Concomitant evaluation of cardiovascular and cerebrovascular controls via Geweke spectral causality to assess the propensity to postural syncope.

The evaluation of propensity to postural syncope necessitates the concomitant characterization of the cardiovascular and cerebrovascular controls and a method capable of disentangling closed loop relationships and decomposing causal links in the frequency domain. We applied Geweke spectral causality (GSC) to assess cardiovascular control from heart period and systolic arterial pressure variability and cerebrovascular regulation from mean arterial pressure and mean cerebral blood velocity variability in 13 control subjects and 13 individuals prone to develop orthostatic syncope. Analysis was made at rest in supine position and during head-up tilt at 60°, well before observing presyncope signs. Two different linear model structures were compared, namely bivariate autoregressive and bivariate dynamic adjustment classes. We found that (i) GSC markers did not depend on the model structure; (ii) the concomitant assessment of cardiovascular and cerebrovascular controls was useful for a deeper comprehension of postural disturbances; (iii) orthostatic syncope appeared to be favored by the loss of a coordinated behavior between the baroreflex feedback and mechanical feedforward pathway in the frequency band typical of the baroreflex functioning during the postural challenge, and by a weak cerebral autoregulation as revealed by the increased strength of the pressure-to-flow link in the respiratory band. GSC applied to spontaneous cardiovascular and cerebrovascular oscillations is a promising tool for describing and monitoring disturbances associated with posture modification.

On the Different Abilities of Cross-Sample Entropy and K-Nearest-Neighbor Cross-Unpredictability in Assessing Dynamic Cardiorespiratory and Cerebrovascular Interactions.

Nonlinear markers of coupling strength are often utilized to typify cardiorespiratory and cerebrovascular regulations. The computation of these indices requires techniques describing nonlinear interactions between respiration (R) and heart period (HP) and between mean arterial pressure (MAP) and mean cerebral blood velocity (MCBv). We compared two model-free methods for the assessment of dynamic HP-R and MCBv-MAP interactions, namely the cross-sample entropy (CSampEn) and k-nearest-neighbor cross-unpredictability (KNNCUP). Comparison was carried out first over simulations generated by linear and nonlinear unidirectional causal, bidirectional linear causal, and lag-zero linear noncausal models, and then over experimental data acquired from 19 subjects at supine rest during spontaneous breathing and controlled respiration at 10, 15, and 20 breaths·minute-1 as well as from 13 subjects at supine rest and during 60° head-up tilt. Linear markers were computed for comparison. We found that: (i) over simulations, CSampEn and KNNCUP exhibit different abilities in evaluating coupling strength; (ii) KNNCUP is more reliable than CSampEn when interactions occur according to a causal structure, while performances are similar in noncausal models; (iii) in healthy subjects, KNNCUP is more powerful in characterizing cardiorespiratory and cerebrovascular variability interactions than CSampEn and linear markers. We recommend KNNCUP for quantifying cardiorespiratory and cerebrovascular coupling.

Multimodal immunogenomic biomarker analysis of tumors from pediatric patients enrolled to a phase 1-2 study of single-agent atezolizumab.

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.

Yield of overnight pulse oximetry in screening commercial drivers for obstructive sleep apnea.

PURPOSE: To assess the efficacy of overnight pulse oximetry in screening male commercial drivers (CDs) for obstructive sleep apnea (OSA). METHODS: Consecutive male CDs undergoing their annual scheduled occupational health visit were enrolled from ten transportation facilities. All subjects underwent a home sleep apnea test (HSAT) to determine the Respiratory Event Index (REI). Oxygen desaturation indices (ODIs) below the 3% and 4% thresholds were computed using the built-in HSAT pulse oximeter. We then assessed the association between ODI values and the presence of OSA (defined as an REI ≥ 5 events/hour) as well as moderate to severe OSA (REI ≥ 15 events/hour). RESULTS: Of 331 CDs recruited, 278 (84%) completed the study protocol and 53 subjects were excluded due to inadequate HSAT quality. The included and excluded subjects were comparable in demographics and clinical characteristics. The included CDs had a median age of 49 years (interquartile range (IQR) = 15 years) and a median body mass index of 27 kg/m2 (IQR = 5 kg/m2). One hundred ninety-nine (72%) CDs had OSA, of which 48 (17%) were with moderate OSA and 45 (16%) with severe OSA. The ODI3 and ODI4 receiving operating characteristic curve value were 0.95 for predicting OSA and 0.98-0.96 for predicting moderate to severe OSA. CONCLUSION: Overnight oxygen oximetry may be an effective means to screen CDs for OSA.

