Zeitschriftenartikel: „629.802 89“

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Beringer, Richard E. „Media Review“. Teaching History: A Journal of Methods 13, Nr. 2 (05.05.1988): 76–79. http://dx.doi.org/10.33043/th.13.2.76-79.

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Leaders of the 20th Century. 26 videocassettes, each 24 minutes. Film study guides for each film and a companion volume. Available in 1/2" VHS, 1/2" Beta I or II, and 3/4" U-Matic. Order from Learning Corporation of America, 108 Wilmot Road, Deerfield, IL 60015. 1-800-621-2121. $89 per unit ($79 per unit if order ten or more). Review by Richard E. Beringer of the University of North Dakota.

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Ozturk, Fahrettin, Serkan Toros, Suleyman Kilic und Ilyas Kacar. „Evaluation of Anisotropy by Two Different Tests for TRIP800 Steel“. Key Engineering Materials 622-623 (September 2014): 1139–44. http://dx.doi.org/10.4028/www.scientific.net/kem.622-623.1139.

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For the process modeling, material properties such as anisotropy values at different orientation are very important. The most commonly used method for the determining of the anisotropy values is the tensile test that is performed for samples are prepared at different orientation. Besides the tensile test, the anisotropy parameters of TRIP 800 steel are measured with the hole-expansion test. The effects of the test methods on the yield surfaces are determined for using two different anisotropic yield criteria are Hill-48 and Barlat-89. Results illustrated that a significant difference is observed in the yield surfaces for the two test methods. The material under biaxial deformation is deformed plastically faster than the uniaxial deformation mode.

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Jontof-Hutter, Daniel, Paul A. Dalba und John H. Livingston. „TESS Observations of Kepler Systems with Transit Timing Variations“. Astronomical Journal 164, Nr. 2 (07.07.2022): 42. http://dx.doi.org/10.3847/1538-3881/ac7396.

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Abstract We identify targets in the Kepler field that may be characterized by transit timing variations and are detectable by the Transiting Exoplanet Survey Satellite (TESS). Despite the reduced signal-to-noise ratio of TESS transits compared to Kepler, we recover 48 transits from 13 systems in Sectors 14, 15, 26, 40 and 41. We find strong evidence of a nontransiting perturber orbiting Kepler-396 (KOI-2672) and explore two possible cases of a third planet in that system that could explain the measured transit times. We update the ephemerides and mass constraints where possible at KOI-70 (Kepler-20), KOI-82 (Kepler-102), KOI-94 (Kepler-89), KOI-137 (Kepler-18), KOI-244 (Kepler-25), KOI-245 (Kepler-37), KOI-282 (Kepler-130), KOI-377 (Kepler-9), KOI-620 (Kepler-51), KOI-806 (Kepler-30), KOI-1353 (Kepler-289), and KOI-1783 (Kepler-1662).

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Qin, Lu, Dongqi Wang, Zhe Zhang, Xiaoxiao Li, Guodong Chai, Yishan Lin, Cong Liu et al. „Impact of Dissolved Oxygen on the Performance and Microbial Dynamics in Side-Stream Activated Sludge Hydrolysis Process“. Water 15, Nr. 11 (23.05.2023): 1977. http://dx.doi.org/10.3390/w15111977.

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Dissolved oxygen (DO) plays an important role in the performance of biological wastewater treatment systems. This study investigated the effect of the DO concentration on nutrient removal performance and microbial community structure in side-stream activated sludge hydrolysis (SSH) and conventional anaerobic/anoxic/aerobic (A2O) processes. The results showed that the change in DO had little effect on the removal performance of chemical oxygen demand (COD), and the removal efficiencies were about 90% for both reactors. Compared with the high DO level (4.1–6.9 mg/L), the A2O and SSH reactors had better nitrogen removal performance at low (0.5–2.2 mg/L) and moderate (2.2–3.9 mg/L) DO levels, with ammonia (NH4+-N) removal efficiencies of 88–89% and 89–91%, respectively, and total nitrogen (TN) removal efficiencies of 74–76% and 75–81%, respectively. Directly reducing the DO concentration from high to low reduced the phosphate removal efficiencies of the A2O and SSH reactors from 80.2% and 86.2% to 63.1% and 70.6%, respectively, while re-elevating the DO concentration to moderate levels significantly improved the phosphate removal efficiencies to 94.6% and 96.0%, respectively. Compared to the A2O reactor, the SSH reactor had more stable and better nutrient removal performance under different DO conditions, partly due to the additional carbon sources produced through the sludge fermentation in the side-stream reactor. The decrease in the DO concentration resulted in a decrease in the relative abundance of Acinetobacter but an increase in the relative abundance of Competibacter, potentially leading to the deterioration in phosphorus removal.

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Yu, Helena Alexandra, Camelia S. Sima, Ronglai Shen, Samantha Lindsay Kass, Mark G. Kris, Marc Ladanyi und Gregory J. Riely. „Comparison of the characteristics and clinical course of 677 patients with metastatic lung cancers with mutations in KRAS codons 12 and 13.“ Journal of Clinical Oncology 31, Nr. 15_suppl (20.05.2013): 8025. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.8025.

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8025 Background: Patients (pts) with KRAS mutant lung cancers have a shorter survival compared to pts with KRAS/EGFR wild type tumors (Johnson et al, Cancer 2012). Whether outcomes for patients with KRAS mutant metastatic lung cancers differ by smoking status or specific amino acid substitution is unknown. In order to understand the impact of KRAS mutation subtype in the metastatic setting, we analyzed a large cohort of patients with KRAS mutant metastatic lung cancer. Methods: We identified all pts with KRAS mutant metastatic or recurrent lung cancers from Feb 2005 to Aug 2011. KRAS mutation type, clinical characteristics, and outcomes from diagnosis were obtained from the medical record. A multivariate cox proportion hazard model was used to identify factors associated with overall survival. Results: KRAS mutations were identified in 677 pts (53 at codon 13, 624 at codon 12). Median age: 66 (range 31-89), women: 62%, never smokers: 7%. Pts with transition mutations (n=157) were more likely to be never-smokers (p<0.0001). There was no difference in outcome for pts with KRAS transition versus transversion mutations (p=1) or when comparing current/former smokers to never smokers (p=0.33). There was no difference in overall survival (OS) when comparing specific amino acid substitutions (G12C=366, G12V=141, G12D=114, G12A=68, G13C=27, G13D=23, G12S=19, G12F=11)(p=0.20). Pts with KRAS codon 13 mutant tumors had inferior OS compared to pts with codon 12 mutant tumors, median 13 months (mo) (95% CI 13-17 mo) and 16 mo (95% CI 9-16 mo), respectively (p=0.009). There was no difference in frequency of receiving platinum-based chemotherapy or chemotherapy of any kind between pts with codon 12 and 13 mutant tumors. In a multivariate Cox model which included age, gender and smoking status, KRAS codon 13 mutation was associated with worse overall survival than KRAS codon 12 mutation (HR 1.52 95% CI 1.11-2.08 p=0.008). Conclusions: Among pts with KRAS mutant metastatic lung cancers, smoking history, and specific amino acid substitution do not affect outcome. Patients with KRAS codon 13 mutant metastatic lung cancer have shorter survival compared to pts with KRAS codon 12 mutant lung cancer.

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Arciero, P. J., A. W. Gardner, J. Calles-Escandon, N. L. Benowitz und E. T. Poehlman. „Effects of caffeine ingestion on NE kinetics, fat oxidation, and energy expenditure in younger and older men“. American Journal of Physiology-Endocrinology and Metabolism 268, Nr. 6 (01.06.1995): E1192—E1198. http://dx.doi.org/10.1152/ajpendo.1995.268.6.e1192.

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Age-related differences in energy expenditure, fat oxidation, and norepinephrine (NE) kinetics after caffeine ingestion were examined using a placebo-controlled double-blind study in 10 older (O, 65-80 yr) and 10 younger (Y, 19-26 yr) men who were moderate consumers of caffeine. Caffeine ingestion resulted in similar increases in Y and O men for plasma caffeine levels (Y = 89 +/- 100 to 6,340 +/- 1,938 ng/ml, P < 0.05; O = 124 +/- 38 to 7,066 +/- 2,366 ng/ml, P < 0.05) and energy expenditure (Y = 11%, 1.38 +/- 0.15 to 1.52 +/- 0.22 kcal/min, P < 0.05; O = 9.5%, 1.15 +/- 0.13 to 1.26 +/- 0.20 kcal/min, P < 0.05). However, caffeine ingestion increased fatty acid concentrations (362 +/- 159 to 803 +/- 253 mumol/l, P < 0.05) and tended to increase rate of appearance of fatty acids (624 +/- 376 to 1,394 +/- 1,331 mumol/l, P = 0.07) in younger but not older men. Rates of fat oxidation and NE appearance and clearance did not significantly differ from baseline values in either group. In conclusion, older and younger men show a similar thermogenic response to caffeine ingestion, whereas older men show a smaller increase in fatty acid availability after a caffeine challenge. These metabolic differences are not related to alterations in NE kinetics or fat oxidation.

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Quoix, E. A., J. Oster, V. Westeel, E. Pichon, G. Zalcman, L. Baudrin, A. Lavole, J. Dauba, M. Lebitasy und B. J. Milleron. „Weekly paclitaxel combined with monthly carboplatin versus single-agent therapy in patients age 70 to 89: IFCT-0501 randomized phase III study in advanced non-small cell lung cancer (NSCLC).“ Journal of Clinical Oncology 28, Nr. 18_suppl (20.06.2010): 2. http://dx.doi.org/10.1200/jco.2010.28.18_suppl.2.

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2 Background: Incidence of advanced NSCLC in the elderly is increasing. Specific trials for elderly are seldom and those patients are not optimally treated. Current recommendations are monotherapies with gemcitabine or vinorelbine. Methods: French multicentric randomized phase III study in pts aged 70 to 89, PS 0-2 with advanced NSCLC not irradiable, comparing a 3-weekly single agent therapy (gemcitabine 1,150 mg/m2 or vinorelbine 30 mg/m2, d1, d8: arm A) with carboplatin AUC 6 every 4 weeks + paclitaxel 90 mg/m2 (d1,8,15) doublet (arm B). Five cycles of single agent and 4 cycles of the doublet were to be given. Second-line in case of toxicity or progressive disease was fixed with erlotinib 150 mg/d. The main endpoint was overall survival. Results: 451 pts were included from 04/2005 to 12/2009 by 60 centers. Males were 73.8%, median age was 77.2 years (range 70-89). PS was 0-1 in 73.6%. The 2 arms were well-balanced for pts characteristics. At time of second planned intermediate analysis (after two-third of expected deaths, i.e. 224), 451 pts were randomized, out of the 522 initially planned. The steering committee advice was to stop the inclusions. Overall survival of the 313 pts analysed at this time was significantly longer in arm B (median: 10.4 months, 95%CI: [8.2; 15.0] vs. 6.2 months, 95%CI: [5.3; 7.5] for arm A, (HR = 0.60, 95%CI : [0.46; 0.78], p = 0.0001). Median PFS was 6.3 months, 95%CI: [5.5; 6.9] in arm B vs. 3.2 months, 95%CI: [0.44; 0.70] (HR = 0.55, 95%CI: [0.44; 0.70], p < 0.0001). Grade 3-4 haematological toxicities were significantly more frequent in arm B (17.9% vs. 54.1%). No significant difference was observed in early deaths (arm A: 23.7%, arm B: 16.6%). Survival, response and toxicity data for the whole series of 451 pts will be updated at time of the meeting. Conclusions: Paclitaxel and carboplatin doublet provides a significantly longer survival in elderly pts with advanced NSCLC than current standard single agent therapy, with acceptable toxicity, making it a new treatment paradigm for PS 0-2 pts ≥ 70 years. [Table: see text]

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Rady, Mostafa M., Mohamed M. M. Salama, Sebnem Kuşvuran, Alpaslan Kuşvuran, Atef F. Ahmed, Esmat F. Ali, Hamada A. Farouk, Ashraf Sh Osman, Khaled A. Selim und Amr E. M. Mahmoud. „Exploring the Role of Novel Biostimulators in Suppressing Oxidative Stress and Reinforcing the Antioxidant Defense Systems in Cucurbita pepo Plants Exposed to Cadmium and Lead Toxicity“. Agronomy 13, Nr. 7 (20.07.2023): 1916. http://dx.doi.org/10.3390/agronomy13071916.

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The use of bio-stimulants (BSs) has become an important policy in managing many stressed crop plants through the regulation of the balance of phytohormones, osmo-protectors (OPs), antioxidant systems, and gene expression, all of which reflect plant growth and productivity. Garlic + onion extract (GOE) at a concentration of 2.0–3.0% and diluted bee honey solution (BHs) at a concentration of 1.0–1.5% were applied exogenously to squash (Cucurbita pepo) plants subjected to cadmium (Cd) + lead (Pb) stress (0.3 mM CdCl2 + 0.3 mM PbCl2). The objective was to determine the effects of these treatments on growth characteristics, organic metabolites/biomolecules, and mineral nutrients. Cd + Pb stress significantly increased electrolyte leakage (EL, 103%) and malondialdehyde (MDA, 90%) because of an increase in hydrogen peroxide (H2O2, 145%) and superoxide (O2•−, 152%) levels, and contents of abscisic acid (ABA, 164%), Cd (674–711%), and Pb (754–805%). Consequently, marked increases in the contents of OPs and non-enzymatic antioxidants (28–133%), activities of antioxidant enzymes (48–80%), and expressions of enzyme genes (60–84%) were observed. The administration of Cd + Pb treatment reduced plant growth and development parameters (25–59%), yield components (61–86%), photosynthetic components (27–67%), leaf proportional water content (26%), indole-3-acetic acid (IAA, 44%), gibberellic acid (GA3, 56%), and cyto-kinin (CKs, 49%) contents. Nonetheless, the administration of GOE, BHs, and GOE + BHs attenuated the adverse impacts of Cd + Pb stress. The best treatment was GOE + BHs which significantly decreased EL (52%) and MDA (49%) because of a reduction of O2•– (61%), H2O2 (60%), ABA (63%), Cd (89–91%), and Pb (89–91%) levels. This positive outcome was linked to an increase in the OPs’ (22–46%) and non-enzymatic antioxidant (27–46%) levels, activities of enzymes (26–44%), and enzyme gene expressions (35–40%), all of which contributed to the promoted relative water content (RWC, 37%), pigment contents (47–194%), hormonal levels (82–132%), growth traits (31–149%), yield components (154–626%), and fruit quality traits (31–92%). From these results, it can be concluded that treatment of GOE + BHs is recommended as a foliar application to reduce the adverse effects of Cd + Pb stress treatment in squash.

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Jones, Robert J., Syed A. Hussain, Andrew S. Protheroe, Alison Birtle, Prabir Chakraborti, Robert A. Huddart, Satinder Jagdev et al. „Randomized Phase II Study Investigating Pazopanib Versus Weekly Paclitaxel in Relapsed or Progressive Urothelial Cancer“. Journal of Clinical Oncology 35, Nr. 16 (01.06.2017): 1770–77. http://dx.doi.org/10.1200/jco.2016.70.7828.

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Purpose Two previous single-arm trials have drawn conflicting conclusions regarding the activity of pazopanib in urothelial cancers after failure of platinum-based chemotherapy. Patients and Methods This randomized (1:1) open-label phase II trial compared the efficacy of pazopanib 800 mg orally with paclitaxel (80 mg/m2 days 1, 8, and 15 every 28 days) in the second-line setting. The primary end point was overall survival (OS). Results Between August 2012 and October 2014, 131 patients, out of 140 planned, were randomly assigned. The study was terminated early on the recommendation of the independent data monitoring committee because of futility. Final analysis after the preplanned number of deaths (n = 110) occurred after a median follow-up of 18 months. One hundred fifteen deaths had occurred at the final data extract presented here. Median OS was 8.0 months for paclitaxel (80% CI, 6.9 to 9.7 months) and 4.7 months for pazopanib (80% CI, 4.2 to 6.4 months). The hazard ratio (HR) adjusted for baseline stratification factors was 1.28 (80% CI, 0.99 to 1.67; one-sided P = .89). Median progression-free survival was 4.1 months for paclitaxel (80% CI, 3.0 to 5.6 months) and 3.1 months for pazopanib (80% CI, 2.7 to 4.6 months; HR, 1.09; 80% CI, 0.85 to 1.40; one-sided P = .67). Discontinuations for toxicity occurred in 7.8% and 23.1% for paclitaxel and pazopanib, respectively. Conclusion Pazopanib did not have greater efficacy than paclitaxel in the second-line treatment of urothelial cancers. There was a trend toward superior OS for paclitaxel.

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Pabst, Gabriel, Katharina Prochazka, Gudrun Pregartner, Frank G. Rücker, Ellen Heitzer, Albert Woelfler, Armin Zebisch, Andrea Berghold, Konstanze Döhner und Heinz Sill. „Impact of TP53 Mutated Subclones in Acute Myeloid Leukemia“. Blood 132, Supplement 1 (29.11.2018): 1483. http://dx.doi.org/10.1182/blood-2018-99-110667.

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Abstract Introduction Acute myeloid leukemia (AML) with "TP53 mutation, chromosomal aneuploidy or both" has recently been described as a distinct AML subgroup exhibiting an exceedingly adverse prognosis. Therefore, testing for TP53 mutations has become an essential part of the European LeukemiaNet 2017 recommendations for risk classification. However, the incidence and pathogenic role of subclonal TP53 mutations defined by a variant allele frequency (VAF) <20% has not been addressed in this disorder yet. Methods We evaluated the prognostic value of TP53 VAFs in a cohort of 1537 patients with newly diagnosed AML, prospectively treated within 3 trials of the "German-Austrian AML Study Group". Mutation testing was performed by targeted deep sequencing and patients with TP53 mutations were categorized into 3 groups defined by VAFs <20%, 20%-40% and >40%, respectively. Results A total of 108 TP53 mutations were identified in 98 patients (6.4%). Amongst those, 61 patients showed a VAF >40%, 19 a VAF between 20% and 40% and 18 a VAF <20%. In either group, the majority of mutations were missense substitutions (VAF >40%, 49/61 [80%]; 20%-40%, 17/19 [89%]; <20%, 17/18 [94%]) and were located in the DNA binding domain of the gene (VAF >40%, 49/61 [80%]; 20%-40%, 16/19 [84%]; <20%, 16/18 [89%]). Compared to AML with clonal TP53 mutations, those with subclonal ones showed significantly fewer complex karyotypes and chromosomal losses. The number of cooperating driver mutations was low with 0-5 per case and did not differ between the 3 TP53 mutated groups. The complete remission (CR) rate was significantly inferior in the TP53 mutated cohort (48.0% versus 84.9% for TP53 wild-type patients, P <0.001) but equally distributed among the VAF-based subgroups (TP53 VAF >40%, 42.6%; 20%-40%, 57.9%; <20%, 55.6%; P=0.424). The estimated median overall survival (OS) for all 1537 AML patients was 28.1 months (95% CI, 24.3-33.5) but differed substantially between TP53 wild-type and TP53 mutated patients (33.6 months [95%CI, 28.4-45.0] versus 6.5 months [95%CI, 5.0-8.2]). As depicted in Figure 1, OS rates were comparably low in all TP53 mutated subgroups (TP53 VAF >40%, 5.8 months; 20%-40%, 6.9 months; <20%, 6.9 months).The median estimated event-free survival (EFS) for all 1537 AML patients was 15.0 months (95% CI, 13.6-16.5) with that for TP53 wild-type patients being 16.5 months (95% CI, 15.0-18.2) and for TP53 mutated patients 5.7 months (95% CI, 4.3-7.4). Median EFS rates were comparably low in all TP53 mutated subgroups (TP53 VAF >40%, 5.2 months; 20%-40%, 6.9 months; <20%, 6.5 months). In Cox regression analyses adjusting for age, white blood cell count, cytogenetic risk and type of AML, the adverse prognostic effect of TP53 mutations remained significant, with subclonal mutations showing the strongest impact (hazard ratio, 3.71 [95% CI, 2.11-6.51] for OS). Conclusion In our study on a large cohort of AML patients, TP53 mutated subclones defined by VAF <20% account for ~18% of all TP53 mutated AML cases. We here provide evidence that subclonal TP53 mutations are associated with a comparable negative impact on prognosis as clonal TP53 mutations. These findings may have implications for TP53 screening methods and for future risk stratification in AML. Disclosures No relevant conflicts of interest to declare.

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Johnson, Sarah May, Jhia Jiat Teh, Thomas Joshua Pasvol, Sara Ayres, Hermione Lyall, Sarah Fidler und Caroline Foster. „Hospitalisation rates for youth living with perinatally acquired HIV in England“. PLOS ONE 19, Nr. 3 (19.03.2024): e0295639. http://dx.doi.org/10.1371/journal.pone.0295639.

