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We propose a novel model selection algorithm based on a penalized maximum likelihood estimator (PMLE) for functional hidden dynamic geostatistical models (f-HDGM). These models employ a classic mixed-effect regression structure with embedded spatiotemporal dynamics to model georeferenced data observed in a functional domain. Thus, the regression coefficients are functions. The algorithm simultaneously selects the relevant spline basis functions and regressors that are used to model the fixed effects. In this way, it automatically shrinks to zero irrelevant parts of the functional coefficients or the entire function for an irrelevant regressor. The algorithm is based on an adaptive LASSO penalty function, with weights obtained by the unpenalised f-HDGM maximum likelihood estimators. The computational burden of maximisation is drastically reduced by a local quadratic approximation of the log-likelihood. A Monte Carlo simulation study provides insight in prediction ability and parameter estimate precision, considering increasing spatiotemporal dependence and cross-correlations among predictors. Further, the algorithm behaviour is investigated when modelling air quality functional data with several weather and land cover covariates. Within this application, we also explore some scalability properties of our algorithm. Both simulations and empirical results show that the prediction ability of the penalised estimates are equivalent to those provided by the maximum likelihood estimates. However, adopting the so-called one-standard-error rule, we obtain estimates closer to the real ones, as well as simpler and more interpretable models.

The air in the Lombardy region, Italy, is one of the most polluted in Europe because of limited air circulation and high emission levels. There is a large scientific consensus that the agricultural sector has a significant impact on air quality. To support studies quantifying the role of the agricultural and livestock sectors on the Lombardy air quality, this paper presents a harmonised dataset containing daily values of air quality, weather, emissions, livestock, and land and soil use in the years 2016–2021, for the Lombardy region. The daily scale is obtained by averaging hourly data and interpolating other variables. In fact, the pollutant data come from the European Environmental Agency and the Lombardy Regional Environment Protection Agency, weather and emissions data from the European Copernicus programme, livestock data from the Italian zootechnical registry, and land and soil use data from the CORINE Land Cover project. The resulting dataset is designed to be used as is by those using air quality data for research.

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Purpose:Atezolizumab [anti–programmed death-ligand 1 (PD-L1)] selectively targets PD-L1 to block its interaction with receptors programmed death 1 and B7.1, thereby reinvigorating antitumor T-cell activity. We evaluated the long-term safety and activity of atezolizumab, along with biological correlates of clinical activity endpoints, in a cohort of patients with melanoma in an ongoing phase Ia study (NCT01375842).Patients and Methods:Patients with unresectable or metastatic melanoma were enrolled to receive atezolizumab 0.1 to 20 mg/kg or ≥10 mg/kg every 3 weeks. Primary study objectives were safety and tolerability. Secondary objectives included investigator-assessed efficacy measures; pharmacodynamic and predictive biomarkers of antitumor activity were explored.Results:Forty-five patients were enrolled and were evaluable for safety. Most treatment-related adverse events (AE) were grade 1/2 (60%). Fatigue (44%), pruritus (20%), pyrexia (18%), and rash (18%) were the most common treatment-related AEs of any grade. No treatment-related deaths occurred. Overall response rate was 30% among 43 efficacy- evaluable patients, with a median duration of response of 62 months [95% CI, 35–not estimable (NE)]. Clinically meaningful long-term survival was observed, with a median overall survival of 23 months (95% CI, 9–66). Baseline biomarkers of tumor immunity [PD-L1 expression on immune cells, T effector (Teff), and antigen presentation gene signatures) and tumor mutational burden (TMB) were associated with improved response, progression-free survival, and overall survival.Conclusions:Atezolizumab was well tolerated, with durable responses and survival in patients with melanoma. PD-L1 expression, TMB, and Teff signatures may indicate improved benefit with atezolizumab in these patients.

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Purpose:Atezolizumab [anti–programmed death-ligand 1 (anti-PD-L1)] is well tolerated and efficacious in multiple cancers, but has not been previously evaluated in metastatic castration-resistant prostate cancer (mCRPC). This study examined the safety, efficacy, and biomarkers of atezolizumab monotherapy for mCRPC.Patients and Methods:This phase Ia, open-label, dose-escalation and dose-expansion study (PCD4989g) enrolled patients with mCRPC who had progressed on sipuleucel-T or enzalutamide. Atezolizumab was given intravenously every 3 weeks until confirmed disease progression or loss of clinical benefit. Prespecified endpoints included safety, efficacy, biomarker analyses, and radiographic assessments.Results:All 35 evaluable patients [median age, 68 years (range, 45–83 years)] received atezolizumab after ≥1 prior line of therapy; 62.9% of patients had received ≥3 prior lines. Treatment-related adverse events occurred in 21 patients (60.0%), with no deaths. One patient had a confirmed partial response (PR) per RECIST 1.1, and 1 patient had a PR per immune-related response criteria. The confirmed 50% PSA response rate was 8.6% (3 patients). Median overall survival (OS) was 14.7 months [95% confidence interval (CI): 5.9–not evaluable], with a 1-year OS rate of 52.3% (95% CI: 34–70); 2-year OS was 35.9% (95% CI: 13–59). Median follow-up was 13.0 months (range, 1.2–28.1 months). Biomarker analyses showed that atezolizumab activated immune responses; however, a composite biomarker failed to reveal consistent correlations with efficacy.Conclusions:Atezolizumab was generally well tolerated in patients with mCRPC, with a safety profile consistent with other tumor types. In heavily pretreated patients, atezolizumab monotherapy demonstrated evidence of disease control; however, its limited efficacy suggests a combination approach may be needed.

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ObjectivesEpigenomic alterations in cancer interact with the immune microenvironment to dictate tumour evolution and therapeutic response. We aimed to study the regulation of the tumour immune microenvironment through epigenetic alternate promoter use in gastric cancer and to expand our findings to other gastrointestinal tumours.DesignAlternate promoter burden (APB) was quantified using a novel bioinformatic algorithm (proActiv) to infer promoter activity from short-read RNA sequencing and samples categorised into APBhigh, APBint and APBlow. Single-cell RNA sequencing was performed to analyse the intratumour immune microenvironment. A humanised mouse cancer in vivo model was used to explore dynamic temporal interactions between tumour kinetics, alternate promoter usage and the human immune system. Multiple cohorts of gastrointestinal tumours treated with immunotherapy were assessed for correlation between APB and treatment outcomes.ResultsAPBhigh gastric cancer tumours expressed decreased levels of T-cell cytolytic activity and exhibited signatures of immune depletion. Single-cell RNAsequencing analysis confirmed distinct immunological populations and lower T-cell proportions in APBhigh tumours. Functional in vivo studies using ‘humanised mice’ harbouring an active human immune system revealed distinct temporal relationships between APB and tumour growth, with APBhigh tumours having almost no human T-cell infiltration. Analysis of immunotherapy-treated patients with GI cancer confirmed resistance of APBhigh tumours to immune checkpoint inhibition. APBhigh gastric cancer exhibited significantly poorer progression-free survival compared with APBlow (median 55 days vs 121 days, HR 0.40, 95% CI 0.18 to 0.93, p=0.032).ConclusionThese findings demonstrate an association between alternate promoter use and the tumour microenvironment, leading to immune evasion and immunotherapy resistance.