Paediatric Strategy Forum for medicinal product development in mitogen-activated protein kinase pathway inhibitors: ACCELERATE in collaboration with the European Medicines Agency with participation of the Food and Drug Administration.

As the mitogen-activated protein kinase (MAPK) signalling pathway is activated in many paediatric cancers, it is an important therapeutic target. Currently, a range of targeted MAPK pathway inhibitors are being developed in adults. However, MAPK signals through many cascades and feedback loops and perturbing the MAPK pathway may have substantial influence on other pathways as well as normal development. In view of these issues, the ninth Paediatric Strategy Forum focused on MAPK inhibitors. Development of MAPK pathway inhibitors to date has been predominantly driven by adult indications such as malignant melanoma. However, these inhibitors may also target unmet needs in paediatric low-grade gliomas, high-grade gliomas, Langerhans cell histiocytosis, juvenile myelomonocytic leukaemia and several other paediatric conditions. Although MAPK inhibitors have demonstrated activity in paediatric cancer, the response rates and duration of responses needs improvement and better documentation. The rapid development and evaluation of combination approaches, based on a deep understanding of biology, is required to optimise responses and to avoid paradoxical tumour growth and other unintended consequences including severe toxicity. Better inhibitors with higher central nervous systempenetration for primary brain tumours and cancers with a propensity for central nervous system metastases need to be studied to determine if they are more effective than agents currently being used, and the optimum duration of therapy with MAPK inhibition needs to be determined. Systematic and coordinated clinical investigations to inform future treatment strategies with MAPK inhibitors, rather than use outside of clinical trials, are needed to fully assess the risks and benefits of these single agents and combination strategies in both front-line and in the refractory/relapse settings. Platform trials could address the investigation of multiple similar products and combinations. Accelerating the introduction of MAPK inhibitors into front-line paediatric studies is a priority, as is ensuring that these studies generate data appropriate for scientific and regulatory purposes. Early discussions with regulators are crucial, particularly if external controls are considered as randomised control trials in small patient populations can be challenging. Functional end-points specific to the populations in which they are studied, such as visual acuity, motor and neuro psychological function are important, as these outcomes are often more reflective of benefit for lower grade tumours (such as paediatric low-grade glioma and plexiform neurofibroma) and should be included in initial study designs for paediatric low-grade glioma. Early prospective discussions and agreements with regulators are necessary. Long-term follow-up of patients receiving MAPK inhibitors is crucial in view of their prolonged administration and the important involvement of this pathway in normal development. Further rational development, with a detailed understanding of biology of this class of products, is crucial to ensure they provide optimal benefit while minimising toxicity to children and adolescents with cancer.

Development of a pediatric physiologically-based pharmacokinetic model to support recommended dosing of atezolizumab in children with solid tumors.

Background: Atezolizumab has been studied in multiple indications for both pediatric and adult patient populations. Generally, clinical studies enrolling pediatric patients may not collect sufficient pharmacokinetic data to characterize the drug exposure and disposition because of operational, ethical, and logistical challenges including burden to children and blood sample volume limitations. Therefore, mechanistic modeling and simulation may serve as a tool to predict and understand the drug exposure in pediatric patients. Objective: To use mechanistic physiologically-based pharmacokinetic (PBPK) modeling to predict atezolizumab exposure at a dose of 15 mg/kg (max 1,200 mg) in pediatric patients to support dose rationalization and label recommendations. Methods: A minimal mechanistic PBPK model was used which incorporated age-dependent changes in physiology and biochemistry that are related to atezolizumab disposition such as endogenous IgG concentration and lymph flow. The PBPK model was developed using both in vitro data and clinically observed data in adults and was verified across dose levels obtained from a phase I and multiple phase III studies in both pediatric patients and adults. The verified model was then used to generate PK predictions for pediatric and adult subjects ranging from 2- to 29-year-old. Results: Individualized verification in children and in adults showed that the simulated concentrations of atezolizumab were comparable (76% within two-fold and 90% within three-fold, respectively) to the observed data with no bias for either over- or under-prediction. Applying the verified model, the predicted exposure metrics including Cmin, Cmax, and AUCtau were consistent between pediatric and adult patients with a geometric mean of pediatric exposure metrics between 0.8- to 1.25-fold of the values in adults. Conclusion: The results show that a 15 mg/kg (max 1,200 mg) atezolizumab dose administered intravenously in pediatric patients provides comparable atezolizumab exposure to a dose of 1,200 mg in adults. This suggests that a dose of 15 mg/kg will provide adequate and effective atezolizumab exposure in pediatric patients from 2- to 18-year-old.