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Introduction Complex challenges amongst ageing cohorts of adolescents and adults living with perinatally acquired HIV (PaHIV) may impact on hospitalisation. We report hospitalisation rates and explored predictive factors for hospitalisation in adolescents and adults (10–35 years) living with PaHIV in England. Method Retrospective observational cohort study over a three-year period 2016–2019. Data collected included cause and duration of hospitalisation, HIV viral load and CD4 lymphocyte count. The primary outcome was overnight hospitalisation. Patients exited at study end/ transfer of care (TOC)/ loss to follow up (LTFU) or death. Maternity/hospital admissions at other centres were excluded. Admission rates per 100 person-years (95% CI) were calculated by age group. Negative binomial regression with generalized estimating equations was performed. Results 255 patients contributed 689 person-years of follow up. 56% were female and 83% were of a Black, Black British, Caribbean or African ethnicity. At baseline, the median age was 19 years (IQR 16–22). 36 individuals experienced a total of 62 admissions which resulted in 558 overnight stays (median stay was 5 nights). One person died (lymphoma), six had TOC and one was LTFU by the end of the three-year study period. Crude incidence of admission for the whole cohort was 9.0 per 100 PY (6.9–11.6). The respective crude incidence rates were 1.5 PY (0.0–8.2) in those aged 10–14 years and 3.5 PY (1.5–7.0) in the 15–19-year-olds. In those aged 20–24 years it was 14.5 PY (10.1–20.2) and in those >25 years the crude incidence rate was 11.7 PY (6.9–18.5). Factors significantly associated with admission were a CD4 lymphocyte count <200 cells/uL, adjusted IRR 4.0 (1.8–8.8) and a history of a CDC-C diagnosis, adjusted IRR 2.9 (1.6–5.3). 89% admissions were HIV-related: 45% new/current CDC-C diagnoses, 76% due to infection. Conclusions Hospitalisation rates were four-fold higher in adults (>20 years of age) compared to adolescents (10–19-year-olds). The continuing challenges experienced by PaHIV youth require enhanced multidisciplinary support throughout adulthood.

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Lee, So-Ryoung, Chan Soon Park, Eue-Keun Choi, Hyo-Jeong Ahn, Kyung-Do Han, Seil Oh und Gregory Y. H. Lip. „Hypertension Burden and the Risk of New-Onset Atrial Fibrillation“. Hypertension 77, Nr. 3 (03.03.2021): 919–28. http://dx.doi.org/10.1161/hypertensionaha.120.16659.

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The association between the cumulative hypertension burden and the development of atrial fibrillation (AF) is unclear. We aimed to investigate the relationship between hypertension burden and the development of incident AF. Using the Korean National Health Insurance Service database, we identified 3 726 172 subjects who underwent 4 consecutive annual health checkups between 2009 and 2013, with no history of AF. During the median follow-up of 5.2 years, AF was newly diagnosed in 22 012 patients (0.59% of the total study population; 1.168 per 1000 person-years). Using the blood pressure (BP) values at each health checkup, we determined the burden of hypertension (systolic BP ≥130 mm Hg or diastolic BP ≥80 mm Hg), stratified as 0 to 4 per the hypertension criteria. The subjects were grouped according to hypertension burden scale 1 to 4: 20% (n=742 806), 19% (n=704 623), 19% (n=713 258), 21% (n=766 204), and 21% (n=799 281). Compared with normal people, subjects with hypertension burdens of 1, 2, 3, and 4 were associated with an 8%, 18%, 26%, and 27% increased risk of incident AF, respectively. On semiquantitative analyses with further stratification of stage 1 (systolic BP of 130–139 mm Hg or diastolic BP of 80–89 mm Hg) and stage 2 (systolic BP ≥140 mm Hg or diastolic BP ≥90 mm Hg) hypertension, the risk of AF increased with the hypertension burden by up to 71%. In this study, both a sustained exposure and the degree of increased BP were associated with an increased risk of incident AF. Tailored BP management should be emphasized to reduce the risk of AF.

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Djordjevic, Zorana, Slobodan Jankovic, Olgica Gajovic, Nela Djonovic, Nevena Folic und Zoran Bukumiric. „Hospital infections in a neurological intensive care unit: incidence, causative agents and risk factors“. Journal of Infection in Developing Countries 6, Nr. 11 (26.11.2012): 798–805. http://dx.doi.org/10.3855/jidc.2659.

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Introduction: Hospital infections (HIs), which are frequently associated with hospital treatment, increase morbidity, mortality and treatment costs. The aim of this study was to establish the incidence of HIs in a neurological intensive care unit (nICU), and to determine the most prevalent causative agents and risk factors for HIs. Methodology: A cross-sectional study with nested case-control design was conducted between 1 July 2009 and 30 June 2010 at an 18-bed neurological intensive care unit at the Clinical Center Kragujevac, Serbia. Results: In total, 537 patients were enrolled in the study, with 6,549 patient-days. There were 89 patients with 101 HIs. The incidence of patients with HIs was 16.57%, and incidence of HIs was 18.81%, while density of HIs was 15.42 per 1,000 patient-days. The most frequent anatomical sites of HIs were urinary tract (73.27%), blood (10.89%), and skin and soft tissues (10.89%). The following risk factors were identified: co-morbidity (OR=3.9; 95% CI=1.9-7.9), surgical intervention in the last 30 days (OR=5.6; 95% CI=1.5-20.4), urinary bladder catheterization longer than seven days (OR=3.8; 95% CI=1.8-8.2), value of Glasgow coma scale £ 9 (OR=3.7; 95% CI=1-6.9), and longer hospital stay (OR=1.1; 95% CI=1.1-1.2). Conclusions: Hospitalization in an nICU bears high risk of HIs, especially of urinary tract infections caused by Gram-negative bacteria, in patients with longer hospital stay or co-morbidities, and in those who have had surgical interventions or prolonged use of a urinary bladder catheter. Special attention should be paid to these patients to prevent HIs.

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Abdollahpour, Soha, Azam Rahbar, Reza Mohammadhassan, Yasamin Talebi und Yegane Bahrami Hesari. „An in silico Drug Repurposing Study to Inhibit the Spike Protein of SARS-CoV2“. Momona Ethiopian Journal of Science 16, Nr. 2 (14.09.2024): 347–69. http://dx.doi.org/10.4314/mejs.v16i2.11.

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SARS-CoV2 has caused the recent mortal pandemic known as COVID-19. The drug repurposing approach can be employed to find the potential drugs capable of binding SARS-CoV2 structural and nonstructural proteins. The present study aimed to repurpose some common FAD-approved antiviral and non-antiviral drugs computationally for SARS-CoV2 treatment. In the in silico study, 89 FDA-approved drugs and Remdesivir, as the control, were analyzed by molecular docking to inhibit the SARS-CoV2 spike (S) protein as the key player in virus-cell binding. First, the Uniport website was used to find receptor and ganglioside binding domains (RBD and GBD, respectively) of the S protein as the target. The structure of the target was downloaded from RCSB, and 'the ligands' structures were downloaded from PubChem. All structures were refined using SPDV and PyRx software. AutoDock Vina was employed for the docking process. The result showed that 8 drugs, including Ledipasvir, Montelukast, Domperidone, Aprepitant, Folic acid, Losartan, Ticagrelor, and Rivaroxaban, can bind S protein and then inhibit the protein function. In addition, Ledipasvir, Montelukast, and Domperidone can bind GBD of the S protein with higher binding energy (-8.2, -8, -7.9 kcal/mol, respectively). On the other hand, higher RBD binding energy was calculated for Ticagrelor (-6.9 kcal/mol), Folic acid, Montelukast, and Domperidone (-6.5 kcal/mol). Generally, the ligands could inhibit GBD more than RBD. According to the binding energy to S protein and low side effects of the studied medications, Ledipasvir and Losartan can be introduced as the most effective candidates for repurposed drugs. Also, Gly496 and Asn137 are the most engaged amino acids in the ligand-receptor interaction from RBD and GBD, respectively.

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Hrbáček, Filip, Daniel Nývlt, Kamil Láska, Michaela Kňažková, Barbora Kampová, Zbyněk Engel, Marc Oliva und Carsten W. Mueller. „Permafrost and active layer research on James Ross Island: An overview“. Czech Polar Reports 9, Nr. 1 (01.01.2019): 20–36. http://dx.doi.org/10.5817/cpr2019-1-3.

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This study summarizes the current state of the active layer and permafrost research on James Ross Island. The analysis of climate parameters covers the reference period 2011–2017. The mean annual air temperature at the AWS-JGM site was -6.9°C (ranged from -3.9°C to -8.2°C). The mean annual ground temperature at the depth of 5 cm was -5.5°C (ranged from -3.3°C to -6.7°C) and it also reached -5.6°C (ranged from -4.0 to -6.8°C) at the depth of 50 cm. The mean daily ground temperature at the depth of 5 cm correlated moderately up to strongly with the air temperature depending on the season of the year. Analysis of the snow effect on the ground thermal regime confirmed a low insulating effect of snow cover when snow thickness reached up to 50 cm. A thicker snow accumulation, reaching at least 70 cm, can develop around the hyaloclastite breccia boulders where a well pronounced insulation effect on the near-surface ground thermal regime was observed. The effect of lithology on the ground physical properties and the active layer thickness was also investigated. Laboratory analysis of ground thermal properties showed variation in thermal conductivity (0.3 to 0.9 W m-1 K-1). The thickest active layer (89 cm) was observed on the Berry Hill slopes site, where the lowest thawing degree days index (321 to 382°C·day) and the highest value of thermal conductivity (0.9 W m-1 K-1) was observed. The clearest influence of lithological conditions on active layer thickness was observed on the CALM-S grid. The site comprises a sandy Holocene marine terrace and muddy sand of the Whisky Bay Formation. Surveying using a manual probe, ground penetrating radar, and an electromagnetic conductivity meter clearly showed the effect of the lithological boundary on local variability of the active layer thickness.

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Bhardwaj, S. C., M. Prashar, S. Kumar, S. K. Jain und D. Datta. „Lr19 Resistance in Wheat Becomes Susceptible to Puccinia triticina in India“. Plant Disease 89, Nr. 12 (Dezember 2005): 1360. http://dx.doi.org/10.1094/pd-89-1360a.

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Lr19, a resistance gene originally transferred from Agropyron elongatum to wheat (Triticum aestivum L.), has remained effective worldwide against leaf rust (Puccinia triticina Eriks.) except in Mexico (1). This report records a new pathotype of P. triticina virulent on Lr19 from India. From 2003 to 2004, 622 wheat leaf rust samples from 14 states were subjected to pathotype analysis. Samples were established on susceptible wheat cv. Agra Local, and pathotypes were identified on three sets of differentials following binomial nomenclature (3). Virulence on Lr19 (Agatha T4 line) was observed in approximately 2% of samples. These samples were picked from Lr19 (NIL), cvs. Ajit, Lal Bahadur, Local Red, Lok1, and Nirbhay from Karnataka and Gujarat states. All Lr19 virulent isolates were identical. The reference culture is being maintained on susceptible wheat cv. Agra Local and has also been put under long-term storage in a national repository at Flowerdale. From 2004 to 2005, this pathotype was detected in 6.3% of samples from central and peninsular India. There is no wheat variety with Lr19 under cultivation in India, however, it is being used in wheat breeding programs targeted at building resistance against leaf and stem rusts. NIL's Lr19/Sr25 (LC25) and Lr19/Sr25 (82.2711) were also susceptible to this isolate, whereas Lr19/Sr25 (spring accession) was resistant. The new isolate, designated as 253R31 (77-8), appears to be close to the pathotype 109R31 (4) with additional virulence for Lr19. The avirulence/virulence formula of pathotype 253R31 is Lr9, 23, 24, 25, 26, 27+31, 28, 29, 32, 36, 39, 41, 42, 43, 45/Lr1, 2a, 2b, 2c, 3, 10, 11, 12, 13, 14a, 14b, 14ab, 15, 16, 17, 18, 20, 21, 22a, 22b, 30, 33, 34, 35, 37, 38, 40, 44, 48, and 49. To our knowledge, this is the first report of virulence on Lr19 from two states of India. On international rust differentials, it is designated as TGTTQ (2), and is different from CBJ/QQ (1), the other isolate reported virulent on Lr19 from Mexico. The Mexican isolate is avirulent on Lr1, 2a, 2b, 2c, 3ka, 16, 21, and 30 to which the Indian isolate is virulent. However, both isolates are avirulent on Lr9, 24, 26, 36, and Lr42. Among the wheat cultivars identified during the last 6 years, HD2824, HD2833, HD2864, HI1500, HS375, HUW 510, HW 2044, HW 5001, Lok 45, MACS 6145, MP4010, NW 2036, PBW 443, PBW 498, PBW 502, PBW 524, Raj 4037, UP 2565, VL 804, VL 829, and VL 832 and lines of wheat possessing Lr9, Lr23, Lr24, and Lr26 showed resistance to this pathotype. PBW 343, which occupies more than 5 million ha in India, is also resistant to this pathotype along with PBW 373. An integrated strategy using a combination of diverse resistance genes, deployment of cultivars by using pathotype distribution data, slow rusting, and adult plant resistance is in place to curtail selection of new pathotypes and prevent rust epiphytotics. References: (1) J. Huerta-Espino and R. P. Singh. Plant Dis. 78:640,1994. (2) D. V. Mc Vey et al. Plant Dis. 88:271, 2004. (3) S. Nagarajan et al. Curr. Sci. 52:413, 1983. (4) S. K. Nayar et al. Curr. Sci. 44:742, 1975.

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Strangfeld, A., B. Manger, M. Worsch, T. Schmeiser, A. Zink und M. Schaefer. „OP0116 ELDERLY PATIENTS ARE NOT AT INCREASED RISK OF SERIOUS INFECTIONS WHEN RECEIVING BDMARDS OR JAK INHIBITORS COMPARED TO CSDMARD TREATMENT“. Annals of the Rheumatic Diseases 80, Suppl 1 (19.05.2021): 64.2–65. http://dx.doi.org/10.1136/annrheumdis-2021-eular.763.

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Background:Elderly rheumatoid arthritis (RA) patients are generally at increased risk of serious infections (SI). At the same time, treatment with bDMARDs has been associated with a higher SI risk than treatment with csDMARDs (1). However, long-term use of bDMARDs did not increase the risk of SI in a small group of elderly patients over 65 (2). The extent to which elderly patients are exposed to a higher SI risk when treated with JAK inhibitors (JAKi) is an open question.Objectives:To assess the effects of bDMARDs and specifically JAKi on the risk of SI in elderly patients with RA.Methods:The German register RABBIT is a prospective, longitudinally followed cohort of RA patients enrolled with a new start of a DMARD after at least one csDMARD failure. This analysis comprises patients over 70 years of age who were enrolled between 01/2007 and 04/2020 and had at least one follow-up.Results:Of 13,491 patients followed-up in RABBIT, 2274 with an age > 70 years were included in the analysis. 626 SI were observed in 425 of these patients. Baseline characteristics at start of the respective DMARD are shown in Table 1. In most characteristics, patients on JAKi were more comparable to patients under bDMARDs than to those on csDMARDs. JAKi patients received glucocorticoids (GC) less frequently than patients on other treatments. The HR for SI was lower than 1 in patients receiving bDMARDs or JAKi compared to csDMARDs, but without statistical significance (Figure 1). GC use (HR 1.6, 95% CI: 1.2 – 2.2 for ≤ 10 mg/d), higher DAS28-ESR values (HR 1.1, 95% CI: 1.0 – 1.2 per 1 point increase), COPD or pulmonary fibrosis (HR 1. 8, 95% CI: 1.3 – 2.4), chronic kidney disease (HR 1.5, 95% CI: 1.2 – 1.9) and diabetes mellitus (HR 1.3, 95% CI: 1.0 – 1.7) were associated with an increased risk of SI. Better physical capacity was associated with a decreased risk of SI (HR 0.9, 95% CI: 0.88 – 0.98 for a 10 point increase).Table 1.Patient characteristics by treatment at baselineParametercsDMARDsTNFiRTXABAIL-6iJAKiN=758N=840N=209N=147N=212N=108Age (years)75.9 (3.9)75.5 (3.6)74.8 (3.6)76.1 (3.9)75.9 (3.7)76.7 (3.7)Male sex184 (24.3)220 (26.2)50 (23.9)36 (24.5)46 (21.7)28 (25.9)Ever smoker249 (32.8)287 (34.2)77 (36.8)50 (34)73 (34.4)39 (36.1)Disease duration (years)7.9 (8.8)12.3 (11.4)17 (11.1)12.8 (10)13.8 (11.7)11.9 (10.9)Seropositivity487 (64.3)671 (79.9)201 (96.2)126 (85.4)182 (85.8)79 (73.5)Number of previous DMARDs1.4 (0.7)2.5 (1.3)4.2 (1.8)3.6 (1.9)3.3 (1.8)2.6 (1.5)DAS28-ESR4.6 (1.2)5.1 (1.2)5.4 (1.3)5.3 (1.3)5.3 (1.3)5 (1.2)Proportion of full physical function64.8 (23.1)57.1 (23.6)50.4 (23.7)52.9 (23.5)55.3 (24.1)55.2 (23.7)Number of comorbidities3.1 (2.5)3.8 (2.6)4.2 (2.6)4.6 (2.9)3.6 (2.4)3.8 (2.2)No comorbidity52 (6.9)29 (3.5)4 (1.9)4 (2.7)9 (4.2)5 (4.6)Three and more comorbidities385 (50.8)528 (62.9)147 (70.3)107 (72.8)131 (61.8)76 (70.4)COPD or pulmonary fibrosis69 (9.1)89 (10.6)29 (13.9)26 (17.7)12 (5.7)11 (10.2)Chronic kidney disease94 (12.4)151 (18)28 (13.4)21 (14.3)39 (18.4)22 (20.4)Diabetes mellitus151 (19.9)172 (20.5)31 (14.8)23 (15.6)42 (19.8)25 (23.1)GCs (last 6 months)347 (45.8)526 (62.6)143 (68.8)82 (56.2)127 (59.9)44 (40.7)GCs (<5mg)447 (58.9)384 (45.7)101 (48.2)88 (60)118 (55.8)72 (66.7)GCs (5-9mg)252 (33.3)375 (44.6)81 (38.7)43 (29)72 (34.2)27 (25.1)GCs (>=10mg)59 (7.8)82 (9.8)274 (13.1)16 (11)21 (10)9 (8.2)Results are presented as mean ± SD for continuous variables and number (percentage) for discrete variables.Figure 1.Hazard ratios for serious infections with 95% confidence intervalsConclusion:Treatment with JAKi as well as treatment with bDMARDs was not associated with an increased risk of SI in elderly patients above 70 years of age. Key comorbidities such as diabetes mellitus, chronic pulmonary and kidney diseases were associated with increased risk, as was concomitant GC use and higher disease activity.References:[1] Listing J et al., Rheumatology 2013; 52 (1): 53-61.[2] Kawashima H. et al., Rheum. Intern. 2017; 37: 369-376.Acknowledgements:RABBIT is supported by a joint, unconditional grant from AbbVie, Amgen, BMS, Celltrion, Fresenius-Kabi, Gilead, Hexal, Lilly, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi-Aventis, UCB, and Viatris.Disclosure of Interests:None declared

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Descourt, Renaud, Laurent Greillier, Maurice Perol, Charles Ricordel, Jean-Bernard Auliac, Lionel Falchero, Pierre Demontrond et al. „First-line pembrolizumab monotherapy for PD-L1-positive (TPS ≥ 50%) advanced non-small cell lung cancer (aNSCLC) in the real world: A national French bispective multicentric cohort—ESCKEYP trial (GFPC 05-2018).“ Journal of Clinical Oncology 39, Nr. 15_suppl (20.05.2021): 9091. http://dx.doi.org/10.1200/jco.2021.39.15_suppl.9091.

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9091 Background: To determine real-world outcomes with first line pembrolizumab monotherapy, for aNSCLC with PD-L1 TPS ≥50%. Methods: Bispective, national and multicentric study including consecutively aNSCLC patients who initiated first-line pembrolizumab monotherapy from May 5, 2017 (marketing authorization of pembrolizumab monotherapy in France) to Nov 22, 2019 (marketing authorization of pembrolizumab-chemotherapy for non-squamous aNSCLC). Data were collected on medical charts. Responses were locally assessed according to RECIST v1.1; overall survival (OS) and real-world progression-free survival (rwPFS) were assessed by Kaplan-Meier method. Results: 845 patients (pts) were included by 33 centres: 67.8% were men, PS 0/1/≥2: 25.5%/46.9%/27.6%, active/former/nonsmokers: 39.1%/51.7%/6.4%, adenocarcinoma: 70.8%; stage IV at diagnosis: 91.6%; median number of metastatic sites at baseline: 2±1 (brain (20.8%), liver (13.9%) and bone (35%)); KRAS mutated: 27.7%, PDL1 TPS > 75%: 53.7% At the cut off date (31 December 2020), on the 783/845 (92.7%) evaluable pts, CR, PR, disease stabilization and progression were reported on 4.7%, 42.6%, 24.1% and 28.6% of cases, respectively; 588 (69.6%) pts had discontinued pembrolizumab, 390 (66.4%) had a first disease progression; 320/390 (82.1%) received a second line treatment, mainly platinum-based chemotherapy (90.6%). With a median follow up of 25,8 [95%CI: 24,8-26,7] months, median rwPFS and median OS were 8,2 [95%CI: 6,9-9,5] and 22,6 [95%CI: 18,5-27,4] months, respectively; 6, 12, 18-months survival rates were 76,8%, 64,8% and 54,3%. 835 adverse events were reported in 48% of the patients, grade ≥3 in 13.8% of cases, mainly asthenia, colitis, pneumonitis. For evaluable patients receiving a platinum-based doublet in second line (266/290, 89%), CR, PR, disease stabilization and progression were reported on 1.9%, 41%, 35.3% and 21.8% of cases, respectively. Uni and multivariate analysis of factors related to OS will be presented at the congress. Conclusions: Despite a less stringent selection of patients, pembrolizumab as a single agent achieves similar tumor shrinkage, rwPFS and OS than those of pivotal clinical trials.