We propose a novel model selection algorithm based on a penalized maximum likelihood estimator (PMLE) for functional hidden dynamic geostatistical models (f-HDGM). These models employ a classic mixed-effect regression structure with embedded spatiotemporal dynamics to model georeferenced data observed in a functional domain. Thus, the parameters of interest are functions across this domain. The algorithm simultaneously selects the relevant spline basis functions and regressors that are used to model the fixed-effects relationship between the response variable and the covariates. In this way, it automatically shrinks to zero irrelevant parts of the functional coefficients or the entire effect of irrelevant regressors. The algorithm is based on iterative optimisation and uses an adaptive least absolute shrinkage and selector operator (LASSO) penalty function, wherein the weights are obtained by the unpenalised f-HDGM maximum-likelihood estimators. The computational burden of maximisation is drastically reduced by a local quadratic approximation of the likelihood. Through a Monte Carlo simulation study, we analysed the performance of the algorithm under different scenarios, including strong correlations among the regressors. We showed that the penalised estimator outperformed the unpenalised estimator in all the cases we considered. We applied the algorithm to a real case study in which the recording of the hourly nitrogen dioxide concentrations in the Lombardy region in Italy was modelled as a functional process with several weather and land cover covariates.

Functional data are generally curves indexed over a time domain, and land-use regression (LUR) is a promising spatial technique for generating high-resolution spatial estimation of retrospective long-term air pollutants. We developed a methodology for the novel functional land-use regression (FLUR) model, which provides high-resolution spatial and temporal estimations of retrospective pollutants. Long-term fine particulate matter (PM2.5) in the megacity of Tehran, Iran, was used as the practical example. The hourly measured PM2.5 concentrations were averaged for each hour and in each air monitoring station. Penalized smoothing was employed to construct the smooth PM2.5 diurnal curve using averaged hourly data in each of the 30 stations. Functional principal component analysis (FPCA) was used to extract FPCA scores from pollutant curves, and LUR models were fitted on FPCA scores. The mean of all PM2.5 diurnal curves had a maximum of 39.58 µg/m3 at 00:26 a.m. and a minimum of 29.27 µg/m3 at 3:57 p.m. The FPCA explained about 99.5% of variations in the observed diurnal curves across the city using just three components. The evaluation of spatially predicted long-term PM2.5 diurnal curves every 15 min provided a series of 96 high-resolution exposure maps. The presented methodology and results could benefit future environmental epidemiological studies.

Purpose: Atezolizumab [anti–programmed death-ligand 1 (anti-PD-L1)] is well tolerated and efficacious in multiple cancers, but has not been previously evaluated in metastatic castration-resistant prostate cancer (mCRPC). This study examined the safety, efficacy, and biomarkers of atezolizumab monotherapy for mCRPC. Patients and Methods: This phase Ia, open-label, dose-escalation and dose-expansion study (PCD4989g) enrolled patients with mCRPC who had progressed on sipuleucel-T or enzalutamide. Atezolizumab was given intravenously every 3 weeks until confirmed disease progression or loss of clinical benefit. Prespecified endpoints included safety, efficacy, biomarker analyses, and radiographic assessments. Results: All 35 evaluable patients [median age, 68 years (range, 45–83 years)] received atezolizumab after ≥1 prior line of therapy; 62.9% of patients had received ≥3 prior lines. Treatment-related adverse events occurred in 21 patients (60.0%), with no deaths. One patient had a confirmed partial response (PR) per RECIST 1.1, and 1 patient had a PR per immune-related response criteria. The confirmed 50% PSA response rate was 8.6% (3 patients). Median overall survival (OS) was 14.7 months [95% confidence interval (CI): 5.9–not evaluable], with a 1-year OS rate of 52.3% (95% CI: 34–70); 2-year OS was 35.9% (95% CI: 13–59). Median follow-up was 13.0 months (range, 1.2–28.1 months). Biomarker analyses showed that atezolizumab activated immune responses; however, a composite biomarker failed to reveal consistent correlations with efficacy. Conclusions: Atezolizumab was generally well tolerated in patients with mCRPC, with a safety profile consistent with other tumor types. In heavily pretreated patients, atezolizumab monotherapy demonstrated evidence of disease control; however, its limited efficacy suggests a combination approach may be needed.

The final workshop of the Italy-Croatia Interreg project GUTTA took place in Lecce, at the premises of the Fondazione CMCC, on May 4th, 2022. It reviewed the state of the art of maritime decarbonisation from multiple viewpoints: the regulatory institutions, the research and academia, the industry, and an advocacy organisation. It also provided a special focus on the impact of COVID-19 on the maritime sector, and how it may have affected its pathway towards its decarbonisation. The workshop attempted to bring the latest technical advancements to the broadest audience. The speakers were committed to an effort for plain communication, also to foster cross-cutting interactions among them. The workshop was moderated by a television journalist, and several students from local high schools attended it. On this webpage, all presentations, given in person or remotely, are documented through their slides. The abstracts and CV of the speakers are available here, while the integral video recordings available here. Agenda: Session A Introduction 9:00 Welcome and moderation Marina Lalovic Journalist at RAI – Rainews24 9:10 Institutional greetings/1 Alessandro Delli Noci Regione Puglia, Councillor 9:20 Institutional greetings/2 Maja Markovčić Kostelac EMSA, Director 9:30 An overview of the GUTTA project Paola Agostini CMCC, Senior Scientific Manager Session B Decarbonisation 9:40 Reduction of CO2 emissions from shipping Tristan Smith UCL Energy Institute, Associate Professor and UMAS, Director 10:10 EU legislative proposals for maritime decarbonisation María Alfayate EU Commission, DG-Clima, Policy Officer 10:30 Coffee break 11:00 EU shipping proposals: fit for maritime decarbonisation? Delphine Gozillon T&E, Sustainable Shipping Policy Officer 11:20 Maritime decarbonisation: European framework and shipyards perspective in Italy Chiara Notaro CETENA, Research and WATERBORNE, Board 11:40 The GUTTA-VISIR service for least-CO2 ferry routes Gianandrea Mannarini CMCC, Senior Scientist 12:00 Panel discussion of session B 13:00 Lunch session C COVID-19 14:30 Digitisation in Ports and Shipping at the time of COVID-19 Michele Fiorini IET-Italy, Chair 14:50 The pandemic’s impact on global maritime mobility Paolo Braca NATO STO-CMRE, Senior Research Scientist 15:10 The Epidemic Renormalization Group and people mobility in the Adriatic region Giacomo Cacciapaglia CNRS, Senior Researcher 15:40 Statistical modelling of COVID-19 impact on maritime carbon emissions Alessandro Fassò University of Bergamo, Full Professor 16:00 Panel discussion of session C 16:45 Final remarks Marina Lalovic Journalist at RAI – Rainews24 17:00 end of workshop, This workshop was supported by the European Regional Development Fund through the Italy-Croatia Interreg programme, project GUTTA, grant number 10043587.

Unprecedented socioeconomic conditions during the COVID-19 pandemic impacted shipping. We combined ferry CO2 emissions in Europe (from the EU-MRV) with port call data and vessel parameters, and analysed them using mixed-effects linear models with interactions. We found a generalized reduction in unitary emissions in 2020, confirming its causal relation with COVID-19. Furthermore, for larger ferries, additional and COVID-19-related reductions between 14% and 31% occurred, with the larger reductions for those built before 1999. Ferries operating in the Baltic and Mediterranean Seas experienced comparable reductions in their unitary emissions, but in the North Sea per-ship emissions decreased by an additional 18%. Per-ship emissions at berth, while showing increases or decreases depending on ferry type, did not significantly change at the fleet level. We believe that our methodology may help assess the progress of shipping toward decarbonisation in the presence of external shocks.

