The canonical polyadic decomposition (CPD) is one of the most popular tensor-based analysis tools due to its usefulness in numerous fields of application. The Q-order CPD is parametrized by Q ...matrices also called factors which have to be recovered. The factors estimation is usually carried out by means of the alternating least squares (ALS) algorithm. In the context of multi-modal big data analysis, i.e., large order (Q) and dimensions, the ALS algorithm has two main drawbacks. Firstly, its convergence is generally slow and may fail, in particular for large values of Q , and secondly it is highly time consuming. In this paper, it is proved that a Q-order CPD of rank-R is equivalent to a train of Q 3-order CPD(s) of rank-R. In other words, each tensor train (TT)-core admits a 3-order CPD of rank-R. Based on the structure of the TT-cores, a new dimensionality reduction and factor retrieval scheme is derived. The proposed method has a better robustness to noise with a smaller computational cost than the ALS algorithm.
Very efficient in particles detection, light scattering also offers fast non-invasive full-mapping wafer surface state. This sensitivity was used in the case of germano-silicide process development. ...As a matter of fact, we report on haze measurement performances, compared to the usual methods used to investigate thermal stability of Ni(Si1-xGex), such as sheet resistance (SR), X-ray diffraction (XRD) and scanning electron microscopy (SEM). We observed defectivity related to thermal agglomeration and Ge-segregation of Ni(Si1-xGex) on strain Si1-xGex (x30%) by haze measurement (like SEM observations) earlier than SR measurement. Moreover, we noticed that a high Ge content affects at lower temperature the stability of Ni(Si1-xGex) with a segregation phenomena.
Drug-induced urticaria Cousin, F; Philips, K; Favier, B ...
EJD. European journal of dermatology,
05/2001, Letnik:
11, Številka:
3
Journal Article
Recenzirano
The occurrence of acute urticaria during treatment with drugs is a frequent event which poses two problems: 1) is the urticaria connected with the drug administration or with the underlying pathology ...which led to the prescription of the drug; 2) is the urticaria allergic in origin, i.e. due to specific immunity triggers, in particular IgE directed against the drug, or is the urticaria pseudo-allergic in origin, i.e. due to non-specific activation of mastocytes 1? This question is of major importance because allergic events caused by IgE are potentially fatal while pseudo-allergic events are only rarely life-threatening. In this article we will not deal with contact urticaria where the cause is easily identifiable 2.
4-Hydroxy-2-nonenal (HNE), one of the main aldehydic compounds released during lipid peroxidation, has been proposed to react with DNA bases in cells. Several classes of DNA lesions involving ...addition of either HNE or its 2, 3- epoxide (epox-HNE) have been identified. In the present work, HPLC associated with tandem mass spectrometry was used to determine the pattern of HNE-induced DNA lesions. First, adducts were quantified within isolated DNA treated with HNE under peroxidizing conditions. The 1, N super(2)-propano-2'- deoxyguanosine adduct of HNE (HNE-dGuo) was found to be the major lesion under all conditions studied. 1, N super(6)-Ethenoadenine and 1, N super(2)- ethenoguanine together with their (1, 2-dihydroxyheptyl)-substituted derivatives, which all arise from the reaction of epox-HNE with DNA, were produced in significantly lower yields, even in the presence of 20 mM H sub(2)O sub(2). The pyrimidopurinone malondialdehyde-2'-deoxyguanosine adduct was also found to be produced, although in very low yield. Similar results were obtained in cultured human monocytes incubated with HNE, because the HNE-dGuo adduct represented more than 95% of the overall adducts to DNA. In addition, the former lesion was poorly repaired, in contrast to 1, N super(2)- ethenoguanine and, to a lesser extent, 1, N super(6)-ethenoadenine. Altogether, these results suggest than HNE-dGuo may represent the best biomarker of the genotoxic effects of HNE.
To investigate the effect of current intensity and choice of the stimulated muscle group on train-of-four (TOF) interpretation in the intensive care unit (ICU).
Intervention study in a surgical ...intensive care unit.
13 ventilated patients requiring prolonged muscle relaxation.
Prior to blockade TOF responses of left and right orbicularis oculi, adductor pollicis, and plantar flexors were recorded by setting the current intensity at 20, 40, 60, and 80 mA. The minimal current intensity (MCI) providing a supramaximal response was then identified for each muscle. Cisatracurium was then infused aiming to continuously observe a TOF at 2/4 on the left orbicularis oculi at 40 mA. The responses to TOF on all the muscle sites were further recorded at 40, 60, and 80 mA when the endpoint was reached for the first time, and after a 48-h infusion. After cessation of infusion the delay to observe 4/4 responses at TOF was recorded at each site at 40 mA or at MCI if MCI was above 40 mA. MCI did not differ between muscle groups. When the fixed endpoint was reached for the first time on left orbicularis oculi, the TOF response at 40 mA on right orbicularis oculi differed significantly. In contrast, no difference was observed between left and right sides at 40 mA at the other sites, nor at any sites at 60 and 80 mA. The TOF response on orbicularis oculi (left and right sides together) was different at 40 mA, compared to 60 and 80 mA. TOF responses at orbicularis oculi at 60 or 80 mA significantly differed from responses on adductor pollicis or plantar flexor, orbicularis oculi being less sensitive to cisatracurium than adductor pollicis or plantar flexor. After a 48-h infusion the same differences in sensitivities were observed between the muscle groups. At any current intensity the recovery was slower at adductor pollicis than at orbicularis oculi or plantar flexor.
