2 beds) by 12.2 m long. A 3.0-m long section of nontreated plants separated replicates.

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Scarpellini, J. R. „SELETIVIDADE FISIOLÓGICA DE AFICIDAS SOBRE JOANINHA CYCLONEDA SANGUINEA (LINNAEUS, 1763) (COLEOPTERA, COCCINELLIDAE) EM ALGODOEIRO“. Arquivos do Instituto Biológico 75, Nr. 2 (Juni 2008): 195–202. http://dx.doi.org/10.1590/1808-1657v75p1952008.

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RESUMO Com o objetivo de verificar o efeito do tiametoxam, diafentiuron e pimetrozina sobre a joaninha Cycloneda sanguinea e sua presa Aphis gossypii em algodoeiro cultivar Deltaopal foi realizado este estudo, em Ribeirão Preto, SP. Foram testados os seguintes tratamentos (g i.a./ha): Tiametoxan 250 WG (50,0); Pimetrozina 500 PM (100); Diafentiuron 500 SC (250); Tiametoxan 250 WG mais Pimetrozina 500 PM (42,5 + 75); Carbosulfano (160); Imidacloprido 200 SC (50) e testemunha. Foram amostradas 25 plantas inteiras por parcela, avaliando-se o número de pulgões. O estudo de seletividade constou de aplicação sobre as joaninhas e plantas com pulgões; aplicação em plantas com pulgões e colocação das joaninhas nas gaiolas (15 x 30 cm), trabalhando com amostras de cinco insetos adultos, além de ensacamento (filós) de 4 plantas por parcela com cinco joaninhas antes da aplicação bem como após a aplicação, no experimento de campo. Avaliou-se a sobrevivência até aos 5 dias após a aplicação ou exposição ao tratamento. No campo, verificouse bom controle do pulgão, não diferindo os tratamentos entre sí, mas todos diferiram da testemunha, enquanto, para joaninha, todos os tratamentos não diferiram entre sí no primeiro dia após a aplicação, tanto sob aplicação direta, quanto exposição indireta. Nos dias subseqüentes ocorreu muito mais mortalidade que no mesmo tipo de experimento em laboratório, quando o tiametoxam, pimetrozina e diafentiuron mostraram menor efeito sobre estes predadores, em relação ao padrão carbosulfano.

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Skinner Taylor, C. M., G. A. López-Uriarte, L. Pérez Barbosa, E. Barriga-Maldonado, I. Perez-Onofre, A. Elizondo-Plazas und D. Á. Galarza-Delgado. „AB0002 CONGENITAL DEFECTS IN A COHORT OF PREGNANT WOMEN FROM A CLINIC OF RHEUMATIC DISEASES AND PREGNANCY“. Annals of the Rheumatic Diseases 79, Suppl 1 (Juni 2020): 1305.2–1305. http://dx.doi.org/10.1136/annrheumdis-2020-eular.4537.

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Background:Some studies have suggested an increased risk of adverse health outcomes for the child of patients with Rheumatic Diseases (RD), including neurodevelopmental disorders, congenital heart defects, hematological malignancies and autoimmune diseases. It is well known that 2 to 3% of live births have a congenital defect. About 7 % of all newborn deaths are due to birth defects.Objectives:Describe Genetical Evaluation in a cohort of pregnant patients with RDMethods:We included 22 women from February to December 2019 from a Clinic of Pregnancy and Rheumatic Diseases in Hospital Universitario in Monterrey, Mexico. All spontaneous pregnancies (21 singletons, 1 double twin), with adequate prenatal control. Ten Rheumatoid Arthritis, Antiphospholipid Syndrome in 4 cases; 5 Systemic Lupus Erythematosus, 2 Sjögren’s Syndrome and a case of Dermatomyositis. In the perinatal genetics approach, medical and familial history was obtained, and pedigree was developed; ultrasound information of 12 and 22 weeks of gestation was integrated, risks for aneuploidies were adjusted according to maternal age. At birth, the dysmorphological description was made, somatometry is performed, and the newborn screening were evaluated (metabolic, hearing, cardiac). Thus, giving genetic counseling for each case.Results:Two patients were excluded, so 20 women with follow-up, 12 (60%) were born without complications or birth defects; in 3(15%) there were adverse events (a spontaneous abortion at 12 weeks-of-gestation [wg]; a fetal death in the case of twin pregnancy, at 34.1 wg, with facial asymmetry, intrauterine growth restriction; and a premature delivery, at 36.5 wg; no defects; there were 5(25%) congenital defects: a preauricular appendix, with normal renal ultrasound. A congenital heart disease (transposition of large vessels, tricuspid stenosis). A case of macrosomia (diabetic fetopathy); a heart block with perinatal pacemaker placement (mom with lupus). And in the latter case, Krabbe disease, even without confirming it. Table 1.Table 1.Maternal diagnosisEffects on fetus/neonateN (%)Congenital Defects5 (25%)Antiphospholipid syndromeCongenital Heart DiseaseLupus erythematosus systemicHeart Block with Perinatal Pacemaker PlacementRheumatoid arthritisKrabbe DiseaseRheumatoid arthritisPreauricular appendixSjögren DiseaseDiabetic FetopathyAdverse events3 (15%)Rheumatoid arthritisSpontaneous AbortionAntiphospholipid syndromeFetal deathRheumatoid arthritisPremature deliveryConclusion:One out of every 4 pregnancies of women with rheumatic diseases presented a congenital defect, of which, the heart diseases (CHD) have been described as of greater presentation in these groups.It is very important that women with rheumatic diseases are well attached to a comprehensive clinic in which, in addition to receiving proper attention of their rheumatic disease, they have adequate preconception and prenatal control of their pregnancies, since there is a greater risk of congenital alterations and of perinatal adverse events, as shown by this cohort. Further research is needed to fully elucidate the potential disease-related factors that might lead to the increased risk of adverse health outcomes in offspring, as well as to improve the monitoring and control of their rheumatic diseases.References:[1]Soh, MC; Nelson-Piercy, C. (2015). Highrisk Pregnancy and the Rheumatologist.Rheumatology, 54(4):572587.[2]Sanchez-Manubens, J.et al.(2013). Recién nacidos de madre con enfermedad autoinmunitaria. Experiencia en un hospital comarcal.Reumatol Clin. 9(3):161–165. 2012.08.002.[3]Vinet, E., Bernatsky, S. (2017). Outcomes in Children Born to Women with Rheumatic Diseases. Rheum Dis Clin N Am.Disclosure of Interests:None declared

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Lee, Yueh-Sheng, Kuo-Lung Ku, Chi-Shih Chu und Kuo-Lung Chen. „The Optimal Supplementation of Fermented Product Produced by Bacillus subtilis Strain LYS1 with High Surfactin Yield for Improving Growth Performance, Intestinal Villi Morphology, and Tibial Bone Strength in Broilers“. Animals 14, Nr. 14 (16.07.2024): 2079. http://dx.doi.org/10.3390/ani14142079.

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This study aimed to investigate the physiochemical characterizations of the fermented product (FP) produced by the high-yield surfactin strain Bacillus subtilis LYS1 (LYS1), as well as its effects on growth performance, carcass traits, intestinal morphology, tibial bone characteristics, and clinical blood biochemistry in broilers. Accordingly, the optimal supplementation of FP for improving growth performance, intestinal villi development, and tibial bone strength in broilers was elucidated using a broken-line quadratic (BLQ) ascending model. Three hundred and sixty 0-day-old Ross 308 broiler chicks, with equal numbers of both sexes, were randomly assigned to dietary supplementation of 2.5% fish meal or 0, 1, 1.5, 2, or 2.5% FP. Each treatment had six replicates, and the experimental period was 5 wk. The LYS1 count, surfactin content, and surfactin composition of the FP were 9.1 log CFU/g, 11.23 mg/g, and C12 to C18, respectively. The FP-supplemented groups improved feed intake, weight gain (WG), and production efficiency factor at 0 to 5 weeks old (p < 0.05) compared with the 0% group. The villus height/crypt depth (V/C) in the jejunum and ileum of the FP-supplemented groups was higher than in the 0% group (p < 0.05). The tibiotarsal index, Ca, and P in the tibia showed a linear effect with increased FP supplementation (p < 0.05). Moreover, the tibiotarsus weight/length index (TWLI) showed a quadratic effect with increased FP supplementation (p < 0.05). The optimal supplementation of FP for WG, V/C in the jejunum and ileum, and TWLI was 1.8, 1.9, and 1.6%, respectively. In conclusion, dietary supplementation with 1 to 2.5% LYS1 FP in broilers can improve their growth performance and the development of intestinal villi. Moreover, 1.9% is the optimal supplementation of LYS1 FP in the diet, based on the fitting results obtained with the BLQ model.

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Ingle, Y. V., K. A. Lengare, P. R. Damre und K. T. Lahariya. „Chemical Fungicides and Antagonists as Potential Treatments for Ganoderma lucidum-Associated Basal Stem Rot in Mandarin Trees“. Journal of Advances in Biology & Biotechnology 27, Nr. 7 (25.06.2024): 988–96. http://dx.doi.org/10.9734/jabb/2024/v27i71059.

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Ganoderma lucidum causes basal stem rot disease in mandarin trees, resulting in a variety of symptoms including dieback, foliage discoloration, an unhealthy appearance and eventual tree declines or death. Prior to field application, it is imperative to assess the efficacy of newer molecules and possible potential antagonists through In vitro testing. In this study, ten chemical fungicides and four antagonists were evaluated for their effectiveness against G. lucidum using the poison food method and dual culture technique, respectively. Among the chemical fungicides tested, Copper oxychloride 50% WP (@3g/l), Fluxapyroxad 167 G/L + Pyraclostrobin 333 G/L SC (@0.6 g/l), and Metiram 55% + Pyroclostribin 5% WG (@1g/l) demonstrated the highest effectiveness, entirely suppressing (100%) pathogen growth. In the dual culture technique, the fungal antagonists Trichoderma harzianum (79.63%) and Trichoderma asperellum (77.57%) exhibited superior effectiveness compared to Pseudomonas fluorescence and Bacillus subtilis against G. lucidum. These findings highlight the efficacy of chemical fungicides and antagonists in treating G. lucidum-induced basal stem rot in mandarin trees.

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N T, DILEEP KUMAR, und BIRADAR A P. „Bio-efficacy of bio-rationals against citrus leaf miner (Phyllocnistis citrella) in acid lime (Citrus aurantiifolia)“. Indian Journal of Agricultural Sciences 94, Nr. 5 (15.05.2024): 545–51. http://dx.doi.org/10.56093/ijas.v94i5.132715.

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The field experiment was conducted during winter (rabi) 2020–21 and rainy (kharif) season of 2021–22 at College of Agriculture (University of Agricultural Sciences, Dharwad), Vijayapura, Karnataka to evaluate efficacy of bio-rationals against citrus leaf miner (Phyllocnistis citrella Stainton). The experiment was conducted in a randomized block design (RBD) with 8 treatments, viz. bio digester solution (10%); pongamia leaf extract (5%); Prosopis juliflora leaf extract (5%); Beauveria bassiana (2 × 108 conidia/g) (1 kg/ha); Bacillus thuringiensis 8 L (1 L/ha); neem-based insecticide (10000 ppm) (1.5 L/ha); thiamethoxam 25 wg (125 ml/ha) (standard check); and untreated control (water spray), replicated thrice. Among the selected bio-rationals, two application of neem (Azadirachta indica)-based insecticide recorded significantly lesser number of live mines/shoot followed by bio-digester solution (10%) and these treatments were found superior in controlling citrus leaf miner on acid lime [Citrus aurantiifolia (Christm.) Swingle]. The pongamia leaf extract, Bacillus thuringiensis 8 L and Beauveria bassiana were proved to be moderately affective against this pest. The bio-rationals found effective can be used in integrated management of citrus leaf miner on acid lime.

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Kipps, T. J., A. Österborg, J. Mayer, S. Stilgenbauer, A. Hellmann, C. D. Williams, R. Furman, G. Chan, C. Russell und W. G. Wierda. „Clinical improvement with a novel CD20 mAb, ofatumumab, in fludarabine-refractory chronic lymphocytic leukemia (CLL) also refractory to alemtuzumab or with bulky lymphadenopathy“. Journal of Clinical Oncology 27, Nr. 15_suppl (20.05.2009): 7043. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.7043.

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7043 Background: Patients (pts) with CLL refractory tofludarabine and alemtuzumab (double-refractory, DR) or refractory to fludarabine with bulky (>5 cm) lymphadenopathy (bulky fludarabine-refractory, BFR) have a poor prognosis. Ofatumumab is a human mAb specific for a distinctive small-loop epitope of CD20 that appears more potent than rituximab in eliciting complement-dependent lysis of B cells in vitro. We report, for the first time, results from the planned interim analysis of the clinical benefit observed in pts with DR or BFR CLL treated with ofatumumab in an international pivotal clinical study. Methods: Pts with DR or BFR CLL received 8 weekly then 4 monthly ofatumumab infusions (Dose 1, 300 mg; Doses 2–12, 2,000 mg). Primary endpoint was overall response rate (ORR; 1996 NCI-WG criteria), as assessed by an Independent Review Committee, over 24 wks. Results: Of 138 treated pts (DR: N = 59; BFR: N = 79; median age 64 and 62 yrs, respectively), 63% had Rai stage III/IV disease at screening. Pts had a median of 5 prior therapies. ORR (99% CI) was 58% (40, 74%) in the DR and 47% (32, 62%) in the BFR groups, and median overall survival (95% CI) was 13.7 mo (9.4, NR) and 15.4 mo (10.2, 20.2), respectively. Resolution of disease symptoms (maintained for ≥2 mo) were observed in a large proportion of pts (Table), including in pts considered nonresponders by NCI-WG criteria. Improvements in hematologic values were also observed in some pts with abnormal baseline values, particularly for platelet counts. Pts with thrombocytopenia at baseline (n = 73) experienced sustained increases in median platelet counts from 65 × 109/L to over 100 × 109/L by Wk 8; a similar pattern of rapid improvement was observed in Hgb values. Conclusions: Ofatumumab as single-agent achieves high ORR, and improves disease symptoms and hematologic parameters in heavily pretreated pts with DR and BFR disease who lack standard treatment options. [Table: see text] [Table: see text]

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Davis, Andrew A., Wade Thomas Iams, David Chan, Michael S. Oh, Robert William Lentz, Rohith Srivas, Nicole Lambert et al. „A prospective study tracking longitudinal changes in genome-wide cell-free DNA (cfDNA) methylation to identify early nonresponders to cancer treatment.“ Journal of Clinical Oncology 37, Nr. 15_suppl (20.05.2019): 3042. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.3042.