Although immune checkpoint inhibitors (ICIs) are established as effective cancer therapies, overcoming therapeutic resistance remains a critical challenge. Here we identify interleukin 6 (IL-6) as a correlate of poor response to atezolizumab (anti-PD-L1) in large clinical trials of advanced kidney, breast, and bladder cancers. In pre-clinical models, combined blockade of PD-L1 and the IL-6 receptor (IL6R) causes synergistic regression of large established tumors and substantially improves anti-tumor CD8

We study the class of nonholonomic mechanical systems formed by a heavy symmetric ball that rolls without sliding on a surface of revolution, which is either at rest or rotates about its (vertical) figure axis with uniform angular velocity $$\Omega $$ Ω . The first studies of these systems go back over a century, but a comprehensive understanding of their dynamics is still missing. The system has an $$\mathrm {SO(3)}\times \mathrm {SO(2)}$$ SO ( 3 ) × SO ( 2 ) symmetry and reduces to four dimensions. We extend in various directions, particularly from the case $$\Omega =0$$ Ω = 0 to the case $$\Omega \not =0$$ Ω ≠ 0 , a number of previous results and give new results. In particular, we prove that the reduced system is Hamiltonizable even if $$\Omega \not =0$$ Ω ≠ 0 and, exploiting the recently introduced “moving energy,” we give sufficient conditions on the profile of the surface that ensure the periodicity of the reduced dynamics and hence the quasiperiodicity of the unreduced dynamics on tori of dimension up to three. Furthermore, we determine all the equilibria of the reduced system, which are classified in three distinct families, and determine their stability properties. In addition to this, we give a new form of the equations of motion of nonholonomic systems in quasi-velocities which, at variance from the well-known Hamel equations, use any set of quasi-velocities and explicitly contain the reaction forces.

The global climate observing system Reference Upper Air Network (GRUAN) provides reference measurements of the essential climate variables and their measurement uncertainty. An important aspect of the measurement uncertainty is the interpolation uncertainty. This problem arises, for example, when GRUAN processes atmospheric profiles collected by Vaisala RS41 radiosondes. For various reasons, the radiosonde sensor may fail to collect some values along the vertical profile in the atmosphere. As a consequence, estimation techniques to fill the data gaps and to provide an evaluation of the related interpolation uncertainty are welcome. This paper aims to understand and quantify the interpolation uncertainty of the relative humidity (RH). In particular, we consider linear and Gaussian process interpolation either unidimensional or multidimensional. We provide results in terms of interpolation distance in seconds, which measures the distance of an interpolated data from the interpolating data. We also consider measurement altitude and launch site. Although the Gaussian interpolation results to be generally better than linear interpolation, the difference in uncertainty is relatively small. The average column uncertainty difference is in the order of 0.2% and for large data gaps around 0.4%. The interpolation uncertainty is larger in the lower atmosphere. For example at 2–4 km altitude, the uncertainty is around 2% at 10 s distance, around 5% at 40 s and 10% at 90 s. In the upper atmosphere, RH and its uncertainty decrease. For example, at 14–16 km altitude, the latter is smaller than 2% RH at all interpolation distances.

We study some aspects of the dynamics of the nonholonomic system formed by a heavy homogeneous ball constrained to roll without sliding on a steadily rotating surface of revolution. First, in the case in which the figure axis of the surface is vertical (and hence the system is $\textrm{SO(3)}\times\textrm{SO(2)}$-symmetric) and the surface has a (nondegenerate) maximum at its vertex, we show the existence of motions asymptotic to the vertex and rule out the possibility of blow up. This is done passing to the 5-dimensional $\textrm{SO(3)}$-reduced system. The $\textrm{SO(3)}$-symmetry persists when the figure axis of the surface is inclined with respect to the vertical -- and the system can be viewed as a simple model for the Japanese kasamawashi (turning umbrella) performance art -- and in that case we study the (stability of the) equilibria of the 5-dimensional reduced system.

In this paper, we give a new characterization of the cut locus of a point on a compact Riemannian manifold as the zero set of the optimal transport density solution of the Monge–Kantorovich equations, a PDE formulation of the optimal transport problem with cost equal to the geodesic distance. Combining this result with an optimal transport numerical solver, based on the so-called dynamical Monge–Kantorovich approach, we propose a novel framework for the numerical approximation of the cut locus of a point in a manifold. We show the applicability of the proposed method on a few examples settled on 2d-surfaces embedded in ℝ3, and discuss advantages and limitations.

Observational records are more often than not influenced by residual non-climatic factors which must be detected and adjusted for prior to their usage. In this work, we present a novel approach, named Radiosounding HARMonization (RHARM), providing a homogenized data set of temperature, humidity and wind profiles along with an estimation of the measurement uncertainties for 697 radiosounding stations globally. The RHARM method has been used to adjust twice daily (0000 and 1200 UTC) radiosonde data holdings at 16 pressure levels in the range 1,000–10 hPa, from 1978 to present, provided by the Integrated Global Radiosonde Archive. Relative humidity (RH) data are limited to 250 hPa. The applied adjustments are interpolated to all reported levels. RHARM is the first data set to provide homogenized time series with an estimation of the observational uncertainty at each sounding pressure level. By construction, RHARM adjusted fields are not affected by cross-contamination of biases across stations and are fully independent of reanalysis data. Analysis of trends for temperature, RH and winds highlights increased geographical coherency of trends over 1978–2000 globally, but especially in the Northern Hemisphere and South America. RHARM shows warming trends of 0.39 K/decade at 300 hPa in the Northern Hemisphere and of 0.25 K/ decade in the tropics. The RHARM adjustments also reduce differences with the European Centre for Medium-Range Weather Forecast ERA5 reanalysis, with the strongest effect in the Northern Hemisphere for temperature and relative humidity. For wind speed, the comparison indicates a good agreement with ERA5 in the troposphere.

The solar disk is a bright gamma-ray source in the sky. The interactions of cosmic rays with the solar atmosphere produce secondary particles which can reach the Earth. In this work we present a comprehensive calculation of the yields of secondary particles such as gamma-rays, electrons, positrons, neutrons and neutrinos, performed with the FLUKA code. We also estimate the intensity at the Sun and the fluxes at the Earth of these secondary particles by folding their yields with the intensities of cosmic rays impinging on the solar surface. The results are sensitive to the assumptions on the magnetic field near the Sun and to the cosmic-ray transport in the magnetic field in the inner solar system.

This paper is motivated by the fact that, although temperature readings made by Vaisala RS41 radiosondes at GRUAN sites (http://www.gruan.org) are given at 1 s resolution, for various reasons, missing data are spread along the atmospheric profile. Such a problem is quite common in radiosonde data and other profile data. Hence, (linear) interpolation is often used to fill the gaps in published data products. In this perspective, the present paper considers interpolation uncertainty. To do this, a statistical approach is introduced giving some understanding of the consequences of substituting missing data by interpolated ones. In particular, a general frame for the computation of interpolation uncertainty based on a Gaussian process (GP) set-up is developed. Using the GP characteristics, a simple formula for computing the linear interpolation standard error is given. Moreover, the GP interpolation is proposed as it provides an alternative interpolation method with its standard error. For the Vaisala RS41, the two approaches are shown to give similar interpolation performances using an extensive cross-validation approach based on the block-bootstrap technique. Statistical results about interpolation uncertainties at various GRUAN sites and for various missing gap lengths are provided. Since both provide an underestimation of the cross-validation interpolation uncertainty, a bootstrap-based correction formula is proposed. Using the root mean square error, it is found that, for short gaps, with an average length of 5 s, the average uncertainty is smaller than 0.10 K. For larger gaps, it increases up to 0.35 K for an average gap length of 30 s, and up to 0.58 K for a gap of 60 s.