Comparing Cross-Sample Entropy and K-Nearest-Neighbor Cross-Predictability Approaches for the Evaluation of Cardiorespiratory and Cerebrovascular Dynamic Interactions.

Quantification of the cardiorespiratory and cerebrovascular couplings is a relevant clinical issue given that their changes are considered signs of pathological status. The inherent nonlinearity of mechanisms underlying cardiorespiratory and cerebrovascular links requires nonlinear tools for their reliable evaluation. In the present study we compare two nonlinear methods for the assessment of coupling strength between two time series, namely cross-sample entropy (CSampEn) and k-nearest-neighbor cross-predictability (KNNCP). CSampEn uses a strategy that fixes the pattern length, while KNNCP optimizes the pattern length to maximize cross-predictability. CSampEn and KNNCP were applied to the beat-to-beat series of heart period (HP) and respiration (R) during a controlled breathing protocol with the aim at assessing cardiorespiratory coupling and to the beat-to-beat series of mean cerebral blood flow (MCBF) and mean arterial pressure (MAP) during an orthostatic stressor with the aim at evaluating cerebrovascular coupling. Although both the methods have the possibility to quantify the degree of HP-R and MCBF-MAP association, they exhibited different statistical power and even diverse trends in response to the considered physiological challenges. CSampEn and KNNCP are not interchangeable and should be utilized in association more than in alternative for the quantification of the HP-R and MCBF-MAP coupling strength. Clinical Relevance - This study proves that cross-entropy and cross-predictability might lead to different conclusions about cardiorespiratory and cerebrovascular couplings.

Spectral decomposition of cerebrovascular and cardiovascular interactions in patients prone to postural syncope and healthy controls.

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.

Exploring metrics for the characterization of the cerebral autoregulation during head-up tilt and propofol general anesthesia.

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 ρ. The aim of this study is to assess the two metrics for ARI computation in 13 healthy subjects (age: 27 ± 8 yrs., 5 males) at rest in supine position (REST) and during 60° head-up tilt (HUT) and in 19 patients (age: 64 ± 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 ρ 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.

Poor performance of screening questionnaires for obstructive sleep apnea in male commercial drivers.

PURPOSE: Screening commercial drivers (CDs) for obstructive sleep apnea (OSA) reduces the risk of motor vehicle accidents. We evaluated the accuracy of standard OSA questionnaires in a cohort of CDs. STUDY DESIGN AND METHODS: We enrolled consecutive male CDs at 10 discrete transportation companies during their yearly scheduled occupational health visit. The CDs had their anthropometric measures taken; completed the Berlin, STOP, STOP-BANG, OSAS-TTI, SACS, EUROSAS, and ARES questionnaires; and underwent a home sleep apnea test (HSAT) for the determination of their respiratory events index (REI). We assessed the questionnaires' ability to predict OSA (REI ≥ 5 events/h) and moderate-to-severe OSA (REI ≥ 15 events/h). RESULTS: Among 315 CDs recruited, 243 (77%) completed the study protocol, while 72 subjects were excluded for inadequate HSAT quality. The demographics and clinical data were comparable in both the included and excluded subjects. The included CDs had a median age of 50 years (interquartile range (IQR) 25-70) and a mean body mass index of 27 ± 4 kg/m2. One hundred and seventy-one subjects (71%) had OSA, and 68 (28%) had moderate-to-severe OSA. A receiver operating characteristic curve of the questionnaires were 0.51-0.71 for predicting OSA and 0.51-0.66 for moderate-to-severe OSA. The STOP-BANG questionnaire had an unsatisfactory positive predictive value, while all of the other questionnaires had an inadequate negative predictive value. CONCLUSIONS: Standard OSA questionnaires are not suited for screening among CDs. The use of the HSAT could provide an objective evaluation of for OSA in this special population.