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3042 Background: Methylation is an epigenetic modification linked to cancer pathogenesis. The aim was to determine if changes in cfDNA methylation patterns before and after initiation of treatment could predict non-response to treatment prior to routine imaging and clinical follow-up. Methods: We prospectively collected clinical data and blood from 28 patients with metastatic malignancies (13 lung, 11 breast, 4 other). Blood was drawn prior to start of a new treatment, after first cycle (median 30 days), and/or second cycle (median 57 days). We performed whole-genome (WG) bisulfite sequencing (median depth 18X) on plasma cfDNA to determine methylation levels. By tracking how methylation levels deviate from unaffected individuals, from baseline to subsequent timepoints, we classified patients as either progressors (greater deviance) or non-progressors. Treatment response at first follow-up imaging (FUI) was determined by RECIST 1.1. Study endpoints were agreement with first FUI and progression-free survival (PFS) by cfDNA classification. Results: The cohort consisted of 68% females and the median age was 70. Main treatment regimens were chemo- (N = 12), immuno- (6), endocrine (5), or targeted-therapy (5). PFS was significantly shorter (log-rank p = 8 x 10-7) in patients classified as progressors by cfDNA (N = 8; median: 62 days) compared to non-progressors (N = 20, median: 263 days). For patients classified as progressors, the cfDNA assay preceded imaging and clinical evaluation by a median of 34 days. 7 out of 8 patients classified as cfDNA progressors were later confirmed to progress at first follow-up evaluation (88% positive predictive value). The one patient who was classified as progressor based on cfDNA was stable based on FUI (day 93 of treatment) but was later confirmed as progression on day 128 by FUI. For the remaining patients, 18 of 20 did not progress (90% negative predictive value). Thus, sensitivity for the assay for identifying progression was 78% and specificity was 95%. Conclusions: Our results show that WG cfDNA methylation change is a novel signature with potential to identify patients whose treatment regimen is ineffective prior to imaging.

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Śmierzchalski-Wachocz, Dariusz. „The clergy of the Gorzow (Gorzów) Church repressed under the penal-administrative procedure. A historical analysis on the example of the Statement of Office “C” of the Ministry of the Interior from the years 1945–1963. Outline of the issues“. Studia Koszalińsko-Kołobrzeskie 31 (2024): 193–224. https://doi.org/10.18276/skk.2024.31-11.

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Po II wojnie światowej komunistyczny aparat bezpieczeństwa szantażował, prześladował i mordował księży stawiających opór wobec ekipy rządowej. W każdym procesie politycznym przeciw obywatelom Polski na ławie oskarżonych zasiadał jakiś ksiądz lub inny duchowny. Oprócz zarzutów podżegania do wojny modne były oskarżenia o deprawacje moralne młodzieży i dzieci, o defraudację, o próby obalenia ustroju, o szpiegostwo na rzecz obcego wywiadu itp. W zasobie Biura Udostępniania i Archiwizacji Dokumentów Oddziału Instytutu Pamięci Narodowej w Warszawie przechowywany jest zbiór dokumentów liczący 37 kart maszynopisu o tytule: Zestawienie faktów i przejawów wrogiej działalności dokonanych przez osoby duchowne Kościoła rzymsko-katolickiego na terenie diecezji gorzowskiej w okresie lat 1945–1963. Strona tytułowa zbioru wskazuje, że został on wytworzony w Biurze „C” Ministerstwa Spraw Wewnętrznych z zachowaniem klauzury „tajne”. Został on odtajniony decyzją Szefa Urzędu Ochrony Państwa z dnia 5 października 1999 roku i przekazany do zasobu Oddziału IPN w Warszawie, z chwilą powstania tej instytucji, gdzie nadano mu sygnaturę: IPN BU 0397/468, t. 4. Na potrzeby kwerendy archiwalnej prowadzonej w siedzibie Biura Udostępniania i Archiwizacji Dokumentów Oddziału IPN w Szczecinie w ramach realizowanego projektu badawczego zostały wykonane 25 czerwca 2009 roku kopie tych dokumentów i trafiły w posiadanie autora. Na podstawie tego zbioru archiwalnego została dokonana analiza historyczna wg charakteru przestępstw dotyczących wrogiej działalności kleru Kościoła Rzymskokatolickiego w ujęciu terminologii prawnej i propagandowej z okresu PRL. Były to klasyfikacje przestępstw: działalność związana z podziemiem, szpiegostwo, nielegalne posiadanie broni, wroga propaganda (m.in.: przeciwko patriotom i organizacjom politycznym, przeciwko zasadom ustrojowym PRL, przeciwko polityce państwo wobec Kościoła i inne) oraz wystąpienia przeciwko ustawodawstwu PRL (tj. dekret o wolności sumienia i wyznania, ustawa o zgromadzeniach, ustawa o dopuszczalności przerywania ciąży, świeckość szkoły, przepisy i zarządzenia finansowe, przepisy o budownictwie, kolportaż bez debitu i inne). Wg zawartych tam danych ogółem wrogo wystąpiło przeciwko władzy 162 księży, odnotowanych faktów wrogich wystąpień duchowieństwa 215.

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Moreno, Carol, Neus Villamor, Jordi Esteve, Dolors Colomer, Francesc Bosch, Elias Campo und Emili Montserrat. „Clinical Significance of Minimal Residual Disease (MRD), as Assessed by Different Techniques, after Stem Cell Transplantation (SCT) for Chronic Lymphocytic Leukemia (CLL).“ Blood 106, Nr. 11 (16.11.2005): 2018. http://dx.doi.org/10.1182/blood.v106.11.2018.2018.

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Abstract MRD detection has been associated with a higher relapse risk in patients with CLL having achieved complete response (CR) by conventional NCI-WG criteria. Although there are a number of techniques to evaluate MRD, their respective clinical value is still controversial. Against this background, we analyzed MRD, as assessed by consensus PCR, real time quantitative PCR (qPCR), and flow cytometry, in peripheral blood (PB) and/or bone marrow (BM) in 40 patients with CLL submitted to SCT (25 autologous and 15 allogeneic). Patients were considered MRD positive if a monoclonal pattern was obtained by consensus PCR, qPCR MRD levels were ≥ 10−5 or flow cytometry MRD levels were ≥ 10−4. 97.4%, 89% and 100% of the patients could be studied by consensus PCR, qPCR, and flow cytometry, respectively. One hundred sixty-four of 248 samples were MRD negative by consensus PCR. Among those, CLL cells were detected by qPCR and by flow cytometry in 47% (77/164) and 23% (39/164) of the cases, respectively, whereas all 84 PCR positive samples had detectable CLL cells by qPCR and flow cytometry. A good correlation was seen between MRD levels detected by flow cytometry and by qPCR (n: 254, r: 0.826; p<0.001). Also, a good relationship between MRD in PB and BM was observed, although in 10% (3/28) cases PB and BM results were not concordant. After a median follow-up of 47.3 months (range: 14–107), 15/25 autografted patients have relapsed, with increasing levels of MRD being observed before clinical relapse in all of them. Of note, MRD detected as soon as 3–6 months post-transplantation identified patients with a higher relapse risk, all techniques being similarly useful to that purpose, although consensus PCR had inferior predictive value. In contrast, MRD-negativity identified a small group of autografted patients (n=5) who have not relapsed yet. In allografted patients, MRD status assessed at different time points did not correlate with outcome. After a median follow up of 71 months (range: 6–163), only 2/15 patients have relapsed. Conversion from MRD-positive to MRD-negative status was observed in 5 patients within the first two years post-allotransplantation Moreover, 5 patients with persistent detectable MRD after allotransplantation remain in clinical CR at 6, 48, 60, 72 and 84 months after transplant. To summarize, in this series of patients with CLL submitted to SCT, quantitative methods to detect MRD (flow cytometry and qPCR) were more accurate than consensus PCR to predict clinical evolution. Importantly, detection of MRD within the first six months after autologous transplantation allowed to identify patients with a high relapse risk. On the contrary, MRD detection after allotransplantation had no clinical value, most likely because of the graft-vs.-CLL effect. Finally, these results might be useful to design treatment strategies aimed at exploring the potential benefits of treating autografted patients with persistent (MRD-positive) disease, before overt clinical relapse occurs.

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J.O, Alagbe,, Oluwafemi R.A und Halima Abdullahi. „Effect of Dietary Inclusion of Ginger and Garlic Oil Mixture on the Growth Performance and Caecal Microbial Population of Broiler Chickens“. International Journal of Clinical Case Reports and Reviews 8, Nr. 5 (29.10.2021): 01–05. http://dx.doi.org/10.31579/2690-4861/161.

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The objective of the present study was to determine effect of dietary inclusion of (Zingiber officinale) and garlic (Allium sativum) oil mixture (GIGM) on the growth performance and caecal microbial population of broiler chickens. One hundred and fifty one-day-old broiler chicks (Ross 308) were randomly allocated into 5 treatments with three replicates consisting of 10 birds each in a completely randomized design. Birds in treatment 1 (T1) was fed basal diet with 0 % inclusion of GIGM while T2, T3, T4 and T5 were given 0.1 %, 0.2 %, 0.3 % and 0.4 % respectively. Clean feed and water were offered ad libitum and all other management practices were strictly observed throughout the experiment which lasted for 56 days. Results obtained were used to determine weight gain (WG), average daily weight gain (ADWG), total feed intake (TFI), average daily feed intake (ADFI), feed conversion ratio (FCR) and microbial population of E.coli, Salmonella spp and Lactobacillus spp. ADWG, ADFI and FCR were significantly (P ˂ 0.05) influenced by the dietary inclusion of GIGM. ADWG were highest in T5 (47.80 g), T4 (45.75 g) and T3 (45.09 g), intermediate in T2 (39.59 g) and lowest in T1 (30.72 g). Lactobacillus spp increased as the level of dietary inclusion of GIGM increases (P ˂ 0.05). E.coli and Salmonella spp counts were significantly (P ˂ 0.05) different among the treatments. It was concluded that GIGM could be included in the diet of broilers up to 0.4 % without causing any deleterious effect on the performance and health of birds.

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GUEVARA-GONZÁLEZ, J. A., R. MOUHBI, J. M. ARROYO, M. R. ALVIR und J. GONZÁLEZ. „Effects of correcting for microbial contamination and the use of sodium sulphite in neutral detergent fibre analyses on the ruminal fibre degradability of several feeds“. Journal of Agricultural Science 153, Nr. 2 (06.06.2014): 361–70. http://dx.doi.org/10.1017/s0021859614000513.

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SUMMARYSodium sulphite is used in an optional way to remove insoluble proteins from neutral detergent fibre (NDF) residue. To determine whether the recovery of both NDF and insoluble nitrogen (N) in NDF solution (NDIN) are altered by its use, both parameters were measured in a set of 12 feeds, including cereal grains: maize (MG), rye (RG) and wheat (WG); cereal co-products: maize gluten feed (MGF), distilled dried grains from barley (DDGB) and wheat (DDGW) and wheat bran (WB); protein concentrates: rapeseed meal (RSM) and expeller palm kernel (EPK); dehydrated sugar beet pulp (DBP) and oat (OH) and ryegrass (RGH) hays. Associated effects on thein situeffective degradability (ED) of both NDF and NDIN were also studied in DDGW, WB, RSM, EPK, DBP, OH and RGH. Also, ED of acid detergent fibre (ADF) and its N (ADIN) were studied in hays. Errors due to microbial contamination in the rumen on the ED of NDF, ADF, NDIN and ADIN were also established in these last seven samples using15N infusion methods. Three rumen and duodenum cannulated wethers were used in the study. The sulphite use in NDF solution led to reductions (DDGB, DDGW, RSM and OH) and increases (RG, WG, WB and DBP) of the NDIN proportion, as well as the contribution of crude protein to NDF. These variations were associated with irregular effects on NDF residues and on ED of both NDIN and NDF. As a consequence, sulphite use does not assure the reduction of the insoluble protein contamination and it may even increase it. This methodology may also alter the degradability estimates of NDIN or NDF. Mean ruminal microbial contamination in NDF was 7·0, 10·8, 13·3, 5·4, 12·0, 35·3 and 20·0 g/kg in WB, DDGW, RSM, EPK, DBP, OH and RGH, respectively. The associated contents of microbial N in NDIN were: 59·3, 29·9, 26·2, 19·8, 37·3, 441 and 150 g/kg, respectively. Microbial contamination in ADF and ADIN (g/kg) was 3·6 and 94·5 in OH and 1·7 and 41·2 in RGH. Not correcting this contamination led to consistent undervaluations of ED of NDIN and NDF in all tested feeds, although errors only reached significance for NDIN in hays and DBP. Microbial-corrected ED of NDIN was 0·685, 0·826, 0·481, 0·389, 0·166, 0·718 and 0·425 in WB, DDGW, RSM, EPK, DBP, OH and RGH, respectively, whereas values for ADIN were 0·504 (OH) and 0·469 (RGH).

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Greer, Felicia, Jacobo Morales und Michael Coles. „Wingate performance and surface EMG frequency variables are not affected by caffeine ingestion“. Applied Physiology, Nutrition, and Metabolism 31, Nr. 5 (Oktober 2006): 597–603. http://dx.doi.org/10.1139/h06-030.

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The ergogenic effect of caffeine and its mechanism of action on short-term, high-intensity exercise are controversial. One proposed mechanism is caffeine’s stimulatory effect on the central nervous system and thus, motor-unit excitation. The latter is non-invasively determined from surface electromyographic signal (EMG) frequency measures. The purpose of this study was to determine if power output and surface EMG frequency variables during high-intensity cycling were altered following caffeine ingestion. Eighteen recreationally active college males (mean ± SD age, 21.5 ± 1.8 y; height, 181.8 ± 0.5 cm; body mass, 84.7 ± 11.4 kg) performed the Wingate test (WG) after ingestion of gelatin capsules containing either placebo (PL; dextrose) or caffeine (CAFF; 5 mg/kg body mass). The trials were separated by 1 week and subjects were asked to withdraw from all caffeine-containing products for 48 h before each trial. From the resulting power–time records, peak power (PP; highest power output in 5 s), minimum power (MP; lowest power output in 5 s), and the percent decline in power (Pd) were calculated. Surface EMG records of the right vastus lateralis (VL) and the gastrocnemius (GA) muscles corresponding to the PP and MP periods were collected and used to determine the integrated electromyogram (IEMG), the mean (MNPF), and the median (MDPF) of the signal’s power spectrum. A 2-way repeated measures analysis of variance (ANOVA) (treatment × time) was conducted to determine the effect of caffeine on these variables across levels of time. Caffeine ingestion had no effect on PP (PL, 1049 ± 192 W; CAFF, 1098 ± 198 W), MP (PL, 762 ± 104 W; CAFF, 802 ± 124 W), or the Pd (PL, 47% ± 8.9%; CAFF, 48.2% ± 7.3%) compared with the placebo. For both muscles, MNPF and MDPF diminished significantly (p < 0.001) across time and to a similar degree in both the CAFF and PL trials. Regardless of muscle, CAFF had no effect on the percent change in IEMG from the first 5 s to the last 5 s. For both treatments, the GA displayed a significantly (p < 0.05) greater pre vs. post percent decline in the EMG signal amplitude compared with the VL. These results indicate that caffeine does not impact power output during a 30 s high-intensity cycling bout. Furthermore, these data suggest that caffeine does not impact the neuromuscular drive as indicated by the similar IEMG scores between treatments. Similarly, caffeine does not seem to impact the frequency content of the surface EMG signal and thus the nature of recruited motor units before and after the expression of fatigue. The lack of decline in the IEMG in the VL despite the decline in power output over the course of the WG suggests a peripheral as opposed to a neural mechanism of fatigue in this muscle. The significant difference in the pre vs. post percent decline in the GA IEMG score further supports this notion. The pre vs. post decline in the IEMG noted in the GA may suggest a fatigue-triggered change in pedaling mechanics that may promote dominance of knee extensors with less reliance on plantar flexors.

