Many people spend an increasing amount of time in front of computer screens equipped with light-emitting diodes (LED) with a short wavelength (blue range). Thus we investigated the repercussions on melatonin (a marker of the circadian clock), alertness, and cognitive performance levels in 13 young male volunteers under controlled laboratory conditions in a balanced crossover design. A 5-h evening exposure to a white LED-backlit screen with more than twice as much 464 nm light emission {irradiance of 0,241 Watt/(steradian × m(2)) [W/(sr × m(2))], 2.1 × 10(13) photons/(cm(2) × s), in the wavelength range of 454 and 474 nm} than a white non-LED-backlit screen [irradiance of 0,099 W/(sr × m(2)), 0.7 × 10(13) photons/(cm(2) × s), in the wavelength range of 454 and 474 nm] elicited a significant suppression of the evening rise in endogenous melatonin and subjective as well as objective sleepiness, as indexed by a reduced incidence of slow eye movements and EEG low-frequency activity (1-7 Hz) in frontal brain regions. Concomitantly, sustained attention, as determined by the GO/NOGO task; working memory/attention, as assessed by "explicit timing"; and declarative memory performance in a word-learning paradigm were significantly enhanced in the LED-backlit screen compared with the non-LED condition. Screen quality and visual comfort were rated the same in both screen conditions, whereas the non-LED screen tended to be considered brighter. Our data indicate that the spectral profile of light emitted by computer screens impacts on circadian physiology, alertness, and cognitive performance levels. The challenge will be to design a computer screen with a spectral profile that can be individually programmed to add timed, essential light information to the circadian system in humans.

In commodity LC flat-panel displays, the traditional CCFL backlight is being replaced more and more by LEDs. The typical spectrum of LED-lit displays shows a significantly higher amount of blue light in the range around 464 nm. Blue light in this wavelength area suppresses the melatonin level in humans and thus effects the biological clock. Our hypothesis was that the amount of blue light reaching the human eye from a LED-backlit display is sufficient to have a significant effect on the biological clock. The results of clinical user studies comparing the effects of LED- vs. CCFL-backlit displays on humans, resulting from the emitted amount of 464-nm light, will be presented. It was found that the LED-backlit display causes significant suppression of melatonin, which effects the biological clock of the test persons, indicating the necessity for displays with a controllable 464-nm emission. A technical concept for a display with such functionality will be presented

Heart-rate variability patterns of 18 women during a 40-h constant routine of prolonged wakefulness under controlled laboratory conditions were analyzed. The authors tested the circadian timing of the autonomic nervous system and the relationship between the sympathetic and vagal branches in women with both a functional disorder of vascular regulation (main symptom: cold hands and feet) and prolonged sleep onset and controls without these symptoms. Spectral analysis of R-R intervals during paced breathing episodes revealed significantly lower power values in the high-frequency band (HF; 0.15-0.4 Hz) but not in the low-frequency band (LF; 0.04-0.15 Hz), leading to a significantly elevated LF/HF ratio in the former group. A significant circadian rhythm in LF power and heart rate occurred in both groups, and a significant correlation was found between sleepiness and sympathovagal balance (r = .53, p < .05). These findings indicate not only an autonomic imbalance in the first group compared with controls, but also two strategies of the autonomic nervous system to fight against fatigue in women. One implies circadian control and the other homeostatic control, and both are reflected by the LF/HF ratio.