Dynamic cerebrovascular autoregulation in patients prone to postural syncope: Comparison of techniques assessing the autoregulation index from spontaneous variability series.

Three approaches to the assessment of cerebrovascular autoregulation (CA) via the computation of the autoregulation index (ARI) from spontaneous variability of mean arterial pressure (MAP) and mean cerebral blood flow velocity (MCBFV) were applied: 1) a time domain method (TDM); 2) a nonparametric method (nonPM); 3) a parametric method (PM). Performances were tested over matched and surrogate unmatched pairs. Data were analyzed at supine resting (REST) and during the early phase of 60° head-up tilt (TILT) in 13 subjects with previous history of postural syncope (SYNC, age: 28 ± 9 yrs.; 5 males) and 13 control individuals (noSYNC, age: 27 ± 8 yrs.; 5 males). Analysis was completed by computing autonomic markers from heart period (HP) and systolic arterial pressure (SAP) variability series via spectral approach. HP and SAP spectral indexes suggested that noSYNC and SYNC groups exhibited different autonomic responses to TILT. ARI analysis indicated that: i) all methods have a sufficient statistical power to separate matched from unmatched pairs with the exception of nonPM applied to impulse response; ii) ARI estimates derived from different methods might be uncorrelated and, even when correlated, might exhibit a significant bias; iii) orthostatic stressor did not induce any evident ARI change in either noSYNC or SYNC individuals; iv) this conclusion held regardless of the method. Methods for the ARI estimation from spontaneous variability provide different ARIs but none indicate that noSYNC and SYNC subjects have different dynamic component of CA.

Categorizing the Role of Respiration in Cardiovascular and Cerebrovascular Variability Interactions.

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: 64±8 yrs; 17 males) before and after induction of propofol-based general anesthesia prior to coronary artery bypass grafting, and in 13 healthy subjects (age: 27±8 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.

An Empirical Mode Decomposition Approach to Assess the Strength of Heart Period-Systolic Arterial Pressure Variability Interactions.

This work proposes an empirical mode decomposition (EMD) method to assess the strength of the interactions between heart period (HP) and systolic arterial pressure (SAP) variability. EMD was exploited to decompose the original series (OR) into its first, and fastest, intrinsic mode function (IMF1) and the residual (RES) computed by subtracting the IMF1 from OR. EMD procedure was applied to both HP and SAP variability series. Then, the cross correlation function (CCF) was computed over OR, IMF1 and RES series derived from HP and SAP variability in 13 healthy subjects (age 27±8 yrs, 5 males) at rest in supine position (REST) and during head-up tilt (TILT). The first CCF maximum at negative time lags and the first CCF minimum at positive time lags were taken respectively as indexes of the coupling along the feedback baroreflex and feedforward mechanical arms of HP-SAP closed-loop control. Results showed that the coupling strength is increased during TILT on both arms and this result holds on REST. At REST the coupling along both arms was stronger when computed over IMF1 because interactions were mainly governed by respiration. This result was not observed during TILT possibly due to the reduced importance of respiration compared to other mechanisms acting at slower time scales. The proposed method allowed the investigation of the strength of HP-SAP variability interactions according to the time scales of the physiological mechanisms.The proposed EMD-based method allows the quantification of the strength of the HP-SAP closed-loop variability interactions according to the different time scales of respiration and slower baroreflex-mediated reflexes.

Validity of the STOP-Bang Questionnaire in Identifying OSA in a Dental Patient Cohort.

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 ≥ 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 ≥ 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 ≥ 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 < 0.0001). Moreover, 153/482 subjects at risk for OSAS (31.7%) accepted further examination with a type 3 polygraph. Presence of OSAS (AHI ≥ 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 ≥ 15). Conclusion: the high prevalence of OSAS highlights the role of dentists as "epidemiological sentinels". The STOP-Bang questionnaire is a simple and efficacious instrument for screening sleep apnea patients.