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Ghadirinejad, Nickyar, Fredric Ottermo, Raheleh Nowzari, Naif Alsaadi und Mazyar Ghadiri Nejad. „Optimizing a Green and Sustainable Off-Grid Energy-System Design: A Real Case“. Sustainability 15, Nr. 17 (24.08.2023): 12800. http://dx.doi.org/10.3390/su151712800.

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In recent years, unquestionable warnings like the negative effects of CO2 emissions, the necessity of utilizing sustainable energy sources, and the rising demand for municipal electrification have been issued. Therefore, users are encouraged to provide off-grid and sustainable energy systems for their own homes and businesses, especially if they are located rurally and far from grids. Hence, this study aims to design an off-grid hybrid energy system, in order to minimize both the baseline cost of energy and the net current expenditure in the desired system. To construct such a system, wind generators (WG), photovoltaic arrays (PV), battery banks, and bi-directional converters are considered in the real case of a supermarket with a 20-year lifespan in Malmö, Sweden. Some significant assumptions, such as the usage of renewable energy resources only, electricity production close to the business location, and a maximum allowance of 0.1% unmet are incorporated. To optimize the considered problem, a particle swarm optimization (PSO) approach as developed to provide the load requirements and establish the number of WGs, PVs, and other equipment. Moreover, to verify the obtained results, the developed system was simulated using HOMER Pro software, and the results are compared and discussed. The results indicated that the designed hybrid energy system is able to perform completely off-grid, while satisfying 99.9% of the yearly electricity demand. The best results obtained by the proposed PSO offered 160, 5, and 350 PVs, WGs, and batteries, respectively, while the best solution found by the simulation method was the use of 384 PVs, 5 WGs, and 189 batteries for the considered off-grid system. This study contributes to decentralized local electrification by utilizing renewable energy sources that have the potential to revolutionize green energy solutions.

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Sacha, Dariusz, Agnieszka Skibińska und Wojciech Krasodomski. „Analiza możliwości wykorzystania aparatu PetroOxy do oznaczania stabilności termooksydacyjnej smarów plastycznych metodą RSSOT (Rapid Small-Scale Oxidation Test)“. Nafta-Gaz 78, Nr. 4 (April 2022): 299–311. http://dx.doi.org/10.18668/ng.2022.04.06.

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W warunkach eksploatacji smar podlega działaniu szeregu czynników, które powodują jego destrukcję. Smar spełniający swoje podstawowe funkcje w układzie smarowania narażony jest przede wszystkim na działanie wysokiej temperatury, a dominującym procesem starzenia, bezpośrednio wpływającym na okres użytkowania smaru, jest utlenianie. Stabilność termooksydacyjna ma decydujący wpływ na jakość i długość czasu pracy smarów w węzłach tarcia i układach smarowania. W 2018 r. ukazała się nowa procedura badawcza określająca stabilność oksydacyjną smarów plastycznych według normy ASTM D8206 (Standardowa metoda badania stabilności oksydacyjnej smarów – szybki test utleniania w małej skali RSSOT). Metoda badania polega na umieszczeniu badanej próbki smaru plastycznego w ilości 4,00 g (±0,01 g) w szklanym naczynku. Powierzchnia smaru znajdującego się w naczyniu reakcyjnym musi być dobrze wyrównana. Proces ten należy przeprowadzić w temperaturze otoczenia. Szklane naczynie ze smarem plastycznym wkłada się do komory reakcyjnej aparatu badawczego i napełnia komorę tlenem do ciśnienia 700 kPa (±5 kPa). Komora reakcyjna jest ogrzewana do zadanej temperatury (140°C lub 160°C). Ciśnienie w naczyniu jest rejestrowane w odstępach 1 s. Badanie prowadzi się do osiągnięcia punktu końcowego, czyli spadku ciśnienia o 10% od wartości maksymalnej. Test trwa od kilku minut do maksymalnie kilku godzin – w zależności od właściwości badanego obiektu. Artykuł omawia różnice w ocenie stabilności termooksydacyjnej smarów plastycznych oznaczanej wg metody ASTM D8206 z wykorzystaniem dwóch różnych aparatów: PetroOxy i RapidOxy 100. Budowa i sposób działania obu aparatów są zbliżone i zgodne z wymaganiami wyżej wymienionej normy, jednak wyniki uzyskane przy ich wykorzystaniu nie mieszczą się w odtwarzalności metody. W artykule została przedstawiona próba wyjaśnienia przyczyn tego zjawiska.

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Helal, M. Rezuana Binte, und Shamim Shamsi. „In Vitro Screening of Fungicides and Plant Extracts Against Pathogenic Fungi Associated With Infected Fruits of Carica Papaya L“. Journal of Bangladesh Academy of Sciences 42, Nr. 2 (30.12.2018): 121–28. http://dx.doi.org/10.3329/jbas.v42i2.40039.

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Five fungicides viz., Autostin 50 WDG, Dithane M 45, Greengel 72 WP, Ridomil Gold MZ 68 WG and Tilt 250 EC exclusively were tested against three pathogenic fungi viz., Colletotrichum gloeosporioides (Penz.) Sacc., Fusarium nivale (Fr.) Ces. and Fusarium sp. associated with Carica papaya L. following poisoned food technique. At 100 ppm Autostin showed complete growth inhibition of C. gloeosporioides, F. nivale and Fusarium sp., while Tilt 250 EC showed complete growth inhibition of C. gloeosporioides at the same concentration. These fungicides at 400 and 500 ppm showed complete growth inhibition of F. nivale. Tilt 250 EC showed complete growth inhibition of Fusarium sp. at 300, 400 and 500 ppm. Eight plants extract, viz., Adhatoda vasica, Azadirachta indica, Curcuma longa, Ocimum sanctum, Lantana camara, Tagetes erecta, Thuja orientalis and Vitex negundo were also tested for their efficacy at 5, 10, 15 and 20% concentrations against these pathogenic fungi. Out of the eight plant extracts, Ocimum sanctum showed highest (88.57%) radial growth inhibition of C. gloeosporioides at 20% concentration. Curcuma longa showed highest (88.55%) radial growth inhibition of F. nivale and Adhatoda vesica showed highest (80.02%) radial growth inhibition of Fusarium sp. at the same concentrations. The present investigation suggests Autostin 50 WDG and Tilt 250 EC as best inhibiting chemical fungicides for C. gloeosporioides, F. nivale and Fusarium sp. Extracts of O. sanctum, C. longa and Adhatoda vesica were found to be superior to other plant extracts tested. Journal of Bangladesh Academy of Sciences, Vol. 42, No. 2, 121-128, 2018

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Stonys, Ričardas, und Dalius Vitkus. „Assessing Non-Laboratory Healthcare Professionals’ Attitude towards the Importance of Patient Preparation for Laboratory Tests“. Healthcare 12, Nr. 10 (10.05.2024): 989. http://dx.doi.org/10.3390/healthcare12100989.

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(1) Background: Various guidelines address patient preparation and its importance for venous blood sampling, such as the GP41 guideline issued by the Clinical Laboratory Standards Institute (CLSI) and the blood collection guidelines published by the World Health Organisation. Recommendations provided by national societies or international organisations in the field of radiology, such as The Contrast Media Safety Committee of the European Society of Urogenital Radiology, or in the field of laboratory medicine, such as the Working Group for Preanalytical Phase (WG-PRE) of the European Federation of Clinical Chemistry and Laboratory Medicine (EFLM) and the Latin American Working Group for Preanalytical Phase (WG-PRE-LATAM) of the Latin American Confederation of Clinical Biochemistry (COLABIOCLI), also guide this practice. There is a notable lack of understanding regarding the viewpoints held by non-laboratory healthcare professionals concerning the significance of patient preparation for laboratory testing and the impact of typical factors associated with patient preparation. This study endeavours to bridge this gap by assessing the attitude of non-laboratory healthcare professionals in Lithuania regarding these pivotal aspects. (2) Methods: A self-designed anonymous questionnaire was disseminated among 141 public healthcare institutions in Lithuania. The internal consistency of the questionnaire was evaluated by computing Cronbach’s alpha. Descriptive statistics were utilised for the variables, while comparisons of attitude among groups were conducted using Mann–Whitney U (for two groups) or Kruskal–Wallis (for more than two groups) for categorical and discrete indicators. The Kruskal–Wallis post-hoc test was employed for pairwise comparisons. A significance level of p-Value < 0.05 was applied to establish statistical significance. (3) Results: A total of 158 respondents constituted two distinct groups of healthcare professionals: nurses and physicians. Most of the participants either agreed or strongly agreed that patient preparation could introduce bias into laboratory test results. Professionals with less than 20 years of work experience or those who attended training in patient preparation for sampling within a 5-year timeframe exhibited stronger agreement regarding different preanalytical factors in patient preparation and their impact on laboratory test results compared to their counterparts. (4) Conclusions: Non-laboratory healthcare professionals who participated in this survey consider proper patient preparation for laboratory testing to be a significant step towards obtaining accurate test results. They also recognize the commonly acknowledged preanalytical factors as important for ensuring reliable test results. However, attitudes towards the importance of several preanalytical factors vary depending on whether non-laboratory healthcare professionals have more or less than 20 years of work experience, as well as whether they have attended any training on this topic within the last five years or have never attended such training.

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Thum, Gregor, Maria Grazia Cappai, Ralf Bochert, Hendrik Schubert und Petra Wolf. „Nutrient Profile of Baltic Coastal Red Algae (Delesseria sanguinea), Baltic Blue Mussel (Mytilus spp.) and King Ragworm (Alitta virens) as Potential Feed Material in the Diet of Rainbow Trout (Oncorhynchus mykiss Walbaum, 1792): A Preliminary Assessment“. Agriculture 12, Nr. 2 (31.01.2022): 196. http://dx.doi.org/10.3390/agriculture12020196.

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The use of selected Baltic coastal organisms as potential alternative feed material in the formulation of rainbow trout diets was studied. German coastal water organisms (Delesseria sanguinea, seaweed red algae (A); Mytilus spp., Baltic blue mussel (M); Alitta virens, king ragworm (W)) were analyzed for nutrient, amino acid and mineral composition, and tested in comparative feeding trials. Five dietary treatments were supplied to a total of 165 juvenile rainbow trout (778 ± 111 g) for 75 days, allotted in 15 special brackish (3–5 practical salinity units (PSU)) water basins consisting of 11 fish each (3 fish tanks (300 L) at 12 °C per feeding group). The fish were fed as follows: C group, 100% basic diet (control); A group, 10% red algae in C diet; M group, 10% mussel in C diet; W group, 35% ragworm in C diet; AW group, 10% algae + 30% ragworm in C diet. Feed provision was performed manually, once a day, with the feed offer adjusted to 1.8% of fish weight for the respective tank. The fish weight gain (WG) and feed conversion ratio (FCR) were recorded. In the proximate analysis of the different coastal organisms, the lowest crude protein content in dry matter (DM) was found in blue mussels (10.9%), whereas it was almost doubled in algae (21.8%), with the highest being found in the ragworm (63.1%). By contrast, the crude ash content was the highest in the mussel (84.4%, mostly due to CaCO3 from the shell), much less in the red algae (28.1%) and the lowest in the ragworms (20.1%). The gross energy (GE) concentration was the highest in the ragworm (18.8 MJ × kg−1), 12.1 MJ × kg−1 in the algae and the lowest in the blue mussel (2.93 MJ × kg−1). The final weight of the fish ranged between 1780 and 2310 g at the end of the feeding trial, being the lowest for the fish fed the diet combined with red algae (A diet group) and the highest for the fish fed the control diet. No differences in FCR were found for the fish fed the five dietary treatments (p > 0.05), except for the W diet group (king ragworm has a lower FCR than that of the A group red algae, p < 0.05). The results from this trial suggest that at the tested amounts, both king ragworm and blue mussels are promising alternative feed material for rationing the rainbow trout diet, but not red algae, unless combined with ragworms.

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Rondon, Gabriela, Rima M. Saliba, Julianne Chen, Celina Ledesma, Amin M. Alousi, Betul Oran, Chitra M. Hosing et al. „Fluid Overload As New Toxicity Category Has a Strong Impact on Non Relapse Mortality and Survival in Allogeneic Hematopoietic Stem Cell Transplantation“. Blood 126, Nr. 23 (03.12.2015): 4321. http://dx.doi.org/10.1182/blood.v126.23.4321.4321.

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Abstract Background: Fluid retention/overload (FO) is common during hospitalization for allogeneic stem cell transplantation (ASCT) and is associated with weight gain (WG), edema, and other symptoms such as shortness of breath. It is unknown if symptomatic FO impacts transplant outcomes. We hypothesized that FO is associated with non-relapse mortality (NRM) and worse survival after ASCT. Methods: FO was scored by an independent team using the following criteria: grade 1 - asymptomatic weight gain <10% from baseline requiring occasional diuretics; grade 2 -symptomatic and or WG 10%-20% from baseline requiring continuing diuretics grade 3 WG ≥20% from baseline requiring further treatment (dialysis) with or without renal, pulmonary, and or cardiac dysfunction; grade 4 - major organ dysfunction. Results: We initially evaluated FO in a cohort of haploidentical transplant patients with hematologic malignancies (N=145) all treated with identical conditioning (melphalan-based) regimen, and received predominantly a bone marrow graft (94%). The median follow-up was 18 months. 43% of patients were in CR1/2. Median age for this group was 45 years (range 19-69), 58% were males. Median weight was 82 kg (37-180kgs) at study entry before starting the preparative regimen. The median creatinine was 0.75 with >1.0 mg/dl in 16% of the patients. Median DLCO was 70 and EF was normal (>40%) in all except 2 patients. Thirty patients (21%) developed ≥ grade 2 FO. Factors associated with Day100 NRM were ≥ grade 2 FO (HR 15, CI 4.2-55, p<0.001), cr>1 (HR 4.7, CI 1.6-14, p=0.005) and age>55 (HR 4.5, CI 1.5-13, p=0.008) by univariate analysis. In multivariate analysis (MVA) factors that retained significance were FO ≥ grade 2 (HR 13.1, CI 3.4-50, p<0.001) and cr>1 at study entry (HR 3.5, CI 1.1-11, p=0.03). We verified the prognostic value of FO in a separate cohort of HLA matched transplants [N= 449, 190 matched related donor (MRD) and 259 matched unrelated donor (MUD)] with AML/MDS treated with fludarabine and busulfan conditioning. The median follow-up for this group was 23 months. The median age was 58 years (range 18-77). 42% were in CR1/2 at transplant. 68% had a peripheral blood graft. Median weight was 81kg (47-170). Median creatinine at transplant was 0.8, 19% had >1 mg/dl. Median DLCO was 71 and EF was normal (>40%) in all except 2 patients. Significant factors associated with Day100 NRM by univariate analysis, were FO ≥ grade 2 (HR 11, CI 4.5-25, p<0.001) and advanced disease status at transplant (not in CR1/2) (HR 3.5, CI 1.2-10, p=0.02). By MVA, FO≥ grade 2 was the only factor highly associated with Day100 NRM (HR 34, CI 7.2-158, p<0.001), and advanced disease status in patients with FO<2 (HR 5, CI 1.1-22, p=0.03). Worse NRM translated in significantly worse 3-years survival for patients with FO in both haploidentical and HLA matched transplants group (Figure). Haploidentical transplant patients with FO≥2 were more likely to have weight < 80 kgs(57% vs.33%, p=0.02), but there was no such correlation in the matched transplants group. Conclusions: FO should be considered an important adverse event post ASCT. Grade 2 or greater FO is strongly associated with NRM and worse survival. FO is likely related to the rate of intravenous fluid administration and other factors (oncotic pressure, capillary leak and major organ dysfunction post-transplant). Caution is warranted to prevent excessive hydration and weight gain in the early post-transplant period. Other factors potentially associated with weight gain will be evaluated. Figure 1. (A) NRM and (B) OS in haploidenticaltransplants; (C) NRM and (D) OS in matched transplants. Figure 1. (A) NRM and (B) OS in haploidenticaltransplants; (C) NRM and (D) OS in matched transplants. Disclosures Alousi: Therakos, Inc: Research Funding.

