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We report herein an exploratory biomarker analysis of refractory tumors collected from pediatric patients before atezolizumab therapy (iMATRIX-atezolizumab, NCT02541604). Elevated levels of CD8+ T cells and PD-L1 were associated with progression-free survival and a diverse baseline infiltrating T-cell receptor repertoire was prognostic. Differential gene expression analysis revealed elevated expression of CALCA (preprocalcitonin) and CCDC183 (highly expressed in testes) in patients who experienced clinical activity, suggesting that tumor neoantigens from these genes may contribute to immune response. In patients who experienced partial response or stable disease, elevated Igα2 expression correlated with T- and B-cell infiltration, suggesting that tertiary lymphoid structures existed in these patients’ tumors. Consensus gene co-expression network analysis identified core cellular pathways that may play a role in antitumor immunity. Our study uncovers features associated with response to immune-checkpoint inhibition in pediatric patients with cancer and provides biological and translational insights to guide prospective biomarker profiling in future clinical trials.

Techniques grounded on the simultaneous utilization of Tiecks' second order differential equations and spontaneous variability of mean arterial pressure (MAP) and mean cerebral blood flow velocity (MCBFV), recorded from middle cerebral arteries through a transcranial Doppler device, provide a characterization of cerebral autoregulation (CA) via the autoregulation index (ARI). These methods exploit two metrics for comparing the measured MCBFV series with the version predicted by Tiecks' model: normalized mean square prediction error (NMSPE) and normalized correlation rho. The aim of this study is to assess the two metrics for ARI computation in 13 healthy subjects (age: 27 & PLUSMN; 8 yrs., 5 males) at rest in supine position (REST) and during 60 head-up tilt (HUT) and in 19 patients (age: 64 & PLUSMN; 8 yrs., all males), scheduled for coronary artery bypass grafting, before (PRE) and after (POST) propofol general anesthesia induction. Analyses were carried out over the original MAP and MCBFV pairs and surrogate unmatched couples built individually via time-shifting procedure. We found that: i) NMSPE and rho metrics exhibited similar performances in passing individual surrogate test; ii) the two metrics could lead to different ARI estimates; iii) CA was not different during HUT or POST compared to baseline and this conclusion held regardless of the technique and metric for ARI estimation. Results suggest a limited impact of the sympathetic control on CA.

Objective: Respiration disturbs cardiovascular and cerebrovascular controls but its role is not fully elucidated. Methods: Respiration can be classified as a confounder if its observation reduces the strength of the causal relationship from source to target. Respiration is a suppressor if the opposite situation holds. We prove that a confounding/suppression (C/S) test can be accomplished by evaluating the sign of net redundancy/synergy balance in the predictability framework based on multivariate autoregressive modelling. In addition, we suggest that, under the hypothesis of Gaussian processes, the C/S test can be given in the transfer entropy decomposition framework as well. Experimental protocols: We applied the C/S test to variability series of respiratory movements, heart period, systolic arterial pressure, mean arterial pressure, and mean cerebral blood flow recorded in 17 pathological individuals (age: 648 yrs; 17 males) before and after induction of propofol-based general anesthesia prior to coronary artery bypass grafting, and in 13 healthy subjects (age: 278 yrs; 5 males) at rest in supine position and during head-up tilt with a table inclination of 60. Results: Respiration behaved systematically as a confounder for cardiovascular and cerebrovascular controls. In addition, its role was affected by propofol-based general anesthesia but not by a postural stimulus of limited intensity. Conclusion: The C/S test can be fruitfully exploited to categorize the role of respiration over causal variability interactions. Significance: The application of the C/S test could favor the comprehension of the role of respiration in cardiovascular and cerebrovascular regulations.