The connection between the dynamics in relative periodic orbits of vector fields with noncompact symmetry groups and periodic control for the class of control systems on Lie groups known as '(robotic) locomotion systems' is well known, and has led to the identification of (geometric) phases. We take an approach which is complementary to the existing ones, advocating the relevance——for trajectory generation in these control systems——of the qualitative properties of the dynamics in relative periodic orbits. There are two particularly important features. One is that motions in relative periodic orbits of noncompact groups can only be of two types: either they are quasi-periodic, or they leave any compact set as \begin{document}$ t\to\pm\infty $\end{document} ('drifting motions'). Moreover, in a given group, one of the two behaviours may be predominant. The second is that motions in a relative periodic orbit exhibit 'spiralling', 'meandering' behaviours, which are routinely detected in numerical integrations. Since a quantitative description of meandering behaviours for drifting motions appears to be missing, we provide it here for a class of Lie groups that includes those of interest in locomotion (semidirect products of a compact group and a normal vector space). We illustrate these ideas on some examples (a kinematic car robot, a planar swimmer).

Introduction Atezolizumab, an anti-programmed death-ligand 1 (PD-L1) antibody, inhibits PD-L1:PD-1 and PD-L1:B7.1 interactions, restoring anticancer immunity. Here, we report final analyses from the non-small-cell lung cancer (NSCLC) cohort of the first atezolizumab phase I study. Methods Patients with NSCLC received atezolizumab 1–20 mg/kg or 1200 mg intravenously every 3 weeks. Baseline PD-L1 expression on tumour cells (TCs) and tumour-infiltrating immune cells (ICs) was assessed (VENTANA SP142 immunohistochemistry assay). Exploratory subgroup analyses investigated responses by baseline PD-L1 expression and oncogenic mutational status. Results Eighty-nine patients, 98% of whom had received previous systemic therapy, were evaluable for safety and antitumour activity. Atezolizumab was well tolerated, with grade III/IV treatment-related adverse events (TRAEs) observed in 10 patients (11%). All-grade TRAEs occurring in >10% of patients were fatigue, nausea and decreased appetite; grade III/IV TRAEs occurring in >2% of patients were fatigue, dyspnoea, hyponatremia and hypoxia. One patient died from treatment-unrelated pneumonia. Objective response rate (ORR) was 50% (95% confidence interval [CI], 28%–72%), 33% (20%–48%), 29% (18%–41%) and 11% (1%–35%) for the TC3 or IC3, TC2/3 or IC2/3, TC1/2/3 or IC1/2/3 and TC0 and IC0 subgroups, respectively. All-patient ORR was 23% (95% CI, 14%–33%). Median duration of response was 16.4 months (range, 7.2–53.4+). One-, 2-, and 3-year survival rates were 63% (95% CI, 53%–73%), 37% (26%–47%) and 28% (18%–38%), respectively. Conclusions Single-agent atezolizumab was well tolerated with long-term clinical benefits, including durable responses and survival, in pretreated NSCLC. Improved responses and survival rates were seen with increasing baseline PD-L1 expression. ClinicalTrials.gov identifier NCT01375842 .

Glioblastoma is the most common primary malignant brain tumor. No standard treatment exists for recurrent disease. Glioblastoma is associated with an immunosuppressive tumor microenvironment. Immune checkpoint inhibitors, including atezolizumab (anti-programmed death-ligand 1), have demonstrated clinical activity in various cancers. Here, we present the safety and efficacy of atezolizumab in patients with glioblastoma from the phase 1a PCD4989g clinical trial (NCT01375842). Eligible patients had confirmed recurrent glioblastoma and measurable disease per RANO criteria. Atezolizumab (1200 mg) was administered intravenously every 3 weeks until progression or unacceptable toxicity. Patients were monitored for safety; response was evaluated at least every 6 weeks. Baseline biomarkers were evaluated. All 16 patients enrolled had received prior chemotherapy, and 50% prior bevacizumab. Ten patients (63%) experienced a treatment-related event. No treatment-related grade 4–5 events were reported. All deaths occurred due to progression or during follow-up. One patient experienced a partial response (5.3 months); 3 experienced disease stabilization. The median overall survival was 4.2 months (range 1.2 to 18.8+ months). Association between peripheral CD4+ T cells and efficacy was observed. Two patients with IDH1-mutant tumors and 1 with a POLE-mutant tumor experienced ≥ 16 months survival. Atezolizumab was safe and well tolerated in this group of patients with recurrent glioblastoma. Our preliminary findings suggest that biomarkers, including peripheral CD4+ T cells and hypermutated tumor status, may help guide selection of patients with recurrent glioblastoma who might receive most benefit from atezolizumab therapy, supporting further atezolizumab combination studies in glioblastoma.

Background: Metastatic triple negative breast cancer (mTNBC) has a poor prognosis with limited treatment options. Atezolizumab (atezo) is a humanized monoclonal antibody that inhibits the binding of PD-L1 to PD-1 and B7.1. Atezo has demonstrated promising activity in the mTNBC cohort of the phase 1 PCD4989g study. Clinical activity was previously linked to higher PD-L1 expression by IHC (ORR: 13% vs 5%) and TILs (ORR: 13% vs 7%) (Schmid et al., AACR 2017, NCT01375842). Here we characterize molecular features of tumors from atezo-treated patients and explore their potential association with clinical activity. Methods & Results: Molecular characterization of pre-treatment tumor tissue was performed to investigate potential biological mechanisms associated with the clinical activity of atezo in mTNBC. DNA mutational analysis of tumors from 78 patients was performed with the Foundation Medicine One panel. Median tumor mutation burden (TMB) was 4.6 Mut/Mb (CI 95% 3.604 - 5.405). TMB was not associated with either TILs or immune biomarkers by IHC (PD-L1 or CD8) or with clinical activity (ORR, PFS or OS). The prevalence of loss of heterozygosity or mutations in TP53 or BRCA1/2 in this mTNBC cohort was 65%, 95%, and 10%, respectively. None of these genomic alterations were associated with clinical activity to atezo. RNA-Seq based analyses were performed in tissue from 96 patients. PAM50 profiling classified these tumors as 84% basal-like, 9% HER-2-enriched, 4% luminal A and 2% luminal B. TNBC subtyping (Burstein et al., CCR 2015) classified 42% of the tumors as basal-like (BL) immune activated (BLIA), 35% BL immune suppressed (BLIS), 17% luminal androgen receptor (LAR) and 2% mesenchymal (MES). Histopathology immune biomarkers TILs, PD-L1 and CD8 were highest in BLIA, intermediate in LAR and lowest in BLIS. ORRs by RECIST 1.1 were highest in BLIA and LAR, and lowest in BLIS and MES (17.5%, 18.8%, 0% and 0%, respectively). Although univariate analysis showed that the BLIA subgroup had significantly longer PFS and OS, multivariate analysis showed an association for both the BLIA and LAR subgroups with improved PFS and OS. High expression of pre-specified B- and T-cell RNA signatures were significantly associated with better ORR, PFS, and OS. Conclusion: Comprehensive molecular characterization of tumors from this non-randomized phase 1 mTNBC cohort showed a low TMB. Mutations in BRCA1/2, TP53, or loss of heterozygosity did not impact atezo clinical activity. Clinical benefit from atezo was enriched in BLIA and LAR TNBC subtypes, both representing tumors with a rich tumor immune microenvironment. Citation Format: Molinero L, Chang C-W, Udyavar A, Fasso M, O'Hear C, Emens L, Cruz C, Hegde P, Schmid P. Molecular characterization of tumors from metastatic TNBC patients treated with atezolizumab (atezo) [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-09-13.