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Robak, Tadeusz, Anna Dmoszynska, Raouf Fetni, Ying Wang, Malika Belkacz, Cynthia Sirard, Mark Goldberg, Aleksander Skotnicki, Jiri Mayer und Peter Hillmen. „Incidence of Genomic Aberrations and Associated Efficacy from a Phase III Study Comparing Alemtuzumab (CAMPATH®, MABCAMPATH®) vs Chlorambucil as First Line Therapy for B-Cell Chronic Lymphocytic Leukemia (BCLL).“ Blood 108, Nr. 11 (01.11.2006): 2092. http://dx.doi.org/10.1182/blood.v108.11.2092.2092.

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Abstract CAM307 is a randomized Phase III trial comparing the efficacy and safety of alemtuzumab (CAM) with chlorambucil (CHLO). The trial enrolled 297 previously untreated patients (pts) requiring therapy according to NCI-WG criteria. Pts were randomized 1:1 to CAM (n=149) vs CHLO (n=148) using standard dosing regimens. Fluorescence in situ hybridization (FISH) on interphase nuclei of lymphocytes isolated from blood was analyzed for cytogenetic abnormalities prior to the start of therapy. FISH analysis was performed using 13 DNA probes to detect chromosomal aberrations in 17p13.1 (P53), 13q14 (RB1, D13S319 and D13S25), 11q22.3-11q23 (ATM and MLL), 6q27 (subtelomere), 6q21 (chromosome 6q21/alphasatellite 6 cocktail probe), trisomy 8q24 (c-myc), trisomy 12 (CEP12) and translocations involving the locus of immunoglobulin heavy chain gene (IGH, 14q32.33). Samples were analyzed in 282 pts (95%); chromosomal aberrations were detected in 231 pts (82%) while 51 pts (18%) exhibited a normal interphase FISH pattern. The most frequent abnormalities were deletions (del) at loci 13q (49%), sole del 13q (24%), 11q (19%), 17p (7 %), 6q (4 %), and trisomies 12 (14%) and 8q (5%). Translocations IGH, 14q32.33 were detected in 10 pts (4%). An exploratory analysis was performed to correlate time to event variables (assessed by an independent response review panel) with cytogenetics. Overall 165 pts (59%) revealed combination abnormalities. The most frequently observed chromosomal associations were: del 13q + del 14q (N=20, 12%), del 11q + del 13q (N=17, 10%), del 11q + del 13q + del 14q (N=11, 7%), del 11q + del 14q (N=7, 4%), trisomy 12 + del 13q (N=5, 3%), del 13q + del 17p (N=4, 2%), del 11q + trisomy 12 (N=3, 2%) and del 17p + del 6q (N=3, 2%). Coexistence of del 17p and del 11q was not observed. Although del 13q was observed with all chromosome abnormalities, nearly half of the cases del 13q14.3 (D13S25 and D13S319) coincided with an ATM deletion (11q22.3). FISH analysis has allowed the detection of uncommon abnormalities: tetraploidy (n=1), hyperdiploidy (n=1), trisomy 18 (n=1) and c-myc oncogene amplification (>15 copies per nuclei) (n=2). The latter is a well known abnormality in solid tumors but rarely seen in leukemia. In addition, del of the IGH variable region was detected in 70 pts. The biological and clinical significance of this abnormality is to be investigated. Conclusions: Overall, 82% of treatment naïve BCLL pts revealed cytogenetic aberrations and 59% were combination abnormalities. CAM307 demonstrates a significant improvement in PFS in pts treated with CAM vs CHLO who present with del 13q as the sole abnormality; no difference in pts with del 11q. However, a trend towards improved PFS was observed in pts with trisomy 12 and del 17p, which did not reach significance due to small sample size. Further investigation of CAM therapy in high risk cytogenetic subgroups is warranted.

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Hull, Larry A. „Apple, Concentrate and Dilute Acaricide Evaluation Test, 1992“. Insecticide and Acaricide Tests 18, Nr. 1 (01.01.1993): 42–43. http://dx.doi.org/10.1093/iat/18.1.42.

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Abstract Treatments were applied to single-tree plots in a randomized block design consisting of 3 replicates of ‘Yorking’ and 2 replicates of ‘Golden Delicious’. Trees were planted to a spacing of 20 x 20 ft and were 19 years old. All treatments were applied with a Myers Mity Mist sprayer calibrated to deliver 100 gal/acre, driven at 2 mph, except for HHE-3736 70 WG and Savey 50 WP which were applied dilute to run-off with a high pressure handgun at approximately 4 gal of spray per tree. Application dates varied between treatments and are as listed in the tables. All plots received a regular maintenance schedule of fungicides (captan 50 WP, Nova 40 WP, Penncozeb 80 WP and Topsin 85 DF) and nutrients (Solubor and CaCl). Post-bloom insecticides (Guthion 35 WP, Lannate 1.8 L) were applied at 1- to 2-wk intervals beginning at petal-fall in early May. Effectiveness of treatments on ERM was evaluated by counting mites at approximately weekly intervals during the season on samples of 25 leaves/tree (125 leaves/treatment). Effects of treatments on SP were measured by 3 minute counts of adults and larvae around the periphery of trees. Russet ratings are based on 30 ‘Golden Delicious’ apples/replicate, 60/treatment. Fruits were rated as 0 (no russet), 1 (raised lenticels), 2 (1-10% russeted surface), 3 (11-25% russeted surface), 4 (26-50% russeted surface), or 5 (>51% russeted surface). Possible ranges are 0-30 (none to raised lenticels), 31-60 (raised lenticels to 1-10% russeted surface), 61-90 (1-10% to 11-25% russeted surface), 91-120 (11-25% to 26-50% russeted surface), and 121-150 (26-50% to >51% russeted surface).

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Wierda, William G., Januario Castro, Robier A. Aguillon, Deepa Sampath, Annette Jalayer, Charles Prussak, Michael J. Keating und Thomas J. Kipps. „Active Immune Gene Therapy Using ISF35: Responses Associated with Priming for Death Receptor-Induced Apoptosis and Sensitivity to Fludarabine in Patients with CLL and Del 17p“. Blood 112, Nr. 11 (16.11.2008): 3530. http://dx.doi.org/10.1182/blood.v112.11.3530.3530.

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Abstract CLL cells can be transduced with adenovirus vector to express CD40-ligand (CD154). Ad-ISF35 is the Ad-vector that encodes a novel molecule capable of ligating CD40 on CLL cells. We conducted a phase I clinical trial to evaluate tolerability, toxicities, and clinical activity of a single infusion of autologous ISF35-transduced CLL cells. Doses of 1×108, 3×108, and 1×109 transduced cells were administered. Three patients (pts) were treated at each dose level. All pts had active disease with an NCI-WG ‘96 indication for treatment, 2 were previously untreated and 7 were previously treated. Four of the previously treated pts had del 17p by FISH prior to ISF35. Pts experienced Grade 1–2 flu-like symptoms that resolved within 2–3 days. Infusions were associated with reduction in leukemia counts and lymph node size at all dose levels; there was no dose-response. These responses were associated with in vivo apoptosis of CLL cells demonstrated by Annexin V staining, including cells collected form pts with del 17p. In vivo phenotypic and biochemical changes occurred in bystander leukemia cells of treated pts, again including cells collected from pts with del 17p. These changes included increased expression of CD95 (FAS) and death receptor 5 (DR5). A notable biochemical change included de novo expression of bid, including in cells from pts with del 17p, which lasted several weeks. Bid links the intrinsic and extrinsic apoptosis pathways and facilitates death-receptor-induced killing. Leukemia cell sensitivity to purine analogue-based therapy can be increased following expression of p73 in CLL cells with del 17p or mutated TP53. We demonstrated that ISF35 induced in vivo expression of p73 following infusion of transduced cells. Treatment of patients with del 17p with purine-analogue based regimens resulted in responses, including complete remissions. Increases in T cell counts were also observed at all dose levels; there was no dose-response relationship. T-cell increases peaked at 1–4 wks post-infusion. These results demonstrate that Ad-ISF35-transduced autologous leukemia cells can be given safely up to 1×109 transduced cells, without dose limiting toxicities, and resulting in phenotypic and biochemical changes in bystander cells in vivo that render them able to present antigen and primes them for death-receptor induced apoptosis.

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Serhyenko, V., und O. Shyta. „Weed control in maize crops with various schemes of herbicide application“. Interdepartmental Thematic Scientific Collection of Plant Protection and Quarantine, Nr. 67 (20.12.2021): 196–211. http://dx.doi.org/10.36495/1606-9773.2021.67.196-211.

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Goal. Carry out a comparative evaluation of the effectiveness of different schemes of application of modern herbicides in maize crops. Methods. Field, phenological, statistical. Conducted spraying of corn crops to seedlings (ВВСН 00) with herbicides Adengo 465 SC, hp (thiencarbazone-methyl, 90 g/l + isoxaflutol, 225 g/l + cyprosulfamide, 150 g/l), 0.5 l/ha, Primextra TZ Gold 500 SC, (S-metachlor. 312.5 g/l + terbuthylazine, 187.5 g/l), 4.5 l/ ha, Merlin Flex Duo 475 SC, (isoxaflutop, 50 g/l + cyprosulfamide, 50 g/l + terbuthylazine, 375 g/l, 2.0 l/ha. After germination in the phase of 4—5 leaves (ВВСН 14—15) applied insurance herbicides Milagro 040 SC, (nicosulfuron, 40 g/l), Basis 75 v.g. rimsulfuron, 500 g/kg + thifensulfuron-methyl, 250 g/l), MаisTer Power OD (foramsulfuron, 31.5 g/l + iodosulfuron-methyl sodium, 1.0 g/l + thiencarbazone-methyl, 10 g/l + cyprosulfamide, 15 g/l), Laudis 30 WG, VG (tembotrione, 200 g/kg + isoxadifen-ethyl, 100 g/kg) and Stellar, RK (topramezone, 50 g/l + dicamba, 160 g/k) in the recommended consumption rates. The experimental plots were 1000 m2 in the first experiment, the recurrence of 3-fold and 25 m2 in the second experiment, the recurrence of 4-fold. Observations were made for meteorological indicators. Statistical processing of the results was performed according to computer «Statgraphic plus» programs. Results. Mixed type of segetal vegetation prevailed in the experimental plots. Among the perennial weeds dominated by Sonchus arvensis L., Cirsium vulgare Savi Ten., Convolvulus arvensis L., among annuals — Setaria glauca L., Setaria viridis L., Echinochloa crus-galli L., Polygonum convolvulus L., Calinsoga parviflora L., Stellaria media (L.) Vill.), Chenopodium album L., Raphanus raphanistrum L., Thlaspi arvense L., Amaranthus retroflexus L. The application of pre-emergence herbicides effectively inhibited the growth and development of weeds. 60 days after application, the effectiveness of herbicides was 87—97% against cereals and 89—98% against dicotyledonous weeds, which did not require the application of insurance herbicides. During the critical periods of maize development, a sufficient level of soil moisture was recorded during the research years. After 60 days, the effectiveness of herbicides applied after crop germination was 65—95% against dicotyledonous and 65—92% against cereal weeds. The highest effect in killing weeds was provided by MaysTer Power, 1.5 l/ha, Laudis 30 WG, VG, 0.5 kg/ha + surfactant Mero, 2.0 l/ha and Stellar, RK, 1.25 l/ha + surfactant Metholate, 1.25 l/ha. The application of herbicides has significantly reduced the aboveground mass of weeds and increased crop yields. Maize grain yield from weed-protected areas was at the level of 8.0—9.7 t/ha against 4.1—4.9 t/ha in the control. Conclusions. Both herbicide application schemes under favorable weather conditions provide effective weed control of maize crops The efficiency of pre-emergence herbicides was at the level of 87—98%, post-emergence — 65—95%. At the same time, the reduction of aboveground mass of weeds was 75—95%, and crop yields increased by 1.6—2.2 times depending on the drug.

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Robak, Tadeusz, Jerzy Z. Blonski, Krzysztof Jamroziak, Joanna Gora-Tybor, Beata Stella-Holowiecka, Lech Konopka, Bernadeta Ceglarek et al. „Randomized Comparison of Cladribine Plus Cyclophosphamide with Fludarabine Plus Cyclophosphamde in Untreated Patients with Chronic Lymphocytic Leukemia: Report of the Polish Adult Leukemia Group (PALG-CLL3).“ Blood 112, Nr. 11 (16.11.2008): 2103. http://dx.doi.org/10.1182/blood.v112.11.2103.2103.

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Abstract Purine nucleoside analogues, cladribine(2-CdA) and fludarabine (FA), especially combined with cyclophosphamide (CY) are potent cytotoxic drugs for the treatment of chronic lymphocytic leukemia (CLL). In this randomized study we aimed to establish whether combination of 2-CdA plus CY (CC) with FA plus (FC) provide similar benefit to previously untreated patients with CLL. The trial was started in January 2004 and the recruitment was ended in May 2007. The study primary endpoints were overall response (OR) and complete response (CR). The secondary endpoints included progression free survival (PFS), overall survival (OS), minimal residual disease negativity (MRD/-/) and treatment related toxicity. Eligible patients were randomly assigned to receive 6 courses of either 2-CdA 0.12 mg/kg/d i.v. + CY 250 mg/m2/d i.v. or FA 25 mg/m2/d i.v. + CY 250 mg/m2/d, both combinations for 3 consecutive days. The treatment response and toxicity were evaluated according to NCI-WG guidelines. MRD was evaluated in patients with CR using four-color flow cytometry assay. There were no significant difference in the rates of OR, CR, MRD negativity, grade 3/4 neutropenia, thrombocytopenia and infections. PFS and OS were also similar in both groups. In conclusion, CC and FC regimens are similarly active and toxic in previously untreated CLL, however trend of longer OS in CC group is observed. Characteristic CC arm FC arm P value Pts enrolled 212 211 - Pts evaluated 184 187 - No of courses (median, range) 6 (2–6) 5 (2–6) 0.56 OR (%) 163 (88.6) 159 (85.0) 0.31 CR (%) 86 (46.7) 91 (48.7) 0.43 MRD/–/ (%) 33 (68.8) 44 (72.1) 0.70 PFS (median, years) 2.195 2.361 0.86 Thrombocytopania gr 3/4 (%) 23 (12.6) 22 (11.6) 0.77 Neutropenia gr 3/4 (%) 39 (21.4) 43 (22.8) 0.76 Infection gr 3/4 (%) 53 (29.1) 54 (28.6) 0.91 OS (median, years) 4.066 2.531 0.10 Death (%) 37 (20.2) 53 (27.9) -

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Janakiram, Murali, und Timothy E. O’Brien. „Pegfilgrastim Use and Risk of Bleomycin Induced Pulmonary Toxicity in Hodgkin Lymphoma“. Blood 112, Nr. 11 (16.11.2008): 4950. http://dx.doi.org/10.1182/blood.v112.11.4950.4950.