Background PV is a clonal myeloid neoplasm characterized by activating mutations in JAK2 and increased red blood cell production. Reduction of thrombosis risk through lowering of hematocrit (Hct) and thus blood viscosity is critical, but management of constitutional symptoms is also important. HU is an effective and well-tolerated first-line treatment (tx) for PV, but pts who develop resistance to or intolerance of HU have limited tx options. A Phase I study of idasanutlin, an MDM2 antagonist leading to increased p53 activity, showed encouraging efficacy and potential disease-modifying effects via rapid reduction in JAK2 V617F variant allele frequency in 11 pts with PV. These results prompted the larger, international Phase II study of idasanutlin in HU-resistant/intolerant PV (NCT03287245); data from the initial phase of the study are reported here. Methods Pts meeting the 2016 WHO criteria for PV were eligible for inclusion if they had HU-resistant/intolerant disease according to the European LeukemiaNet (ELN) criteria and were phlebotomy dependent (≥ 1 phlebotomy in the 16-wk period prior to screening). Prior PV tx with ruxolitinib (rux) or interferon was allowed. Idasanutlin was given orally once daily on days 1-5 of 28-day cycles for up to 24 mo. The starting dose was 150 mg; increase to 200 mg was allowed for non-responders at cycle 3, day 28, and reduction to 100 mg was permitted for toxicity and for pts treated beyond cycle 12. Antiemetic prophylaxis was mandatory in cycle 1 throughout the study and later became mandatory in all cycles. The primary endpoint (wk 32) was the composite response of Hct control (HTC) and spleen volume reduction &gt; 35% by CT/MRI in pts with splenomegaly (&gt; 450 cm3) and HTC alone in pts without splenomegaly. Key secondary endpoints included safety, complete hematologic response (CHR; defined as HTC and normalization of platelets/leukocytes) and ELN response. Results A total of 27 pts were included in this study and received tx with idasanutlin. Median age was 56 years (range, 34-74) and 16 pts (59.3%) were male (Table 1). All pts had JAK2 V617F mutation; 7 had previous exposure to rux. Median tx duration was 257 days (range, 5-677); the median number of treatment cycles was 8 (range, 1-23). Dose modifications occurred in 17 pts (63.0%; Table 2). A total of 3 serious AEs occurred: atrial flutter, atrial fibrillation and nausea/vomiting (n = 1 each). The serious cardiac AEs occurred in pts with pre-existing hypertension and a past incident of heart failure not symptomatic upon enrollment, respectively. No deaths, transformation to acute myeloid leukemia, progression to myelofibrosis or thrombotic events occurred during the study. AEs occurring in ≥ 15% of pts are listed in Table 3; gastrointestinal toxicity and fatigue were the most common events. The population for primary endpoint evaluation consisted of pts with response assessed at wk 32 (n = 16). One of 13 pts with baseline splenomegaly achieved a composite response (7.7%; Table 4). Nine of 16 pts (56.3%) among all evaluable pts achieved HTC: 6 of 11 rux-naive pts (54.5%) and 3 of 5 rux-exposed pts (60.0%). Eight of 13 pts (61.5%) among all pts had HTC duration ≥ 12 wk beyond wk 32: 5 of 9 rux-naive pts (55.6%) and 3 of 4 rux-exposed pts (75.0%). At wk 32, 8 of 16 pts (50.0%) achieved a CHR, with 6 of 13 (46.2%) having a CHR duration ≥ 12 wk beyond wk 32. Overall response rates per modified ELN response criteria in pts with baseline splenomegaly, pts without baseline splenomegaly and in all pts were 69.2% (9 of 13), 66.7% (2 of 3) and 68.8% (11 of 16), respectively; 9 of 15 pts (60%) among all pts had a response duration ≥ 12 wk beyond wk 32. Median (range) laboratory value changes at wk 32 were: platelets, −253 × 109/L (−2083 to +175) and leukocytes, −4.8 × 109/L (−25.3 to +3.4). At wk 32, 6 of 14 pts (42.9%) had a ≥ 50% reduction in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score. Conclusions Idasanutlin showed relevant clinical activity in pts with HU-resistant/intolerant PV and also in a subset of pts with prior rux tx. However, the low-grade gastrointestinal toxicity profile of idasanutlin was not effectively mitigated with antiemetic prophylaxis and led to frequent discontinuations. These results iterate the importance of tolerability of novel therapies administered over the long term for pts with PV. Disclosures Mascarenhas: Celgene, Prelude, Galecto, Promedior, Geron, Constellation, and Incyte: Consultancy; Incyte, Kartos, Roche, Promedior, Merck, Merus, Arog, CTI Biopharma, Janssen, and PharmaEssentia: Other: Research funding (institution). Higgins:Roche: Current Employment, Current equity holder in publicly-traded company, Other: Support of parent study and funding of editorial support. Anders:Roche: Current Employment, Other: Support of parent study and funding of editorial support. Burbury:Roche: Other: Support of parent study and funding of editorial support. El-Galaly:F. Hoffmann-La Roche: Current Employment, Other: Support of parent study and funding of editorial support. Gerds:Roche/Genentech: Research Funding; Apexx Oncology: Consultancy; AstraZeneca/MedImmune: Consultancy; Pfizer: Research Funding; Imago Biosciences: Research Funding; Gilead Sciences: Research Funding; Incyte Corporation: Consultancy, Research Funding; Sierra Oncology: Research Funding; CTI Biopharma: Consultancy, Research Funding; Celgene: Consultancy, Research Funding. Gupta:Pfizer: Consultancy; Incyte: Honoraria, Research Funding; Bristol MyersSquibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kovic:Roche: Other: Support of parent study and funding of editorial support. Maffioli:Roche: Other: Support of parent study and funding of editorial support. Mesa:AbbVie: Research Funding; Sierra Oncology: Consultancy; CTI BioPharma: Research Funding; LaJolla Pharmaceutical Company: Consultancy; Bristol Myers Squibb: Research Funding; Genentech: Research Funding; Samus Therapeutics: Research Funding; Promedior: Research Funding; Novartis: Consultancy; Incyte: Research Funding. Rambaldi:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support of parent study and funding of editorial support. Received travel support., Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Advisory board and speaker fees from Pfizer.; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); BMS/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); University of Milan: Current Employment; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support from Gilead.; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Omeros: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Astellas: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Research grant from Amgen Inc.. Vannucchi:AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Blueprint: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yacoub:Roche: Other: Support of parent study and funding of editorial support; Dynavax: Current equity holder in publicly-traded company; Novartis: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Incyte: Speakers Bureau; Hylapharm: Current equity holder in private company; Cara Therapeutics: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company.