Background The iMATRIX-atezolizumab study was a phase I/II, multicenter, open-label study designed to assess the safety and pharmacokinetics of atezolizumab in pediatric and young adult patients. We describe the pharmacokinetics (PK), exposure-safety, and immunogenicity of atezolizumab in pediatric and young adults with metastatic solid tumors or hematologic malignancies enrolled in this study. Methods Patients aged

We present a framework for the linear parametric analysis of pairwise interactions in bivariate time series in the time and frequency domains, which allows the evaluation of total, causal and instantaneous interactions and connects time- and frequency-domain measures. The framework is applied to physiological time series to investigate the cerebrovascular regulation from the variability of mean cerebral blood flow velocity (CBFV) and mean arterial pressure (MAP), and the cardiovascular regulation from the variability of heart period (HP) and systolic arterial pressure (SAP). We analyze time series acquired at rest and during the early and late phase of head-up tilt in subjects developing orthostatic syncope in response to prolonged postural stress, and in healthy controls. The spectral measures of total, causal and instantaneous coupling between HP and SAP, and between MAP and CBFV, are averaged in the low-frequency band of the spectrum to focus on specific rhythms, and over all frequencies to get time-domain measures. The analysis of cardiovascular interactions indicates that postural stress induces baroreflex involvement, and its prolongation induces baroreflex dysregulation in syncope subjects. The analysis of cerebrovascular interactions indicates that the postural stress enhances the total coupling between MAP and CBFV, and challenges cerebral autoregulation in syncope subjects, while the strong sympathetic activation elicited by prolonged postural stress in healthy controls may determine an increased coupling from CBFV to MAP during late tilt. These results document that the combination of time-domain and spectral measures allows us to obtain an integrated view of cardiovascular and cerebrovascular regulation in healthy and diseased subjects.

Background and objectives: Obstructive Sleep Apnea represents a widespread problem in the population, but it is often not diagnosed and not considered a true pathology. Different diagnostic tools are available for the diagnosis of sleep apnea. This study aims to demonstrate the ability of the STOP-Bang (Snoring, Tiredness, Observed apnea, high blood Pressure, Body mass index, Age, Neck circumference, and Gender) questionnaire in identifying subjects with Obstructive Sleep Apnea (OSA) Syndrome, highlighting the role of dentists as epidemiological sentinels. Materials and methods: the STOP-Bang questionnaire was administered to a cohort of 1000 patients, assessing three private dental clinics in Italy. Excessive daytime sleepiness was measured using Epworth Sleepiness Scale (ESS) and defined as &ge, 10. Subjects were considered at risk of OSA if they had three or more positive items at STOP-Bang and were invited to undergo further examination with a type 3 polygraph. Presence of OSA was measured with the apnea-hypopnea index (AHI) and defined as AHI &ge, 5. Results: 482/1000 subjects (48.2%) had three or more positive items in the STOP-Bang questionnaire and were considered at risk for Obstructive Sleep Apnea Syndrome (OSAS). Excessive daytime sleepiness (EDS &ge, 10) was more frequent among subjects at risk for OSAS (73/482, 15.1%) vs. those not at risk for OSAS (30/518, 5.8%) (p &lt, 0.0001). Moreover, 153/482 subjects at risk for OSAS (31.7%) accepted further examination with a type 3 polygraph. Presence of OSAS (AHI &ge, 5) was suggested in 121/153 subjects (79.1%, 95% CI 71.6% to 85.1%), with 76/121 subjects (62.8%) needing treatment (AHI &ge, 15). Conclusion: the high prevalence of OSAS highlights the role of dentists as &ldquo, epidemiological sentinels&rdquo, The STOP-Bang questionnaire is a simple and efficacious instrument for screening sleep apnea patients.