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Abstract Background Filgrastim may increase the risk of bleomycin induced pulmonary toxicity (BPT) in Hodgkin lymphoma patients, particularly those >age 40 [Martin WG, J Clin Onc, 2005; 23(30): 7614]. It is not clear if pegylated filgrastim, with a longer 1/2 life and delayed onset of action, also increases this risk. Methods: 38 cases of Hodgkin lymphoma treated with a bleomycin containing regimen were included in this analysis. 29 of these pts (Group A) also received pegfilgrastim and 9 pts (Group B) did not receive any growth factor support. All of the patients who received pegfilgrastim had it administered the day after chemotherapy and in all cases it was given to maintain dose intensity and prevent treatment delays. BPT was defined by the presence of pulmonary symptoms, interstitial infiltrates on chest x ray or computed tomography and the absence of infection. Results: Grp A: 60% male, 40% female, mean age 39 (19 to 73), stage-I 2/29, II -14/29, III -5/29, IV-8/29; subtype- NS 20, MC 5, LP 3, LD 1. 27/29 received full dose ABVD (which included 10 units/m2 of bleomycin q 2weeks); one received ABD and one received full dose ABVD then had bleomycin held after 3 cycles. Mean number of cycles= 6 (4–8), median duration of treatment =160 days (71 to 231 days). Average ANC during treatment: 6590/mm3 (790 to 17273). Total # of bleomycin treatments: 274. Total # pegfilgrastim treatments: 203. Only 1/29 pts (age 44) developed BPT. There were no serious infections. Response to chemo: 22/29 CR, 5/29 PR, data not available in 2/29. At a median follow up of 18 months (range 4 to 48) 2/29 had relapsed. Grp B: 9 patients; mean age 39 (22 to 51), stage- II: 5/9; III: 4/9; subtype- NS 7, LP 2. All patients received full dose ABVD; ave # cycles= 6 (range 4–8), median duration of treatment= 145 days (30–220 days); average ANC during treatment: 2721/mm3 (2101 to 3535/mm3). Total # bleomycin treatments= 80. 1/9 pts (age 42) developed BPT. Response to chemo: 7/9 CR; 1 PR, 1 w/o response data. At a median follow up of 39 months (range 4–71), 2/9 relapsed. Conclusions: In this small series, pegfilgrastim use with ABVD chemotherapy did not lead to a high risk of BPT in Hodgkin lymphoma, with only 1/29 patients (which included 203 treatments with both pegfilgrastim and bleomycin) developing BPT, as compared with 1/9 patients treated with ABVD and no pegfilgrastim. Both of the patients who developed BPT were >age 40. Larger studies will need to be performed to confirm our findings.

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Bartalucci, Niccolò, Francesco Mannelli, Danilo Tarantino, Barbara Scappini, Alessio Enderti, Giacomo Gianfaldoni, Matteo Piccini et al. „Identification of Genomic Structural Variants (SVs) with Adverse Prognostic Significance in Normal-Karyotype (nk) Acute Myeloid Leukemia (AML) Patients“. Blood 144, Supplement 1 (05.11.2024): 65. https://doi.org/10.1182/blood-2024-198342.

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Background: nkAML accounts for 40% of all AML. Although nkAML pts are included into favorable (fav) and intermediate (int) European Leukemia Net (ELN2022) risk category, the outcome is highly heterogeneous, and poses therapeutic challenges particularly as regards indication to stem cell transplant (SCT). Aim: To improve ELN-based prognostication, we characterized genomic SVs in nkAML pts through Long-Read Whole Genome Sequencing (WG-LRS). Methods: A total of 311 intensively treated nkAML pts were included; a discovery cohort (DC) was made up of 162 pts from the prospective NILG 02/06 and GIMEMA 1310 trial, a validation cohort (VC) included 149 cases from Florence center. WG-LRS was performed on blast-enriched samples by GridION platform to median depth of 5x. SVs identified in the DC were correlated to overall (OS) and event-free (EFS) survival by machine learning and Cox regression. Results: In the DC, 120 SVs were retained after extensive filtering based on technical parameters and database information; 80.3% insertions, 15.6% deletions, 2.5% duplications, 1.6% inversions, average span 269 bp (range, 52-3.1x10³). Feature selection identified 38 SVs negatively associated with OS that were introduced into a multivariable model including NPM1, FLT3-ITD, CEBPA, ASXL1, TP53 and RUNX1 mutation status. Cox-based model identified 5 SVs with statistical significance for OS: chr2p13.1_del (HR 2.8; 95%CI:2.2-6.6; P=0.016), chr3p34.3_ins (HR 7.1; 2.2-23.2; P=0.001), chr5p12_ins (HR 6.2; 1.9-20.4; P=0.002), chr9q34.3_del (HR 7.6; 2.7-21.6 P≤0.001), chr18q23_ins (HR 3.3; 1.2-9.2; P=0.002). All other input covariates lost significance. Overall, 21 (13%) DC pts had >1 high-risk SVs (HRSV+); their median OS (9.7mo, 95%CI:0-19.4) was significantly shorter compared to HRSV- (not reached, NR; P<0.001), HR of 4.1 (2.5-6.9; P<0.001), median FU of 52.4mo (47.4-57.3). Findings were confirmed in the VC: 15.4% of pts were HRSV+, median OS 15.3mo (11.9-18.6) vs 44.4mo (30.2-58.6) (P=0.014). No significant difference in mutation profile (ELN criteria) was found between HRSV+ and HRSV- pts. HRSV+ pts had lower CR attainment rate (65.9% vs 82.4%, P=0.009) and higher relapse rate (68.9% vs 45%, P=0.015). Median EFS was 5.3mo (2.1-8.6) for HRSV+ and 19.3mo (12.6-25.9; P<0.001) for HRSV- pts. Censoring at SCT had no impact. HRSVs were prognostically informative also in the NPM1+ subset (162 pts): 14.8% were NPM1+HRSV+, median OS 8.2mo (5.5-10.9) compared to NR in NPM1+HRSV- pts (P<0.001). Using ELN2022 criteria, median OS was NR in the fav category (44.3%), 22.6 and 20.4mo, respectively (P=0.39), in the int (35.6%) and adverse (adv) (20.1%) category, highlighting the limited resolution of ELN scoring in nkAML pts. Using ELN fav group as reference, the HR of death was 1.98 (1.3-3) and 2.14 (1.32-3.46), respectively, for ELN int and adv category, compared to 4.4 (2.78-6.95) for HRSV+ category (P<0.001); of note, 73.2% of HRSV+ pts belonged to ELN fav or int category. We then introduced HRSV+ as independent adv variable in the ELN2022 risk score. The resulting model led to improved outcome prediction for the int and adv group, with median OS of 27.4mo and 17.6mo (P=0.034) and HR of 1.9 and 3 compared to fav category (OS, NR). HRSV+ enhanced ELN model showed better Akaike and Concordance Index compared to ELN only: 1576.73 and 0.62 vs 1587.98 and 0.58, respectively. Since HRSVs mapped to genomic regions coding for CCL28, ATP9B, PMPCA, LINC0267, and a topologically associated domain involving ZNF638 and DYSF, we comparatively assessed the mRNA levels of those genes in blasts of HRSV+ and HRSV- pts. In HRSV+, ZNF638 and ATP9B mRNA was upregulated (2.5 and 2.62-fold, respectively), while CCL28 and DYSF mRNA was downregulated (0.72 and 0.27-fold) (all P<0.05). Immunohistochemistry analysis of bone marrow blasts was consistent with mRNA changes. Conventional PCR-based methods for each HRSVs were developed to facilitate integration in diagnostic paths. Conclusions. We identified a set of 5 SVs that marks a subgroup of nkAML pts with outmost dismal prognosis and helps refining ELN 2022 risk stratification, including NPM1+ pts. Preliminary findings in a separate cohort of additional 100 pts with non-adverse (ELN 2022) abnormal karyotype (presented at meeting) support that HRSVs+ maintains prognostic informativeness across a wide range of genomic-defined categories of AML. Supp. by AIRC-MYNERVA, GIMEMA FI2018-ID.13, Zottola legacy.

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Wierda, William G., Thomas J. Kipps, Jiri Mayer, Tadeusz Robak, Martin JS Dyer, Richard R. Furman, Peter Hillmen et al. „Final Analysis From the International Trial of Single-Agent Ofatumumab In Patients with Fludarabine-Refractory Chronic Lymphocytic Leukemia“. Blood 116, Nr. 21 (19.11.2010): 921. http://dx.doi.org/10.1182/blood.v116.21.921.921.

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Abstract Abstract 921 Background: Patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab (FA-ref) or refractory to fludarabine with bulky (>5 cm) lymphadenopathy (BF-ref) have poor prognosis with salvage regimens (Tam et al. Leuk Lymphoma 2007). Ofatumumab, a human CD20 monoclonal antibody, was recently approved by the US FDA and EMEA for treatment of CLL refractory to fludarabine and alemtuzumab based on the interim analysis of the pivotal international clinical trial, which included data from 138 patients with FA-ref and BF-ref CLL. At the interim analysis, the overall response rate (ORR; primary endpoint) with single-agent ofatumumab was 58% (99% CI: 40, 74) in the FA-ref group and 47% (99% CI: 32, 62) in the BF-ref group (Wierda et al. J Clin Oncol 2010). Here, we report the final result for the primary endpoint in 206 patients with FA-ref or BF-ref CLL enrolled in this study. Methods: Patients with FA-ref or BF-ref CLL received 8 weekly doses of ofatumumab followed by 4 monthly doses (dose 1, 300 mg; doses 2–12, 2000 mg). Premedication included acetaminophen, antihistamine and glucocorticoid. The primary endpoint (ORR, 1996 NCI-WG criteria) was evaluated over the 24-week treatment period by an Independent Endpoint Review Committee (IRC). Secondary endpoints included duration of response, progression-free survival (PFS), overall survival (OS) and safety. Results: Baseline characteristics are summarized in the Table; 89% and 50% of patients completed 8 and 12 ofatumumab doses, respectively. The ORR (95% CI) by IRC evaluation was 51% (40, 61) for the FA-ref group and 44% (35, 64) for the BF-ref group. Two patients in the BF-ref group achieved complete remission (Table). Results for time-to-event analyses are shown in the Table. Infusion-related AEs occurred in 63% of patients, which primarily occurred during doses 1 and 2, and diminished with subsequent doses. Infusion-related reactions were grade 1–2 events in 95% of patients; no fatal reactions were reported. The most common (≥5% of all patients) grade ≥3 adverse events (AEs) that occurred from start of treatment until 30 days after the last infusion were infections (24%), neutropenia (12%) and anemia (5%). The most common grade ≥3 infection was pneumonia (8% of patients). Fatal infections occurred in 8% of patients (13% in FA-ref; 5% in BF-ref groups). Grade 3–4 thrombocytopenia occurred in 8 patients (4%), febrile neutropenia in 4 patients (2%) and autoimmune hemolytic anemia in 2 patients (1%). Early death (within 8 weeks from start of treatment) occurred in 5 patients (5%) in the FA-ref group (infections, n=5) and 4 patients (4%) in the BF-ref group (infections, n=2; myocardial infarction, n=1; pulmonary edema, n=1). Conclusions: These final results from the pivotal trial clearly demonstrate the efficacy and safety of ofatumumab monotherapy in this heavily pretreated patient population with FA-ref and BF-ref CLL. Additional data analyses are ongoing, and efficacy outcomes for patient subgroups will be presented. Disclosures: Wierda: GlaxoSmithKline: Honoraria, Research Funding. Kipps:GlaxoSmithKline: Research Funding. Mayer:GlaxoSmithKline: Consultancy, Research Funding. Robak:GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Genmab: Consultancy, Research Funding; Roche: Consultancy, Honoraria, Research Funding. Furman:GlaxoSmithKline: Consultancy, Speakers Bureau; Genentech: Consultancy, Speakers Bureau; Cephalon, Inc.: Speakers Bureau; Celegene: Consultancy; Calistoga: Consultancy. Stilgenbauer:Amgen: Research Funding; Bayer: Consultancy, Honoraria, Research Funding; Boehringer-Ingelheim: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; GSK: Consultancy, Honoraria, Research Funding; Mundipharma: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Sanofi Aventis: Research Funding. Cartron:GlaxoSmithKline: Honoraria; Roche: Honoraria. Padmanabhan:GlaxoSmithKline: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chan:GlaxoSmithKline: Employment. Gupta:GlaxoSmithKline: Employment. Gorczyca:GlaxoSmithKline: Employment. Davis:GlaxoSmithKline: Employment. Losic:Genmab A/S: Employment, Equity Ownership. Lisby:Genmab A/S: Employment. Österborg:GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Merck KGaA: Research Funding.

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Ciccone, Maria, Candida Vitale, Christina Hinojosa, Michael J. Keating, Naveen Pemmaraju, Susan O'Brien, Jan A. Burger et al. „Early Results of a Phase II Study of Ofatumumab As Front-Line Treatment in Elderly, Unfit Patients with Chronic Lymphocytic Leukemia (CLL)“. Blood 124, Nr. 21 (06.12.2014): 5656. http://dx.doi.org/10.1182/blood.v124.21.5656.5656.