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Miller, James, Ryan Avery, Natalie Urie, Matthew Branan und Joan M. Burke. „211 United States Department of Agriculture National Animal Health Monitoring System Goat 2019 study: Regional prevalence of gastrointestinal nematodes and lungworms in the United States“. Journal of Animal Science 102, Supplement_3 (01.09.2024): 403–4. http://dx.doi.org/10.1093/jas/skae234.459.

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Abstract One objective of the United States Department of Agriculture National Animal Health Monitoring System Goat 2019 study (September 2019-April 2020) was to determine the prevalence of gastrointestinal nematode (GIN) and lungworm infection in goats across the US. Feces were collected from 5,176 animals on 318 operations in 24 states and results were consolidated into 4 regions: Northwest (3 states, 34 operations), Northeast (9 states, 89 operations), Southeast (9 states, 132 operations) and Southwest (3 states, 63 operations). Feces from each operation were mixed and cultured to allow eggs to hatch and develop, The Baermann technique was used to recover infective third-stage larvae from cultures. GIN identification included Haemonchus, Trichostrongylus, Teladorsagia, Oesophagostomum and Nematodirus. Lungworm (Muellerius/Protostrongylus) first-stage larval presence was also noted. Frequencies were calculated and Haemonchus were found on 18.6 ± 3.5 % of the operations (Northwest, 27.0 ± 16.5 %; Northeast, 13.1 ± 4.7 %; Southeast, 15.9 ± 5.1 % and Southwest, 29.2 ± 9.4) %); Trichostrongylus on 97.2 ± 1.4 % of the operations (Northwest, 100 %; Northeast, 98±1.1 %; Southeast, 97.0 ± 2.2 % and Southwest, 95.7±4.2 %); Teladorsagia on 80.3 ± 4.0% of the operations (Northwest, 97.1 ± 2.4%; Northeast, 71.6 ± 9.1%; Southeast, 88.6 ± 4.6% and Southwest, 75.7 ± 7.3%); Oesophagostomum on 38.2 ± 4.3% of the operations (Northwest, 73.1 ± 9.2%; Northeast, 39.6 ± 7.1 %, Southeast, 46.4 ± 8.2% and Southwest, 15.5 ± 6.0%); Nematodirus on 7 ± 2.6 % of the operations (Northwest, 7 ± 5.1%; Northeast, 5.2 ± 4.7 %, Southeast, 0 % and Southwest, 20.8 ± 8.6 %); and lungworms on 35.4 ± 4.2 % of the operations (Northwest, 69.1 ± 9.8 %; Northeast, 52.2 ± 9.1 %, Southeast, 33.4±6.9% and Southwest, 8.3±3.3%). Results indicated that Trichostrongylus was the most prevalent followed by Teladorsagia, Oesophagostomum, lungworms, Haemonchus and Nematodirus. Prevalence of all GIN and lungworms were similar within regions except Nematodirus and lungworms, which were less in the southeast and southwest, respectively. Due to project seasonal timing and sampling logistics, fecal collection was conducted from fall through early spring which may have influenced prevalence, specifically the most pathogenic GIN, Haemonchus. This study provided valuable insight into USA regional prevalence of GIN and lungworms in goats.

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Hlubocky, Fay J., David Cella, Tamara Sher und Christopher K. Daugherty. „Impact of death anxiety (DA) on the psychological well-being and survival of patients with advanced cancer (ACP) in phase I trials and their spousal caregivers (SC).“ Journal of Clinical Oncology 41, Nr. 16_suppl (01.06.2023): e24213-e24213. http://dx.doi.org/10.1200/jco.2023.41.16_suppl.e24213.

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e24213 Background: ACP and their SC experience psychological distress living with future uncertainty regarding their cancer. Yet, little is known how existential DA adversely impacts the psychological well-being and overall survival of ACP participating in Phase I trials and their SC. Methods: A prospective study of ACP enrolling in phase I trials and their SC were assessed at baseline (T1) and one month (T2) using quantitative symptom measures including: depression (CES-D), state anxiety (STAI-S), quality of life/qol (FACIT-Pal), and global health (SF-36). Semi-structured interviews evaluated DA: suffering; meaning, and worry re death. Results: To date, 158 participants (79 Phase I ACP and 79 SC) have been separately interviewed at T1 and T2. For the total population: median age 62 (28-79y); 50% male; 100% married; 89% Ca; 69% > HS educ; 59% GI dx; ACP median survival 8.2 month (.51-18.8) 53% income < $65,000 yr. At T1, 83% of ACP experienced worry re death, and 77% reported suffering. For SC at T1, 75% reported worry re ACP death; 88% worried re own death; and 85% reported experiencing suffering and 84% lost meaning during the ACP illness. For both ACP and SC, rates remained consistent for both ACP and SC. At T2, ACP with worry re death had higher STAI-S (32±11 v. 28±9, p = 0.04) and CES-D scores (12±10 v. 11±10, p = 0.03). SC with self-reported suffering had higher STAI-S anxiety (38±15 v. 34±12, p = 0.02) at T2. Regression analyses revealed ACP with worry had worsening FACIT-Pal QOL over time. Also, SC with suffering at T2 was negatively associated with SF-36 scores. Regarding survival, ACP with DA had shorter survival compared to ACP without DA (4.4 v. 6.9 months, p = 0.02). Conclusions: Phase I ACP and SC report worry re death and suffering negatively impacting their psychological well-being and survival. Supportive couple-based, dyadic psychological interventions for ACP-SC designed to address DA coping are needed.

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Erina, A. M., O. P. Rotar, V. N. Solntsev, S. A. Shalnova, A. D. Deev, E. I. Baranova, O. A. Konradi, S. A. Boytsov und E. V. Shlyakhto. „Epidemiology of Arterial Hypertension in Russian Federation – Importance of Choice of Criteria of Diagnosis“. Kardiologiia 59, Nr. 6 (27.06.2019): 5–11. http://dx.doi.org/10.18087/cardio.2019.6.2595.

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Purpose. Assessment of prevalence of arterial hypertension (AH), need for prescription of antihypertensive therapy (AHT), and efficacy of AHT in Russian population in accordance with novel guideline of the American College of Cardiology/American Heart Association (“American recommendations”) on diagnosis and treatment of AH (2017).Materials and methods. Epidemiological study ESSE-RF (ЭССЕ-РФ) was carried out in 12 regions of Russian Federation (RF) with different climatic-geographic characteristics. Number of examined residents of RF aged 25–65 years was 20 652. The sample was stratified by gender and age. Examination included anthropometry, laboratory tests, blood pressure (BP) measurement with the OMRON tonometer. The SCORE scale was used for evaluation of risk of development of cardiovascular diseases (CVD). In American recommendations AH was defined as follows: 1-st degree – systolic BP (SBP) 130–139 and/or diastolic BP (DBP) 80–89 mm Hg, 2-nd degree – BP ≥140/90 mm Hg and/or presence of AHT. In recommendations of the European Society of Cardiology (2013, 2018) (“European recommendations”) AH was defined as BP ≥140/90 mm Hg and/or presence of AHT.Results. We analyzed data of examination of 20 607 participants – 7806 men (37.9%) and 12 801 women (62.1%). According to European recommendations AH was diagnosed in 10 347 persons (50.2%) – 3987 men (51.1%) men and 6 360 women (49.7%). According to American recommendations AH was registered in 14 853 persons (72.1%) – 6 059 men (77.6%) and 8 794 women (68.7%). AHT received 6324 persons (61.1% of those with AH); according to American recommendations, the onset of AHT was indicated to additional 620 persons with 1-st degree AH because of high CVD risk. Among all participants with AH (on and without AHT) strengthening of AHT for achievement of target BP level was required in 77.8 and 92.6% of patients according to European and American recommendations, respectively.Conclusion. Application of novel criteria of AH diagnosis from 2017 ACC/AHA guideline to Russian population would increase prevalence of AH up to 72.1%. Onset of AHT would be indicated in 13.8% of patients with 1-st degree AH, while in 93% of patients receiving AHT its strengthening would be required.

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Oliver, William M., Samuel G. Molyneux, Timothy O. White, Nick D. Clement und Andrew D. Duckworth. „Return to work and sport after a humeral shaft fracture“. Bone & Joint Open 3, Nr. 3 (01.03.2022): 236–44. http://dx.doi.org/10.1302/2633-1462.33.bjo-2021-0198.r1.

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Aims The primary aim of this study was to determine the rates of return to work (RTW) and sport (RTS) following a humeral shaft fracture. The secondary aim was to identify factors independently associated with failure to RTW or RTS. Methods From 2008 to 2017, all patients with a humeral diaphyseal fracture were retrospectively identified. Patient demographics and injury characteristics were recorded. Details of pre-injury employment, sporting participation, and levels of return post-injury were obtained via postal questionnaire. The University of California, Los Angeles (UCLA) Activity Scale was used to quantify physical activity among active patients. Regression was used to determine factors independently associated with failure to RTW or RTS. Results The Work Group comprised 177 patients in employment prior to injury (mean age 47 years (17 to 78); 51% female (n = 90)). Mean follow-up was 5.8 years (1.3 to 11). Overall, 85% (n = 151) returned to work at a mean of 14 weeks post-injury (0 to 104), but only 60% (n = 106) returned full-time to their previous employment. Proximal-third fractures (adjusted odds ratio (aOR) 4.0 (95% confidence interval (CI) 1.2 to 14.2); p = 0.029) were independently associated with failure to RTW. The Sport Group comprised 182 patients involved in sport prior to injury (mean age 52 years (18 to 85); 57% female (n = 104)). Mean follow-up was 5.4 years (1.3 to 11). The mean UCLA score reduced from 6.9 (95% CI 6.6 to 7.2) before injury to 6.1 (95% CI 5.8 to 6.4) post-injury (p < 0.001). There were 89% (n = 162) who returned to sport: 8% (n = 14) within three months, 34% (n = 62) within six months, and 70% (n = 127) within one year. Age ≥ 60 years was independently associated with failure to RTS (aOR 3.0 (95% CI 1.1 to 8.2); p = 0.036). No other factors were independently associated with failure to RTW or RTS. Conclusion Most patients successfully return to work and sport following a humeral shaft fracture, albeit at a lower level of physical activity. Patients aged ≥ 60 yrs and those with proximal-third diaphyseal fractures are at increased risk of failing to return to activity. Cite this article: Bone Jt Open 2022;3(3):236–244.

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Jhaveri, K. L., G. Ulaner, M. Fazio, A. Eaton, S. Patil, L. Evangelista, C. Serna-Tamayo, H. L. McArthur, C. Hudis und P. G. Morris. „Standardized uptake value (SUV) by positron emission tomography/computed tomography (PET/CT) as a prognostic variable in metastatic breast cancer (MBC).“ Journal of Clinical Oncology 29, Nr. 27_suppl (20.09.2011): 3. http://dx.doi.org/10.1200/jco.2011.29.27_suppl.3.

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3 Background: The accurate prediction of outcome from MBC could be useful if it could guide more effective therapies. Because PET/CT combines anatomical with functional imaging it could enable greater individualization of treatment. However, there is substantial SUV variation by anatomic site. In this retrospective, single-institution study, we examine baseline SUV on PET/CT as a predictor of outcome from MBC. Methods: Patients (Pts) with ≥1 metastatic lesion on PET/CT performed ≤60 days of diagnosis of MBC from 01/01/2001-12/31/2008 were identified through institutional databases. Pts who rcvd chemotherapy within 30 days prior to PET/CT were excluded. Electronic medical record reports were reviewed and maximum SUV (SUV-MAX) by site for lesions in bone, liver, lung and lymph node (LN) was recorded. In a secondary analysis, PET/CT scans were reviewed and SUV-MAX recalculated. Relationships between SUV-MAX and OS were assessed using Cox regression by site. Results: We identified 285 pts, median (med) age 57 yrs (range 27-90) who had PET/CT at med of 2.3 yrs (range 0–41) from primary BC (67% ER+ and 21% HER2+). Med time between PET/CT and MBC diagnosis was -9 days (range -58–59). At med follow-up of 53 mths, 163 pts have died. Med OS is 41 mths (95%CI 34-48). The SUV-MAX by site was; bone (N=159) med 7.0 (range 2.1–29.6); liver (N=55) med 8.2 (range 2.9–51.2); lung (N=89) med 4.7 (range 1.1–24.0); LN (N=180) med 6.9 (range 1.2–34.0). On univariate analysis, higher SUV in bone was associated with shorter survival (p<0.001; table). This was maintained in multivariate analyses after adjusting for known prognostic variables (p=0.02). A similar trend for shorter survival for higher SUV was noted in liver (p=0.07). However, no relationship between SUV and OS was noted in lung (p =0.34) and LN (p=0.6). Conclusions: This large retrospective study of pts with chemotherapy-naïve MBC suggests that SUV-MAX in bone strongly correlates with prognosis. [Table: see text]

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Müller, Martin C., Benjamin Hanfstein, Michael Lauseker, Philipp Erben, Ulrike Proetel, Susanne Schnittger, Hans-Jochem Kolb et al. „Time-Related Interpretation of Molecular Response Levels According to Long Term Overall and Progression-Free Survival of CML Patients on First-Line Imatinib Treatment“. Blood 118, Nr. 21 (18.11.2011): 1681. http://dx.doi.org/10.1182/blood.v118.21.1681.1681.

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Abstract Abstract 1681 Introduction: The prognostic impact of different levels of molecular remission (BCR-ABL transcript expression according to International Scale, IS) at various time points on survival under imatinib treatment is still unclear. Whereas recently published data from the IRIS trial described relevant milestones at 6, 12, and 18 months for event-free and progression-free survival (PFS; Hughes et al., Blood 2010), little is known about an association of molecular response with overall survival (OS). The aim of this evaluation of the German CML Study IV was to elucidate the risk of disease progression and death as a function of the depth of molecular response in order to provide guidance in the interpretation of BCR-ABL levels in the clinical setting. Methods: 1,340 patients (median age 52 years, range 16–88, 60% male) were recruited into the randomized German CML Study IV and treated with an imatinib-based therapy as follows: imatinib 400 mg/d, n=381; imatinib 800 mg/d, n=399; imatinib 400 mg/d + interferon alpha, n=402; imatinib 400 mg/d + low-dose cytarabine, n=158. A total of 1,262 patients with typical b2a2 and b3a2 BCR-ABL transcripts were evaluable. Molecular responses were assessed in 811, 764, 671, and 619 patients at 6, 12, 18, and 24 months, respectively. Disease progression was defined as accelerated phase or blastic phase, or death from any reason. Landmark analyses and log-rank tests for OS and PFS were performed according to the achievement of different BCR-ABL response levels at different time points. Results: Patients were grouped according to the degree of molecular response (<0.1%, 0.1%-1%, 1%-10%, >10% BCR-ABL IS) at each of the 4 time points and evaluated for 5-year OS and PFS. Estimated 5-year OS for the different molecular response categories was: 97% vs 96% vs 90% vs 88% (6 months, p=0.009); 96% vs 95% vs 89% vs 69% (12 months, p<0.001); 98% vs 97% vs 92% vs 66% (18 months, p<0.001); 97% vs 96% vs 96% vs 68% (24 months, p<0.001). Applying the 4 response categories revealed estimated 5-year PFS of 97% vs 96% vs 91% vs 86% (p=0.004) at 6 months, 97% vs 92% vs 89% vs 72% (p<0.001) at 12 months, 99% vs 95% vs 90% vs 77% (p<0.001) at 18 months, and 97% vs 97% vs 93% vs 65% (p<0.001) at 24 months (s. Table). Conclusions: Faster and deeper response to imatinib-based treatment revealed to be associated with improved overall and progression-free survival. Inferior OS and PFS can be deducted from the synopsis of BCR-ABL expression and treatment duration, e.g. >1% BCR-ABL IS at 6 months or 12 months might be, and >10% BCR-ABL IS should be a trigger for a treatment change. Thereby this analysis might provide decision guidance for alteration or continuation of primary imatinib treatment. Disclosures: Schnittger: Münchner Leukämie Labor: Equity Ownership. German CML Study Group:EU: Research Funding; BMBF: Research Funding; Novartis: Research Funding; Deutsche Krebshilfe: Research Funding; Roche: Research Funding; Essex: Research Funding.

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Galsky, Matt D., Dean F. Bajorin, J. Alfred Witjes, Jürgen E. Gschwend, Yoshihiko Tomita, Federico Nasroulah, Jun Li et al. „Analysis of disease-free survival in CheckMate 274 by PD-L1 combined positive score and tumor proportion score.“ Journal of Clinical Oncology 40, Nr. 6_suppl (20.02.2022): 491. http://dx.doi.org/10.1200/jco.2022.40.6_suppl.491.

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491 Background: CheckMate 274 demonstrated a significant improvement in disease-free survival (DFS) with nivolumab (NIVO) versus placebo (PBO) both in the intent-to-treat population (hazard ratio [HR], 0.70; 98.22% confidence interval [CI], 0.55–0.90; P < 0.001) and in patients (pts) with tumor programmed death ligand 1 (PD-L1) expression ≥ 1% assessed by the tumor proportion score (TPS) (HR, 0.55; 98.72% CI, 0.35–0.85; P < 0.001). An exploratory subgroup analysis showed a trend toward a DFS benefit with NIVO in pts with TPS < 1% (0.82; 95% CI, 0.63–1.06). To further characterize the relationship between PD-L1 expression and NIVO efficacy, we report an analysis of DFS based on PD-L1 expression in both tumor and immune cells using the combined positive score (CPS). Methods: CheckMate 274 is a phase 3, randomized, double-blind, multicenter trial of NIVO versus PBO in pts with high-risk muscle-invasive urothelial carcinoma after radical surgery. Pts were randomized 1:1 to NIVO 240 mg or PBO every 2 weeks intravenously for 1 year of adjuvant treatment. The primary endpoints of the study are DFS in the intent-to-treat population and in pts with TPS ≥ 1%. The Dako PD-L1 IHC 28-8 pharmDx assay was used to evaluate TPS. CPS was determined retrospectively from previously stained immunohistochemistry slides using the CPS algorithm. CPS was calculated as the number of both PD-L1 positive tumor and immune cells divided by the number of viable tumor cells in the evaluable tumor area, multiplied by 100; TPS was similarly calculated with the number of PD-L1 positive tumor cells as the numerator. This analysis only included pts with both quantifiable CPS and TPS. Results: Of the 629 pts with quantifiable TPS and CPS, 249 (40%) had TPS ≥ 1% (NIVO, n = 124; PBO, n = 125), 380 (60%) had TPS < 1% (NIVO, n = 191; PBO, n = 189), 557 (89%) had CPS ≥ 1 (NIVO, n = 281; PBO, n = 276), and 72 (11%) had CPS < 1 (NIVO, n = 34; PBO, n = 38). Within TPS < 1% pts, 81% (n = 309) had CPS ≥ 1. The number of pts and the DFS outcomes in pts with TPS ≥ 1% and CPS ≥ 1 are shown in the Table. In pts with TPS < 1% who also had CPS ≥ 1, median DFS (95% CI) was 19.2 (15.6–33.4) months with NIVO versus 10.1 (8.2–19.4) months with PBO. The HR for NIVO versus PBO in these pts was 0.73 (95% CI, 0.54–0.99). Conclusions: This exploratory analysis of PD-L1 expression by CPS showed a higher proportion of pts with CPS ≥ 1 than TPS ≥ 1%, and that most pts with TPS < 1% had CPS ≥ 1. In the CPS ≥ 1 subgroup, median DFS with NIVO was more than double that with placebo. These results support the conclusion that pts with TPS < 1% also benefit from adjuvant NIVO. Clinical trial information: NCT02632409. [Table: see text]

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MCCRAW, R. „Baby basics Color, sound, 120 minutes. Produced and directed by Adrienne Miesmer. Written and co-produced by Lisa McElaney, 1987. Available in -inch VHS videocassette format from Vida Health Communications, 22 Riverview Drive, Wayne, NJ 07470. (201) 628-9111 or (800) 524-1013. Purchase price $39.95 plus $3.50 shipping and handling. Massachusetts residents add $2.00 sales tax. 24-page index and companion booklet included. The video plus accompanying materials are available in English and Spanish“. Journal of Nurse-Midwifery 34, Nr. 4 (Juli 1989): 225–26. http://dx.doi.org/10.1016/0091-2182(89)90101-8.