For a good TOF interpretation in the ICU the current intensity should be tested before onset of blockade. The orbicularis oculi is less sensitive to cisatracurium than adductor pollicis and plantar flexor both at onset and after a prolonged infusion. The recovery from relaxation is faster on orbicularis oculi and plantar flexor than on adductor pollicis.
Abstract
Background
We raise the hypothesis that a STOP and GO strategy with induction by double immunotherapy Nivolumab + Ipilimumab combination during 6 months, followed by observation in patients ...with disease control (DC) at 6 months, would not be inferior to immunotherapy combination continuation until progression or unacceptable toxicity, in terms of progression-free survival, allowing lower toxicities cumulative rates, better quality of life and lower costs. Such strategy should not penalize overall survival, provided resuming immunotherapy at disease progression before second-line platinum-based chemotherapy.
Trial design
This is an open-label, randomized, phase III study in adult (≥18 years) patients, with stage IV non-small cell lung cancer, PD-L1 positive tumors, previously untreated for advanced disease. Subjects will first be locally assessed for PD-L1 expression, using 1% cut-off. Patients with enough tumor samples for central PD-L1 expression assessment, will be given first-line Nivolumab+Ipilumumab combination as followed: Nivolumab administered IV over 30 minutes at 3 mg/kg every 2 weeks combined with Ipilimumab administered IV over 30 minutes at 1 mg/kg every 6 weeks.
Only patients with DC (objective response or stable disease), confirmed at 6 months, after a 1rst tumor evaluation at 3 months or beyond in case of pseudo-progression needing tumor reassessment, and without drug-related toxicity commanding treatment discontinuation will be randomized 1:1 either to continuation of Nivolumab+Ipilumumab combination until disease progression or unacceptable toxicity, or to clinical and radiological observation from week 24.
Subjects receiving Nivolumab+Ipilimumab beyond investigator assessed progression must also continue tumor assessments until treatment discontinuation.
Enrollment will end after approximately 868 subjects have been randomized (25/months). The primary endpoint of the study is Progression-Free Survival.
Clinical trial identification
NCT03469960.
Legal entity responsible for the study
IFCT (French Cooperative Thoracic Intergroup).
Funding
Bristol-Myers Squibb.
Disclosure
All authors have declared no conflicts of interest.
Abstract
Background
Nintedanib is a multikinase inhibitor whose main targets are VEGFR 1/2/3, PDGFR and FGFR1. It is approved for idiopathic pulmonary fibrosis and non-small-cell lung cancer. The ...randomized phase II CHIVA trial tested it as an add-on to chemotherapy in the neo-adjuvant/adjuvant setting in advanced ovarian cancer eligible for debulking surgery. We report a nintedanib exposure-response relationship in the nintedanib arm.
Methods
Data from 122 pts in the nintedanib arm were available. A population pharmacokinetic model could not be used, due to the sampling schedule (mostly trough concentrations). Therefore, raw serum nintedanib values were used as indicative of exposure. An ascending step-wise multivariate Cox model building strategy was used, without any a priori requirement for exposure to be in the final model, starting from 26 possible predictors. The outcome of interest (response) was overall survival. The existence and optimal value of a threshold was investigated using effect size and model likelihood with different thresholds. HRs and 95% CI are reported for each variable in the final model. Exposure-safety analyses on grade 3-4 and grade 4 adverse events were performed using similar model-building strategies in time-to-event analyses (Cox models) and in per-visit analyses (logistic models). Sensitivity analyses tested the robustness of the findings.
Results
The final model included average serum nintedanib, ECOG status, resection score, histological type, and renal function. The HR for death per extra 30 ng/mL average serum nintedanib was 0.61 (95% CI, 0.41-0.92). The threshold with highest model likelihood and highest effect on survival was around 50-55 ng/mL(100 nM), which is in the range of known IC50 values for nintedanib targets. 75% of pts were below this value, 25% were below 12 ng/mL. No exposure-safety relationships were found.
Conclusions
An exposure-response relationship was found for nintedanib in ovarian cancer. These exploratory results suggest that while it is difficult to maintain consistent nintedanib exposure, survival gains could reward success on that front. Future nintedanib trials may benefit from therapeutic drug monitoring with a threshold trough concentration of 100 nM.
Clinical trial identification
2011-006288-23.
Legal entity responsible for the study
ARCAGY-GINECO.