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Abstract Background Patients with chronic lymphocytic leukemia (CLL) that are elderly and have multiple comorbidities show poor tolerance to chemoimmunotherapy. This population is frequent in the real-world clinical practice, but is usually excluded from participating in clinical trials. We, therefore, decided to investigate the activity and toxicity of ofatumumab, a fully human anti-CD20 monoclonal antibody in elderly unfit patients. Methods Patients with untreated CLL requiring therapy (2008 NCI-WG guidelines), aged ≥65 years, who had an ECOG performance status of 2-3 or ECOG 0-1 and a Charlson comorbidity index ≥2 were considered eligible. Patients with another malignancy or with an ongoing serious medical condition were allowed to participate in this trial. Treatment consisted of ofatumumab given as intravenous infusions weekly for the first month (300 mg day 1 and 1,000 mg day 8, 15, 22), then monthly (1,000 mg day 1) for a total of 12 months. The trial was amended after the first 8 patients, and the dose of ofatumumab was increased from 1,000 to 2,000 mg in subsequent patients in view of reports of increased efficacy with the 2,000 mg dose. Acetaminophen, prednisolone and diphenhydramine were administered prior to ofatumumab infusion to ameliorate infusion reactions. Results From January 2012 to the present time, 18 patients have been enrolled in this trial. Patients’ characteristics at treatment initiation are summarized as follows: Table 1 Number of patients 18 Age, years, median (range) 73 (67-85) Male/Female 8/10 Rai stage 3-4 7 (39%) Absolute lymphocyte count, 106/µl, median (range) 30.5 (6.1-149.7) β2 microglobulin, mg/L, median (range) 3.6 (1.6-11.9) Months from diagnosis, median (range) 14 (0-166) FISH1 normal/del(13q) tris(12) del(11q) del(17p) 7 (39%) 5 (28%) 5 (28%) 1 (5%) IGVH Unmutated2 5 (56%) ZAP70 positive2 3 (33%) CD38 positive 12 (67%) 1Hierarchical classification. 2Data available for 9 patients. Six patients (33%) had other cancers (melanoma, basal cell carcinoma, squamous cell carcinoma, papillary thyroid carcinoma, cervical cancer, colorectal cancer, meningioma, essential thrombocythemia). At the time of study entry 6 patients had a positive direct antiglobulin test, and one patient had immune-mediated thrombocytopenia. At the present time, 13 patients are evaluable for response and 5 patients are too early for response evaluation having not yet completed 6 months of therapy. Nine patients achieved a response for an overall response rate of 69%; complete responses were observed in 3 patients (23%), and partial responses in 6 patients (46%). None of the patients obtained minimal residual disease negativity. Of note, the increase in ofatumumab dose appears to be associated with a superior efficacy, with responses observed in all the 5 patients treated at the 2,000 mg dose, whereas only 4 of the 8 patients treated at the 1,000 mg dose achieved a response. At a median follow up of 24 months, 6 patients remain progression-free, 7 patients have progressed and required subsequent treatment with a median time to next treatment of 15 months. None of the patients died on study; one patient died of infectious complications two years after receiving ofatumumab, while receiving subsequent therapies. Eighteen patients are evaluable for toxicity. The most common treatment-related adverse events (AEs) were infusion-related reactions, grade (G)3 in one patient (5%) and G1-2 in 6 patients (33%). Additional G3 AEs, reported in 4 patients, were diarrhea (2 patients), hyperglycemia (1 patient) and neutropenia (1 patient). No G4 AEs were observed. Conclusions Based on our experience, therapy with ofatumumab as frontline single agent for elderly unfit CLL patients is feasible, well tolerated, and clinically effective, obtaining response in 69% of patients. This treatment was safely administered to patients with other cancer diagnoses. Disclosures O'Brien: MorphoSys, Acerta, TG Therapeutics: Research Funding; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Amgen, Celgene, GSK: Consultancy.

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Kay, Neil E., Wenting Wu, John C. Byrd, Brian Kabat, Diane F. Jelinek, Clive S. Zent, Timothy Call, Thomas Lin und Tait Shanafelt. „Cyclophosphamide Remains An Important Component of Treatment in CLL Patients Receiving Pentostatin and Rituximab Based Chemoimmunotherapy“. Blood 112, Nr. 11 (16.11.2008): 43. http://dx.doi.org/10.1182/blood.v112.11.43.43.

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Abstract BACKGROUND: We have previously studied and reported that the combination of pentostatin (P, 2 mg/m2), cyclophosphamide (C 600 mg/m2) and rituximab (R 375 mg/m2) in previously untreated CLL is highly effective with an overall response (OR) rate of over 90% and a complete response rate (CR) of 41% (Blood109:405–411, 2007). We also found that this regimen can be effective even in older patients (>70 y), those with elevated beta-2 microglobulin levels, and patients with mildly reduced creatinine clearances (Cancer. 109:2291–2298, 2007). To determine whether similar benefit could be achieved without inclusion of an alkylating agent, we conducted a follow-up trial testing pentostatin and rituximab without cyclophosphamide and employing a higher pentostatin dose (4 mg/m2). METHODS: Eligible pts had documentation of active CLL by standard NCI-WG criteria, and were previously untreated. Treatment schema consisted of 6 cycles of pentostatin (4 mg/m2) and rituximab given every 21 days. Pentostatin was given on the first day of each cycle following infusion of rituximab. Rituximab was given at 100mg/m2 IV at day 1, then 375 mg/m2 IV on days 3 and 5 of the first treatment cycle. During cycles 2 to 6, Rituximab was given at 375 mg/m2 as a single IV infusion day 1 of week 4, 7, 10, 13 and 16. All patients were staged two months after completion of the 6 cycles of PR using the NCI-WG criteria. PATIENT CHARACTERISTICS: Overall, 33 patients were enrolled at Mayo Clinic and Ohio State University between July 2005 and February 2008. All 33 were eligible: 82% male, median age 65 (range: 45–81), with 9 (27%) being 70 years or older. 76% had a baseline ECOG PS of 0, and the rest were ECOG PS 1. Overall, 36% of patients had intermediate Rai risk (stage I–II) and 63% high Rai risk (stage 3–4) disease. Prognostic testing revealed that 36% were CD38+, 50% were Zap-70 +, and 39% had an unmutated IgVh status. Chromosome analysis by FISH found that 99% had detectable FISH panel defect, including 61%, 27% and 3% of patients with 1, 2, or 3 FISH detects, respectively. RESULTS: 28 of 33 patients (85%) completed therapy. While on treatment, 6 pts (18%) had a dose held or modified with 4 of these delays due to hematologic AE. For adverse events deemed at least possibly related to treatment, 4 (12%) pts experienced grade 3+ hematologic toxicity and 5 (15%) experienced grade 3+ non-hematologic toxicity. Out of all 33 enrolled patients, the overall response rate was 79% with 10 CR, 6 nPR, and 10 PR. At the time of this analysis, 29/33 patients are still alive with a median follow-up time of 14 months on surviving patients. To date 17/33 (52%) of patients have progressed with an estimated median time to progression of 12 months (95% CI: 8.5–21 months). 13/26 responders have progressed. Median duration of response is 12.5 months ((95% CI: 11–21 months). Finally, since eligibility were nearly identical and enrollment accrued at the same two academic centers, we compared the patient characteristics, response rates, and PFS of the 33 patients treated with PR to the 64 patients previously treated on our PCR trial. Patients in the two studies were generally similar with respect to demographic and prognostic characteristics, although patients in the PR trial had higher WBC and were less likely to be IgVH unmutated (Table). Although the differences in ORR and CR rate were not significantly different, the PFS appeared to be inferior in patients treated with PR as compared to PCR (12 months vs. 31 months; p=0.003). CONCLUSION: Although the PR regimen achieves a high OR response rate, the PFS appears inferior to PCR therapy. These findings suggest that increasing the purine nucleoside analogue dose does not eliminate the need to include cyclophosphamide in chemoimmunotherapy for patients with CLL. PCR Trial N=64 PR Trial N=33 P value Age, median(range) 63 years (38–80) 65 years (45–81) 0.34 ≥70 years(%) 28% 27% Male 77% 82% 0.61 Rai stage 0 5% 0 0.46 Rai stage I–II 42% 36% Rai stage III–IV 53% 64% White Cell Count, median(range) 79 × 109/L (11–519) 127 × 109/L (8–430) 0.04 <50 × 109/L 36% 28% 50–149 × 109/L 44% 25% >150 × 109/L 20% 47% Serum B2-microglobulin, median(range) 3.97 (1.8–13.5) 3.80 (2.0–8.2) 0.81 >2 × Upper Limit Normal(%) 57% 58% CD38 Positive 34% 36% 1.00 ZAP-70 Positive 36% 50% 0.26 IgVH Unmutated 71% 39% 0.004 FISH Normal, 11% 9% 13q- 35% 42% +12 21% 24% 6q- 2% 0 11q- 22% 18% 17p- 6% 3% other 3% 3% Overall Response Rate 91% 79% 0.12 Complete Response Rate 41% 30% 0.38 Median PFS 31 months 12 months 0.003

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Shanafelt, Tait D., Mark C. Lanasa, Clive S. Zent, Jose F. Leis, Timothy G. Call, Betsy R. LaPlant, Han Tun et al. „Ofatumumab Based Chemoimmunotherapy (CIT) for Patients with Previously Untreated CLL“,. Blood 118, Nr. 21 (18.11.2011): 3898. http://dx.doi.org/10.1182/blood.v118.21.3898.3898.

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Abstract Abstract 3898 Background: Although chemoimmunotherapy (CIT) has substantially improved response rates, treatment free survival, and overall survival in patients with chronic lymphocytic leukemia (CLL), only 4050 of patients achieve a complete remission and the majority have residual disease when evaluated using sensitive assays. There remains interest in identifying new approaches to improve the effectiveness of CIT. Ofatumumab is a humanized anti-CD20 monoclonal antibody that is approved for patients with relapsed CLL refractory to fludarabine and alemtuzumab. The single agent activity of ofatumumab in patients with refractory CLL suggests it may have greater efficacy than rituximab in patients with CLL. To explore the efficacy of ofatumumab based CIT, we initiated a clinical trial studying the effect of ofatumumab in combination with pentostatin and cyclophosphamide (PCO) for patients with previously untreated CLL. METHODS: Eligible patients were previously untreated and had CLL in need of treatment according to the NCI-WG criteria (Blood 111:5446). The treatment schema included 6 cycles of ofatumuamb (300 mg on day 1 of cycle 1;1000 mg on day 2 of cycle 1 and day 1 of cycles 26) followed by pentostatin (2 mg/m2) and cyclophosphamide (600 mg/m2) administered every 21 days. All patients underwent complete response evaluation including evaluation for MRD using sensitive flow cytometry (Leukemia 21:956) at the completion of treatment. RESULTS: 33 patients were enrolled at Mayo Clinic and Duke University between 3/2010 and 9/2010. All patients were eligible for treatment and have completed active treatment. Clinical characteristics included: 76 male, median age 63 (range: 5083); intermediate Rai risk 27; and high Rai risk 73. On prognostic testing 33 were CD38, 48 Zap-70 , 58 IGHV unmutated, and 6 had high risk FISH (del 17p13; del 11q22). 26 of 33 eligible patients (79) completed all 6 cycles of PCO induction. Seven patients went off treatment early (toxicity: n5; refusal: n1; progression: n1). Adverse events deemed at least possibly related to PCO induction included 8 (24) patients with grade 3 hematologic toxicity and 5 (15) with grade 3 non-hematologic toxicity. The overall response rate to PCO induction was 94 (31/33) with 15 (45) CR/CRi, 5 (15) CCR, 9 (27) nPR, and 2 (6) PR. 2/10 (20) patients with CR's tested for MRD were also MRD negative by 6 color flow cytometry analysis. Finally, we compared this cohort of patients treated with ofatumuamb-based CIT to our prior 108 patient cohort of patients treated with rituximab-based CIT both of which used an identical chemotherapy backbone (pentostatin and cyclophosphamide). Although the age, gender, ALC, and prognostic profile (CD38, ZAP-70, and IGHV mutation status) of treated patients were similar (all p0.3), the ofatumumab cohort included more advanced stage patients (Rai stage III/IV: 73 vs. 41 p0.002). Ofatumumab-based CIT appeared to be better tolerated than our previous experience with rituximab-based CIT (grade 3 hematologic toxicity ofatumumab-CIT 24 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} ${\scriptstyle \raisebox{1ex}{8$}\!\left/ \!\raisebox{-1ex}{$33$}\right.}\]$ \end{document} vs. rituximab-CIT51 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} ${\scriptstyle \raisebox{1ex}{55$}\!\left/ \!\raisebox{-1ex}{$108$}\right.}\]$ \end{document}, p0.009; grade 3 non-hematologic toxicity ofatumumab-CIT 15 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} ${\scriptstyle \raisebox{1ex}{5$}\!\left/ \!\raisebox{-1ex}{$33$}\right.}\]$ \end{document} vs. rituximab-CIT 24 \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} ${\scriptstyle \raisebox{1ex}{26$}\!\left/ \!\raisebox{-1ex}{$108$}\right.}\]$ \end{document}, p0.34). Despite a higher proportion of Rai Stage III/IV patients in the ofatumumab cohort, the efficacy of ofatumumab-based CIT also compared favorably to our previous experience with rituximab based CIT (Table). CONCLUSION: Front-line ofatumumab-based CIT appears to be well-tolerated in patients with CLL. Compared to our historic experience with rituximab based CIT, ofatumumab-based CIT appeared to have less hematologic toxicity and improved efficacy. This trial has been expanded to provide a larger experience with ofatumumab-based CIT. Disclosures: Shanafelt: Hospira: Research Funding; Glaxo-Smith-Kine: Research Funding; Genentech: Research Funding. Off Label Use: Off label use of pentostatin and Ofatumumab. Lanasa:GlaxoSmithKline: Consultancy, Speakers Bureau. Zent:GlaxoSmithKline: Research Funding; Genentech: Research Funding; Genzyme: Research Funding. Tun:Celgene: Research Funding. Kay:Biothera: Research Funding; Clegene: Research Funding; Cephalon: Research Funding; Genentech: Research Funding; Glaxo Smith Kline: Research Funding; Hospira: Research Funding; Novartis: Research Funding; Supergen: Research Funding; Calistoga: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Emergent Biosolutions (Formerly Trubion): Membership on an entity's Board of Directors or advisory committees.

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Montillo, Marco, Francesca Ricci, Alessandra Tedeschi, Sara Miqueleiz, Giovanni Grillo, Eleonora Vismara, Antonino Greco, Silvio Veronese und Enrica Morra. „Impact on Progression Free Survival of Autologous Stem Cell transplantation after Consolidation with Alemtuzumab in Chronic Lymphocytic Leukemia.“ Blood 112, Nr. 11 (16.11.2008): 2182. http://dx.doi.org/10.1182/blood.v112.11.2182.2182.