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Tu, Tsung-Hsi, Chao-Hung Kuo, Wen-Cheng Huang, Li-Yu Fay, Henrich Cheng und Jau-Ching Wu. „Effects of smoking on cervical disc arthroplasty“. Journal of Neurosurgery: Spine 30, Nr. 2 (Februar 2019): 168–74. http://dx.doi.org/10.3171/2018.7.spine18634.

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OBJECTIVECigarette smoking can adversely affect bone fusion in patients who undergo anterior cervical discectomy and fusion. However, there is a paucity of data on smoking among patients who have undergone cervical disc arthroplasty (CDA). The present study aimed to compare the clinical and radiological outcomes of smokers to those of nonsmokers following CDA.METHODSThe authors retrospectively reviewed the records of consecutive patients who had undergone 1- or 2-level CDA for cervical disc herniation or spondylosis and had a minimum 2-year follow-up. All patients were grouped into a smoking group, which consisted of those who had consumed cigarettes within 6 months prior to the CDA surgery, or a nonsmoking group, which consisted of those who had not consumed cigarettes at all or within 6 months of the CDA. Clinical outcomes were evaluated according to the visual analog scale for neck and arm pain, Neck Disability Index, Japanese Orthopaedic Association Scale, and Nurick Scale at each time point of evaluation. Radiological outcomes were assessed using radiographs and CT for multiple parameters, including segmental range of motion (ROM), neutral lordotic curve, and presence of heterotopic ossification (HO).RESULTSA total of 109 patients completed at least 2 years of follow-up and were analyzed (mean follow-up 42.3 months). There were 89 patients in the nonsmoking group and 20 in the smoking group. The latter group was younger and predominantly male (both p < 0.05) compared to the nonsmoking group. The two groups had similar improvements in all clinical outcomes after CDA compared to preoperatively. Radiological evaluations were also very similar between the two groups, except for two factors. The smoking group had well-preserved segmental ROM after CDA at an average of 8.1° (both pre- and postoperation). However, while the nonsmoking group remained mobile, segmental ROM decreased significantly (8.2° to 6.9°, p < 0.05) after CDA. There was a trend toward more HO development in the nonsmoking group than in the smoking group, but the difference was without significance (59.6% vs 50.0%, p = 0.43).CONCLUSIONSDuring an average 3.5 years of follow-up after 1- and 2-level CDA, cigarette smokers and nonsmokers had similar improvements in clinical outcomes. Moreover, segmental mobility was slightly better preserved in smokers. Since smoking status did not negatively impact outcomes, CDA may be a reasonable option for selected patients who have smoked.

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Schultz, Nicolai Aagaard, Ib Jarle Christensen, Jens Werner, Nathalia Giese, Benny Vittrup Jensen, Ole Larsen, Jon Kroll Bjerregaard et al. „Pretreatment plasma concentrations of YKL-40 and IL-6 in patients with pancreatic cancer: Potential diagnostic and prognostic biomarkers.“ Journal of Clinical Oncology 31, Nr. 4_suppl (01.02.2013): 164. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.164.

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164 Background: To test the hypothesis that high pretreatment plasma YKL-40 and IL-6 associate with pancreatic cancer (PC) and short overall survival (OS). Methods: 556 patients with PC from Denmark (N=445) and Germany (N=111) were included in the present prospective biomarker study. 152 (27%) patients were operated and treated postoperative with adjuvant gemcitabine. 404 (73%) had locally advanced or metastatic PC and received palliative chemotherapy (primarily gemcitabine). Pretreatment plasma YKL-40 and IL-6 were determined by ELISA with known reference intervals in healthy subjects. Results: The OR for prediction of PC in the whole study population was significant for all 3 biomarkers with CA 19-9 having the highest AUC (YKL-40: OR=4.50, 95% CI 3.99-5.08, p<0.0001, AUC=0.87; IL-6: OR=3.68, 3.08-4.44, p<0.0001, AUC=0.87; CA 19-9: OR=2.28, 1.97-2.68, p<0.0001, AUC=0.93). YKL-40, IL-6 and CA-19-9 increased with more advanced stage (YKL-40 median (IQR): Stage IA-IIA 100 (68-157), IIB-III 101 (59-179), IV 166 (89-296) μg/L, p<0.0001; IL-6: Stage IA-IIA 4.2 (1.9-8.9), IIB-III 4.0 (2.1-8.2), IV 7.4 (3.6-18) ng/L, p<0.0001); CA-19-9: Stage IA-IIA 58 (10-622), IIB-III 209 (54-856), IV 1041 (146-9178) ng/L, p<0.0001). Univariate Cox analysis in resected patients showed that only pretreatment IL-6 and CA 19-9 (dichotomized according to normal values) were associated with short OS (YKL-40: HR=1.38, 0.87-2.18, p=0.17; IL: HR=2.23, 1.41-3.52, p=0.0006; CA 19-9: HR=2.80, 1.54-5.09, p=0.0007). In non-resectable patients all 3 biomarkers were associated with short OS (YKL-40: HR=1.54, 1.23-1.93, p=0.0001; IL: HR=1.63, 1.29-2.06, p<0.0001; CA 19-9: HR=1.48, 1.02-2.15, p=0.039). Multivariate Cox analysis in non-resectable patients (YKL-40, IL-6, CA 19-9 (log transformed base 2), age, sex, and stage) demonstrated that YKL-40 (HR=1.12, 1.02-1.23, p=0.021), IL-6 (HR=1.20, 1.09-1.31, p=0.0001) and CA 19-9 (HR=1.10, 1.07-1.14, p<0.0001) were independent biomarkers for short OS. This was not found in resected patients. Conclusions: Pretreatment plasma concentrations of YKL-40 and IL-6 may be new diagnostic and prognostic biomarkers in patients with PC.

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Waterhouse, David, Saurabh Ray, Keith A. Betts, Sophie Gao, Yong Yuan, Manasvi Sundar, Shumin Rui und David Stenehjem. „Abstract 3819: Real-world long-term survival outcomes of first-line immunotherapy-based regimens in advanced non-small cell lung cancer“. Cancer Research 84, Nr. 6_Supplement (22.03.2024): 3819. http://dx.doi.org/10.1158/1538-7445.am2024-3819.

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Abstract Background: The real-world survival outcomes of first-line (1L) immunotherapy (IO)-based regimens for the treatment of advanced non-small cell lung cancer (aNSCLC) were assessed utilizing the Flatiron Health database from January 2011 to June 2023. Methods: Adult patients (pts) with aNSCLC receiving 1L IO monotherapy or single-agent IO + chemotherapy on or after January 1, 2016, were identified. Pts were excluded if they had EGFR/ALK mutations or unknown histological type. Overall survival (OS) and real-world progression-free survival (rwPFS) of 1L IO monotherapy and IO + chemotherapy were described using Kaplan-Meier analyses. Results: A total of 14,320 pts were included (5,166 pts receiving IO monotherapy; 9,154 pts receiving IO + chemotherapy). Among pts receiving IO monotherapy, the 1-, 2-, 3-, and 4-year OS rates were 52.3%, 36.5%, 27.4%, and 21.9%, respectively. The corresponding rwPFS rates were 29.2%, 17.5%, 12.7%, and 9.2%. Among pts receiving IO + chemotherapy, the 1-, 2-, 3-, and 4-year OS rates were 50.7%, 32.6%, 23.9%, and 19.2%. The corresponding rwPFS rates were 27.0%, 15.1%, 10.3%, and 7.8%. Table 1 presents the 4-year OS and rwPFS rates stratified by histological type, tumor programmed death ligand 1 (PD-L1) expression level, and Eastern Cooperative Oncology Group (ECOG) performance status. Patients with lower PD-L1 expression level (<1%), worse ECOG performance status (≥2), and squamous cell carcinoma had worse survival outcomes, regardless of the type of 1L treatment received. Conclusions: The real-world survival rates for patients with aNSCLC who were treated with 1L IO-based regimens were lower than those observed in pivotal trials, which indicates an unmet need for the management of newly-diagnosed aNSCLC. However, on average approximately 1 in 11 pts receiving IO monotherapy and 1 in 13 pts receiving IO + chemotherapy remained progression-free at the four year landmark and achieved an extended period of survival. Table: 4-year OS and rwPFS rates 1L IO monotherapy 1L IO + chemotherapy PD-L1 <1% PD-L1 ≥1-49% PD-L1 ≥50% PD-L1 <1% PD-L1 ≥1-49% PD-L1 ≥50% OS by histological type (sample size; 4-year rate, %) Squamous 122; 12.7 329; 14.0 814; 15.1 585; 11.7 647; 15.1 295; 23.3 Non-squamous 231; 16.7 516; 20.0 2563; 26.3 2263; 14.9 2058; 20.8 1313; 28.9 OS by ECOG performance status (sample size; 4-year rate, %) 0-1 193; 17.0 439; 20.8 1880; 27.6 1852; 16.8 1802; 21.9 1065; 28.0 ≥2 89; 6.7 261; 14.5 840; 12.7 478; 5.6 452; 11.1 241; 22.8 rwPFS by histological type (sample size; 4-year rate, %) Squamous 122; 7.6 329; 4.4 814; 6.8 585; 5.2 647; 8.3 295; 9.2 Non-squamous 231; 5.1 516; 10.0 2563; 11.2 2263; 4.3 2058; 6.3 1313; 14.7 rwPFS by ECOG performance status (sample size; 4-year rate, %) 0-1 193; 6.9 439; 10.4 1880; 11.9 1852; 5.4 1802; 6.8 1065; 14.5 ≥2 89; NA 261; 3.7 840; 5.0 478; 2.2 452; 3.9 241; 8.2 Citation Format: David Waterhouse, Saurabh Ray, Keith A. Betts, Sophie Gao, Yong Yuan, Manasvi Sundar, Shumin Rui, David Stenehjem. Real-world long-term survival outcomes of first-line immunotherapy-based regimens in advanced non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3819.

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MCCRAW, R. „Your child has a fever Color, sound, 15 minutes. Written and produced by Richard Usatine and Martin Smietanka, 1985. Available from Churchill Films, 662 North Robertson Blvd., Los Angeles, CA 90069. (213) 657–5110. Purchase price: $235.00 plus $2.00 postage and handling for video formats; not available in 16-mm film. Available for rental from Audience Planners, Inc., 5107 Douglas Fir Road, Calabasas, CA 91302. (800) 624–8613. Rental price: $60.00 (3-day). Brief discussion guide included“. Journal of Nurse-Midwifery 34, Nr. 1 (Januar 1989): 53–54. http://dx.doi.org/10.1016/0091-2182(89)90137-7.

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Smoljanić, Jovana, Nathan B. Morris, Sheila Dervis und Ollie Jay. „Running economy, not aerobic fitness, independently alters thermoregulatory responses during treadmill running“. Journal of Applied Physiology 117, Nr. 12 (15.12.2014): 1451–59. http://dx.doi.org/10.1152/japplphysiol.00665.2014.

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We sought to determine the independent influence of running economy (RE) and aerobic fitness [maximum oxygen consumption (V̇o2max)] on thermoregulatory responses during treadmill running by conducting two studies. In study 1, seven high (HI-FIT: 61 ± 5 ml O2·kg−1·min−1) and seven low (LO-FIT: 45 ± 4 ml O2·kg−1·min−1) V̇o2max males matched for physical characteristics and RE (HI-FIT: 200 ± 21; LO-FIT: 200 ± 18 ml O2·kg−1·km−1) ran for 60 min at 1) 60%V̇o2max and 2) a fixed metabolic heat production (Hprod) of 640 W. In study 2, seven high (HI-ECO: 189 ± 15.3 ml O2·kg−1·km−1) and seven low (LO-ECO: 222 ± 10 ml O2·kg−1·km−1) RE males matched for physical characteristics and V̇o2max (HI-ECO: 60 ± 3; LO-ECO: 61 ± 7 ml O2·kg−1·min−1) ran for 60 min at a fixed 1) speed of 10.5 km/h and 2) Hprod of 640 W. Environmental conditions were 25.4 ± 0.8°C, 37 ± 12% RH. In study 1, at Hprod of 640 W, similar changes in esophageal temperature (ΔTes; HI-FIT: 0.63 ± 0.20; LO-FIT: 0.63 ± 0.22°C; P = 0.986) and whole body sweat losses (WBSL; HI-FIT: 498 ± 66; LO-FIT: 497 ± 149 g; P = 0.984) occurred despite different relative intensities (HI-FIT: 55 ± 6; LO-FIT: 39 ± 2% V̇o2max; P < 0.001). At 60% V̇o2max, ΔTes ( P = 0.029) and WBSL ( P = 0.003) were greater in HI-FIT (1.14 ± 0.32°C; 858 ± 130 g) compared with LO-FIT (0.73 ± 0.34°C; 609 ± 123 g), as was Hprod (HI-FIT: 12.6 ± 0.9; LO-FIT: 9.4 ± 1.0 W/kg; P < 0.001) and the evaporative heat balance requirement (Ereq; HI-FIT: 691 ± 74; LO-FIT: 523 ± 65 W; P < 0.001). Similar sweating onset ΔTes and thermosensitivities occurred between V̇o2max groups. In study 2, at 10.5 km/h, ΔTes (1.16 ± 0.31 vs. 0.78 ± 0.28°C; P = 0.017) and WBSL (835 ± 73 vs. 667 ± 139 g; P = 0.015) were greater in LO-ECO, as was Hprod (13.5 ± 0.6 vs. 11.3 ± 0.8 W/kg; P < 0.001) and Ereq (741 ± 89 vs. 532 ± 130 W; P = 0.007). At Hprod of 640 W, ΔTes ( P = 0.910) and WBSL ( P = 0.710) were similar between HI-ECO (0.55 ± 0.31°C; 501 ± 88 g) and LO-ECO (0.57 ± 0.16°C; 483 ± 88 g), but running speed was different (HI-ECO: 8.2 ± 0.6; LO-ECO: 7.2 ± 0.4 km/h; P = 0.025). In conclusion, thermoregulatory responses during treadmill running are not altered by V̇o2max, but by RE because of differences in Hprod and Ereq.

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Corash, Laurence, Fabrice Cognasse, Jean-Claude Osselaer, Natalie Messe und Olivier Garraud. „Release of Immune Modulation Factors from Platelet Concentrates during Storage after Photochemical Pathogen Inactivation.“ Blood 108, Nr. 11 (16.11.2006): 941. http://dx.doi.org/10.1182/blood.v108.11.941.941.

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Abstract Background. Platelets (plt) prepared for transfusion contain multiple molecules that modulate immune function, mediate acute transfusion reactions, induce immune responses, and affect hemostasis. These cytokines/chemokines are secreted differentially from plt during storage (Transfusion2006;46:1184), and may be affected by processing, including pathogen inactivation. Aims. The INTERCEPT Blood System (IBS) for platelets utilizes amotosalen-HCl (S-59) with ultraviolet A (UVA) light to inactivate a broad spectrum of pathogens and leukocytes. This study was designed to evaluate the effects of photochemical treatment on in vitro release of immune modulation molecules after processing during 7 days (d) of storage. Methods. Platelet concentrates (n = 10) collected by aphaeresis (CPA) with process leuko-reduction (< 106) containing 8.15x1011 ± 0.8 platelets were suspended in 35% donor plasma and 65% platelet additive solution (Intersol, Baxter, France) and divided into two equal components. One served as an untreated control (C) and the other was prepared with 150 uM amotosalen and a 3 J/cm2 UVA photochemical treatment (PCT) and stored at 22°C with shaking for 7 days. Platelet concentration (106/uL), pH and levels of immune modulation factors were measured: CD62p(ng/mL), PDGF-AB(ng/mL), IL8(pg/mL), sCD40L(pg/mL), IL1β(pg/mL) and TNFα(pg/mL). The concentration of each factor was determined by specific enzyme linked immunosorbent assays in plt and supernatant (s) fractions isolated from stored PCT and C plt components. Mean values ± SD were calculated and compared by paired t-test. Results. Platelet content, pH and cytokine/chemokine content and release from CPA prepared with photochemical treatment were not statistically different (p > 0.05) from C during 7 d of storage (Table). From d1 to d7, the pH of PCT and C units decreased similarly, but remained within acceptable ranges. No detectable IL1β and TNFα were observed in PCT or C CPA. During platelet storage CD62p, PDGF-AB, IL8, and sCD40L increased similarly in supernatants of PCT and C units. The increase in supernatant levels correlated with a decrease of these cytokines in plt. Platelets in PCT and C retained measurable levels of CD62, IL8, sCD40L and PDGF-AB though 7 d. Levels of sCD40L demonstrated marked variation. Conclusions. Cytokines increased moderately in the supernatants of CPA and decreased in platelets during storage. After 7 d C and PCT platelets in CPA retained detectable levels of cytokines. PCT had no differential influence on release of immune modulation molecules in vitro over 7 d of storage. Day O O 5 5 7 7 Product C PCT C PCT C PCT pH 7.1 ±.1 7.1 ±.1 6.9 ±.1 6.8 ±.1 6.9 ±.1 6.8 ±.1 Plt ct 1.29 ±.3 1.30 ±.2 1.30 ±.3 1.19 ±.2 1.27 ±.2 1.18 ±.2 CD62p-s 89 ± 21 87 ± 17 110 ± 23 115 ± 27 117 ± 22 119 ± 25 CD62p-plt 149 ± 33 151 ± 33 141 ± 23 141 ± 25 139 ± 25 139 ± 26 PDGF-s 14.5 ± 3.5 13.6 ± 3.5 17.7 ± 2.4 15.8 ± 1.5 18.0 ± 2.1 17.5 ± 1.8 PDGF-plt 28.3 ± 3.5 30.3 ± 3.1 25.2 ± 3.6 24.9 ± 2.5 23.2 ± 4.0 23.3 ± 3.3 IL8-s 107 ± 17 108 ± 14 136 ± 42 116 ± 9 123 ± 20 120 ± 22 IL8-plt 135 ± 29 134 ± 28 110 ± 11 117 ± 12 103 ± 17 119 ± 32 CD40L-s 51 ± 86 66 ± 94 172 ± 157 237 ± 214 188 ± 198 201 ± 167 CD40L-plt 990 ± 805 1098 ± 747 485 ± 373 474 ± 331 346 ± 293 314 ± 282

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MCCRAW, R. „Infant care: The first weeks Color, sound, 22 minutes. Produced and directed by Linda Jassim, 1987. Available for purchase in 16-mm film and all video formats from Churchill Films, 662 North Robertson Blvd., Los Angeles, CA 90069. (213) 657–5110. Purchase price: $330.00 plus $2.00 postage and handling for video; $440.00 plus $4.00 postage and handling for 16-mm film. Available for rental from Audience Planners, Inc., 5107 Douglas Fir Road, Calabasas, CA 91302. (800) 624–8613. Rental price: $60.00 (3-day). Brief discussion guide included“. Journal of Nurse-Midwifery 34, Nr. 1 (Januar 1989): 53. http://dx.doi.org/10.1016/0091-2182(89)90136-5.

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MCCRAW, R. „AIDS: Issues for healthcare workers Color, sound, 23 minutes. Produced and directed by Leslie Hill, 1988. Available for purchase in 16-mm and all video formats from Churchill Films, 662 North Robertson Boulevard, Los Angeles, CA 90069. (213) 657-5110. Purchase price: $295.00 plus $2.00 postage and handling for video formats; $395.00 plus $4.00 postage and handling for 16-mm film. Available for rental from Audience Planners, Inc., 5107 Douglas Fir Road, Calabasas, CA 91302. (800) 624-8613. Rental price: $60.00 for 3-day rental. Brief discussion guide included.“ Journal of Nurse-Midwifery 34, Nr. 3 (Mai 1989): 155. http://dx.doi.org/10.1016/0091-2182(89)90067-0.

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Bower, H., T. Frisell, D. DI Giuseppe, B. Delcoigne und J. Askling. „OP0133 DO JAKIS WORK THE BEST AMONG THOSE RA PATIENTS WHERE THEIR SAFETY CONCERNS ARE THE HIGHEST?“ Annals of the Rheumatic Diseases 82, Suppl 1 (30.05.2023): 88.1–88. http://dx.doi.org/10.1136/annrheumdis-2023-eular.346.