Background Metastatic TNBC (mTNBC) has a poor prognosis and few treatment options. The anti-PD-L1 antibody atezolizumab demonstrated clinical activity in mTNBC patients with PD-L1-positive tumor-infiltrating immune cells. The current study describes the tumor immune microenvironment (TiME) and genomic evolution across sequential therapies in a patient with a 31-year history of TNBC and a complete response (CR) to atezolizumab monotherapy. Materials and methods In 1986, the patient had surgery and radiotherapy (XRT) for newly diagnosed TNBC, followed by surgery and adjuvant chemotherapy for two locoregional recurrences. She developed mTNBC in 2009 and was sequentially treated with capecitabine, gemcitabine-carboplatin-iniparib (GCI), XRT and an experimental vaccine. She experienced disease progression (PD) to all these therapies. In 2013, she had a PD-L1 positive tumor and enrolled in a phase 1 atezolizumab monotherapy study (PCD4989g; NCT01375842). She received atezolizumab for 1 year with initial pseudo-progression followed by a partial response. After 1 year without treatment she experienced PD, reinitiated atezolizumab and subsequently achieved CR. Tumor specimens were collected at numerous times between 2008 and 2015 and assessed by immunohistochemistry, RNA-seq and DNA-seq. Results TiME biomarkers, including CD8, ICs and PD-L1 on IC, increased after capecitabine and remained high after GCI, XRT and through pseudo-progression on atezolizumab. At PD post-atezolizumab exposure, TiME biomarkers decreased but PD-L1 status remained positive. Immune-related RNA signatures confirmed these findings. TNBC subtyping revealed evolution from luminal androgen receptor (LAR) to basal-like immune activated (BLIA). Genomic profiling showed truncal alterations in RB1 and TP53, while the presence of other genomic alterations varied over time. Tumor mutational burden peaked after XRT and declined after atezolizumab exposure. Conclusions This case report describes the evolution of TiME and TNBC molecular subtypes/genomics over time with sequential therapies in a TNBC patient with a CR to atezolizumab monotherapy. These data suggest the TiME is pliable and may be manipulated to maximize response to immunotherapy (NCT01375842, https://clinicaltrials.gov/ct2/show/NCT01375842?term=NCT01375842&rank=1).

Live-attenuated Listeria monocytogenes has shown encouraging potential as an immunotherapy platform in preclinical and clinical settings. However, additional safety measures will enable application across malignant and infectious diseases. Here, we describe a new vaccine platform, termed Lm-RIID (L. monocytogenes recombinase-induced intracellular death), that induces the deletion of genes required for bacterial viability yet maintains potent T cell responses to encoded antigens., Live-attenuated Listeria monocytogenes has shown encouraging potential as an immunotherapy platform in preclinical and clinical settings. However, additional safety measures will enable application across malignant and infectious diseases. Here, we describe a new vaccine platform, termed Lm-RIID (L. monocytogenes recombinase-induced intracellular death), that induces the deletion of genes required for bacterial viability yet maintains potent T cell responses to encoded antigens. Lm-RIID grows normally in broth but commits suicide inside host cells by inducing Cre recombinase and deleting essential genes flanked by loxP sites, resulting in a self-limiting infection even in immunocompromised mice. Lm-RIID vaccination of mice induces potent CD8+ T cells and protects against virulent challenges, similar to live L. monocytogenes vaccines. When combined with α-PD-1, Lm-RIID is as effective as live-attenuated L. monocytogenes in a therapeutic tumor model. This impressive efficacy, together with the increased clearance rate, makes Lm-RIID ideal for prophylactic immunization against diseases that require T cells for protection.

Objective Patients with advanced/recurrent epithelial ovarian and uterine cancers have limited treatment options beyond platinum chemotherapy. Both tumor types can express programmed death-ligand 1 (PD-L1), providing a potential therapeutic target for these patients. Here we present data from the ovarian and uterine cancer cohorts of the Phase I atezolizumab monotherapy study (PCD4989g). Methods This Phase I, multi-center, first-in-human, open-label, dose-escalation/expansion clinical trial investigated single-agent atezolizumab in cohorts of patients with recurrent epithelial ovarian or uterine cancer. The primary objective was to evaluate the safety and tolerability of single-agent atezolizumab. Anti-tumor activity and preliminary assessment of potential biomarkers were evaluated as secondary and exploratory objectives, respectively. Results The ovarian and uterine cancer cohorts enrolled 12 and 15 patients, respectively (10 [83%] and 5 [33%], respectively, had PD-L1 ≥ 5% on tumor-infiltrating immune cells). Atezolizumab was generally well tolerated with no new safety signals identified. The safety profiles in both cohorts were consistent with the known profile of atezolizumab monotherapy. Treatment-related adverse events (AEs) were mostly Grade ≤ 2, with no treatment-related Grade ≥ 4 AEs reported. Preliminary anti-tumor activity, with long durations of response, was observed in 2 patients from each cohort (ovarian cancer, 8.1 and 30.6+ months; uterine cancer, 7.3 and 16.6+ months). High microsatellite instability and tumor mutational burden were noted in the responders from the uterine cancer cohort. Conclusions Atezolizumab monotherapy was well tolerated in patients with epithelial ovarian or uterine cancer and may have clinical activity warranting further investigation. Trial registration ClinicalTrials.gov identifier: NCT01375842

Purpose: Atezolizumab [anti–programmed death-ligand 1 (PD-L1)] selectively targets PD-L1 to block its interaction with receptors programmed death 1 and B7.1, thereby reinvigorating antitumor T-cell activity. We evaluated the long-term safety and activity of atezolizumab, along with biological correlates of clinical activity endpoints, in a cohort of patients with melanoma in an ongoing phase Ia study (NCT01375842). Patients and Methods: Patients with unresectable or metastatic melanoma were enrolled to receive atezolizumab 0.1 to 20 mg/kg or ≥10 mg/kg every 3 weeks. Primary study objectives were safety and tolerability. Secondary objectives included investigator-assessed efficacy measures; pharmacodynamic and predictive biomarkers of antitumor activity were explored. Results: Forty-five patients were enrolled and were evaluable for safety. Most treatment-related adverse events (AE) were grade 1/2 (60%). Fatigue (44%), pruritus (20%), pyrexia (18%), and rash (18%) were the most common treatment-related AEs of any grade. No treatment-related deaths occurred. Overall response rate was 30% among 43 efficacy- evaluable patients, with a median duration of response of 62 months [95% CI, 35–not estimable (NE)]. Clinically meaningful long-term survival was observed, with a median overall survival of 23 months (95% CI, 9–66). Baseline biomarkers of tumor immunity [PD-L1 expression on immune cells, T effector (Teff), and antigen presentation gene signatures) and tumor mutational burden (TMB) were associated with improved response, progression-free survival, and overall survival. Conclusions: Atezolizumab was well tolerated, with durable responses and survival in patients with melanoma. PD-L1 expression, TMB, and Teff signatures may indicate improved benefit with atezolizumab in these patients.