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Abstract The role of an intensified program of autologous stem cell transplantation (ASCT) following a consolidation phase with alemtuzumab (A) in pts with chronic lymphocytic leukemia (B-CLL) who received a fludarabine-based regimen (Fbr) as debulking is still considered questionable. The reported evidence of a prolonged treatment free-survival and survival associated to the absence of minimal residual disease (MRD) in B-CLL pts treated with A doesn’t seem to justify an intensification with ASCT in case of MRD-. We have already reported our experience in B-CLL pts treated with Fbr who after a median period of discontinuation of 16 weeks, received A sc (10 mg x 3/w for six weeks) in order to obtain the maximum response of MRD negative remission. Pts obtaining a successful peripheral blood stem cell harvest (PBSC) were considered eligible for ASCT. After a longer follow-up period we analyze here the outcome of autografted pts. Furthermore results were compared with those of pts treated with the same regimen but excluded from transplant procedure. Overall 48 pts have been considered for the analysis. Twenty-nine pts underwent an ASCT. Mobilization regimen consisted in all but 1 pt of Ara-C (800 mg/ sqm/12h x 3 days) followed by granulocyte colony-stimulating factor (G-CSF) while the last patient received only G-CSF. Reason for exclusion from ASCT procedure in the 19 non transplanted pts was: 9 refusal, 4 progressive disease, 1 evolution to Richter syndrome, 2 priming failure, 3 physician decision. Initially, in the group of non-transplanted pts, 9 (47%) were in stage A, 9 (47%) B, 1 (6%) C; ZAP70 was positive in 4 (21%) cases. Response after consolidation with A was: 7 MRD- CR (37%), 7 MRD+ CR (37%), 1 PRn (5%), 4 PR (21%). As regards the transplanted pts: 9 (31%) were in stage Binet A, 16 (55%) B, 4 (14%) C; ZAP70 was positive in 10 (34%) cases. Disease status after A was as follows: 18 MRD- CR (62%), 6 MRD+ CR (21%), 5 PRn (17%). Median age at transplant was 55 years (range 44–64). In all pts a reassessment of response status was ruled out before transplant to exclude a disease progression. ASCT procedure was performed after a median of 12 mos from last A administration (range 6.5–16.8). One pt who reactivated a virus B hepatitis after consolidation was successfully transplanted after 16.8 mos interval from alemtuzumab. Conditioning regimen consisted of 12 Gy total body irradiation plus cyclophosphamide 120 mg/kg in 21 pts <60 years, and melphalan 180 mg/m2 in 8 pts ≥60 years. Median number of CD34+ cells reinfused was 14x106/kg (range 3.1–41); in 15 cases (52%) the reinfused product was polyclonal for IgH rearrangement. The median time for PMN ≥500/mcL and PLT ≥20,000/mcL recovery was 9 (range 6–10 days) and 10 days (range 3–13 days) respectively. No incidence of grade 3–4 non hematologic toxicity was observed. None of the patients developed CMV reactivation, even in pts who showed a CMV reactivation during A treatment. One patient died (TRM 3.4%) due to a pulmonary fungal infection sustained by Aspergillus terreus. Disease assessment after transplant showed MRD- CR in 25 (86.2%) pts, in the remaining pts 2 MRD+ CR and 1 PRn were detected. In the transplanted population after a median follow-up of 46.3 mos (range 15.2–73.4) from last A administration and 35 mos from ASCT (range 2–59.8 months) 82% of pts are in CR according to NCI WG criteria. After the same follow-up period 20 (69%) pts are still in MRD- CR. Two pts died, one in MRD- CR for a lung cancer and one for fungal infection after transplant, two relapsed, after 45 and 15 mos respectively. In the non-transplanted pts after a median followup of 12 mos (range 1.5–64.2) from A 13 (68%) pts relapsed. Six pts died, 3 for disease progression, 1 for breast cancer, 1 for Richter syndrome and 1 for IMA while in MRD- CR. In conclusion in our experience ASCT following a chemo-immunotherapy confers a long disease free survival at 5 years (82%). Even if the population of non transplanted is not directly comparable, as transplanted pts were selected based on their response and the adequacy of the stem cell harvest, it is remarkable that in those pts the 5 year disease free survival is only of 32%. The in vivo “purging” effect of A given as consolidation facilitated the achievement of an high rate of MRD- PBSC collections. We can speculate that the reduced contamination of the reinfused product translated in sustained molecular remission after transplant. Moreover, this prospective single centre survey showed a low treatmentrelated mortality and absence of secondary MDS.

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Geyer, Mark Blaine, Jae H. Park, Isabelle Riviere, Brigitte Senechal, Xiuyan Wang, Terence J. Purdon, Michel W. Sadelain und Renier J. Brentjens. „Implications of Concurrent Ibrutinib Therapy on CAR T-Cell Manufacturing and Phenotype and on Clinical Outcomes Following CD19-Targeted CAR T-Cell Administration in Adults with Relapsed/Refractory CLL“. Blood 128, Nr. 22 (02.12.2016): 58. http://dx.doi.org/10.1182/blood.v128.22.58.58.

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Abstract Introduction: CD19-targeted chimeric antigen receptor-modified (CAR) T cells have demonstrated considerable therapeutic efficacy in patients (pts) with relapsed and/or refractory (R/R) B cell ALL (B-ALL), resulting in rapid and often durable complete responses (CR). In contrast, a smaller subset of pts with R/R CLL have achieved CR following CD19-targeted CAR T cell therapy. Ibrutinib (IBR), which has considerable efficacy as a single agent in pts with R/R CLL, may modulate antitumor T cell immune responses. Others have observed enhanced ex vivo expansion of autologous T cells collected from pts with IBR exposure in response to CD3/CD28 bead stimulation, and improved CD19-targeted CAR T cell engraftment and antitumor efficacy in human xenograft models (Fraietta et al., Blood, 2016). Herein, we report on adults with CLL treated with IBR at the time of autologous T cell collection and/or around the time of CAR T cell infusion enrolled in our phase I clinical trial of CD19-targeted CAR T cells for adults with R/R CLL or B-cell NHL (NCT00466531). Methods: Eligible pts underwent leukapheresis and T cells were transduced with a retroviral vector encoding a CAR comprising a CD19-specific scFv and CD28 and CD3ζ signaling domains (19-28z). The present analysis is limited to pts with CLL. We identified pts with CLL treated with IBR at the time of leukapheresis and/or around the time of conditioning chemotherapy (CCT) and CAR T cell infusion. As a control group, we additionally identified all evaluable IBR-naïve pts with CLL treated on this study. Response was assessed by NCI-WG criteria. Cytokine levels were measured prospectively before and after CCT and CAR T cell infusion. Results: 5 pts (male, n=3), median age 58 at CAR T cell infusion (range, 43-66) with R/R CLL (TP53 loss, n=2) underwent therapy with IBR at leukapheresis (n=4) and/or immediately prior to or through CCT (cyclophosphamide [Cy], n=2; fludarabine [Flu]+Cy, n=3) and CAR T cell infusion (n=5). 6 additional evaluable pts with R/R CLL remained IBR-naïve through CCT (Cy, n=4; bendamustine, n=2) and CAR T cell infusion. A non-significant trend toward greater median cumulative fold T cell expansion ex vivo was noted in the 4 pts on IBR (vs the 7 not on IBR) at leukapheresis (374 [171-1518] vs 160 [49-468], p=0.13), with similar median manufacturing time (13.5 vs 15 days). End of process (EOP) T cells in pts undergoing collection while on IBR (vs those not on IBR) demonstrated a greater fraction of CD8+CAR+ T cells with a CD62L+CD127+ (central memory) phenotype (mean 29.0 vs 4.3%, p=0.10) and decreased fraction of CD62L- T cells (effector/effector memory phenotype) across CD8+CAR+ (mean 26.5 vs 54.4%, p=0.06) and CD4+CAR+ (mean 24.0 vs 57.8%, p=0.03) T cell subsets (Fig 1). IBR-treated pts received median 1x107 19-28z+ CAR T cells/kg (3x106-3x107/kg) and IBR-naïve pts received median 1x107 19-28z+ CAR T cells/kg (6x106-4x107/kg). Fevers developed in all 11 pts and began on the first day of infusion in 4/5 IBR-treated pts (vs 2/6 IBR-naïve pts); 2/5 IBR-treated pts (vs 0/6 IBR- naïve pts) developed severe CRS and required vasopressors for hypotension in addition to tocilizumab. IBR-treated pts additionally exhibited greater median peak levels of multiple immunoregulatory cytokines associated with CRS, including IL-6, IL-10, IL-2, IL-5, IFN-γ, FLT3L, fractalkine, and GM-CSF. In total, 5 of 11 enrolled pts with CLL (45%) treated with CCT and 19-28z CAR T cells achieved objective response (minimal residual disease [MRD]- CR, n=2; maintenance of MRD+ CR, n=1; PR, n=2); ORR was 4/5 among IBR-treated pts (1 MRD- CR, 1 MRD+ CR, 2 PR; p=0.08 for ORR between IBR-treated vs IBR-naïve pts). 2 pts remain in MRD- CR at 16 and 50 months. Maximal CAR T cell persistence observed to date is 159 days; peak vector copy levels by qPCR were highest in the 2 pts attaining MRD-negative CR. Conclusions: Prior therapy with IBR may influence EOP CAR T cell phenotypes. Prior ± concurrent IBR may improve antitumor responses following 19-28z CAR T cell administration, though small numbers of pts and differences in CCT regimens limit firm conclusions based on these data. Additionally, prior ± concurrent IBR may amplify CRS, though more intensive CCT (e.g. Flu/Cy vs Cy) may also enhance CAR T cell expansion in vivo and intensify CRS. Further strategies to overcome the inhibitory microenvironment and enhance CAR T cell expansion and efficacy in pts with R/R CLL are in preparation. Disclosures Park: Amgen: Consultancy; Genentech/Roche: Research Funding; Juno Therapeutics: Consultancy, Research Funding. Riviere:Juno Therapeutics: Consultancy, Equity Ownership, Patents & Royalties, Research Funding. Sadelain:Juno Therapeutics: Consultancy, Equity Ownership, Patents & Royalties. Brentjens:Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Ross, L., D. Hansen, S. Proudman, D. Khanna, A. Herrick, W. Stevens, M. Baron und M. Nikpour. „OP0235 DEVELOPMENT AND PRELIMINARY VALIDATION OF THE NOVEL SCLERODERMA CLINICAL TRIALS CONSORTIUM ACTIVITY INDEX“. Annals of the Rheumatic Diseases 82, Suppl 1 (30.05.2023): 155–56. http://dx.doi.org/10.1136/annrheumdis-2023-eular.1239.

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BackgroundAccurate measurement of disease activity in systemic sclerosis (SSc) remains a significant challenge. Previous activity indices have been criticised for limitations of face and content validity.ObjectivesThe Scleroderma Clinical Trials Consortium (SCTC) convened an Activity Index Working Group to develop a disease activity index (SCTC AI) that has face, content and construct validity.MethodsConsensus was reached regarding the conceptual definition of disease activity in SSc. All SCTC AI items were required to be measures of the agreed upon construct.See Figure 1 for process of item generation. In all Delphi exercises ana priorithreshold of 70% agreement was applied for items to be included or excluded from subsequent rounds. Items that did not meet the threshold for inclusion across 2 survey rounds were omitted.Data from the Australian Scleroderma Cohort Study were used to reduce and weight items. Items were weighted using time dependent Cox proportional hazards regression analysis relative to a combined endpoint of mortality and morbidity (SF 36 physical component score (PCS) below cohort median value). Seven provisional items were not collected in the ASCS. A discrete choice experiment was performed to generate relative weightings for these items.Group based trajectory modelling (GBTM) was used to identify trajectory groups to compare the survival of low vs high disease activity groups using Kaplan Meier survival analyses. Cox proportional hazard modelling was used to evaluate the association between activity scores and mortality, morbidity and SCTC Damage Index (SCTC DI) scores.ResultsThe definition of disease activity as agreed by the SCTC AI WG is:Activity in SSc refers to aspects of disease, attributable to SSc, that are potentially reversible, or can be arrested, with time and/or effective therapy. Disease activity may be associated with morbidity and uncontrolled activity may lead to organ dysfunction and mortality.A 24 item index, spanning nine domains of disease was generated with a maximum score of 140 (Table 1). GBTM identified 3 trajectory groups: low activity (n=856 (49%) median baseline SCTC AI score 4 (IQR 0-6)); medium activity (n=745 (42%) median baseline SCTC AI score 10 (IQR 6-14)); high activity (n=164 (9%) median baseline SCTC AI score 16 (IQR 10-22)).There was a graded risk of death associated with increasing activity levels. 4 year survival was poorer in the high disease activity group compared to the low disease activity group (75% vs 95%, p<0.01). Patients with a SCTC AI ≥15.5 had a HR 3.5 (2.26-5.42 p<0.01) for death and greater morbidity was observed in individuals with a SCTC AI ≥9.5 (HR 1.90 (1.61-2.24 p<0.01). There was a significant relationship between SCTC AI scores and worsening damage; HR 4.43 (3.51-5.60, p<0.01) for 1 unit increase of SCTC DI for each unit increase in SCTC AI.ConclusionWe present a novel outcome measure to quantify the burden of disease activity in SSc. We have employed a rigorous consensus based methodology in combination with data driven methods, to develop an outcome measure that has face, content and criterion validity. Further work is required to externally validate and confirm the construct and discriminative validity of the SCTC AI.Table 1.SCTC Activity IndexItemScoreItemScoreChange mRSS ≥ +5 points*7New ILD on HRCT4New areas of skin thickening*7Worsening breathlessness**4Worsening skin symptoms**1New pulmonary arterial hypertension on RHC3Current digital tip ulcer, extra score for >1 digital ulcer3 (+1)Active scleroderma renal crisis10Current critical digital ischaemia9Acute or subacute systolic dysfunction5Worsening Raynaud’s phenomenon*1Active myocarditis9Current synovitis6Acute pericarditis6Current tendon friction rub7Elevated troponin8Active skeletal myositis6Elevated BNP8Change FVC ≥ -5%***8Worsening gastrointestinal symptoms**1Change DLCO ≥ -10%***7Elevated CRP6Increase ≥10% ILD extent***7≥10% unintentional weight loss***6*within 3 months**patient-reported in past month***within 6 monthsAcknowledgementsThis work was supported by Scleroderma Clinical Trials Consortium Working Group Grants and a Betty Z Benedict Award and private philanthropic donations.Disclosure of InterestsNone Declared.

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Wierda, W. G., T. Kipps, J. Mayer, S. Stilgenbauer, T. Robak, C. D. Williams, R. Furman, G. Chan, C. Russell und A. Österborg. „Activity of ofatumumab, a novel CD20 mAb, and prior rituximab exposure in patients with fludarabine- and alemtuzumab-refractory or bulky fludarabine-refractory chronic lymphocytic leukemia (CLL)“. Journal of Clinical Oncology 27, Nr. 15_suppl (20.05.2009): 7044. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.7044.

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7044^ Background: Salvage therapy has limited activity (20–26% overall response rate [ORR]) in patients (pts) with CLL refractory to fludarabine and alemtuzumab (double-refractory, DR) or refractory to fludarabine with bulky (>5 cm) lymphadenopathy (bulky fludarabine-refractory, BFR). Ofatumumab (OFA) is a fully human mAb that targets a unique small-loop epitope of CD20 close to the cell surface and elicits more potent in vitro complement-dependent cytotoxicity of B-cell lines and tumor cells vs rituximab (RTX). To determine whether prior RTX exposure impacted activity of OFA in pts with DR or BFR CLL, an analysis was performed to assess efficacy by prior RTX exposure in pts treated with OFA in an international, pivotal study. Methods: Pts with DR or BFR CLL received 8 weekly infusions of OFA followed by 4 monthly infusions (Dose 1, 300 mg; Doses 2–12, 2,000 mg). Primary endpoint was ORR (1996 NCI-WG criteria) assessed by an Independent Review Committee over 24 weeks. Secondary efficacy endpoints included progression-free survival (PFS) and overall survival (OS). Results: Among 138 treated pts (DR, N=59; BFR, N=79) at the planned interim analysis, the ORR (99% CI) was 58% (40, 74%) in the DR group and 47% (32, 62%) in the BFR group. Median PFS (95% CI) was 5.7 mo (4.5, 8.0) and 5.9 mo (4.9, 6.4), and median OS (95% CI) was 13.7 mo (9.4, NYR) and 15.4 mo (10.2, 20.2), respectively. 59% and 54% of DR and BFR pts, respectively, previously received RTX-containing regimens. Both ORR and median PFS were similar in the prior RTX and no prior RTX subgroups (Table), and were comparable to efficacy data for the overall study population. ORR and median PFS were also similar in pts refractory to fludarabine in combination with RTX with or without cyclophosphamide. Conclusions: Single-agent therapy with OFA is effective in pts with DR or BFR CLL, irrespective of prior CD20 mAb therapy with RTX. [Table: see text] [Table: see text] ASCO Conflict of Interest Policy and Exceptions In compliance with the guidelines established by the ASCO Conflict of Interest Policy (J Clin Oncol. 2006 Jan 20;24[3]:519–521) and the Accreditation Council for Continuing Medical Education (ACCME), ASCO strives to promote balance, independence, objectivity, and scientific rigor through disclosure of financial and other interests, and identification and management of potential conflicts. According to the ASCO Conflict of Interest Policy, the following financial and other relationships must be disclosed: employment or leadership position, consultant or advisory role, stock ownership, honoraria, research funding, expert testimony, and other remuneration (J Clin Oncol. 2006 Jan 20;24[3]:520). The ASCO Conflict of Interest Policy disclosure requirements apply to all authors who submit abstracts to the Annual Meeting. For clinical trials that began accrual on or after April 29, 2004, ASCO's Policy places some restrictions on the financial relationships of principal investigators (J Clin Oncol. 2006 Jan 20;24[3]:521). If a principal investigator holds any restricted relationships, his or her abstract will be ineligible for placement in the 2009 Annual Meeting unless the ASCO Ethics Committee grants an exception. Among the circumstances that might justify an exception are that the principal investigator (1) is a widely acknowledged expert in a particular therapeutic area; (2) is the inventor of a unique technology or treatment being evaluated in the clinical trial; or (3) is involved in international clinical oncology research and has acted consistently with recognized international standards of ethics in the conduct of clinical research. NIH-sponsored trials are exempt from the Policy restrictions. Abstracts for which authors requested and have been granted an exception in accordance with ASCO's Policy are designated with a caret symbol (^) in the Annual Meeting Proceedings. For more information about the ASCO Conflict of Interest Policy and the exceptions process, please visit www.asco.org/conflictofinterest .