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BackgroundSafety is a driving factor when selecting treatment, but the risks should be balanced against the treatment benefits, relative to alternative treatment options. In JAKis, recent evidence of increased safety risks in older patients with cardiovascular (CV) risk factors, have led to concerns. However, an increased risk among certain patients might still be offset by an increasing benefit in the same patient segment, and vice versa. A full understanding of the JAKi benefit-risk profile thus requires a better understanding of the relative (JAKi vs other treatments) benefits in those patients where their relative safety profile may be worse.ObjectivesTo assess the observed and adjusted relative effectiveness (remission and response) of JAKis (and non-TNFi bDMARDs) when compared to TNFi, as used in clinical practice, and to assess whether the predicted effectiveness of either drug class is modified by age and the presence of CV risk factors.MethodsRA patients initiating treatment with a JAKi, non-TNFi, or TNFi 2016-2021 were followed using the Swedish Rheumatology Quality Register. Good EULAR response and remission (CDAI<=2.8) at 6 months were assessed at return visits (within 90 to 270 days after treatment initiation). Non-responder imputation was implemented where treatment ended prior to 210 days after initiation.Crude probabilities of outcomes were presented by age and having ≥1 CV risk factor (Y/N). Linear regression estimated the risk difference (versus TNFi) in age and CV risk groups, adjusted for sex, baseline DAS28 (response) and CDAI (remission), and line of therapy. Probability of outcome was predicted from logistic regression models, fitted to allow effect modification of treatment cohort by age and CV risk score (ERS-RA score), adjusted for sex, baseline DAS28 (response) and CDAI (remission), and line of therapy.Results10,309 treatment episodes contributed data on response at 6 months, and 12,016 episodes with data on remission. Overall, 21% achieved good EULAR response and 11% reached CDAI remission (Table 1).Crude observed risks overall indicated superior response and remission with TNFi versus JAKi (Table 1). Adjusted risk differences suggested superior outcomes in JAKi versus TNFi, overall, and in those with no CV risk for CDAI remission. Patterns of predicted response and remission varied across age and CV ERS-RA score (Figure 1), with JAKis having superior effectiveness overall once adjusting for line of therapy.ConclusionAge and CV risk may modify the absolute and relative effectiveness of JAKis vs. TNFi. Further analyses are planned with the aim of presenting these results at EULAR.Table 1.Observed crude proportions of patients who achieved response and remission, and adjusted* risk differences between JAKi, non-TNFi and TNFi using the latter as referenceProportion (N) achieving outcomeAdjusted* risk difference, versus TNFi (95%CI)JAKiNon-TNFiTNFiJAKiNon-TNFiGood EULAR responseN Treatments101220224032Overall20% (339)19% (595)24% (1490)4.0% (1.1, 7.0)2.2% (-0.1, 4.5)<65 years, no CV21% (142)23% (277)27% (803)3.5% (-0.3, 7.3)2.4% (-0.6, 5.5)<65 years, ≥1 CV32% (24)29% (35)26% (60)14.6% (1.3, 28.0)10.7% (-0.1, 21.5)≥65 years, no CV25% (83)24% (168)30% (352)4.3% (-1.4, 10.1)-0.0% (-4.3, 4.3)≥65 years, ≥1 CV23% (29)29% (64)29% (89)1.4% (-8.4, 11.1)3.3% (-4.9, 11.5)CDAI remissionN Treatments139927565533Overall11% (73)9% (114)15% (425)4.0% (2.3, 6.8)2.2% (0.1, 3.6)<65 years, no CV6% (4)5% (6)12% (26)5.0% (2.0, 8.1)2.7% (0.3, 5.0)<65 years, ≥1 CV13% (40)10% (64)14% (159)-1.8% (-9.3, 5.8)-2.9% (-8.7, 3.0)≥65 years, no CV10% (12)12% (26)8% (23)5.7% (1.0, 10.5)0.4% (-3.0, 3.9)≥65 years, ≥1 CV11% (73)9% (114)15% (425)6.9% (-0.2, 14.0)6.9% (0.9, 13.0)*adjusted for sex, baseline DAS28 (response) and CDAI (remission), line of therapy≥1 CV= more than one CV risk factorFigure 1.Predicted probability of response and remission at 6 months by age and CV risk of patients with RA treated with JAKi, non-TNFi and TNFi in Sweden, adjusted for sex, baseline DAS28 (response) and CDAI (remission), and line of therapyREFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsNone Declared.

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Marzo-Ortega, H., X. Juanola, T. Okano, Y. Schymura, A. Bradley, J. Gerwien, B. Monsberger, S. Liu Leage, D. Aletaha und M. Østergaard. „POS0926 NORMALIZATION OF HIGH SENSITIVITY CRP VERSUS CLINICAL RESPONSE TO IXEKIZUMAB AT WEEK 16 IN PATIENTS WITH RADIOGRAPHIC & NON-RADIOGRAPHIC AXIAL SPONDYLOARTHRITIS: RESULTS FROM THE COAST STUDIES“. Annals of the Rheumatic Diseases 80, Suppl 1 (19.05.2021): 725–26. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2079.

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Background:C-reactive protein (CRP), an objective marker of inflammation, can be used to monitor treatment response to biologics in patients with axial spondyloarthritis (axSpA) in addition to evaluating signs & symptoms. CRP is not elevated in all patients with active axSpA questioning its validity as a universal biomarker of response. Ixekizumab (IXE) demonstrated efficacy in axSpA treatment irrespective of baseline (BL) CRP levels. However, response to IXE categorized on CRP change from BL is unknown.Objectives:To evaluate response to IXE treatment from BL through week (wk) 16 in patients with axSpA categorized according to change in high sensitivity (hs) CRP.Methods:COAST-V (NCT 02696785),-W (NCT02696798), & -X (NCT02757352), were phase 3, multicentre, randomized, controlled trials, investigating the efficacy of IXE 80 mg every 4 & 2 wks in patients with: r-axSpA naïve to biologic disease-modifying antirheumatic drugs (bDMARDs; COAST-V); or who were inadequate responders/intolerant to tumour necrosis factor inhibitors (TNFi; COAST-W); or who fulfilled Assessment of SpondyloArthritis International Society (ASAS) criteria for non-radiographic (nr)axSpA (COAST-X).This post hoc analysis focuses on approved dosing regimens. Depending on BL and wk 16 hsCRP values, patients were categorised as stable low (hsCRP ≤5 mg/L at BL & ≤5 mg/L at wk 16), normalized (hsCRP >5 mg/L at BL & ≤5 mg/L at wk 16) or elevated (hsCRP >5 mg/L at wk 16, irrespective of BL hsCRP). An absolute cutoff of 5 mg/L was used as the stratification factor in all COAST studies. Data were analyzed by treatment arm. Each trial was analyzed separately.For hsCRP subgroups, patient demographics & other characteristics at BL, as well as trajectory over time for the endpoints ASAS40 & Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) 50 are described. Non-responder imputation was used for missing values.Results:In all studies at BL, disease activity & MRI SPARCC score were higher in normalized & elevated subgroups compared to the stable low subgroup - a.In COAST-V, ASAS40 & BASDAI50 response was observed in IXE-treated patients regardless of hsCRP change status by wk 16 vs placebo. The highest ASAS40 & BASDAI50 response rate was reported in patients with normalized hsCRP - b. Similar findings were observed in COAST-W & -X.Table 1.Baseline Patient demographics & other characteristics - ITT population, per CRP subgroupCOAST-V(r-axSpA, bDMARD naive)COAST-W(r-axSpA, inadequate responders /intolerant to TNFi)COAST-X(non-radiographic axSpA, bDMARD naïve)Stable low (n=79)Norma-lized (n=80)Elevated (n=98)Stable low(n=58)Norma-lized (n=34)Elevated (n=126)Stable low (n=78)Norma-lized(n=40)Elevated (n=81)ParameterAge (years)43.7 (12.1)38.9 (10.9)42.7 (12.0)50.4 (13.3)46.1 (13.8)45.7 (12.5)44.0 (12.8)37.2 (14.6)38.7 (12.8)Male gender, n (%)63 (79.7)71.0 (88.8)78 (79.6)39.0 (67.2)30 (88.2)109 (86.5)35 (44.9)23 (57.5)34 (42)Duration of symptoms since axSpA onset (years)17.5 (11.2)14.4 (9.3)16.1 (9.9)21.7 (12.9)16.8 (11.6)18.9 (10.9)12.1 (9.9)10.3 (9.7)9.5 (9.0)HLA-B27 positive, n (%)69 (87.3)75.0 (93.8)89 (90.8)31.0 (91.2)101 (80.2)101 (80.2)48 (61.5)31 (77.5)67 (82.7)BASDAI Total Score6.5 (1.4)6.7 (1.5)7.0 (1.1)7.4 (1.5)7.3 (1.3)7.4 (1.3)6.9 (1.5)7.1 (1.6)7.2 (1.5)ASDAS Total Score3.1 (0.5)3.9 (0.6)4.2 (0.7)3.5 (0.6)4.3 (0.6)4.4 (0.8)3.2 (0.6)4.2 (0.8)4.2 (0.9)Spinal Pain due to AS7.0 (1.5)7.0 (1.5)7.5 (1.3)7.8 (1.5)7.7 (1.5)7.9 (1.4)7.2 (1.7)7.5 (1.7)7.5 (1.6)Patients with peripheral articular manifestations (>=1 TJC or >=1 SJC)47 (59.5)40 (50)62 (63.3)43 (74.1)24 (70.6)86 (68.3)56 (71.8)33 (82.5)66 (81.5)MRI Spine SPARCC ScoreMRI SIJ SPARCC ScoreMRI SPARCC Score6.7 (11.2)21.8 (27.3)20.7 (25.7)1.2 (2.3)7.0 (7.6)10.4 (17.0)5.2 (6.6)6.1 (8.2)6.2 (10.5)Conclusion:IXE reduced clinical disease activity in patients with axSpA irrespective of hsCRP change from BL to wk 16. Improvement in hsCRP level was associated with overall response rates.Acknowledgements:The authors would like to acknowledge Philana Fernandes, an employee of Eli Lilly and Company, for her for writing and editorial support.Disclosure of Interests:Helena Marzo-Ortega Consultant of: Celgene, Janssen, Eli Lilly, Novartis, Pfizer, UCB, Grant/research support from: Janssen, Novartis, Xavier Juanola: None declared, Tadashi Okano Speakers bureau: Asahi Kasei, Astellas, Abbvie, Ayumi, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Janssen, Mitsubishi Tanabe, Novartis, Ono, Pfizer, Sanofi and Takeda, Grant/research support from: Asahi Kasei, Abbvie, Chugai, Eisai, Yves Schymura Employee of: Eli Lilly, Andrew Bradley Shareholder of: Eli Lilly, Employee of: Eli Lilly, Jens Gerwien Shareholder of: Eli Lilly, Employee of: Eli Lilly, Brigitte Monsberger Shareholder of: Eli Lilly, Employee of: Eli Lilly, Soyi Liu Leage Employee of: Eli Lilly, Daniel Aletaha Speakers bureau: Abbvie, Amgen, Celgene, Lilly, Medac, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi/Genzyme, Grant/research support from: Abbvie, Lilly, Novartis, Roche, Mikkel Østergaard Speakers bureau: Abbvie, Celgene, Eli-Lilly, Janssen, Novartis, Pfizer, Roche, Sanofi and UCB, Consultant of: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Hospira, Janssen, Merck, Novartis, Novo, Orion, Pfizer, Regeneron, Roche, Sandoz, Sanofi and UCB, Grant/research support from: Abbvie, BMS, Merck, Celgene, Novartis

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Flowers, Christopher R., Michael Lill, Luciano J. Costa, Tsiporah B. Shore, William Vaughan, Michael Craig, Cesar O. Freytes et al. „Efficacy Of a Pharmacokinetics-Directed IV Busulfan (Bu), Plus Cyclophosphamide (Cy) and Etoposide (E) Preparative Regimen With Autologous Hematopoietic Stem Cell Transplantation For Lymphoma: Final Report Of a Multi-Center Phase 2 Study In North America“. Blood 122, Nr. 21 (15.11.2013): 768. http://dx.doi.org/10.1182/blood.v122.21.768.768.

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Abstract Background Bu-based conditioning regimens are commonly used prior to autologous hematopoietic stem cell transplantation (ASCT) for lymphoma, but clinical results of an intravenous (IV) Bu-based regimen have been limited to single center studies. This multi-center, single-arm, Phase 2 study prospectively evaluated the safety and efficacy of the IV BuCyE regimen in lymphoma patients undergoing ASCT. Methods The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), transplant-related mortality (TRM) and overall response rate. TRM was defined as a death after transplant due to any cause other than disease progression. Subjects underwent first ASCT for Hodgkin lymphoma (HL) and B-cell non-Hodgkin lymphoma (NHL) that relapsed after initial therapy, was initially refractory to an anthracycline-based chemotherapy, or for high-risk NHL histology in first complete remission (CR) [International Prognostic Index (IPI) score of 4-5, or mantle cell lymphoma (MCL)]. Eligible subjects achieved CR or partial remission (PR) following salvage chemotherapy. The study initially enrolled subjects of 18-80 years, but the protocol was amended to reduce the upper age limit to 65 years due to a high TRM rate at post-transplant 100 days for the subjects >65 years. Therefore, we report safety for all the subjects undergoing ASCT (n=203) and efficacy from those 65 years old or younger (n=186). IV Bu doses were individually adjusted based on pre-conditioning test PK results; the area under the concentration-time curve of Bu was targeted to 20,000 mM*min. Bu was given as a 3-hour infusion once daily from Days -8 through Day -5. E (1.4 g/m2) was administered on Day -4, followed by 2.5 g/m2/day of Cy on Days -3 and -2. Results A total of 207 subjects with HL (n=66) or NHL (n=141) were enrolled from 32 centers in the US and Canada between February 2010 and April 2012. Four subjects did not proceed with ASCT due to insurance or eligibility issues; the remaining 203 underwent ASCT. The final TRM rates at Day 100 for all subjects (n=203), for those older than 65 year old (n=17), and for those 65 years old or younger (n=186) were 4.5% (95% confidence intervals (CI) 2.1-8.3%), 23.5% (95% CI; 6.8-49.9%) and 2.7% (95% CI: 0.9-6.2%), respectively. The most common grade (Gr) 3 or 4 adverse events (CTCAE v3.0) observed from Day -8 through Day 100 were febrile neutropenia (Gr 3: 58.1%; Gr 4: 3.0%), stomatitis (Gr 3: 40.9%; no Gr 4), nausea (Gr 3: 8.9%; no Gr 4), and hypophosphatemia (Gr 3:6.9%; Gr 4: 1.0%). There was no instance of seizure or hepatic veno-occlusive disease (VOD) meeting the Baltimore criteria. Efficacy was analyzed for 186 subjects ≤65 years old with HL (n=65) or NHL (n=121), which included diffuse large B-cell lymphoma (DLBCL; n=63), MCL (n=29) and follicular lymphoma (FL; n=23). The median age was 49 year old (range: 19-65); 36 % were female, 87% were white, 76% had a Karnofsky Score ≥90. Majority of the patients had CR2 or higher, or PR at transplant except that 19 MCL patients and three DLBCL patients with IPI score 4 had CR1. In addition, five patients (3 for NHL; 2 for HL) who had refractory disease to initial chemotherapy and required salvage therapy to achieve CR1 also enrolled this study. With median 20 months follow-up, the estimated 2-year PFS was 33% for HL and 58%, 77%, and 43% for DLBCL, MCL, and FL respectively [Fig. 1]. The estimated 2-year OS was 76% for HL and 65%, 89%, and 89% for DLBCL, MCL, and FL respectively [Fig. 2 ]. Conclusions IV BuCyE regimen provided good early disease control with acceptable safety profiles in B-cell NHL lymphoma patients 65 year old or younger, but there were early declines in PFS in HL patients. Additional comparisons of PFS and OS from the BuCyE regimen with a pre-specified, matched-control group of approximately 800 matched cases (1:4 ratio) obtained from the Center for International Blood and Marrow Transplant Research registry data who received carmustine, E, cytarabine, and melphalan (BEAM) conditioning regimen are underway, and updated results will be presented. Disclosures: Off Label Use: Busulfan, Cyclophosphamide and VP-16 for Autologous Hematopoietic Stem Cell Transplantation. Costa:Otsuka: Research Funding. Freytes:Otsuka America Pharmaceutical: Research Funding, Travel funds for scientific presentation Other. Armstrong:Otsuka: Employment. Smith:Otsuka Pharmacetical Development & Commercialization: Employment. Elekes:Otsuka Pharmaceutical: Employment. Kato:Otsuka Pharmaceutical Development & Commercialization, Inc: Employment.

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De Montalembert, Mariane, Frédéric Galacteros, Jean Antoine Ribeil, Uwe Kordes, Jean Benoit Arlet, M. Dimopoulou, V. Komninaka et al. „Implementation of a European Cohort to Follow Sickle Cell Children and Adults Treated with Hydroxycarbamide“. Blood 124, Nr. 21 (06.12.2014): 564. http://dx.doi.org/10.1182/blood.v124.21.564.564.

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Abstract Hydroxycarbamide (HU) is a myelosuppressive drug marketed since 1968 for the treatment of hematological cancer, and authorized since 2007 in Europe as orphan medicinal product for the prevention of recurrent vaso-occlusive crises including acute chest syndrome in adults and children older than 2 years with sickle cell disease (SCD). ESCORT-HU (European Sickle Cell Disease Cohort – Hydroxyurea) is a multicenter prospective non interventional study implemented in Europe to collect more information about the safety profile of HU and morbi-mortality in SCD patients treated with HU. The study responds to EMA (European Medicines Agency) request and has been approved by the Ethical of Necker Enfants Malades Hospital (Paris, France).The ongoing study involves the largest number so far of patients with SCD treated with HU. Primary endpoints of ESCORT HU are to determine frequency of adverse events, and possible consequent changes of HU treatment. Secondary endpoints are to evaluate morbi-mortality of the disease although in the absence of control group. From June 2008 to June 2014, 483 patients (255 females; 228 males) were enrolled from 3 European countries, Greece (24%), Germany (19%), and France (56%). 67% patients were adults, median aged 37.35 yrs (17-83.5) and 33% were children, median aged 11.06 yrs (2.6-16.9). genotypes were HbS/HbS in 71.4% cases, and compound heterozygotous HbS/β-thalassemia in 22.8 % (Table 1). 137 (28.4%) patients experienced 421 events (Table 2). 132 (32.2%) of these events may be attributed to HU. The safety profile is roughly similar in children and adults. As expected the most frequent side effects were firstly blood disorders (n=86 events, 42.4%) such as neutropenia or thrombocytopenia. In all cases, these cytopenias were rapidly resolved with the transitory stop of HU. 71 events related to skin and subcutaneous tissue disorders were observed, mostly cutaneous dryness, skin reactions, alopecia and nails or skin pigmentation; 4 patients had a leg ulcer (34.8%). Most of these events are ongoing or stabilized despit the decrease of HU. No secondary cancer has been reported until now. Even if HU is an old drug with a relatively well-known safety profile, some uncertainties remain in terms of long-term safety as well as tolerance in the youngest people. The main interest of ESCORT HU is to offer the possibility of safety surveillance of hydroxycarbamide in European sickle cell patients. Table 1 Demographic data Adults Children < 17 years old Total Number of patients 322 (67%) 161 (33%) 483 Females/Males 183/139 72/89 255/228 Median age (yrs) (range) 37.35 (17-83.5) 11.06 (2.6-16.9) 28.58 Genotype SS 206 (64%) 139 (86.3%) 345 (71.4%) SC 1 (0.3%) 3 (1.86%) 4 (0.8%) Sβ0 51 (15.8%) 11 (6.8%) 62 (12.8%) Sβ+ 46 (14.2%) 2 (1.2%) 48 (9.9%) Other 18 (5.5%) 6 (3.7%) 24 (4.9%) Treatment with HU before enrollment in ESCORT HU No of pts 232 83 315 (65%) Median duration (range) of HU treatment before ESCORT HU 8.2 yrs (0.5 ans-24 yrs) 3. 1 yrs ( 71 days – 8.9 yrs) 6.85 (71 days-24 years)] HU ESCORT Daily mean dose (mg/kg/d) 16.11 ± 4.79 19.63 ± 4.69 17.32 ± 4.94 Abstract 564. Table 2 The most frequent events of hydroxycarbamide in the two populations of SCD patients ADULTS CHILDREN No ofGerman(%) No of adults No ofEpisodes(%) No of children Total(% /411) Events Related to HU treatment (Siklos®)(%**) Blood and lymphatic system disorders (%) 32 (17.7) 22 54 (31.03) 28 86 (20.9) 56 (65.1) Skin and subcutaneous tissue disorders (%) 42 (23.2) 28 29 (16.7) 19 71 (17.3) 46 (64.8) Nervous system disorders Headache (24), Dizziness/vertigo (14), 32 (17.7) 23 12(6.9) 10 44 (10.7) 11 (25) Gastrointestinal disorders Nausea (14), diarrhea (8), other (14) 20 (11) 17 23 (13.2) 16 43 (10.4) 7 (16.3) Metabolic and nutrition disorders: vit D deficiency (17), weight gain (5) 13 (7) 11 18 (18.3) 18 36 (8.75) 4 (11.1) Fever 11 (6) 10 12(6.9) 7 23 (5.6) 1 (4.3) Cardiac disorders (hypertension, bradycardia, chest pain, cardiomegaly) 4 4 2 2 6 1 (16.6) General disorders : fatigue 5 5 0 0 5 0 Hepatobiliary disorders 2 2 0 0 2 0 Neoplasms benign, malignant and unspecified (incl. cysts and polyps) Harmatoma, benign vulvar sebaceous cyst 2 2 0 0 2 0 Renal & urinary disorders 2 2 0 0 2 0 Reproductive system and breast disorders 3 3 0 0 3 0 Other 13 13 21 14 34 6 (17.1%) 181 80 /181(24.8%) 174 57 / 174(35.4%) 411 132/411 (32.2%) ** compared to the total number of “system organ class” events Disclosures No relevant conflicts of interest to declare.