Background Programmed death-ligand 1 (PD-L1) protein is expressed in various cancers, including small-cell lung cancer (SCLC). Atezolizumab inhibits PD-L1 signaling, thus restoring tumor-specific T-cell immunity. Here, we report results from the first-in-human phase 1 PCD4989g study ( NCT01375842 ) of atezolizumab, in a cohort of patients with relapsed/refractory SCLC. Patients and Methods Eligible patients with incurable or metastatic SCLC, which was advanced or recurrent since the last antitumor therapy, received atezolizumab 15 mg/kg or 1200 mg intravenously every 3 weeks for 16 cycles or until loss of clinical benefit. The primary endpoint was safety. Efficacy and biomarkers of antitumor activity were also assessed. Results Seventeen patients were enrolled. Any-grade and grade ≥3 treatment-related adverse events (TRAEs) occurred in 11 (64.7%) and 5 (29.4%) patients, respectively. The most common any-grade TRAE was fatigue (4 patients [23.5%]). Partial response to atezolizumab was achieved in 1 patient (5.9%) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and 3 (17.6%) per immune-related response criteria (irRC). Durations of response were 2.8 to > 45.7 months. Median investigator-assessed progression-free survival (PFS) per RECIST v1.1 and irRC was 1.5 (95% confidence interval [CI], 1.2-2.7) and 2.9 (95% CI, 1.2-6.1) months, respectively. Median overall survival (OS) was 5.9 months (95% CI, 4.3-12.6). Patients with high (≥ median expression) T-effector gene signature and PD-L1 mRNA expression appeared to show a trend toward improved PFS (per irRC) and OS. Conclusion Atezolizumab was generally well tolerated and exhibited antitumor activity in a small cohort of patients with relapsed/refractory SCLC.

Importance Atezolizumab (anti–programmed cell death ligand 1 [PD-L1]) is well tolerated and clinically active in multiple cancer types. Its safety and clinical activity in metastatic triple-negative breast cancer (mTNBC) has not been reported. Objective To evaluate the safety, clinical activity, and biomarkers associated with the use of single-agent atezolizumab in patients with mTNBC. Design, Setting, and Participants Women with mTNBC (defined by investigator assessment) were enrolled between January 2013 and February 2016 in a multicohort open-label, phase 1 study at US and European academic medical centers. Median follow-up was 25.3 months (range, 0.4-45.6 months). Eligible patients regardless of line of therapy had measurable disease by Response Evaluation Criteria in Solid Tumors, version 1.1; Eastern Cooperative Oncology Group performance status of 0 to 1; and a representative tumor sample for assessment of immune cell (IC) PD-L1 expression. Interventions Atezolizumab was given intravenously every 3 weeks until unacceptable toxic effects or loss of clinical benefit. Main Outcomes and Measures Primary outcome was safety and tolerability. Activity and exploratory outcomes included objective response rate (ORR), duration of response, progression-free survival (PFS), and overall survival (OS). Outcomes were assessed in all patients and in key patient subgroups. Results Among 116 evaluable patients (median age, 53 years [range, 29-82 years]), treatment-related adverse events occurred in 73 (63%); 58 (79%) were grade 1 to 2. Most adverse events occurred within the first treatment year. The ORRs were numerically higher in first-line (5 of 21 [24%]) than in second-line or greater patients (6 of 94 [6%]). Median duration of response was 21 months (range, 3 to ≥38 months). Median PFS was 1.4 (95% CI, 1.3-1.6) months by RECIST and 1.9 (95% CI, 1.4-2.5) months by irRC. In first-line patients, median OS was 17.6 months (95% CI, 10.2 months to not estimable). Patients with PD-L1 expression of at least 1% tumor-infiltrating ICs had higher ORRs and longer OS (12% [11 of 91]; 10.1 [95% CI, 7.0-13.8] months, respectively) than those with less than 1% ICs (0 of 21; 6.0 [95% CI, 2.6-12.6] months, respectively). High levels of ICs (>10%) were independently associated with higher ORRs and longer OS. Conclusions and Relevance Single-agent atezolizumab was well tolerated and provided durable clinical benefit in patients with mTNBC with stable or responding disease and in earlier lines of treatment. Trial Registration ClinicalTrials.gov identifier:NCT01375842

We consider the the n-dimensional generalisation of the nonholonomic Veselova problem. We derive the reduced equations of motion in terms of the mass tensor of the body and determine some general properties of the dynamics. In particular we give a closed formula for the invariant measure, we indicate the existence of steady rotation solutions, and obtain some results on their stability. We then focus our attention on bodies whose mass tensor has a specific type of symmetry. We show that the phase space is foliated by invariant tori that carry quasi-periodic dynamics in the natural time variable. Our results enlarge the known cases of integrability of the multi-dimensional Veselova top. Moreover, they show that in some previously known instances of integrability, the flow is quasi-periodic without the need of a time reparametrisation., 37 pp

Importance Atezolizumab (anti–programmed death ligand 1) has demonstrated safety and activity in advanced and metastatic urothelial carcinoma, but its long-term clinical profile remains unknown. Objective To report long-term clinical outcomes with atezolizumab therapy for patients with metastatic urothelial carcinoma. Design, Setting, and Participants Patients were enrolled in an expansion cohort of an ongoing, open-label, phase 1 study. Median follow-up was 37.8 months (range, >0.7 to 44.4 months). Enrollment occurred between March 2013 and August 2015 at US and European academic medical centers. Eligible patients had measurable disease per Response Evaluation Criteria in Solid Tumors version 1.1, Eastern Cooperative Oncology Group performance status 0 to 1, and a representative tumor sample. Programmed death ligand 1 expression on immune cells was assessed (VENTANA SP142 assay). Interventions Atezolizumab was given intravenously every 3 weeks until unacceptable toxic effects, protocol nonadherence, or loss of clinical benefit. Main Outcomes and Measures Primary outcome was safety. Secondary outcomes included objective response rate, duration of response, and progression-free survival. Response and overall survival were assessed in key baseline subgroups. Results Ninety-five patients were evaluable (72 [76%] male; median age, 66 years [range, 36-89 years]). Forty-five (47%) received atezolizumab as third-line therapy or greater. Nine patients (9%) had a grade 3 to 4 treatment-related adverse event, mostly within the first treatment year; no serious related adverse events were observed thereafter. One patient (1%) discontinued treatment due to a related event. No treatment-related deaths occurred. Responses occurred in 26% (95% CI, 18%-36%) of patients. Median duration of response was 22.1 months (range, 2.8 to >41.0 months), and median progression-free survival was 2.7 months (95% CI, 1.4-4.3 months). Median overall survival was 10.1 months (95% CI, 7.3-17.0 months); 3-year OS rate was 27% (95% CI, 17%-36%). Response occurred in 40% (95% CI, 26%-55%; n = 40) and 11% (95% CI, 4%-25%; n = 44) of patients with programmed death ligand 1 expression of at least 5% tumor-infiltrating immune cells (IC2/3) or less than 5% (IC0/1), respectively. Median overall survival in patients with IC2/3 and IC0/1 was 14.6 months (95% CI, 9.0 months to not estimable) and 7.6 months (95% CI, 4.7 to 13.9 months), respectively. Conclusions and Relevance Atezolizumab remained well tolerated and provided durable clinical benefit to a heavily pretreated metastatic urothelial carcinoma population in this long-term study. Trial Registration clinicaltrials.gov Identifier:NCT01375842