Atezolizumab for children and young adults with previously treated solid tumours, non-Hodgkin lymphoma, and Hodgkin lymphoma (iMATRIX): a multicentre phase 1-2 study.

BACKGROUND: Atezolizumab is an inhibitor of PD-L1, which can lead to enhanced anticancer T-cell activity. We aimed to evaluate the safety, pharmacokinetics, and activity of atezolizumab in children and young adults with refractory or relapsed solid tumours, with known or expected PD-L1 expression. METHODS: iMATRIX was a multicentre, open-label, phase 1-2 trial of patients (aged <30 years) with solid tumours or lymphomas recruited from 28 hospitals in ten countries (USA, France, Italy, UK, Spain, the Netherlands, Denmark, Israel, Switzerland, and Germany). Eligible patients younger than 18 years received 15 mg/kg atezolizumab (maximum 1200 mg); patients aged 18-29 years received the adult dose (1200 mg) until disease progression or loss of clinical benefit. Co-primary endpoints were safety (assessed by incidence of adverse events) and pharmacokinetics (assessed by serum atezolizumab concentrations). Secondary endpoints included the proportion of patients achieving an objective response. This trial is registered with ClinicalTrials.gov, number NCT02541604. FINDINGS: Between Nov 5, 2015, and April 2, 2018, we screened 115 patients, 25 of whom did not meet the inclusion criteria. 90 patients, with a median age of 14 years (IQR 10-17), were enrolled. At the data cutoff (April 2, 2018), two patients remained on study treatment. 87 (97%) of 90 patients received at least one dose of atezolizumab at 15 mg/kg or 1200 mg and were evaluable for safety. Three patients were not treated owing to either poor clinical condition or withdrawal of consent. In the safety-evaluable population (n=87), the most common adverse events were pyrexia (36 [41%] patients) and fatigue (31 [36%]). The most common grade 3-4 adverse event was anaemia (19 [22%] patients). The most commonly reported serious adverse events were in the categories of infections and infestations; pyrexia was the only serious adverse event reported in more than two patients. 57 (66%) patients had at least one treatment-related adverse event (grade 1-4); fatigue was the most common treatment-related adverse event (17 patients [20%]). There were no fatal adverse events. Mean serum concentrations of atezolizumab were overlapping and comparable between children receiving 15 mg/kg and young adults receiving 1200 mg of atezolizumab every 3 weeks. Serum concentrations of atezolizumab were above the target exposure level in all patients. At 6 months, four patients (5%) achieved an objective response (all partial responses). INTERPRETATION: Although response to atezolizumab was restricted, atezolizumab was well tolerated with generally comparable exposure across populations. Our findings might help to define future development strategies for immune checkpoint inhibitors either by focusing research to specific disease subpopulations that exhibit greater benefit from immune checkpoint inhibitors, or by providing the means to identify therapeutic combination partners that augment T-cell infiltration and proliferation in so-called immune cold tumour microenvironments. FUNDING: F Hoffmann-La Roche.

Population pharmacokinetics, exposure-safety, and immunogenicity of atezolizumab in pediatric and young adult patients with cancer.

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 < 18 years (n = 69) received a weight-adjusted dose of atezolizumab (15 mg/kg every 3 weeks [q3w]; maximum 1200 mg); those aged ≥ 18 years (n = 18) received a flat dose (1200 mg q3w). A prior two-compartment intravenous infusion input adult population-PK (popPK) model of atezolizumab was used as a basis to model pediatric data. RESULTS: A total of 431 atezolizumab serum concentrations from 87 relapse-refractory pediatric and young adult patients enrolled in the iMATRIX-atezolizumab study were used for the popPK analysis. The dataset comprised predominantly patients aged < 18 years, including two infants aged < 2 years, with a wide body weight and age range. The clearance and volume of distribution estimates of atezolizumab were 0.217 L/day and 3.01 L, respectively. Atezolizumab geometric mean trough exposures were ~ 20% lower in pediatric patients versus young adults; this was not clinically meaningful as both groups achieved the target concentration (6 µg/mL). Safety was similar between pediatric and young adult patients with no exposure-safety relationship observed. Limited responses (4/87) precluded an exposure-response assessment on outcomes. A comparable rate (13% vs 11%) of atezolizumab anti-drug antibodies was seen in pediatric and young adult patients. CONCLUSIONS: These findings demonstrate a similar exposure-safety profile of atezolizumab in pediatric and young adult patients, supportive of weight-based dosing in pediatric patients. TRIAL REGISTRATION: NCT02541604.

