Effect of Luting Materials on the Accuracy of Fit of Zirconia Copings: A Non-Destructive Digital Analysis Method.

The marginal accuracy of fit between prosthetic restorations and abutment teeth represents an essential aspect with regard to long-term clinical success. Since the final gap is also influenced by the luting techniques and materials applied, this study analyzed the accuracy of the fit of single-tooth zirconia copings before and after cementation using different luting materials. Forty plaster dies with a corresponding zirconia coping were manufactured based on a single tooth chamfer preparation. The copings were luted on the plaster dies (n = 10 per luting material) with a zinc phosphate (A), glass-ionomer (B), self-adhesive resin (C), or resin-modified glass-ionomer cement (D). The accuracy of fit for each coping was assessed using a non-destructive digital method. Intragroup statistical analysis was conducted using Wilcoxon signed rank tests and intergroup analysis by Kruskal-Wallis and Mann-Whitney U tests (α = 0.05). Accuracy of fit was significantly different before/after cementation within A (0.033/0.110 µm) and B (0.035/0.118 µm; p = 0.002). A had a significantly increased marginal gap compared to C and D, and B compared to C and D (p ≤ 0.001). Significantly increased vertical discrepancies between A and B versus C and D (p < 0.001) were assessed. Of the materials under investigation, the zinc phosphate cement led to increased vertical marginal discrepancies, whereas the self-adhesive resin cement did not influence the restoration fit.

The Circumstance-Driven Bivariate Integer-Valued Autoregressive Model.

The novel circumstance-driven bivariate integer-valued autoregressive (CuBINAR) model for non-stationary count time series is proposed. The non-stationarity of the bivariate count process is defined by a joint categorical sequence, which expresses the current state of the process. Additional cross-dependence can be generated via cross-dependent innovations. The model can also be equipped with a marginal bivariate Poisson distribution to make it suitable for low-count time series. Important stochastic properties of the new model are derived. The Yule-Walker and conditional maximum likelihood method are adopted to estimate the unknown parameters. The consistency of these estimators is established, and their finite-sample performance is investigated by a simulation study. The scope and application of the model are illustrated by a real-world data example on sales counts, where a soap product in different stores with a common circumstance factor is investigated.

Is spontaneous echo contrast associated with device-related thrombus or embolic events after left atrial appendage occlusion? - Insights from the multicenter German LAARGE registry.

BACKGROUND: Interventional left atrial appendage occlusion (LAAO) provides an alternative to oral anticoagulation (OAC) for prophylaxis of thromboembolic events (TEs) in nonvalvular atrial fibrillation patients, predominantly in those with high bleeding risk and contraindications for long-term OAC. Although spontaneous echo contrast (SEC) is a well-known risk factor for atrial thrombus formation, little is known about whether this means an increased risk of device-related thrombus (DRT) or TEs following LAAO. METHODS: This substudy of the prospective, multicenter German LAARGE registry assessed two groups according to absence (SEC -) or presence of SEC (SEC +) in preprocedural cardiac imaging. Clinical and echocardiographic parameters were registered up to 1 year after LAAO. RESULTS: Five hundred eighty-eight patients (SEC - 85.5 vs. SEC + 14.5%) were included. More SEC + patients were implanted for OAC non-compliance (11.8 vs. 4.6%, p = 0.008) and a higher proportion received only antiplatelet therapy without OAC at hospital discharge (96.5 vs. 86.0%, p = 0.007). The SEC + patients had larger LA diameters (50 (47; 54) vs. 47 (43; 51) mm, p < 0.001), wider LAA ostia (21 (19; 23) vs. 20 (17; 22) mm at 45°, p = 0.011), and lower left ventricular ejection fraction (50 (45; 60) vs. 60 (50; 60) %, p < 0.001) on admission. Procedural success was very high in both groups (98.1%, p = 1.00). Periprocedural major adverse cardiac and cerebrovascular events and other major complications were rare in both groups (3.8 vs. 4.7%, p = 0.76). At follow-up, DRT was only detected in the SEC - group (3.8 vs. 0%, p = 1.00). The rates of TEs (SEC - 1.2 vs. SEC + 0%, p = 1.00) after hospital discharge and 1-year mortality (SEC - 12.0 vs. SEC + 11.8%, p = 0.96) were not significantly different between the two groups. CONCLUSIONS: Presence of SEC at baseline was not associated with an increased rate of DRT or TEs at 1-year follow-up after LAAO in LAARGE.

Discrete-Valued Time Series.

Time series are sequentially observed data in which important information about the phenomenon under consideration is contained not only in the individual observations themselves, but also in the way these observations follow one another [...].

Partial Autocorrelation Diagnostics for Count Time Series.

In a time series context, the study of the partial autocorrelation function (PACF) is helpful for model identification. Especially in the case of autoregressive (AR) models, it is widely used for order selection. During the last decades, the use of AR-type count processes, i.e., which also fulfil the Yule-Walker equations and thus provide the same PACF characterization as AR models, increased a lot. This motivates the use of the PACF test also for such count processes. By computing the sample PACF based on the raw data or the Pearson residuals, respectively, findings are usually evaluated based on well-known asymptotic results. However, the conditions for these asymptotics are generally not fulfilled for AR-type count processes, which deteriorates the performance of the PACF test in such cases. Thus, we present different implementations of the PACF test for AR-type count processes, which rely on several bootstrap schemes for count times series. We compare them in simulations with the asymptotic results, and we illustrate them with an application to a real-world data example.