Satellite product validation is a key to ensure the delivery of quality products for climate and weather applications. To do this, a fundamental step is the comparison with other instruments, such as radiosonde. This is especially true for essential climate variables such as temperature and humidity. Thanks to a functional data representation, this paper uses a likelihood-based approach that exploits the measurement uncertainties in a natural way. In particular, the comparison of temperature and humidity radiosonde measurements collected within the network of the Universal Rawinsonde Observation Program (RAOB) and the corresponding atmospheric profiles derived from the infrared atmospheric sounding interferometer aboard MetOp-A and MetOp-B satellites is developed with the aim of understanding the vertical smoothing mismatch uncertainty. Moreover, conventional RAOB functional data representation is assessed by means of a comparison with radiosonde reference measurements given by the Global Climate Observing System (GCOS) Reference Upper-Air Network (GRUAN), which provides high-resolution fully traceable radio-sounding profiles. In this way, the uncertainty related to coarse vertical resolution, or sparseness, of the conventional RAOB is assessed. It has been found that the uncertainty of vertical smoothing mismatch averaged along the profile is 0.50 K for temperature and 0.16 g/kg for water-vapor mixing ratio. Moreover, the uncertainty related to RAOB sparseness, averaged along the profile, is 0.29 K for temperature and 0.13 g/kg for water-vapor mixing ratio.

In nonholonomic mechanical systems with constraints that are affine (linear nonhomogeneous) functions of the velocities, the energy is typically not a first integral. It was shown in [Fass\`o and Sansonetto, JNLS, 26, (2016)] that, nevertheless, there exist modifications of the energy, called there moving energies, which under suitable conditions are first integrals. The first goal of this paper is to study the properties of these functions and the conditions that lead to their conservation. In particular, we enlarge the class of moving energies considered in [Fass\`o and Sansonetto, JNLS, 26, (2016)]. The second goal of the paper is to demonstrate the relevance of moving energies in nonholonomic mechanics. We show that certain first integrals of some well known systems (the affine Veselova and LR systems), which had been detected on a case-by-case way, are instances of moving energies. Moreover, we determine conserved moving energies for a class of affine systems on Lie groups that include the LR systems, for a heavy convex rigid body that rolls without slipping on a uniformly rotating plane, and for an $n$-dimensional generalization of the Chaplygin sphere problem to a uniformly rotating hyperplane., Comment: 25 pages, 1 figure. Final version prepared according to the modifications suggested by the referees of Nonlinearity

L’Europa ha una speranza? A questa domanda, che ci poniamo da anni, improvvisamente è apparso un primo accenno di risposta. Fra la fine di agosto e l’inizio di settembre 2015 migliaia di migranti hanno attraversato Macedonia e Serbia per arrivare alle soglie di quell’Europa centrale che fino a quel momento, al riparo della Convenzione di Dublino del 2013, lasciava che Grecia, Italia e Spagna se la cavassero da sole, obbligate com’erano a trattenere entro i propri confini i disperati che riuscivano a raggiungere le coste del Mediterraneo. Quando finalmente Berlino e Vienna li hanno visti da vicino, allora è riemersa dall’oblio e ha popolato discorsi e interviste quella fraternità che era diventata «la sorella povera di libertà e uguaglianza» (Carlo Petrini). Dai governi (non tutti) alle popolazioni (non tutte) si è levato un moto di solidarietà ; e in pochi giorni l’accoglienza dei rifugiati si è trasformata in obbligo morale e in impegno politico; a Monaco un gruppo di tedeschi ha accolto il treno dei profughi cantando l’Inno alla gioia.

Background: Immune checkpoint blockade by anti-PD-L1 antibody atezolizumab has demonstrated clinical benefits in metastatic triple negative breast cancer (mTNBC). IL-6 and IL-8 myeloid inflammation is linked to poor prognosis in cancer patients treated with chemotherapy, but its association with single agent atezolizumab-treated patients with mTNBC remains unknown. In this study, we investigated the association of biomarkers (BM) of systemic inflammation with clinical outcomes in patients with mTNBC treated with atezolizumab monotherapy. Methods: Baseline pre-treatment plasma samples were collected from mTNBC patients enrolled in the Phase I atezolizumab monotherapy clinical trial PCD4989g (NCT01375842, n = 116). IL-6, IL-8 and CRP were tested by ELISA or Luminex assays and their levels were assessed for association with baseline clinical demographic characteristics and atezolizumab clinical activity for response rate (ORR), progression free (PFS) and overall survival (OS). Results: Baseline IL-6, IL-8, and CRP levels were positively associated with the clinical prognostic traits ECOG performance status (>0), presence of liver metastases, large size of target lesions (>=6.5cm), and increased LDH (>=1.5xULN). Elevated baseline IL-6 and CRP, but not IL-8, were also linked with later lines of therapy (>=2). Univariate analyses showed that IL-6 (>=15pg/ml), IL-8 (>=11.4pg/ml) and CRP (>=3mg/L) were associated with reduced OS and PFS (Table), but only CRP was associated to reduced ORR. Multivariate analyses considering the aforementioned clinical demographic variables showed that IL-6 (HR 2.00 [1.16-3.38]); and CRP (HR 2.74 [1.49-5.28]), but not IL-8 (HR 1.07 [0.78-1.74]), were associated with OS. Conclusion: The systemic IL-6/CRP inflammatory axis is an independent factor linked with poor outcomes of mTNBC patients treated with atezolizumab monotherapy and may play unique roles in affecting the anti-tumor activity in this hard to treat patient population. Table (univariate)BMLow mPFSBMHigh mPFSPFS HR (CI 95%)BMLow mOSBMHigh mOSOS HR (CI 95%)IL-6 (>=15pg/ml)1.45 mo1.35 mo1.87 (1.23-2.83)12.6 mo2.6 mo2.55 (1.63-4.01)IL-8 (>=11.4pg/ml)1.94mo1.34 mo2.00 (1.36-2.95)12.6 mo6.42 mo2.05 (1.34-3.14)CRP (>=3mg/L)2.50 mo1.35 mo2.07 (1.31-3.25)20.5 mo6.9 mo3.33 (1.91-5.79) Citation Format: Yijin Li, Marcella Fassò, Leisha A. Emens, Luciana Molinero. Biomarkers of systemic inflammation associated to reduced clinical activity of atezolizumab monotherapy in patients with metastatic triple negative breast cancer [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 CT001.

Importance Checkpoint inhibition in cancer immunotherapy related to T-cell–driven mechanisms of action associated with acute macular neuroretinopathy (AMN) and diffuse retinal venulitis, an adverse event not previously described, is reported here. Objective To describe 2 patients who developed ophthalmologic events after treatment with the programmed death 1 axis inhibitor, atezolizumab. Design, Setting, and Participants Retrospective review of 2 patients treated with atezolizumab for metastatic breast cancer and colon cancer, respectively, who presented with AMN and diffuse retinal venulitis conducted at 2 tertiary medical centers. Main Outcomes and Measures Multimodal imaging including near infrared, optical coherence tomography, and fluorescein angiography were used to characterize retinal vascular abnormalities. Results Based on optical coherence tomography and multimodal imaging findings, the clinical diagnosis of AMN associated with diffuse retinal venulitis was made in these 2 patients receiving atezolizumab. Conclusions and Relevance While only 2 cases of patients receiving the programmed death ligand 1 inhibitor atezolizumab who experienced AMN and diffuse retinal venulitis are described here, these findings suggest that patients receiving programmed death 1 axis inhibitor therapies may need to be monitored for unexpected immune-related ocular toxicity including abnormalities of the microvasculature and large retinal vessels. Further studies might investigate the potential mechanisms of retinal vascular changes associated with these therapies.