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García-Gutiérrez, Valentín, Dragana Milojkovic, María Luisa Martín Mateos, Simone Claudiani, Concepcion Boque, Luis Felipe Casado, Gloria González et al. „Safety and Efficacy of Bosutinib in Fourth Line Therapy of Chronic Myeloid Leukemia Patients“. Blood 126, Nr. 23 (03.12.2015): 2786. http://dx.doi.org/10.1182/blood.v126.23.2786.2786.

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Abstract BACKGROUND: Despite the excellent prognostic of chronic myeloid leukemia (CML) patients since the introduction of tyrosine kinase inhibitors (TKIs), approximately 50% of patients that are treated with TKIs will discontinue first line treatment due to lack of efficacy or intolerance. Once patients need a second line treatment, a considerable proportion of patients will need third or even fourth line therapy during further evolution. At this moment, there is a lack of data about real benefit of this group of patients. We have recently published our experience of 30 CML patients treated with bosutinib in 4th line. We present an update of the study where we have increased the number of patients, and the follow-up. The aim of this study is to present safety and efficacy data CML chronic phase patients treated with bosutinib in 4th line. METHODS: We have collected data from 59 CML patients treated with bosutinib in 4th line after resistance or intolerance to IM, NI and DA. 51 patients have been treated under the Spanish compassionate use program (36 centers) and 10 patients were treated in a single institution from United Kingdom. Median age of patients at diagnosis was 53 years. The percentage of low, intermediate and high risk Sokal groups were 47%, 37% and 16%. Median time TKIs exposure before bosutinib was 9 years. The most common indication (30/59) was intolerant to DA and NI. Patients' dispositions and main line characteristics are shown in table 1. RESULTS: Median follow-up was 14.3 months. All patients started bosutinib at 500mg/d, median dose of was 450mg/d. Overall probabilities to either achieve or maintain previous response were 96% (57/59), 62% (37/59), 40% (24/59) and 17% (10/59) for complete hematological response (CHR), complete cytogenetic response (CCyR), major molecular response (MMR) and MR4.5 respectively. However, probabilities to obtain responses (in patients without response evaluated at baseline) were 27% (7/26), 26% (12/45) and 12% (7/55) for CCyR, MMR and MR4.5. As expected, probabilities to obtain CCyR were lower for patients resistant to DA and NI patients than for patients intolerant to DA and NI (8% VS 44%). Event free survival (EFS) and progression free survival (PFS) probabilities were 50% and 83% by 27 month. Treatment was discontinued in 20/58 (34%), most frequent reasons being adverse events 9/59(15%), lack of efficacy 5/59 (8.5%), disease progression 2/59 (3.4%) and death 1/59 (1.7%). Two patients discontinued due to stem cell transplantation. The adverse events that led to treatment discontinuation were pleural effusion (3), diarrhea (2), rash, renal impairment, auricular fibrillation and liver enzyme elevation one patient each. Overall, bosutinib was well tolerated. Grade 3-4 hematological toxicities were 3%, 6% and 6% for anemia, thromboctytopenia and neutropenia. Most common non hematological side effects were diarrhea (39%, nauseas 13% and liver alterations 14% and pleural effusion 14%. CONCLUSIONS: Little is known about the therapeutic role of Bosutinib in 4th line. The series presented here is, to our knowledge, the largest being presented. Bosutinib seems to be an appropriate treatment option for patients resistant or intolerant to three prior TKIs. Table 1. IM+NI-I+DA-R (N=4) IM+NI-R+DA-R (N=18) IM+NI-I+DA-I (N=30) IM+NI-R+DA-I (N=7) Total (N=59) Sex, N (%) Male 2 (50) 11 (61.1) 16 (53.3) 2 (28.6) 31 (52.5) Median age of diagnosis, yr (range) 57.32 (50-64) 49.19 (23-73) 54.95 (21-89) 48.87 (26-68) 53.15 (21-89) Median age of Bosutinib initiation, yr (range) 69.13 (61-70) 62.27 (39-79) 64.85 (25-90) 64.79(35-74) 63.7 (25-9) Median follow up, months (range) 18.5(7.8-34.1) 8.4(1.22-36.1) 16.3(0.5-34.7) 23.4(3.3-28.9) 14.3(0.7-36.1) SOKAL Index at diagnosis, N (%) High 2(50.0) 4 (23.5) 1 (4.3) 1 (20) 8 (16.3) Intermediate 1 (25.0) 5 (29.4) 10(43.5) 2 (40) 18 (36.7) Low 1 (25.0) 8 (47.1) 12 (52.2) 2 (40) 23 (46.9) Median Time from first TKI to BOS, (yr, range) 10.3 (4.8-11.9) 9.3 (2.0-11.4) 8.8 (0.7-13.6) 8.2 (5.1-12.3) 8.8 (0.7-13.6) Median duration of prior therapy, months (range) Imatinib 38.8 (11.8-69.8) 32.6 (6.3-96.8) 26.2 (1.6-102.6) 23.1 (8.3-66.8) 28.8 (1.6-102.6) Dasatinib 21.5 (12.6-75) 21.8 (7.7-69) 31.4 (0.4-87.1) 23.7 (10.3-53.6) 23.44 (0.4-87.1) Nilotinib 19.1 (2.1-46.2) 16.7 (5-65.6) 8.9 (0.2-58.5) 30.9 (6.9-49.3) 14.3 (0.2-65.6) BOS: bosutinib, IM, imatinib; DA, dasatinib; NI, nilotinib, I: Intolerance, R: Resistant, Yr: year Disclosures García-Gutiérrez: Ariad: Consultancy; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Milojkovic:Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Boque:Novartis: Honoraria; BMS: Honoraria; Celgene: Honoraria. Casado:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Jiménez:Pfizer: Consultancy, Honoraria. Giraldo:Pfizer: Consultancy. Steegmann:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau.

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Nair, Chandran K., Lingaraj Nayak, Anu Korula, Parathan Karunakaran, Abhilash Menon, Dubashi Biswajit, Gaurav Prakash et al. „Impact of Consolidation Radiotherapy in Bulky Diffuse Large B Cell Lymphoma By PET Based Response Assessment“. Blood 144, Supplement 1 (05.11.2024): 3078. https://doi.org/10.1182/blood-2024-203645.

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The prognostic significance of bulky disease at baseline and the role of routine consolidation radiotherapy (RT) in such cases of diffuse large B cell lymphoma(DLBCL) in Positron Emission Tomography ( PET) era is not very clear. In the landmark MabThera International Trial(MInT trial), RT was administered to all patients with initial bulky disease. The 3 year event free survival(EFS) and overall survival(OS) were inferior in the group with bulk compared to no bulk ( EFS 52 % versus 78 % , OS 81% versus 92%). However the response assessment in this study was not PET-based. A retrospective study from the British Columbia Cancer Agency reported that patients with initial bulky disease , if able to achieve PET negativity at the end of treatment(EOT), had outcomes similar to those without bulk, despite omission of RT . To date there is no published data comparing role of consolidation RT versus omission of RT if a patient with bulky disease achieves EOT PET-complete response (CR) . Since the data is not very clear, the practice of consolidation RT varies largely across different centres. Hence this study aims to assess if there is survival difference between groups with and without consolidation RT in patients with bulky disease who attain EOT PET-CR. A retrospective multicentric study was conducted by collecting data from eleven-member centers of Hematology Cancer Consortium (www.hemecancer.org) using an electronic database. Patients with DLBCL ≥ 18 years treated with curative intent between 2019-2022 were included. Bulk was defined as ≥ 7.5 cm nodal/extranodal lesions. In addition to demographics, details on Eastern Co-operative Oncology Group Performance status(ECOG PS), stage, extranodal involvement, B symptoms, treatment regimen, radiation details, response rates, and survival were collected. A total of 1455 patients had received curative intent treatment. Median age was 52 years( IQR 41-61), and 888 (61 %) were males. ECOG PS was < 2 in 89 %( 1140/1274). Any form of co-morbidities was noted in 41 % (600) patients. Advanced stage ( stage III/IV) was noted in 62 % (855/1374) . Extranodal involvement was noted in 53 % (777), B symptoms in 43% (621) and high LDH in 68% (804/1175) patients. The most common treatment administered was R CHOP in 1200 ( 83%) . A complete remission(CR) was attained in 786 ( 77%). Details on bulk disease status at diagnosis was available in 1326 patients . Five hundred and thirty four ( 40 %) had bulky disease. The following baseline characteristics at diagnosis namely ECOG PS ≥2 ( 34 % Vs 26 %), extranodal involvement( 60 % Vs 52%), high LDH( 82% Vs 62%), B symptoms( 47 % Vs 40 %), advanced stage ( 72 % Vs 57 %) and failure to achieve CR (28 % Vs 20 %) were all significantly higher in those with bulky disease. Among the bulky cases 192 cases attained CR by EOT PET based assessment of which 94 had received consolidation RT and 98 didn't. There was no significant difference in disease related characteristics between RT and non-RT groups except for high LDH in the former (85 % Vs 68 %, p=0.01). With a median follow up of 22 months, progression free survival (PFS) and overall survival (OS) for the entire cohort at 2-years were 77 % and 84 % respectively. Estimated 2-year PFS was inferior in patients with bulky disease versus non-bulky ( 73 % Vs 79 % , p= 0.02) , but OS was similar ( 82 % Vs 85 %, p= 0.16). Among patients attaining EOT PET CR , consolidation RT did not result in any improvement in PFS ( 93 % Vs 91 %, p= 0.84) or OS (96 % Vs 95 %,p=0.75) compared to non-RT group. Presence of bulky disease at baseline is associated with inferior PFS. If bulky disease patients are able to attain CR assessed by EOT PET CT , omission of RT did not result in inferior PFS. These findings have to be confirmed by large prospective trials.

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Yoon, Shinkyo, Dok Hyun Yoon, Shin Kim, Kyoungmin Lee, Eun Hee Kang, Sang-wook Lee, Chan-Jeoung Park, Chan-Sik Park, Jooryung Huh und Cheolwon Suh. „Proposal of New Prognostic Index for Patients with Diffuse Large B-Cell Lymphoma in the Rituximab Era“. Blood 124, Nr. 21 (06.12.2014): 1668. http://dx.doi.org/10.1182/blood.v124.21.1668.1668.

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Abstract Background The International Prognostic Index (IPI) has been useful prognostic tool to predict prognosis of aggressive non-Hodgkin lymphoma in the last 20 years. Since the advent of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) chemotherapy for diffuse large B-cell lymphoma (DLBCL), its utility has been challenged and other prognostic index including revised IPI and National Comprehensive Cancer Network (NCCN)-IPI were proposed, which are not popularly used yet. We aimed to develop new prognostic model for DLBCL in rituximab era. Method Between March 2004 and June 2012, patients with DLBCL treated with R-CHOP were identified in the database of the Asan Medical Center (AMC) Lymphoma Registry. Primary end point was to devise a new prognostic index for DLBCL. Secondary end point was to validate the NCCN-IPI in our cohort. We tested new prognostic index model in the training set of AMC cohort consisted of randomly selected 80% of the sample (503 patients). The remaining 20% (118 patients) was used as an internal validations set. Results The AMC cohort consisted of 621 patients. Median follow-up duration was 43.3 months (6.2-122.5 months). Baseline characteristics of AMC cohort are presented in table 1. Median age was 57 years (range, 16-85 years). Median ϐ-2 microglobulin (ϐ-2 MG) was 2.10 mg/L (range, 1.0-66.0 mg/L). The univariate analysis of baseline characteristics revealed that age (≦60 vs. >60 years), LDH (within normal vs. increased), ECOG performance (0 or 1 vs. ≧2), advanced stage (Ann Arbor stage I/II vs. III/IV), extra-nodal involvement (≦1 vs. >1), B symptoms (no vs. yes), and ϐ-2 MG (≦2.5 vs. >2.5) could predict overall survival (OS), whereas bulky disease and gender did not (p value 0.140, 0.621, respectively). In the multivariate analysis, age, LDH, ECOG performance status, and ϐ-2 MG were significantly associated with OS (p value 0.001, <0.001, 0.004, and 0.019, respectively), while stage, extra-nodal involvement, and B symptom did not (p value 0.057, 0.233, and 0.577, respectively). We developed a new prognostic model with these 4 significant factors in the multivariate analysis. One point is assigned for each of the risk factors without refined categorization. Four risk groups were composed as followings: low (0 point), low-intermediate (1 point), high-intermediate (2-3 points), and high (4 points). The new prognostic model showed better discriminative power compared with classic IPI (Figure 1A). Five-year OS of low- and high-risk subgroup in new scoring model and classic IPI model in AMC cohort were 95% and 32% versus 89% and 45%, respectively. Our model was validated in an internal validation set (Figure 1B). NCCN-IPI also could stratify four risk groups (Figure 1 A and B). Conclusion We propose a new prognostic index model for DLBCL in rituximab era with age, LDH, ECOG performance and ϐ-2 MG, which has good discriminative power and convenient to apply. It warrants further validation using an independent cohort. Table 1. Baseline Characteristics Characteristics Total N=621 % Training set N=503 % Validation set N=118 % Age, years Median, range ≦ 60 years > 60 years 57.0 377 244 16-85 60.7 39.3 57.0 300 203 16-84 59.6 40.4 57.0 77 41 17-85 65.3 34.7 Sex Male Female 343 278 55.2 44.8 273 230 54.3 45.7 70 48 59.3 40.7 ECOG PS 0 or 1 ≧ 2 569 52 91.6 8.4 462 41 91.8 8.2 107 11 90.7 9.3 Serum lactate dehydrogenase levels Normal Elevated 334 287 53.8 46.2 279 224 55.5 44.4 55 63 46.6 53.4 Ann Arbor stage I and II III and IV 293 328 47.2 52.8 236 267 46.9 53.1 57 61 48.3 51.7 Number of extranodal sites <2 ≧ 2 403 218 64.9 35.1 329 174 65.4 34.6 74 44 62.7 37.3 B symptoms No Yes 549 72 88.4 11.6 447 56 88.9 11.1 102 16 86.4 13.6 International prognostic index Low/ low-intermediate High-intermediate/high 404 217 65.1 34.9 327 176 65.0 35.0 77 41 65.3 34.7 ¥Â -2 microglobulin, mg/L Median, range ≦ 2.5 mg/L > 2.5 mg/L 2.1 422 199 1.0-66.0 68.0 32.0 2.1 339 164 1.0-29.6 67.4 32.6 2.1 83 35 1.0-66.0 70.3 28.7 Table 2. Multivariate Analysis for Factors Associated with Overall Survival Factors HR 95% CI P value Score Age, years ≦ 60 years > 60 years 1.000 2.051 1.362-3.090 0.001 1 Serum lactate dehydrogenase levels Normal Elevated 1.000 3.165 1.951-5.135 <0.001 1 ECOG PS 0 or 1 ≧ 2 1.000 2.073 1.261-3.407 0.004 1 ϐ -2 microglobulin, mg/L ≦ 2.5 mg/L > 2.5 mg/L 1.000 1.691 1.0391-2.622 0.019 1 Figure 1. IPI versus NCCN IPI versus new prognostic index model in Asan Medical Center training set (A) and internal validation set (B) Figure 1. IPI versus NCCN IPI versus new prognostic index model in Asan Medical Center training set (A) and internal validation set (B) Disclosures No relevant conflicts of interest to declare.

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Sesin, C., G. Gallo, A. Gellett, A. Kronbergs, A. T. Sprabery, W. Xu, H. Patel, A. Deodhar, B. Combe und G. R. Burmester. „POS1033 SAFETY OF IXEKIZUMAB IN PATIENTS WITH PSORIATIC ARTHRITIS: AN INTEGRATED ANALYSIS OF 4 CLINICAL TRIALS“. Annals of the Rheumatic Diseases 80, Suppl 1 (19.05.2021): 789.1–789. http://dx.doi.org/10.1136/annrheumdis-2021-eular.567.

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Background:Patients with psoriatic arthritis (PsA) require long-term treatment, which may lead to adverse events (AEs). Ixekizumab, an interleukin-17A antagonist, is approved for the treatment of adults with active PsA.Objectives:We report a summary of safety outcomes for patients enrolled in 4 PsA studies with up to 3 years of exposure to ixekizumab.Methods:This integrated safety analysis included all patients with PsA who received at least 1 dose of ixekizumab (80 mg every 2 or 4 weeks) in 4 clinical trials (NCT01695239, NCT02349295, NCT02584855, NCT03151551). Safety outcomes included treatment-emergent adverse events (TEAEs), serious AEs (SAEs), discontinuations due to AEs, deaths, and AEs of special interest.Results:A total of 1401 patients were included in this safety analysis (51.5% female; mean age 49 years), with 2247.6 patient-years of exposure (Table 1). In all, 1131 patients (80.7%) reported ≥1 TEAE (exposure-adjusted incidence rate per 100 patient-years [IR] 50.3, 95% CI 47.5–53.3), mostly mild (32.9%) or moderate (39.7%) in severity. The most common TEAEs were nasopharyngitis (n=202, IR 9.0), upper respiratory infections (n=186, IR 8.3), and injection site reaction (n=156, IR 6.9). SAEs were reported by 134 patients (IR 6.0, 95% CI 5.0–7.1). 115 (8.2%) patients discontinued due to AEs (IR 5.1, 95% CI 4.3–6.1). Six deaths were reported (IR 0.3, 95% CI 0.1–0.6). Allergic reactions/hypersensitivity were reported in 102 patients (IR 4.5, 95% CI 3.7–5.5). Three cases were adjudicated as de novo inflammatory bowel disease (IR 0.13, 95% CI 0.04–0.41); 1 was ulcerative colitis (IR 0.04, 95% CI 0.01–0.32), 2 were Crohn’s disease (IR 0.09, 95% CI 0.02–0.36). Major adverse cardiac events occurred in 12 patients (IR 0.5) and malignancies in 15 (IR 0.7), 9 of which were non-melanoma skin cancer. Opportunistic infections occurred in 40 (2.9%) patients (IR 1.8, 95% CI 1.3–2.4). Candidiasis occurred in 24 patients (oral: IR 0.7, 95% CI 0.4–1.2; oral fungal infection: IR 0.3, 95% CI 0.1–0.6; esophageal infection: IR 0.1, 95% CI 0.0–0.4). No active or reactive cases of tuberculosis were reported. Other opportunistic infections included hepatitis B (IR 0.0, 95% CI 0.0–0.3), herpes simplex (IR 1.8, 95% CI 1.3–2.5), and herpes zoster (IR 0.7, 95% CI 0.4–1.2).Conclusion:The safety profile of ixekizumab across 4 clinical trials and up to 3 years of continuous treatment in patients with active PsA was consistent with the known safety profile reported in previous studies for psoriasis and PsA. No new safety events were found in this analysis.Pooled Ixekizumab(N=1401; Total Patient-Years=2247.6)n (IR)95% CIYear 0–1(n=1401)n (IR)95% CIYear 1–2(n=946)n (IR)95% CIYear 2–3(n=510)n (IR)95% CIYear ≥3(n=89)n (IR)95% CITotal Patient-Years2247.71207.3689.8347.72.9Patients with ≥1 TEAE1131 (50.3)1050 (87.0)496 (71.9)234 (67.3)6 (206.2)47.5–53.381.9–92.465.9–78.559.2–76.592.6–458.9SAEs134 (6.0)72 (6.0)53 (7.7)19 (5.5)1 (34.4)5.0–7.14.7–7.55.9–10.13.5–8.64.8–243.9Discontinuations due to AEs115 (5.1)61 (5.1)37 (5.4)17 (4.9)0 (0)4.3–6.13.9–6.53.9–7.43.0–7.90.0–274.7Hepatic reactions112 (5.0)80 (6.6)32 (4.6)14 (4.0)0 (0)4.1–6.05.3–8.33.3–6.62.4–6.80.0–274.7Allergic reaction/hypersensitivity102 (4.5)83 (6.9)23 (3.3)5 (1.4)0 (0)3.7–5.55.5–8.52.2–5.00.6–3.50.0–274.7Serious infection28 (1.2)18 (1.5)9 (1.3)3 (0.9)0 (0)0.9–1.80.9–2.40.7–2.50.3–2.70.0–274.7Malignancies15 (0.7)4 (0.3)8 (1.2)4 (1.2)0 (0)0.4–1.10.1–0.90.6–2.30.4–3.10.0–274.7Major adverse cardiac events12 (0.5)3 (0.2)8 (1.2)1 (0.3)0 (0)0.3–0.90.1–0.80.6–2.30.0–2.00.0–274.7Inflammatory bowel disease3 (0.1)3 (0.2)1 (0.1)0 (0.0)0 (0.0)0.0–0.40.1–0.80.0–1.00.0–2.30.0–274.7 Ulcerative colitis1 (0.0)1 (0.1)1 (0.1)0 (0.0)0 (0.0)0.0–0.30.0–0.60.0–1.00.0–2.30.0–274.7 Crohn’s disease2 (0.1)2 (0.2)0 (0.0)0 (0.0)0 (0.0)0.0–0.40.0–0.70.0–1.20.0–2.30.0–274.7AE, adverse event; CI, confidence interval; IR, exposure-adjusted incidence rate per 100 patient-years; SAE, serious adverse event; TEAE, treatment-emergent adverse event.Disclosure of Interests:Carlos Sesin Speakers bureau: Amgen, AbbVie, Sanofi, Radius, Pfizer, Eli Lilly and Company, Novartis, Gaia Gallo Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Amanda Gellett Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Andris Kronbergs Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Aubrey Trevelin Sprabery Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Wen Xu Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Himanshu Patel Shareholder of: Eli Lilly and Company, Employee of: Eli Lilly and Company, Atul Deodhar Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Galapagos, Glaxo Smith & Kline, Janssen, Novartis, Pfizer, UCB, Grant/research support from: AbbVie, Eli Lilly and Company, Glaxo Smith & Kline, Novartis, Pfizer, UCB, Bernard Combe Speakers bureau: AbbVie, BMS, Gilead-Galapagos, Eli Lilly and Company, MSD, Pfizer, Roche Chugai, Consultant of: AbbVie, Bayer, Gilead-Galapagos, Janssen, Eli Lilly and Company, Novartis, Roche Chugai, Grant/research support from: AbbVie, Eli Lilly and Company, Pfizer, Roche Chugai, Gerd Rüdiger Burmester Speakers bureau: AbbVie, Janssen, Novartis, Eli Lilly and Company, MSD, Pfizer, Consultant of: AbbVie, Janssen, Novartis, Eli Lilly and Company, MSD, Pfizer.