Funding
Boehringer Ingelheim.
Disclosure
N. Dohollou: Research grant / Funding (institution): Roche; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Lilly. A. Floquet: Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Roche. C. Louvet: Advisory / Consultancy: MSD; Advisory / Consultancy: Roche; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Servier; Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: MSD. J.E. Kurtz: Advisory / Consultancy: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy: Takeda; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: PharmaMar; Travel / Accommodation / Expenses: Tesaro. P. Follana: Advisory / Consultancy: Novartis; Advisory / Consultancy: AstraZeneca; Speaker Bureau / Expert testimony: Novartis; Speaker Bureau / Expert testimony: AstraZeneca; Travel / Accommodation / Expenses: Novartis; Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: Tesaro. M. Leheurteur: Speaker Bureau / Expert testimony: Pfizer; Travel / Accommodation / Expenses: Roche; Travel / Accommodation / Expenses: Eisai. J. Alexandre: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self): PharmaMar; Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen. All other authors have declared no conflicts of interest.
Abstract
Background
Tumour Microvessel density (MVD) is often used as a surrogate marker for tumoral angiogenic activity. In the randomized phase II neo-adjuvant CHIVA trial, ovarian cancer patients ...(pts) treated with standard chemotherapy plus Nintedanib (Ni) compared to chemotherapy alone had a reduced rate of complete surgical resection at interval debulking surgery (IDS), worse PFS and OS. To explain these results we assessed the predictive/prognostic value of MVD at baseline and the MVD decrease from baseline to IDS.
Methods
Paired tumours from baseline and IDS were available from 79/188 randomized pts. A total of 158 virtual slides of immunostained tumor section with anti-CD31 were analysed. MVD was quantified by an image processing on whole tumor section. MVD high level was defined as MVD > 33.5 vessel/mm² which is the highest Youden index on the ROC curve for PFS. The relationship between MVD at baseline and PFS and OS was evaluated using Kaplan-Meier survival estimates.
Results
Main characteristics of the 79 pts were similar to the overall CHIVA population: mean age (62 years), ECOG performance status = 0 (34%), high-grade serous histology (75%). At baseline, MVD was similar in both arms and was low for 35% and 30% of the pts in the Ni and control arm respectively. The rate of complete resection (CC0) was 56% in the Ni arm versus 70% in the control arm.
In the low MVD group median PFS was 13.3 months (95%CI 11 – 22.2) versus 17 months (95%CI 13.7 – 20.5) in the high MVD group (p = 0.85). In the low MVD group, PFS in the Ni and control arm were 12.8 (95%CI 10.7-22.2) and 21.3 months (95%CI 12.5-NA) respectively (p = 0.08). The corresponding PFS in the high MVD group were 18.0 (95%CI 14.4-21.6) vs 14.5 months (95%CI 12.4-22.5) (p = 0.22). No difference was observed for OS. Baseline MVD was not associated with the rate of CC0. There was no significant difference in the decrease of MVD at IDS between the Ni arm (38% of the pts) and the control arm (48%, p = 0.4).
Conclusions
The negative impact of Nintedanib in patients with low baseline MVD tumours may be one explanation of the poor PFS rate observed in the Nintedanib arm of the CHIVA trial.
Clinical trial identification
2011-006288-23.
Legal entity responsible for the study
ARCAGY-GINECO.
Funding
Health ministry grants( PHRC).
Disclosure
C. Blanc-Fournier: Honoraria (self): Roche. N. Raban: Travel / Accommodation / Expenses: Roche. G. Ferron: Honoraria (self): Olympus Europe; Advisory / Consultancy: AstraZeneca; Travel / Accommodation / Expenses: Roche. A. Floquet: Advisory / Consultancy, Travel / Accommodation / Expenses: Tesaro; Advisory / Consultancy: Clovis; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Travel / Accommodation / Expenses: Roche. J. Alexandre: Honoraria (self), Advisory / Consultancy: Roche; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self): Ipsen; Honoraria (self), Advisory / Consultancy, Travel / Accommodation / Expenses: Novartis; Honoraria (self): PharmaMar; Research grant / Funding (institution), Travel / Accommodation / Expenses: Janssen. C. Louvet: Advisory / Consultancy, Travel / Accommodation / Expenses: MSD; Advisory / Consultancy, Travel / Accommodation / Expenses: Roche; Advisory / Consultancy: Halozyme; Advisory / Consultancy: Servier; Advisory / Consultancy: AstraZeneca. J. Florence: Advisory / Consultancy: Roche; Advisory / Consultancy: Novartis; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Travel / Accommodation / Expenses: AstraZeneca; Advisory / Consultancy: Tesaro; Advisory / Consultancy, Travel / Accommodation / Expenses: Ipsen; Advisory / Consultancy: Astellas; Advisory / Consultancy: Bayer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: BMS; Advisory / Consultancy: Sanofi; Travel / Accommodation / Expenses: Janssen. All other authors have declared no conflicts of interest.
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