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Yeh, Albert, Madan Jagasia, Kimberly Dahlman, Jonathan Michael Irish, Anupama Reddy, Sierra Barone, Kate Chilson et al. „Cytomegalovirus Promotes Aberrant Memory CD4 T Cell Differentiation and Immune Function after Allogeneic Stem Cell Transplantation“. Blood 136, Supplement 1 (05.11.2020): 15–16. http://dx.doi.org/10.1182/blood-2020-134829.

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Background: Cytomegalovirus (CMV) serostatus is associated with transplant related mortality, relapse and survival following allogeneic stem cell transplant (SCT). Prior studies have demonstrated that CMV seronegative recipients (R-) receiving a CMV seropositive graft (D+) experience inferior outcomes compared to the R-/D- combination, an observation that is independent of viral reactivation and due to increased bacterial and fungal sepsis (Nichols WG et al, J. Infect. Dis. 2002; 185:273-82). We therefore investigated the hypothesis that CMV exposure, including that by the donor only prior to transplant, promotes endogenous and long-term immunodeficiency after SCT. Methods: A total of 108 patient peripheral blood samples were obtained from the Chronic Graft-vs.-Disease (GVHD) Consortium, which includes both patients with and without chronic GVHD. Seventy-three baseline samples were taken at an average of 458 days (range 63 to 1,965) after SCT, and 35 paired blood samples were taken at an average of 94 days follow-up. Transplant parameters, CMV serostatus, and CMV viral titers after SCT were collected. We performed multiparameter flow cytometry to assess innate and adaptive immunity after SCT in the context of CMV, including transcription factor and cytokine expression, together with TCR/BCR sequencing to assess immune diversity. Results: We demonstrate that CMV exposure (including solely in the donor prior to transplant or in the recipient after transplant) is strongly associated with long-lasting expansion of a terminally differentiated MHC class II-restricted donor memory T cell subset identifiable by the surface markers CD4+/CD57+/CD27-(Figure 1). These cells are CCR7neg/CD45RO+/CD45RA+/-, express T-bet, eomesodermin (EOMES), granzyme B, and secret high amounts of Th1 cytokines IFNγ and TNF (Figure 1). This T cell subset represents an average of 2.8% for D-/R- transplants and >10% (and up to 70%) of total CD4+ T cells in all other serostatus combinations irrespective of the presence or absence of measurable CMV reactivation after SCT (p<0.05 across all pairwise comparisons with D-/R- subset, Figure 2). Furthermore, this phenotype persists in an expanded fashion for years following SCT (samples were taken up to 5 years post-SCT). Follow-up samples from the same patient taken up to 218 days after the initial sample confirm phenotypic stability over time (r=0.90, p<0.0001, Figure 3). Detectable CMV replication after SCT further augmented this memory CD4+ T cell subset, and antiviral treatment for CMV did not limit its expansion. We demonstrate that these differentiated memory CD4+ T cells are associated with a significant loss of T cell receptor diversity (r=-0.60, p=0.004) and reduced proportions of major histocompatibility class (MHC) II expressing classical monocytes (r=-0.43, p=0.0002) and plasmacytoid dendritic cells (r=-0.31, p=0.0085) in peripheral blood. Conclusion: These data describe a temporally stable, expanded MHC class II-restricted memory T cell population with high cytotoxic potential and putative mechanisms by which CMV exposure modifies immune function in the peri-transplant period, namely the limitation of TCR diversity and antigen presentation. This cell population is expanded even in the absence of detectable CMV reactivation post SCT and can be observed for several years following transplant. We thus provide a potential mechanism for the immunodeficiency and broad increase in infection mortality invoked by CMV exposure. In particular, these findings may provide a rationale for supporting the selection of CMV- donors for R- SCT recipients. Disclosures Jagasia: Ocugen: Other; Mallinckrodt: Research Funding; Janssen: Research Funding. Dahlman:Kadmon Holdings, Inc: Other. Lee:Syndax: Research Funding; Pfizer: Consultancy, Research Funding; AstraZeneca: Research Funding; Amgen: Research Funding; Kadmon: Research Funding; Takeda: Research Funding; Novartis: Research Funding; Incyte: Consultancy, Research Funding. Hill:Generon: Consultancy; Roche: Research Funding; Compass Pharmaceuticals: Research Funding; CSL: Research Funding; Implicit Bioscience: Research Funding; Pharmacyclics: Research Funding.

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Mostoviak, S., I. Mostoviak, O. Borzykh und V. Fedorenko. „Ecotoxicological assessment of the application of chemical products of plant protection against pests“. Karantin i zahist roslin, Nr. 3 (26.09.2022): 3–10. http://dx.doi.org/10.36495/2312-0614.2022.3.3-10.

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Goal. To analyze the number of insecticides and acaricides during the cultivation of crops in Ukraine and in the central part of the Right Bank Forest-Steppe of Ukraine and to determine the degree of danger of their application. Methods. Analytical, economic and statistical, comparative analysis. The analysis of the amount of chemical plant protection products for 2018—2020 was conducted according to the State Statistics Service of Ukraine. Ecotoxicological assessment of 23 chemicals was performed using the Methodologies of the Institute of Plant Protection of NAAS of Ukraine according to the safety data sheet of the preparations and the properties of the active ingredient. The assessment of the level of potential danger of insecticides and acaricides was performed according to the integrated classification of pesticides according to the degree of danger of their application, taking into account indicators of pesticide toxicity (LD50) and their half-life (T50) in soil. Results. In 2018—2020, on average, 1,750.5 thousand kg/ year of chemical pesticides were used in Ukraine, including 279.1 thousand kg in the territory of the Central Forest Steppe. The most common in Ukraine are preparations based on active agent chlorpyrifos (743.0 thousand kg/ year), active agent dimethoate (95 thousand kg/ year) and active agent lambda-cyhalothrin (80.2 thousand kg/ year), which are stable in soil and according to the indicator of acute oral toxicity are classified as hazard classes 2 and 3. The most common acaricides against ticks are those based on active agent clofentezine and pyridaben (3.01 and 3.08 thousand kg/ year, respectively). It was found that insecticides Danadim Mix, EC (Dimetoat, 400 g/ l + Gamma-Cyhalothrin, 4 g/ l), Lamdex, mc.s. (Dimetoat, 400 g/ l + Gamma-Cyhalothrin, 4 g/ l), Rimon Fast, SC (Novaluron, 50 g/ l + Bifenthrin, 50 g/ l), Cezar e.c. (Bifenthrin, 100 g/ l), Shaman, EC (Chlorpyrifos, 500 g/ l + Cypermethrin, 50 g/ l) and acaricide Sunmite, m.p. (Pyridabem, 200 g/ kg) with LD50 55—160 mg/ kg. Most preparations are highly resistant chemical compounds with half-life (Т50) in soil 51-386 days. These are: Aktara 25WG, w.g. (Thiamethoxam, 250 g/ kg), Ampligo 150 ZC, FC (Chlorantraniliprole, 100 g/ l + Lambda-Cyhalothrin, 50 g/ l), Voliam Flexi 300 SC, e.c. (Thiamethoxam, 200 g/ l + Lambda-Cyhalothrin, 100 g/ l), Engio 247 SC, s.c. (Lambda-Cyhalothrin, 106 g/ l + Thiamethoxam, 141 g/ l), Coragen 20, s.c. (Chlorantraniliprole, 200 g/ l), Lamdex, mc.s. (Lambda-Cyhalothrin, 50 g/ l), Mavrik, BE (Tau-fluvalinate, 240 g/ l), Rimon Fast, SC (Novaluron, 50 g/ l + Bifenthrin, 50 g/ l), Cezar e.c. (Bifenthrin, 100 g/ l), Shaman e.c. (Chlorpyrifos, 500 g/ l + Cypermethrin, 50 g/ l), Apollo, s.c. (Clofentesin, 500 g/ l), Sunmite, m.p. (Pyridaben, 200 g/ кg). Conclusions. In Ukraine and in the Central Forest-Steppe the amounts of chemical plant protection products are considerable, which increases the emergence of environmental risks in agrophytocenosis. Most pesticides contain active agent with a high rate of acute oral toxicity and are classified as hazard class 2. According to the degree of danger level, preparations Decis Profi WG (Deltamethin, 250 g/ кg), Decis f-Lux 25 EC (Deltamethin, 25 g/ l), Kalipso 480 SC (Thiacloprid, 480 g/ l), Kormoran, EC (Novaluron, 100 g/ l + Acetamiprid, 80 g/ l), Proclaim 5 SG (Emamectin benzoane, 50 g/ кg), Rubizh, e.c. (Dimetoat, 400 g/ l) belong to low-hazardper (danger level 6—7). According to the combination of ecotoxicological and sanitary-hygienic indicators, dangerous pesticides (3 degree) include preparations Ampligo 150 ZC, FK (Chlorantraniliprole, 100 g/ l + Lambda-Cyhalothrin, 50 g/ l), Engio 247 SC, s.c. (Lambda-Cyhalothrin, 106 g/ l + Thiamethoxam, 141 g/ l) and Masai, s.p. (Tebufenpyrad, 200 g/ кg), very dangerous — (2 degree) — Lamdex, mc.s. (Lambda-Cyhalothrin, 50 g/ l), Rimon Fast, SC (Novaluron, 50 g/ l + Bifenthrin, 50 g/ l), Cezar e.c. (Bifenthrin, 100 g/ l) and Sunmite, m.p. (Pyridabem 200 g/ kg). These preparations are highly toxic and decompose in agrophytocenosis slowly, and therefore their use should be limited to reduce environmental risks.

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Osterborg, Anders, Thomas J. Kipps, Jiri Mayer, Stephan Stilgenbauer, Catherine D. Williams, Andrzej Hellmen, Tadeusz Robak et al. „Ofatumumab (HuMax-CD20), a Novel CD20 Monoclonal Antibody, Is An Active Treatment for Patients with CLL Refractory to Both Fludarabine and Alemtuzumab or Bulky Fludarabine-Refractory Disease: Results from the Planned Interim Analysis of An International Pivotal Trial“. Blood 112, Nr. 11 (16.11.2008): 328. http://dx.doi.org/10.1182/blood.v112.11.328.328.

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Abstract Background: The prognosis for patients with CLL refractory to fludarabine and alemtuzumab (double-refractory, DR) or refractory to fludarabine with bulky (>5cm) lymphadenopathy (bulky fludarabine-refractory, BFR) is poor. The overall response rate (ORR) to salvage therapy for such patients is approximately 20% with a median survival of 9 mo (Tam et al, Leuk Lym, 2007). New effective treatments are needed for these patients. Ofatumumab (HuMax-CD20) is a human monoclonal antibody that targets a unique small-loop epitope on CD20 and elicits potent in vitro complement-dependent cytotoxicity, even in malignant B cells with low CD20 expression levels. We report on a planned interim analysis of an international, multicenter, pivotal study of ofatumumab in patients with DR and BFR CLL. Methods: Patients with DR or BFR CLL received 8 weekly infusions of ofatumumab followed by 4 monthly infusions (Dose 1, 300 mg; Doses 2–12, 2000 mg). Patients were premedicated with paracetamol, antihistamine and glucocorticoid. The primary end point was ORR (1996 NCI-WG response criteria) assessed by an Independent end points Review Committee (IRC) over a 24 wk period. Overall survival (OS) and safety were also evaluated. Results: This interim analysis included all 138 treated patients (DR, n=59; BFR, n=79: Table); 54% received all 12 infusions and 90% received □8 infusions. The ORR (99% CI) based upon IRC assessment was 51% (34, 68%) for the DR group and 44% (30, 59%) for the BFR group; 1 patient had CR. Additionally, a considerable number of patients had stable disease (Table). Median time to next CLL therapy was 9 mo for the DR group and 8 mo for the BFR group (Table); clinical progression was typically due to worsening lymphadenopathy. The median OS was about 14 mo for the DR group and 15 mo for the BFR group (Table); based upon a landmark analysis at wk 12, response was significantly correlated with longer survival for both groups. Updated efficacy results will be presented at the meeting. Ofatumumab was associated with infusion-related adverse events on the first infusion day in 46% of patients in the DR group and 38% in the BFR group, which were grade 3 (no grade 4) in 7% and 3%, respectively (only 1 grade 3 event was considered a serious adverse event). These events generally subsided with subsequent infusions. The most common grade 3 or 4 toxicities were infections (25% in DR; 27% in BFR group) and hematologic events including neutropenia (12% in DR; 10% in BFR group) and anemia (8% in DR; 4% in BFR group). Early death (within 8 wks from start of treatment) occurred in 2 patients (3%) in the DR group (sepsis, n=1; fungal pneumonia, n=1) and 3 patients (4%) in the BFR group (PD, n=1; sepsis, n=1; myocardial infarction, n=1). No patient tested developed antibodies to ofatumumab. Conclusions: These results demonstrate the effectiveness of ofatumumab in patients with double-refractory CLL or bulky fludarabine-refractory disease. Ofatumumab was well tolerated with no unexpected toxicities. This monoclonal antibody potentially represents an active treatment option with clinical benefit for patients with very poor prognosis who have exhausted standard treatment options. The encouraging single-agent activity in patients with refractory CLL warrants further investigation of ofatumumab in earlier disease settings, in combination with other agents, as maintenance, and in other B-cell malignancies. Table DR (n=59) BFR (n=79) CI=confidence interval; NR=not reached Characteristic Median(range) Age, yrs 64 (41–86) 62 (43–84) No. of prior treatments 5 (1–14) 4 (1–16) % of patients Rai Stage III/IV 54 70 Binet Stage C 51 65 ECOG performance status 0 44 30 1–2 53 67 Lymph node or CT lesion >5cm 93 100 Prior rituximab-containing regimen 59 54 ORR (%) (99% CI) 51 (34, 68) 44 (30, 59) Complete response 0 1 Partial response 51 43 Stable disease 39 43 Progressive disease 3 10 Median (95% CI) Time to next CLL therapy, mo 9.0 (7.3, 10.7) 7.9 (7.1, 9.3) Overall survival, mo 13.7 (9.4, NR) 15.4 (10.2, 20.2)

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