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Soleto, C. Y., B. Serrano Benavente, L. A. Torrens Cid, J. Martínez-Barrio, J. Molina Collada, J. Rivera, T. González et al. „AB0357 USE OF TOFACITINIB AND REASONS FOR DISCONTINUATION IN CLINICAL PRACTICE“. Annals of the Rheumatic Diseases 79, Suppl 1 (Juni 2020): 1478.2–1479. http://dx.doi.org/10.1136/annrheumdis-2020-eular.5789.

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Background:Tofacitinib is an oral JAK 1 and 3 inhibitor for the treatment of moderate to severe active rheumatoid arthritis (RA) or psoriatic arthritis (PsA) in adults with inadequate response or intolerant to one or more conventional disease-modifying antirheumatic drugs (cDMARDs). Since its approval by the European Medicines Agency (EMA), there is limited data about its use in daily practice in Europe.Objectives:To describe rates and reasons for discontinuation of Tofacitinib in patients with RA and other inflammatory conditionsMethods:We identified patients with a prescription for tofacitinib at our academic center from January 2017 to January 2020. Patients were treated according to their rheumatologist evaluation following standards of care. The following variables were retrospectively collected from the electronic medical chart: age, gender, diagnosis, date of treatment initiation, date and reasons for treatment discontinuation, the use of concomitant or previous cDMARDs and of biologics. A comparison between patients continuing and stopping tofacitinib was performed through chi2or t-test for qualitative and quantitative variables, respectively. Survival analysis was done by Kaplan-Meier methodResults:Ninety patients receiving tofacitinib were identified, 81 with RA, 6 with PsA, 1 with Dermatomyositis, 1 with Sjögren´s and 1 with juvenile idiopathic arthritis. Table 1 shows the baseline characteristics. 84% percent patients were women and the mean (SD) age was 58.5 (14.2) years. 51% patients started tofacitinib in monotherapy. When used, methotrexate was the most frequent cDMARD (61.3%); 10% patients used tofacitinib as first line after cDMARD and the majority used it after 1 or 2 previous biologics (46.7%).Table 2.Clinical coutcome of patients who developed HZ at initiation of baricitinibAll patients(n=90, 100%)Continue Tofacitinib(n=58; 64%)Not continue Tofacitinib(n=32; 35.5%)p-valueFemale (%)76 (84.4)48 (82.7)28 (87.5)0.55Age (year) – mean (SD)58.5 (14.2)58 (12.9)59.5 (16.5)0.63Diagnosis0.66Rheumatoid arthritis81 (90)52 (89.6)29 (90.6)Psoriatic arthritis6 (6.7)4 (6.8)2 (6.2)Other3 (3.3)2 (3.4)1 (3.1)Treatment duration (months) – mean (SD)10.6 (6.9)11.9 (7.3)8.2 (5.5)0.02Prednisone (mg) – mean (SD)1.75 (3.2)1.20 (2.5)2.73 (4.1)0.03Monotherapy (%)46 (51.1)28 (48.2)18 (56.2)0.244Concomitant csDMARDs (%)44 (48.8)30 (51.7)14 (43.7)0.62Methotrexate (%)27 (30)17 (29.3)10 (31.2)Leflunomide (%)10 (11.1)8 (13.7)2 (6.2)Other (%)7 (7.7)5 (8.6)2 (6.2)Prior biologic treatment0.13None (%)9 (10)6 (10.3)3 (9.3)1-2 (%)42 (46.6)28 (48.2)14 (43.7)≥3 (%)39 (43.3)24 (41.3)15 (46.8)Survival rates when used as first or second line were 85% at 6 months and 70% at 12 months; when used as third line or further, 76% and 70%, respectively (graphic 1).Factors associated to tofacitinib discontinuation were treatment duration and baseline prednisone dose. In contrast concomitant csDMARD and number of previous biologics were not. Reasons for tofacitinib discontinuation were: lack/loss of efficacy 46.9%, adverse events 50% (including intolerance -22%- herpes zoster -16%-, other infections 12%) and others.Conclusion:Tofacitinib in our experience is mostly used in RA patients after biologic failure. Overall survival rate at 12 months was good regardless line of therapy. Adverse event rates were similar to other biologic treatments. Herpes zoster was the most common infectious AE.Graphic 1:References:[1]Wollenhaupt J, Lee EB, Curtis JR, et al. Safety and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis: final results of a global, open-label, long-term extension study. Arthritis Res Ther. 2019;21(1):89.Disclosure of Interests:Christian Y Soleto: None declared, Belén Serrano Benavente: None declared, Luis A Torrens Cid: None declared, Julia Martínez-Barrio Consultant of: UCB Pharma, Juan Molina Collada: None declared, Javier Rivera: None declared, Teresa González: None declared, Indalecio Monteagudo: None declared, Carlos Gonzalez Consultant of: Gilead, Janssen, Novartis,, Speakers bureau: Abbvie, Celgene, Gilead, Janssen, Novartis, Pfizer, Roche, Isabel Castrejon: None declared, Jose-Maria Alvaro-Gracia Grant/research support from: Abbvie, Elli-Lilly, MSD, Novartis, Pfizer, Consultant of: Abbvie, BMS, Janssen-Cilag, Elli-Lilly, MSD, Novartis, Pfizer, Sanofi, Tigenix, Roche, UCB, Paid instructor for: Elli-Lilly, Pfizer, Roche, Speakers bureau: Abbvie, BMS, Janssen-Cilag, Elli-Lilly, Gedeon Richter, MSD, Novartis, Pfizer, Sanofi, Tigenix, Roche, UCB

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Mukherjee, Sudipto, Chandana Reddy, Jay Ciezki, Ramon V. Tiu, Edward A. Copelan, Anjali S. Advani, Yogen Saunthararajah et al. „Radiation Treatment for Localized Prostate Cancer and the Risk of Developing Myelodysplastic Syndromes (MDS)“. Blood 118, Nr. 21 (18.11.2011): 120. http://dx.doi.org/10.1182/blood.v118.21.120.120.

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Abstract Abstract 120 Background: Both environmental radiation exposure and use of therapeutic radiation (XRT) in primary solid tumor malignancies increase the risk of secondary MDS. No data exist on the risk of developing secondary MDS in prostate cancer patients (pts) being treated with radiotherapy. Establishing this risk has important clinical implications, as prostate cancer is the leading cancer in men and radiation therapy has increasingly become the preferred modality for treatment of localized prostate cancer. Methods: We performed a prospective case control study of 11,015 pts with localized prostate adenocarcinoma newly diagnosed between 1986 and 2011 at Cleveland Clinic who underwent treatment with either radical prostatectomy (control group) or definitive radiotherapy (external beam radiotherapy [EBRT] or prostate interstitial brachytherapy [PI] – case group), to investigate the risk of radiation-related MDS. Data on demographics, surgery, radiation treatment, and follow-up were collected from merged prostate cancer and MDS databases. Cytogenetic risk groups were per International Prognostic Scoring System (IPSS) for MDS. Univariate and multivariate analyses were performed using the Fine and Gray competing risk model with MDS as a time-dependent endpoint (which incorporates differences in duration of follow-up) and death from any cause as the competing event, comparing radiotherapy groups to the surgical cohort as the reference group, controlling for age and follow-up frequency. Hazard ratios (HR) with 95% confidence intervals (CIs) are reported. Results: For all pts, median age was 64 years (yrs, range, 37 – 88) at the time of prostate cancer diagnosis: 69 yrs in EBRT, 67 yrs in PI, and 60 yrs in surgery pts, respectively (p<0.0001); 5119 (46%) were treated with XRT, 5896 (54%) with prostatectomy. None of the pts had a previous history of another malignancy. Among XRT pts, 2183 (43%) were treated with EBRT, 2936 (57%) with PI. Median follow-up was 3.0 yrs [(range, 0.0 – 25.2): 6.8 yrs in the EBRT group, 2.5 yrs in the PI group and 1.8 yrs in the surgery group, (p<0.0001)] following prostate intervention, longer (4.6 yrs) in pts treated since 1996, when PI was first performed [6.6 yrs in the EBRT group, 3.8 yrs in the PI group and 4.3 yrs in the surgery group, (p<0.0001)]. In the entire cohort, 30 pts developed MDS: 24 in the XRT group and 6 in the surgery group. MDS World Health Organization classification was: RA/RARS (n=12), RCMD (n=3), RAEB-1 (n=3), RAEB-2 (n=3), CMML (n=2), MDS-U (n=3) and unknown (n=4). IPSS cytogenetic risk classification was: good risk (n=17), intermediate risk (n=5), poor risk (n= 4) and unknown (n = 4). For MDS pts within the XRT group, median age at MDS diagnosis was 79 yrs (range, 74 – 89) for EBRT, 80 yrs (range, 64 – 100) for PI. The median time to develop MDS was 8.9 yrs (range, 0.9 – 20.2): 9.1 for EBRT, 8.2 for PI, and 13.0 for prostatectomy pts, respectively (p=0.05). In univariate analyses, older pts (HR=1.14; CI, 1.09 – 1.2; p<0.0001), and those treated with XRT (HR=3.3; CI, 1.35 – 8.08; p=0.009): EBRT (HR=2.6; CI, 1.0 – 6.9; p=0.05), PI (HR=5.87; CI, 2.1 – 16.3; p=0.0007) were significantly more likely to develop MDS. In multivariate analysis though, while advanced age (HR=1.13; CI, 1.0 – 1.2; p < 0.0001) remained significantly associated with MDS development, XRT did not (HR=1.56; CI, 0.56 – 4.38; p=0.4), though a trend remained for PI (HR=2.85; CI, 0.9 – 8.8; p = 0.07). Conclusions: Pts who underwent definitive radiation treatment for localized prostate cancer did not appear to have a significantly increased risk of subsequent MDS, in analyses that controlled for age and incorporated length of follow-up. A trend for MDS development was present for those undergoing XRT with PI. These findings are encouraging for both patients and providers who have concerns about the potential effects of XRT on development of MDS. Disclosures: Maciejewski: Celgene: Membership on an entity's Board of Directors or advisory committees. Sekeres:Celgene: Consultancy, Honoraria, Speakers Bureau.

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Chen, Xue, Lili Yuan, Xiaoli Ma, Fang Wang, Yang Zhang, Panxiang Cao, Jiancheng Fang et al. „Extensive Fusion Gene Profiling in Acute Myeloid Leukemia Revealed By Whole Transcriptome Sequencing of 1614 Cases“. Blood 144, Supplement 1 (05.11.2024): 4326. https://doi.org/10.1182/blood-2024-193221.

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Background Fusion genes (FGs) are critical molecular abnormalities in acute myeloid leukemia (AML), serving as vital markers for diagnosis, classification, risk stratification, and targeted therapy. In 2021, we published the FG map of acute leukemia revealed by whole transcriptome sequencing (WTS) of 1000 cases, including 539 AML patients (Blood Cancer Journal. PMID: 34135310). Building upon this initial study, we have now expanded our study to include 1614 AML cases, aiming to further elucidate the FG landscape and explore additional insights into the clinical implications of these genetic alterations. Methods We enrolled 1614 AML cases diagnosed in our hospital from September 2018 to April 2024, with high-quality WTS data. Among them, 356 (22%) were children (≤18 years, median age 9 years, range 3 months to 18 years), and 1258 (78%) were adults (>18 years, median age 46 years, range 19 to 89 years). We used bone marrow samples from 100 healthy donors as controls. Written informed consent was obtained from all participants or their guardians in accordance with the Declaration of Helsinki. RNA quality assessment, sequencing library preparation, paired-end sequencing, and FGs detection were conducted as we previously reported. High-confidence in-frame FGs detected by WTS were classified into 4 tiers based on pathogenicity. (A) pathogenic: well-known FGs or new members of common FG families (FG-FMs) with definite pathogenicity in hematological malignancies. (B) likely pathogenic: FGs reported in hematologic malignancies without functional verification, or novel FGs involving genes associated with these malignancies. (C) uncertain significance: novel FGs involving genes without known associations with these malignancies. (D) non-pathogenic: FGs found in normal samples. Results A total of 269 different FGs were detected in 907 AML patients, including 90 tier A, 63 tier B, 108 tier C, and 8 tier D FGs. Tier D FGs were unlikely to be pathogenic and not analyzed further. 982 fusion events (771 tier A, 97 tier B, and 114 tier C, respectively) were detected in 889 (55%) cases. Most patients (n=800; 90%) carried only one FG. Additionally, 85 cases had 2 FGs, and 4 cases had 3 FGs. Only 12 patients had coexisting two tier A FGs, accounting for 0.7% of all cases enrolled in this study and 1.3% of all positive cases. We found 51 kinds of recurrent FGs that occurred at least twice, including 42 tier A, 4 tier B, and 5 tier C FGs, respectively. The positivity rate of FGs presented a typical long-tail distribution, with only 10 FGs having a positivity rate >1%: RUNX1::RUNX1T1 (12.2%), PML::RARA (6.9%), CBFB::MYH11 (3.7%), NUP98::NSD1 (3.5%), KMT2A::MLLT3 (3.1%), KMT2A::MLLT4 (1.9%), KMT2A::MLLT10 (1.7%), ZNF292::PNRC1(1.6%), DEK::NUP214 (1.1%), KMT2A::AFDN (1%). Notably, a considerable number of so-far unreported FGs were detected in this study. Totally, 181 kinds of novel FGs were discovered (15 tier A, 58 tier B, and 108 tier C), accounting for 69% of all FGs. However, only 7 of them were recurrent. We classified the 153 distinct tier A and tier B FGs according to FG-FMs, which referred to FGs that involve one protagonist gene and various fusion partners. More than half of them (99/153, 65%) could be classified into 25 FG-FMs, such as KMT2A-FM, NUP98-FM, and RUNX1-FM. When we focused on tier A FGs, 91% (82/90) could be clustered into FG-FMs, indicating the central involvement of key genes in AML pathogenesis. Conclusion This comprehensive analysis of 1614 AML cases using WTS provides an extensive and detailed landscape of FGs in AML. Our findings underscore the significant heterogeneity of FGs in AML, with a substantial proportion of patients harboring novel and previously unreported FGs. The identification of 269 distinct FGs, including 90 well-established pathogenic FGs, highlights the critical role of these genetic alterations in AML pathogenesis. Moreover, the classification into FG-FMs reveals the central involvement of key genes such as KMT2A, NUP98, and RUNX1 in a large proportion of pathogenic FGs. These insights not only enhance our understanding of the molecular complexity of AML but also have important implications for diagnosis, prognosis, and the development of targeted therapies. Future studies should focus on the functional validation of novel FGs and the exploration of their potential as therapeutic targets.

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Williams, Annalynn M., Andrea M. Baran, Philip J. Meacham, Megan Herr, Hugo E. Valencia, Catherine Newsom, Nealansh Gupta, Michelle Janelsins, Paul M. Barr und Clive S. Zent. „High Risk of Infections in Chronic Lymphocytic Leukemia Patients Treated with B-Cell Receptor Inhibitors“. Blood 128, Nr. 22 (02.12.2016): 3203. http://dx.doi.org/10.1182/blood.v128.22.3203.3203.

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Abstract Introduction: Infection is a major source of morbidity and mortality in CLL. Improved treatment efficacy and decreased immune toxicity of treatment could have altered the spectrum and consequences of infections in patients with CLL. A better understanding of infections complicating the course of non-selected patients with CLL could be useful in improving medical management. Methods: Demographic and clinical information was retrospectively extracted from medical records for clinic visits between May 1st, 2000 and May 1st, 2016 for all patients enrolled in the Wilmot Cancer Institute (WCI) CLL database. Data collected on incident infections included site, etiology, treatment, and setting of care. Major infections were defined as requiring either an inpatient stay or IV antimicrobial treatment. Minor infections were defined as any infectious episode requiring oral antimicrobials and outpatient treatment. Incidence rate ratios (IRR) were generated using Poisson regression to compare infection rates across treatment categories. Results: Two hundred and seventy-five CLL patients contributed 937.7 person-years (p-yrs) of follow up from their first clinic visit at WCI (median follow up 2.1 yrs). Median age at diagnosis was 61.6 and only 8.2% of patients had advanced stage CLL. Most patients were CD38 negative (64.7%), ZAP70 negative (54.6%), and IGHV mutated (51.2%, n=89) and 75.1% had either 13q14 deletion as the only defect or no abnormality on FISH analysis. Sixty percent of patients needed treatment for progressive CLL; among those treated, 50.9% were ever treated with either a purine analog or alemtuzumab, 30.4% were treated with other chemotherapies, and 18.6% had non-chemotherapy treatment. B-cell receptor inhibitor (BCR) therapy was used in sixty-seven patients (63 ibrutinib, 4 idelalisib) and was the only therapy in 18 of them (BCR only). Thirty percent of patients experienced at least one major infection (incidence rate 20.4 per 100 p-yrs) and 62.9% experienced at least one minor infection (69.3 per 100 p-yrs). The most common sites of major infections were the lower respiratory tract (7.8 per 100 p-yrs), skin (2.6 per 100 p-yrs), and urogenital tract (2.0 per 100 p-yrs). Minor infections most commonly affected the upper respiratory tract (26.8 per 100 p-yrs), skin (11.0 per 100 p-yrs, including shingles: incidence rate of 2.8 per 100 p-yrs), and bronchi (9.3 per 100 p-yrs). Patients treated for CLL had a higher risk of major infections (IRR 4.15, 95%CI 2.53, 6.80) and minor infections (IRR 1.48, 95%CI 1.23, 1.79) compared to those never treated. The age and gender adjusted risk of both major and minor infections were significantly increased by treatment with a purine analog or alemtuzumab (Table 1). The risk of major infection in the BCR only group was significantly higher than treatment-naive patients (IRR 3.31 95%CI 1.13, 9.80) and was 43% lower compared to patients treated with other modalities (IRR 0.57, 95%CI 0.21,1.55). The BCR group had a significantly higher risk of a minor infection compared to untreated patients (IRR 1.86 95% 1.14, 3.04), but had a slightly lower risk compared to those treated with other modalities (IRR 0.93 95%CI 0.57, 1.48). The BCR only group had a longer infection free survival compared to those on BCR inhibitor salvage therapy (Figure 1). An intra-patient comparison of infection risk for patients receiving BCR inhibitor salvage therapy compared to their previous chemoimmunotherapy showed an 33% increase in the risk of a major infection (IRR 1.33 95%CI 0.96, 1.86) and a 185% increased risk of a minor infection (IRR 2.85 95%CI 1.57, 5.18). Conclusion: CLL is complicated by a large number of infections, especially in patients with progressive disease who require treatment. Minor infections contribute to considerable disease burden and can have serious sequelae (e.g. post herpetic neuralgia). Given their decreased immune toxicity profile, BCR inhibitors may decrease the risk of infections; however, this has not yet been confirmed. Our sample of CLL patients treated solely with BCR inhibitors experienced higher rates of infection compared to untreated patients. Additionally, patients treated with BCR inhibitors as salvage therapy still experienced higher rates of infection compared to their time on chemoimmunotherapy. Therefore, patients treated with BCR inhibitors should be carefully monitored for infections that can cause significant morbidity or mortality. Disclosures Barr: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; AbbVie: Consultancy.

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Rivera, Daniel, Yesid Alvarado, Guillermo Garcia-Manero, Gautham Borthakur, Hagop Kantarjian und Sergej Konoplev. „Clinical Characteristics and Outcomes of Patients Diagnosed with Acute Myeloid Leukemia with Expression of CD71“. Blood 138, Supplement 1 (05.11.2021): 4449. http://dx.doi.org/10.1182/blood-2021-151023.