In environmental monitoring the quality assessment is essentially one-sided. For example quality of air decreases as one or more air pollutants increase. Statistical multivariate monitoring is then concerned with the problem of detecting some non-random one-sided shifts of one or more among various pollutant levels. In this paper, after discussing some change models useful in environmental monitoring, a generalized likelihood ratio test statistic is proposed both for retrospective testing and for on-line change detection. The test is then compared to the approach based on union-intersection of one-sided univariate tests.

Purpose The objective was to determine the safety and clinical activity of atezolizumab (MPDL3280A), a humanized programmed death-ligand 1 (PD-L1) antibody, in renal cell carcinoma (RCC). Exploratory biomarkers were analyzed and associated with outcomes. Patients and Methods Seventy patients with metastatic RCC, including clear cell (ccRCC; n = 63) and non–clear cell (ncc; n = 7) histologies, received atezolizumab intravenously every 3 weeks. PD-L1 expression was scored at four diagnostic levels (0/1/2/3) that were based on PD-L1 staining on tumor cells and tumor-infiltrating immune cells (IC) with the SP142 assay. Primary end points were safety and toxicity; secondary end points assessed clinical activity per Response Evaluation Criteria in Solid Tumors version 1.1 and immune-related response criteria. Plasma and tissue were analyzed for potential biomarkers of atezolizumab response. Results Grade 3 treatment-related and immune-mediated adverse events occurred in 17% and 4% of patients, respectively, and there were no grade 4 or 5 events. Sixty-three patients with ccRCC were evaluable for overall survival (median, 28.9 months; 95% CI, 20.0 months to not reached) and progression-free survival (median, 5.6 months; 95% CI, 3.9 to 8.2 months), and 62 patients were evaluable for objective response rate (ORR; 15%; 95% CI, 7% to 26%). ORR was evaluated on the basis of PD-L1 IC expression (IC1/2/3: n = 33; 18%; 95% CI, 7% to 35%; and IC0: n = 22; 9%; 95% CI, 1% to 29%). The ORR for patients with Fuhrman grade 4 and/or sarcomatoid histology was 22% (n = 18; 95% CI, 6% to 48%). Decreases in circulating plasma markers and acute-phase proteins and an increased baseline effector T-cell–to–regulatory T-cell gene expression ratio correlated with response to atezolizumab. Conclusion Atezolizumab demonstrated a manageable safety profile and promising antitumor activity in patients with metastatic RCC. Correlative studies identified potential predictive and pharmacodynamic biomarkers. These results have guided ongoing studies and combinations with atezolizumab in RCC.

We uncover quantum manifestations of classical Nekhoroshev theory of resonant dynamics using a simple quantum system of two coupled angular momenta with conserved equal magnitudes which corresponds to a perturbed classical integrable anisochronous Hamiltonian system.

The three-dimensional champagne bottle system contains no mondromy, despite being entirely composed of invariant two-dimensional champagne bottle systems, each of which posesses nontrivial monodromy. We explain where the monodromy went in the three-dimensional system, or perhaps, where it did come from in the two-dimensional system, by regarding the three-dimensional system not as completely integrable, but as superintegrable (or non-commutatively integrable), and explaining the role of the singularities of its isotropic-coisotropic pair of foliations.

In 1974, Nelson, Kase, and Svensson published an experimental investigation on muon shielding around SLAC high energy electron accelerators (NIM 120 (1974) 413). They measured muon fluence and absorbed dose induced by 14 and 18 GeV electron beams hitting a copper/water beamdump and attenuated in a thick steel shielding. In their paper, they compared the results with the theoretical models available at that time. In order to compare their experimental results with present model calculations, we use the modern transport Monte Carlo codes MARS15, FLUKA2011 and GEANT4 to model the experimental setup and run simulations. The results are then compared between the codes, and with the SLAC data. Updated results from this campaign are reported in the presentation.

Background: The PD-L1/PD-1 inhibitors activate the immune system both in the tumor microenvironment and peripheral blood. Here we investigated the relationship between peripheral immune system and clinical outcome of metastatic cancer patients treated with atezolizumab (anti-PDL1) across five tumor types. Methods: 426 patients with melanoma (n=45), non-small cell lung cancer (NSCLC, n=89), kidney cancer (RCC, n=72), triple-negative breast cancer (TNBC, n=116) and bladder cancer (UBC, n=104) were treated with atezolizumab in the phase I clinical trial PCD4989g (NCT01375842). Normal/abnormal blood neutrophils, monocytes, eosinophils, basophils and lymphocytes were measured by local laboratories, while T (CD3, CD4 and CD8), B (CD19), and NK (CD56) lymphocyte subsets were centrally analyzed by flow cytometry. Neutrophil:lymphocyte ratio (NLR) and relative lymphocyte counts (RLC) were also evaluated. Association of the immune cell subsets and clinical outcome (ORR, PFS and OS) was assessed in multivariate analyses considering liver metastases, LDH, line of therapy and ECOG performance status. Results: The prevalence of hematologic abnormalities across tumors was: lymphopenia (27-57%), followed by neutrophilia (2-24%), monocytosis (0-15%), eosinophilia (1-13%), eosinopenia (0-14%), basophilia (2-7%) and basopenia (0-6%). Neutrophilia, monocytosis, lymphopenia and low/high eosinophils were associated with worse PFS and OS, although with a different imprint depending on tumor ontogeny: neutrophilia was linked to reduced OS in melanoma and PFS for UBC, monocytosis was associated with lower OS in TNBC and UBC. Lymphopenia was associated with reduced PFS and OS in NSCLC, TNBC and reduced PFS in melanoma. NLR>=5 was associated with reduced PFS in melanoma, NSCLC, RCC, UBC and reduced OS in UBC, NSCLC and TNBC. RLC>=17.5% was linked to longer PFS in melanoma, RCC, UBC and to increased OS in TNBC, NSCLC and UBC. Lymphocyte subset analysis showed lymphopenia in B cells (40-61%), CD3 T cells (32-71%), CD4 T cells (28-66%), CD8 T cells (25-46%) and NK cells (16-23%). CD3 lymphopenia was associated to reduced OS in NSCLC, and CD4 lymphopenia was associated to reduced OS in NSCLC and TNBC. NK lymphopenia was associated to decreased OS and PFS in TNBC. Conclusion: This is the first study showing that higher pretreatment relative lymphocyte counts is associated to improved clinical outcome in patients from different tumor etiologies treated with atezolizumab. The association of peripheral T cell counts to improved outcome in some indications suggests that the local antitumor response may be linked to pre-existing systemic T cells. Citation Format: Yijin Li, Ching-Wei Chang, Marcella Fasso, Carol O'Hear, Priti S. Hegde, Luciana Molinero. Baseline blood lymphocytes are associated with improved clinical outcome in atezolizumab-treated patients across multiple indications [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2616.

TPS9105Background: CIT has demonstrated a significant survival benefit in multiple cancers. Despite this, only subsets of pts experience durable response with CIT monotherapy. Thus, CIT combination...