Objectives The aim of this study was to assess the pharmacokinetics (PK) and safety/tolerability of siponimod in healthy subjects when coadministered with (1) the moderate cytochrome P450 (CYP) 2C9 and CYP3A inhibitor fluconazole (Study A), and (2) with three different CYP2C9 genotype variants (Study B). Methods Study A was an open-label, single-dose study comprising periods 1 (14 days; day 1: siponimod 4 mg) and 2 (20 days; day 1: fluconazole 200 mg twice daily; days 2–19: fluconazole 200 mg once daily; day 3: siponimod 4 mg) in healthy subjects (n = 14) with the wild-type CYP2C9 genotype (CYP2C9*1/*1). Study B was a multicentre, open-label study comprising parts 1 (day 1: siponimod 0.25 mg once daily in the CYP2C9*1/*1, CYP2C9*2/*3 and CYP2C9*3/*3 genotypes) and 2 (days 1–2: 0.25 mg once daily; day 3: 0.5 mg once daily in the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes only) in healthy subjects with polymorphic variants of CYP2C9 (n = 24). Pharmacokinetic parameters were calculated using noncompartmental methods. Results In Study A, coadministration with fluconazole produced an approximately twofold increase in mean area under the curve (AUC) versus siponimod alone (from 1110 to 2160 h*ng/mL), and an increase in maximum plasma concentration (Cmax; from 31.2 to 34.0 ng/mL) and elimination half-life (T½; from 40.6 to 61.6 h). In Study B, the AUCs of siponimod were approximately two to fourfold greater in subjects with the CYP2C9*2/*3 and CYP2C9*3/*3 genotypes, with a minor increase in Cmax versus the CYP2C9*1/*1 genotype. The mean T½ was prolonged in the CYP2C9*2/*3 (51 h) and CYP2C9*3/*3 (126 h) genotypes versus the CYP2C9*1/*1 (28 h) genotype. Siponimod did not result in increased adverse events in healthy subjects in both studies. Conclusions Changes in siponimod PK, when coadministered with fluconazole at steady-state and in subjects with different CYP2C9 genotypes, indicate that the reduced CYP2C9 enzymatic activity does not affect the absorption phase of siponimod but prolongs the elimination phase. These results confirm the relevance of CYP2C9 activity on siponimod metabolism in humans. Electronic supplementary material The online version of this article (10.1007/s40262-018-0700-3) contains supplementary material, which is available to authorized users.

Obstructive sleep apnea (OSA) is a sleep disorder characterized by breathing pauses due to collapse of the upper airways. During OSA the autonomic modulation, as noninvasively assessed through heart period (HP) variability, is altered in a time-varying way even though time-varying properties of HP fluctuations are often disregarded by HP variability studies. We performed a time domain analysis computed over very short epochs corresponding to the sole OSA events explicitly accounting for HP variability nonstationarities. Length-matched epochs were extracted during OSA and quiet sleep (SLEEP) in 13 subjects suffering from OSA (11 males, age 55±11, apnea-hypopnea index 44±19). Mean HP, variance and variance of the residual after exponential detrending were assessed as well as the parameters a and b of the exponential fitting in the form y(n)=a·exp(b·n). HP mean and the parameter a increased during OSA compared to SLEEP. The variance of the residual was significantly lower than original variance during both OSA and SLEEP, while the dispersion of the parameter b was significantly larger. Nonstationarities were evident during both SLEEP and OSA but more dramatically apparent during OSA, thus stressing the need of accounting for them when the autonomic control during OSA is under scrutiny.