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Abstract Introduction Acute myeloid leukemia (AML) is a clonal hematologic malignancy characterized by the proliferation and accumulation of blasts in the bone marrow (BM) which results in hematopoietic failure. Transferrin receptor (CD71) plays an important role by up-taking iron into the cell, and its expression is regulated by cellular iron levels. Recently, CD71 has emerged as a sensitive and specific marker of cell proliferation in solid tumors. The clinical significance of CD71 expression in AML remains unclear. Current efforts are also exploring its potential as a therapeutic target in AML. We aimed to describe the clinical characteristics and outcomes of patients diagnosed with de novo AML who expressed CD71. Methods We conducted a retrospective analysis of 453 patients with newly diagnosed AML that came to our institution from December 2019 to June 2021 in whom CD71 antibody was available at diagnosis. CD71 expression was assessed by flow cytometry immunophenotypic studies performed using bone marrow aspirate specimens at presentation. For each analysis, a minimum of 200,000 events was acquired on FACSCanto II instruments (8-color and 10-color, BD Biosciences). The CD45 dim-blast region including monocytes based on CD45 / side scatter was analyzed. The antibody panel included 5 tubes; CD71 antibody was included in tube 3, which contains the following antigen combination: CD41/CD71/CD56/CD34/CD64/HLA-DR/CD14/CD45. The neoplasm was CD71-positive if at least 20% of blasts demonstrated CD71 expression. Additionally, frontline treatment was categorized into intensive chemotherapy (HiDAC based), and Low-Intensity regimen (double nucleoside analog or hypomethylating agent-based therapies). Outcomes in terms of survival and treatment response were analyzed and reported by age, ELN risk groups (Favorable, Intermediate, and Adverse), and the presence of somatic mutations. Results Baseline characteristics are detailed in table 1. We identified 359 (79%) patients diagnosed with AML in whom CD71 was expressed. Our study focused on 184 (41%) patients diagnosed with previously untreated de novo AML, the median age was 63 years (IQR 50-73). Fifty-seven percent of patients were male. Median hemoglobin and platelet counts were 8.2 g/dL and 40 x10 9/L, respectively. The Median BM blast percentage was 54%, among these patients, there was a higher representation of patients with adverse risk features when compared with the intermediate and favorable group (50%, 34%, and 16% respectively). The molecular landscape of our population showed higher representation of RAS (25%), DMNT3A (23%), TP53 (21%), WT1 (21%), NPM1 (20%), FLT3-ITD (16%), and IDH2 (15%), figure 1. Frontline treatment information was available on 108 patients, of these, 43% were treated with intensive chemotherapy, while 57% of patients were treated with a low-intensity regimen. In terms of outcomes, with a median follow-up time of 6 months, the median overall survival of the whole patient cohort was 9 months (95% CI: 4.3-13.6). Patients aged more than 60 years showed inferior OS compared to younger patients (6 vs. 14 months; p=0.059), respectively, figure 2. Among patients with adverse risk features, the median OS was 5 months (95% CI: 3-6.9, p=0.068) versus those with intermediate (12 months) and favorable risk features (16 months), figure 3. Next, among the somatic mutations with higher representation with known prognostic impact, patients with TP53 mutated showed a significantly inferior OS compared to those with wild type (median 4 vs. 12 months, p=0.006) respectively, figure 4. Patients treated with intensive chemotherapy showed a trend to higher ORR versus low-intensity regimen (89% vs. 74% respectively, p=0.051). Similarly, CR/CRi rates were higher among those treated with intensive chemotherapy compared to those with a low-intensity regimen (85% vs. 70% respectively, p=0.106), figure 5. Conclusion Acute myeloid leukemia is an aggressive hematologic malignancy with a heterogeneous nature. CD71 expression appears to be a common event and was identified in up to 40% of de novo AML cases in our institution. Its expression appears to be associated with cytopenias in addition to the presence of molecular abnormalities commonly associated with an adverse prognosis. Its clinical significance, applicability as a diagnostic marker, and potential as a therapeutic target in AML need to be fully elucidated. Figure 1 Figure 1. Disclosures Alvarado: Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; BerGenBio: Research Funding; CytomX Therapeutics: Consultancy; MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; FibroGen: Research Funding; Sun Pharma: Consultancy, Research Funding. Kantarjian: Immunogen: Research Funding; Astra Zeneca: Honoraria; Ipsen Pharmaceuticals: Honoraria; Jazz: Research Funding; Amgen: Honoraria, Research Funding; Astellas Health: Honoraria; Aptitude Health: Honoraria; Novartis: Honoraria, Research Funding; KAHR Medical Ltd: Honoraria; NOVA Research: Honoraria; BMS: Research Funding; Ascentage: Research Funding; AbbVie: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; Pfizer: Honoraria, Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria.

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Olszewski, Adam J., und Jorge J. Castillo. „Prognosis of HIV-Associated Hodgkin Lymphoma in the Antiretroviral Therapy Era: Analysis of the National Cancer Data Base (NCDB)“. Blood 126, Nr. 23 (03.12.2015): 3861. http://dx.doi.org/10.1182/blood.v126.23.3861.3861.

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Abstract Background: The incidence of Hodgkin lymphoma (HL) among HIV-positive (HIV+) patients remains high despite the use of antiretroviral therapy. HIV+HL is characterized by a higher prevalence of the mixed cellularity (MC) subtype and by expression of Epstein-Barr virus-encoded genes. Despite poor historical outcomes, recent studies show similar overall survival (OS) among HIV+ and HIV-negative HL patients who receive standard therapy. We examined the actual proportions of HIV+HL patients receiving chemotherapy in the United States (US), and their OS, using the NCDB-a clinical oncology database capturing >70% of incident cancer cases in the US. Methods: We analyzed classical HL cases reported to the NCDB between 2004 and 2012, with recorded HIV status. Factors associated with non-receipt of chemotherapy were studied in a mixed-effects logistic model clustered on hospital. OS was compared in Cox models adjusting for age, sex, race, stage, B symptoms and socioeconomic status, reporting adjusted hazard ratio (HR) and 95% confidence intervals (CI). CD4 counts, chemotherapy details or HL recurrences were not available in the NCDB. Results: We identified 2,090 HIV+HL and 24,889 HIV-negative patients. HIV+ patients were on average older (median age 43 vs. 39 years in HIV-negative), more often male (80% vs. 53%), black (37% vs. 12%) or Hispanic (17% vs. 8%%, all P <.00001). The proportion of black patients increased from 31% in 2004 to 49% in 2012. HIV+HL patients had also more often advanced-stage (III/IV) disease (66% vs. 40%), B symptoms (64% vs. 41%), extranodal HL (5% vs. 3%), MC (22% vs. 12%), lymphocyte-depleted (LD, 3% vs. 1%) or undetermined histology (HL-NOS, 40% vs. 26%), and less nodular sclerosis (NS) subtype (32% vs. 57%, all P<.00001). Early (I/II) stage HIV+HL patients were more often treated with chemotherapy alone (51% vs. 46% of HIV-negative), less frequently with combined modality (28% vs. 42%), and 18% received no treatment (vs. 9%, P<.0001). Similarly, in advanced stage they were less likely to receive chemotherapy than HIV-negative patients (84% vs. 91%, P<.0001). The proportion of all HIV+HL cases receiving any chemotherapy was 81%, unchanged between 2004 and 2012 (P =.29). Their risk of not receiving chemotherapy increased with age, and was significantly higher for patients who were black (odds ratio, OR, vs. white, 1.55, CI, 1.14-2.09), uninsured (OR, 1.65, CI, 1.08-2.51), or with HL-NOS (OR vs. NS, 1.73, CI, 1.27-2.35). It varied significantly by hospital (intraclass correlation, 9%, CI, 4-20%), but without difference between community and academic centers (P =.47). OS at 5 years for HIV+HL patients was 66.1% overall (95% CI, 63.7-68.4%), 78.7% in stage I/II, and 59.9% in stage III/IV. Among patients who received chemotherapy, these estimates were 73.0%, 83.5% and 68.0%, respectively. OS did not improve between 2004 and 2011 (P =.18). When HIV+ and HIV-negative HL patients were compared in models adjusting for confounders (Table), OS was not significantly different in the classic NS or MC subtypes as long as patients received chemotherapy. In contrast, HIV+ HL-NOS had significantly worse OS even with chemotherapy, similar to OS of HIV-negative patients with the unfavorable LD subtype. Conclusions: This large contemporary analysis confirms similar survival of HIV- and HIV+HL patients with the classical NS/MC histologies as long as they receive chemotherapy. HL of undetermined histologic subtype (possibly because of atypical, aggressive morphology or difficulty in obtaining an excisional nodal specimen) identifies HIV+ patients with poor prognosis despite standard therapy, who might benefit from novel, alternative approaches. As of 2012, half of HIV+HL patients in the US are black, and they are at high risk of not receiving curative chemotherapy, although it is unclear whether this is because of health care-related factors or worse immune deficiency status. Table 1. Histology All patients Patients receiving chemotherapy 5-year OS (%) Cox model 5-year OS (%) Cox model HIV+ HIV- HR P HIV+ HIV- HR P NS 74.5 85.3 1.42 .0001 80.2 87.1 1.14 .23 MC 73.0 73.1 1.31 .026 77.6 76.8 1.14 .37 Lymphocyte-rich 74.1 81.8 1.25 .59 71.1 83.7 1.49 .38 LD 57.5 55.4 1.09 .76 69.0 62.9 0.95 .89 HL-NOS 55.1 72.0 1.85 <.0001 63.5 77.3 1.57 <.0001 Disclosures Olszewski: Genentech, Inc.: Research Funding; Bristol-Myers Squibb, Inc.: Consultancy.

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Prieto-Peña, D., S. Remuzgo Martinez, F. Genre, V. Pulito-Cueto, B. Atienza-Mateo, B. Sevilla, J. Llorca et al. „POS0113 BAFF-APRIL-BAFFR PATHWAY ON THE PATHOGENESIS OF IMMUNOGLOBULIN-A VASCULITIS“. Annals of the Rheumatic Diseases 80, Suppl 1 (19.05.2021): 267.2–268. http://dx.doi.org/10.1136/annrheumdis-2021-eular.707.

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Background:BAFF, APRIL and BAFFR are genes that encode cytokines with a key role in the development and survival of B-lymphocytes [1-4]: The B cell-activating factor (BAFF, also known as BLyS), a proliferation-inducing ligand (APRIL) and BAFF receptor (BAFF-R), respectively. Previous genetic studies have revealed that the BAFF-APRIL-BAFFR pathway is implicated in the genetic predisposition to several immune-mediated diseases [5].Objectives:To determine whether the BAFF-APRIL-BAFFR pathway represents a novel genetic risk factor for the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory disease in which IgA deposits and B-lymphocytes are crucial [6, 7].Methods:A functional BAFF polymorphism (rs374039502) and two tag variants within APRIL (rs11552708 and rs6608) and BAFFR (rs7290134 and rs77874543) were genotyped in 386 Caucasian IgAV patients (the largest series of Caucasian patients with IgAV ever assessed for genetic studies) and 806 sex and ethnically matched healthy controls by TaqMan assays.Results:No statistically significant differences in the genotype and allele frequencies between patients with IgAV and healthy controls were observed when each genetic variant of BAFF APRIL and BAFFR was analyzed independently (Table 1). Likewise, no statistically significant differences in genotype and allele frequencies of BAFF APRIL or BAFFR were found when patients with IgAV were stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. Similar results were disclosed when haplotype frequencies of APRIL and BAFFR were compared between patients with IgAV and healthy controls as well as patients with IgAV stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations.Conclusion:Our results suggest that the BAFF-APRIL-BAFFR pathway does not contribute to the genetic network underlying IgAV.References:[1]J Exp Med 1999;190:1697-710; [2] Science 1999;285:260-3; [3] Nat Genet 2005;37:829-34; [4] Nat Immunol 2002;3:822-9; [5] N Engl J Med 2017;376:1615-26; [6] N Engl J Med 2013;368:2402-14; [7] Autoimmun Rev 2018;17:301-315.Table 1.Genotype and allele frequencies of BAFF, APRIL and BAFFR genes in patients with IgA vasculitis and healthy controls.PolymorphismLocus1/2Data set1/11/22/212rs374039502BAFFT/APatients91.9 (353)8.1 (31)095.9 (737)4.1 (31)Controls91.5 (733)8.1 (65)0.4 (3)95.6 (1531)4.4 (71)rs11552708APRILG/APatients78.1 (299)20.6 (79)1.3 (5)88.4 (677)11.6 (89)Controls77.9 (625)20.4 (1641.6 (13)88.1 (1414)11.9 (190)rs6608APRILC/TPatients71.9 (277)26.0 (100)2.1 (8)84.9 (654)15.1 (116)Controls70.0 (561)27.6 (221)2.5 (20)83.7 (1343)16.3 (261)rs7290134BAFFRA/GPatients58.0 (224)36.3 (140)5.7 (22)76.2 (588)23.8 (184)Controls57.2 (459)36.4 (292)6.5 (52)75.3 (1210)24.6 (396)rs77874543BAFFRG/CPatients82.7 (316)16.0 (61)1.3 (5)90.7 (693)9.3 (71)Controls83.0 (666)16.6 (133)0.4 (3)91.3 (1465)8.7 (139)Acknowledgements:This study was supported by European Union FEDER funds and “Fondo de Investigaciones Sanitarias” (grant PI18/00042) from ‘Instituto de Salud Carlos III’ (ISCIII, Health Ministry, Spain). DP-P is a recipient of a Río Hortega programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, `Investing in your future´) [grant number CM20/00006]; SR-M is supported by funds of the RETICS Program co-funded by the European Regional Development Fund (ERDF) [grant number RD16/0012/0009]; VP-C is supported by a pre-doctoral grant from IDIVAL [grant number PREVAL 18/01]; BA-M is a recipient of a `López Albo´ Post-Residency Programme funded by Servicio Cántabro de Salud; LL-G is supported by funds of IDIVAL [grant number INNVAL20/06]; RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, `Investing in your future´) [grant number CP16/00033].Disclosure of Interests:Diana Prieto-Peña Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Consultant of: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Grant/research support from: Abbvie, MSD and Roche, Sara Remuzgo Martinez: None declared, Fernanda Genre: None declared, Verónica Pulito-Cueto: None declared, Belén Atienza-Mateo: None declared, Belén Sevilla: None declared, Javier Llorca: None declared, Norberto Ortego: None declared, Leticia Lera-Gómez: None declared, Maite Leonardo: None declared, Ana Peñalba: None declared, J. Narváez: None declared, Luis Martín-Penagos: None declared, Jose Alberto Miranda-Filloy: None declared, LUIS CAMINAL MONTERO: None declared, PAZ COLLADO: None declared, Javier Sanchez Perez: None declared, Diego de Argila: None declared, Esteban Rubio-Romero: None declared, MANUEL LEON LUQUE: None declared, Juan María Blanco-Madrigal: None declared, E. Galindez: None declared, Javier Martin Ibanez: None declared, Santos Castañeda: None declared, Ricardo Blanco Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Consultant of: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Grant/research support from: Abbvie, MSD and Roche, Miguel A González-Gay Speakers bureau: Pfizer, Abbvie, MSD, Grant/research support from: Pfizer, Abbvie, MSD, Raquel López-Mejías: None declared

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Palandri, Francesca, Daniela Bartoletti, Elisabetta Abruzzese, Alessandra Iurlo, Massimiliano Bonifacio, Giovanni Caocci, Elena Maria Elli et al. „Peripheral Blasts Are Associated with Response to Ruxolitinib and Outcome in Patients with Chronic-Phase Myelofibrosis“. Blood 138, Supplement 1 (05.11.2021): 3624. http://dx.doi.org/10.1182/blood-2021-152420.

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Abstract Background: The presence of peripheral blasts (PB) is a negative prognostic factor in patients (pts) with primary and secondary myelofibrosis (PMF/SMF) and PB ≥4% was associated with a particularly unfavorable prognosis (Masarova L et al, Cancer 2020). Ruxolitinib (RUX) is the JAK1/2 inhibitor most used for treatment of MF-related splenomegaly and symptoms. Its role has not been assessed in correlation with PB. Aims: To evaluate the impact of PB percentage on RUX efficacy and prognosis Methods: After IRB approval, the "RUX-MF" retrospective study collected 804 RUX-treated chronic-phase (CP, defined as PB <10%) pts in 26 Hematology Centers. In 794 pts, PB count was evaluated by morphology at RUX start and correlated with treatment success and outcome. Risk category was assessed according to DIPSS (Passamonti F et al, Blood. 2010). Spleen (SR) and symptoms (SyR) response were assessed using IWG-MRT criteria (Tefferi A et al, Blood. 2013). Comparisons of quantitative variables between the 3 groups were carried out by Kruskal-Wallis and Dunn's tests while association between categorical variables was tested by the χ2 test. Variables significantly associated to RUX stop/leukemic transformation (LT)/overall survival (OS) in univariate analysis (Log-rank test) were considered for multivariable analyses, carried out using the Cox regression model, with evaluation of the model's performance in terms of goodness of fit. Results: Pts were categorized according to PB at RUX start: PB-0 (no PB; n. 487, 61.3%), PB-5 (PB 1-5%; n. 283, 35.8%), and PB-9 (PB 6-9%; n. 24, 2.9%). Pts characteristics at RUX start were: median age 68.1y (24-89); males 58.1%; PMF 52.5%; JAK2, CALR and MPL mutated: 80.5%, 13.1% and 2% (4.4% triple negative), high DIPSS: 7.6%; PLT<100/WBC >25 x10 9/l: 10.8%/16.4%; spleen length ≥10 cm: 47.8%, TSS ≥20: 60.6%; ≥1/≥2 high-risk mutation (HMR): 69/18 out of 167 evaluable (41.3%/10.8%); fibrosis grade ≥2: 77.9%; starting/cumulative RUX dose ≥15 mg BID: 61.4%/52.6%. Higher PB count was associated to high DIPSS risk (PB-0: 1.9%, PB-5: 16.2%, PB-9: 21.7%, p<0.001), PLT<100 x10 9/l (PB-0: 17.6%, PB-5: 15.1%, PB-9: 26.1%, p<0.001), fibrosis grade ≥2 (PB-0: 73.3%, PB-5: 84.2%, PB-9: 100%, p<0.001), spleen length ≥10 cm (PB-0: 43%, PB-5: 55.1%, PB-9: 59.1%, p=0.003). At 3 and 6 mos, 26.9% and 30.4% of evaluable pts achieved a SR, while 59.7% and 68.1% were in SyR, respectively. At 3 mos, SR (PB-0: 31.8%, PB-5: 20.6%, PB-9: 10%, p=0.001) and SyR (PB-0: 62.9%, PB-5: 55.5%, PB-9: 36.8%, p=0.02) were less frequently achieved by PB-5 and PB-9 pts compared to PB-0 pts. This association remained significant for SR at 6 mos (PB-0: 35%, PB-5: 23.9%, PB-9: 14.3%, p=0.006) and for both SR (p=0.003) and SyR (p=0.01) at any time. After a median RUX exposure of 1.5 y (0.1-8.9), 491 (61.8%) pts stopped RUX, 110 (13.9%) had a LT and 365 (46%) died. In univariate analysis, at 2y PB-9 pts had higher rates of RUX stop (73.9% vs 40.8% and 34.3% in PB-5 and PB-0 pts, log-rank p<0.001) and LT (38.5% vs 10.2% and 6.2% in PB-5 and PB-0 pts, log-rank p=0.003). Median survival times of PB-0, PB-5 and PB-9 patients were 5.8, 4.9 and 2 years, respectively (log-rank p<0.001) (Figure 1). In multivariable analysis, PB-9 pts confirmed their association with: 1) RUX stop (HR 3.74, 95%CI 1.51-3.70, p<0.001), with TSS>20 (HR 1.66, 95%CI 1.05-2.61, p=0.03), and HMR≥2 (HR 2.69, 95%CI 1.26-4.47, p=0.007); 2) LT (HR 3.71, 95%CI 1.71-8.04, p<0.001), with HMR≥2 (HR 7.10, 95%CI 2.28-22.1, p<0.001); 3) OS (HR 2.40, 95%CI 1.60-3.60, p<0.001), with age≥65 (HR 2.31, 95%CI 1.17-4.57, p=0.02) and HMR≥2 (HR 3.21, 95%CI 1.67-6.20, p<0.001). Unfavorable association with LT and OS was confirmed also in patients with HMR≥1. Conclusions: CP-MF pts with PB>5% have a worse response to RUX and a worse outcome. Personalized approaches beyond RUX monotherapy may be useful in this context. Further clinical trials evaluating combination strategies and new drugs are required. Figure 1 Figure 1. Disclosures Palandri: Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; AOP: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy. Abruzzese: Bristol Myers Squibb: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Iurlo: Bristol Myers Squibb: Speakers Bureau; Pfizer: Speakers Bureau; Novartis: Speakers Bureau; Incyte: Speakers Bureau. Bonifacio: Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. Cuneo: AbbVie: Consultancy, Speakers Bureau; AstraZeneca: Consultancy, Speakers Bureau; Janssen: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau. Pane: AbbVie; Amgen; Novartis: Other: Travel, accommodation, expenses; Novartis Pharma SAS;: Research Funding; AbbVie; Amgen; Novartis, GSK , Incyte: Consultancy; AbbVie; Amgen; Novartis, GSK, Incyte: Speakers Bureau. Lemoli: Celgene: Other: Support for attending meetings and/or travel; Jazz, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie, Daiichi Sankyo, Servier: Honoraria, Speakers Bureau. Cavo: Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Breccia: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Abbvie: Honoraria.

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