No abstract

We present the results of clinical user studies comparing the effects of LED-vs. CCFL-backlit displays on humans, resulting from the emitted amount of 464 nm light. The LED-lit display causes significant effects on the user. We present a concept of a display with controllable 464 nm emission.

No abstract

Background: Myelosuppression, and especially severe and prolonged neutropenia, can make patients (pts) with acute myeloid leukemia (AML) susceptible to fatal infections. Idasanutlin (idasa), a MDM2 antagonist promoting p53 tumor suppressor activity, showed tolerable safety and preliminary clinical activity alone and in combination with cytarabine (C) in pts with AML in a Phase I/Ib study (NCT01773408; NP28679). In the Phase III MIRROS study (NCT02545283; WO29519) comparing idasa + cytarabine (idasa-C) to placebo-C in pts with relapsed or refractory (r/r) AML, idasa-C did not improve overall survival (OS) in TP53-wild type pts (Konopleva, EHA 2020). The proportion of pts with composite complete remission (CR) at end of induction (EoI) was higher with idasa-C vs placebo-C; however, response at EoI did not translate into OS benefit. Longer and more pronounced neutropenia was observed with idasa-C. Here we investigated the contribution of idasa exposure variability to those findings, in particular, the relationship between exposure and toxicity and efficacy in pts with AML. Methods: MIRROS and NP28679 have been previously described (Montesinos, Future Oncol, 2020; Martinelli, EHA 2016). Plasma idasa concentrations were collected during induction and consolidation in 407 pts with AML (MIRROS: 285 with r/r AML; NP28679: 122 with AML), and a population pharmacokinetic (PK) analysis was completed. For each pt, predicted average concentrations values (Cav) were computed, as the ratio of cumulative area under the curve over the duration of the induction treatment period (5 days). Tertiles of Cav (low, medium, high) were used to reflect variability in exposure among pts. Logistic regression models assessed correlations between the probability of occurrence of adverse events (serious AEs [SAEs], febrile neutropenia), the probability of being responders at EoI and idasa exposure. These PK/pharmacodynamic (PD) analyses were restricted to pts treated with the idasa spray-dried powder formulation. In addition, the relationships between concentrations of the p53 target macrophage inhibitory cytokine 1 (MIC-1) and idasa exposure was characterized using an indirect PK/PD model developed in 245 pts with solid tumors (NCT01462175; NP27872), AML (NP28679) or polycythemia vera (NCT03287245; NP39761). Results: Idasa exposure was highly variable with lower exposure mainly associated with higher body weight and male sex. In addition, pts with vomiting during treatment had reduced exposure. However, a large part of the interpatient variability remains mostly unexplained. The exposure-response analysis, conducted in 316 pts with AML, showed a higher risk of SAEs with higher idasa exposure (Cav) during induction (p=0.03). There was also an association between idasa exposure and occurrence of febrile neutropenia (p=0.022; Figure 1). However, due to exposure variability, reducing the dose from 300 mg twice daily to 300 mg daily would result in a similar risk of febrile neutropenia at the median exposures (approximately 40%). No association between idasa exposure and complete remission rates at EoI was observed (N=295, p=0.622; Figure 2). Dose-exposure related increases in MIC-1 were observed at all idasa doses investigated, starting at the 100 mg total daily dose. Pts with AML in the lower tertile of exposure (Cav: 2503-5797 ng/mL) showed lower maximum MIC-1 release from baseline, contrary to pts from the highest tertile (7981-14651 ng/mL). MIC-1 release is present regardless of TP53 mutational status, suggesting a systemic rather than tumor derived induction. No difference was seen between responders and non-responders at EoI. Conclusions: Combined clinical pharmacology data in pts with AML receiving idasa revealed 1) Variability in idasa exposure does not correlate with clinical outcomes in pts treated with idasa-C. 2) p53 engagement (i.e., MIC-1 biomarker release) is seen at all dose levels investigated; however, MIC-1 release does not correlate with clinical response at EoI or TP53 mutational status. 3) The risk of SAEs is higher in pts with greater idasa exposure. 4) Data do not support lowering the dose of idasa to mitigate the risk of febrile neutropenia while sustaining clinical efficacy at idasa-C doses investigated. Disclosures Jamois: Roche: Current Employment, Current equity holder in publicly-traded company, Other: Roche: Support of parent study and funding of editorial support. Anders:Roche: Current Employment, Other: Support of parent study and funding of editorial support. Beckermann:Roche: Current Employment, Current equity holder in publicly-traded company, Other: Support of parent study and funding of editorial support; Novartis: Current equity holder in publicly-traded company. Genevray:Roche: Current Employment, Other: Support of parent study and funding of editorial support. Mundt:Swissmedic (starting September 2020): Current Employment; Roche: Current equity holder in publicly-traded company, Other: Support of parent study and funding of editorial support. Petry:Roche: Current Employment, Current equity holder in publicly-traded company, Other: Support of parent study and funding of editorial support. Yang:Certara: Current Employment; Roche: Other: Support of parent study and funding of editorial support. Kassir:Certara: Current Employment; Roche: Other: Support of parent study and funding of editorial support. Schmitt:F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company.