Introduction The iMATRIX-atezo trial (NCT02541604) assessed the safety and pharmacokinetics (primary objectives) and preliminary activity (secondary objective) of atezolizumab in pediatric and young adult patients with refractory/relapsed solid tumors, including Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). Atezolizumab targets PD-L1 expressed by tumor cells leading to an enhanced anticancer T-cell response. The purpose of this analysis was to investigate the association between PD-L1 expression and response to atezolizumab in patients participating in the iMATRIX-atezo trial. Methods Patients aged Results Eighty-seven patients received ≥1 dose of atezolizumab. Of 11 patients with high PD-L1 expression (TC2/TC3/IC2/IC3) and response data, four had a partial response (PR; two with HL, one with NHL, one with a rhabdoid tumor), one had stable disease (SD) and six had progressive disease (PD). Of 52 patients with low or no PD-L1 expression (TC1/TC0/IC1/IC0) and response data, no responses were observed. Though numerically limited, PD-L1 expression and response were significantly correlated (p=0.0006, Fisher’s exact test). HL (8/9 patients) and NHL (2/3 patients) cohorts had the greatest proportion of patients with high baseline PD-L1. Levels of CD8+ (T cells), CD20+ (B cells) and stromal TILs at baseline were significantly associated with patients’ response status (p Conclusions High PD-L1 expression compared with low or no expression was associated with a greater response to atezolizumab, notably in patients with HL and NHL. Despite small sample sizes and limited responses, these biomarker data support adult studies citing the association between PD-L1 and response to atezolizumab; data suggest that PD-L1 may also be a predictor of atezolizumab response in pediatric and young adult patients. Citation Format: Katherine E. Hutchinson, Minlei Liao, Mufiza Farid-Kapadia, Francis Donaldson, Nga Wan Rachel Tam, Lingyan Helen Fu, Meghna Das Thakur, C. Michel Zwaan, Birgit Geoerger, Lynley V. Marshall, Tanya Trippett, Gianluca Rossato. Correlation between response to atezolizumab and PD-L1 tumor expression in pediatric and young adult patients enrolled in the phase I/II iMATRIX-atezo study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3114.

Cardiovascular and cerebrovascular regulatory systems are vital control mechanisms responsible for guaranteeing homeostasis and are affected by respiration. This work proposes the investigation of cardiovascular and cerebrovascular control systems and the nonlinear influences of respiration on both regulations through joint symbolic analysis (JSA), conditioned or unconditioned on respiration. Interactions between cardiovascular and cerebrovascular regulatory systems were evaluated as well by performing correlation analysis between JSA indexes describing the two control systems. Heart period, systolic and mean arterial pressure, mean cerebral blood flow velocity and respiration were acquired on a beat-to-beat basis in 13 subjects experiencing recurrent syncope episodes (SYNC) and 13 healthy individuals (non-SYNC) in supine resting condition and during head-up tilt test at 60° (TILT). Results showed that JSA distinguished conditions and groups, whereas time domain parameters detected only the effect of TILT. Respiration affected cardiovascular and cerebrovascular regulatory systems in a nonlinear way and was able to modulate the interactions between the two control systems with different outcome in non-SYNC and SYNC groups, thus suggesting that the analysis of the impact of respiration on cardiovascular and cerebrovascular regulatory systems might improve our understanding of the mechanisms underpinning the development of postural-related syncope.

Objectives. To evaluate, in patients with ulnar neuropathy at the elbow (UNE), if ultrasonographic differences in ulnar nerve size correlate with severity score determined by electrodiagnostic studies. Methods. We examined prospectively 38 patients (50 elbows) with UNE. Patients were classified into mild, moderate and severe groups according to electrodiagnostic studies. Cross-sectional areas (CSAs) of the ulnar nerve were measured 4cm proximal to the medial epicondyle (CSA-prox), 4cm distal to the epicondyle (CSA-dist) and at the maximum CSA (CSA-max) of the ulnar nerve found between these points. We used a control group of 50 normal elbows. Results. The CSA-max in the patient group was highly correlated with the severity score obtained by electrodiagnostic studies: mild: 11.1 � 3.4mm 2 , moderate: 15.8 � 3.8mm 2 , severe: 18.3 � 5.1mm 2 (P

The tetrasaccharide 4, a substructure of ganglioside GQ1b?, shows a remarkable affinity for the myelin-associated glycoprotein (MAG) and was therefore selected as starting point for a lead optimization program. In our search for structurally simplified and pharmacokinetically improved mimics of 4, antagonists with modifications of the core disaccharide Gal?(1-3)GalNAc, as well as the terminal ?(2-3)- and the internal ?(2-6)-linked neuraminic acid were synthesized and tested in target-based binding assays. Compared to the reference tetrasaccharide 4, the most potent antagonist 17 exhibits a 360-fold improved affinity. Furthermore, pharmacokinetic parameters such as stability in the cerebrospinal fluid, logD and permeation through the BBB indicate the drug-like properties of antagonist 17.