Strength and Latency of the HP-SAP Closed Loop Variability Interactions in Subjects Prone to Develop Postural Syncope.

The coupling and latency between heart period (HP) and systolic arterial pressure (SAP) variability can be investigated along the two arms of the HP-SAP closed loop, namely along the baroreflex feedback from SAP to HP, and along the feedforward pathway from HP to SAP. This study investigates the HP-SAP closed loop variability interactions through cross-correlation function (CCF). Coupling strength and delay between HP and SAP variability series were monitored in 13 subjects prone to develop orthostatic syncope (SYNC, 28±9 yrs, 5 males) and in 13 subjects with no history of postural syncope (noSYNC, age: 27±8 yrs, 5 males). Analysis was carried out at rest in supine position (REST) and during head-up tilt (TILT) at 60 degrees. The null hypothesis of HP-SAP uncoupling was tested through a surrogate analysis associating the HP series of a subject with a SAP sequence of a different one. Results showed that during TILT the coupling strength increased along the baroreflex and latency augmented along the mechanical feedforward pathway exclusively in noSYNC subjects. Finally, closed loop HP-SAP interactions were detected in about one third of subjects and the situation of full uncoupling was rarely found. CCF analysis was found to be a straightforward and easily applicable method to investigate HP-SAP control deserving a direct comparison with more sophisticated signal processing tools assessing causality.

Effect of Fluconazole Coadministration and CYP2C9 Genetic Polymorphism on Siponimod Pharmacokinetics in Healthy Subjects.

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.

Cerebrovascular and cardiovascular variability interactions investigated through conditional joint transfer entropy in subjects prone to postural syncope.

OBJECTIVE: A model-based conditional transfer entropy approach was exploited to quantify the information transfer in cerebrovascular (CBV) and cardiovascular (CV) systems in subjects prone to develop postural syncope. APPROACH: Spontaneous beat-to-beat variations of mean cerebral blood flow velocity (MCBFV) derived from a transcranial Doppler device, heart period (HP) derived from surface electrocardiogram, mean arterial pressure (MAP) and systolic arterial pressure (SAP) derived from finger plethysmographic arterial pressure device were monitored at rest in supine position (REST) and during 60° head-up tilt (TILT) in 13 individuals (age mean ± standard deviation: 28 ± 9 years, min-max range: 18-44 years, 5 males) with a history of recurrent episodes of syncope (SYNC) and in 13 age- and gender-matched controls (NonSYNC). Respiration (R) obtained from a thoracic belt was acquired as well and considered as a conditioning signal in transfer entropy assessment. Synchronous sequences of 250 consecutive MCBFV, HP, MAP, SAP and R values were utilized to estimate the information genuinely transferred from MAP to MCBFV (i.e. disambiguated from R influences) and vice versa. Analogous indexes were computed from SAP to HP and vice versa. Traditional time and frequency domain analyses were carried out as well. MAIN RESULTS: SYNC subjects showed an increased genuine information transfer from MAP to MCBFV during TILT, while they did not exhibit the expected rise of the genuine information transfer from SAP to HP. SIGNIFICANCE: We conclude that SYNC individuals featured an impaired cerebral autoregulation visible during TILT and were unable to activate cardiac baroreflex to cope with the postural challenge. Traditional frequency domain markers based on transfer function modulus, phase and coherence functions were less powerful or less specific in typifying the CBV and CV controls of SYNC individuals. Conditional transfer entropy approach can identify the impairment of CBV and CV controls and provide specific clues to identify subjects prone to develop postural syncope.

Nonlinear effects of respiration on the crosstalk between cardiovascular and cerebrovascular control systems.

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.