Optimal Stein-type goodness-of-fit tests for count data.

Common count distributions, such as the Poisson (binomial) distribution for unbounded (bounded) counts considered here, can be characterized by appropriate Stein identities. These identities, in turn, might be utilized to define a corresponding goodness-of-fit (GoF) test, the test statistic of which involves the computation of weighted means for a user-selected weight function f. Here, the choice of f should be done with respect to the relevant alternative scenario, as it will have great impact on the GoF-test's performance. We derive the asymptotics of both the Poisson and binomial Stein-type GoF-statistic for general count distributions (we also briefly consider the negative-binomial case), such that the asymptotic power is easily computed for arbitrary alternatives. This allows for an efficient implementation of optimal Stein tests, that is, which are most powerful within a given class  F $\mathcal {F}$ of weight functions. The performance and application of the optimal Stein-type GoF-tests is investigated by simulations and several medical data examples.

Non-parametric tests for serial dependence in time series based on asymptotic implementations of ordinal-pattern statistics.

Ordinal patterns can be used to construct non-parametric hypothesis tests that aim to discover (possibly non-linear) serial dependence in a real-valued time series. We derive the asymptotic distribution of the vector of sample frequencies of ordinal patterns and that of various corresponding tests statistics such that the targeted tests for serial dependence are easily implemented based on asymptotic approximations. Simulations are used to check the finite-sample performance of these tests as well as their power properties with respect to various alternative scenarios. The application and interpretation of the tests in practice are illustrated by an environmental data example.

Efficient accounting for estimation uncertainty in coherent forecasting of count processes.

Coherent forecasting techniques for count processes generate forecasts that consist of count values themselves. In practice, forecasting always relies on a fitted model and so the obtained forecast values are affected by estimation uncertainty. Thus, they may differ from the true forecast values as they would have been obtained from the true data generating process. We propose a computationally efficient resampling scheme that allows to express the uncertainty in common types of coherent forecasts for count processes. The performance of the resampling scheme, which results in ensembles of forecast values, is investigated in a simulation study. A real-data example is used to demonstrate the application of the proposed approach in practice. It is shown that the obtained ensembles of forecast values can be presented in a visual way that allows for an intuitive interpretation.

Impact of HAS-BLED Score on outcome after percutaneous left atrial appendage closure: insights from the German Left Atrial Appendage Occluder Registry LAARGE.

AIM: Percutaneous left atrial appendage (LAA) closure has been established as alternative stroke prophylaxis in patients with non-valvular atrial fibrillation (AF) and high bleeding risk. However, little is known regarding the outcome after LAA closure depending on the HAS-BLED score. METHODS: A sub-analysis of the prospective, multicenter, Left-Atrium-Appendage Occluder Register-GErmany (LAARGE) registry was performed assessing three different groups with respect to the HAS-BLED score (0-2 [group 1] vs. 3-4 [group 2] vs. 5-7 [group 3]). RESULTS: A total of 633 patients at 38 centers were enrolled. Of them, 9% (n = 59) were in group 1, 63% (n = 400) in group 2 and 28% (n = 174) in group 3. The Kaplan-Meier estimated 1-year composite of death, stroke and systemic embolism was 3.4% in group 1 vs. 10.4% in group 2 vs. 20.1% in group 3, respectively (p log-rank < 0.001). The difference was driven by death since stroke and systemic embolism did not show a significant difference between the groups. The rate of major bleeding at 1 year was 0% vs. 0% vs. 2.4%, respectively (p = 0.016). CONCLUSION: The present data show that patients had similarly low rates of ischemic complications 1 year after LAA closure irrespective of the baseline bleeding risk. Higher HAS-BLED scores were associated with increased mortality due to higher age and more severe comorbidity of these patients.

Time Series Modelling.

Time series consist of data observed sequentially in time, and they are assumed to stem from an underlying stochastic process [...].

Analyzing categorical time series in the presence of missing observations.

In real applications, time series often exhibit missing observations such that standard analytical tools cannot be applied. While there are approaches of how to handle missing data in quantitative time series, the case of categorical time series seems not to have been treated so far. Both for the case of ordinal and nominal time series, solutions are developed that allow to analyze their marginal and serial properties in the presence of missing observations. This is achieved by adapting the concept of amplitude modulation, which allows to obtain closed-form asymptotic expressions for the derived statistics' distribution (assuming that missingness happens independently of the actual process). The proposed methods are investigated with simulations, and they are applied in a project on migraine patients, where the monitored qualitative time series are often incomplete.

Left atrial appendage closure in patients with chronic kidney disease: results from the German multicentre LAARGE registry.

OBJECTIVES: Chronic kidney disease (CKD) is associated with an increased complication rate after cardiac interventions. Although CKD has a high prevalence among atrial fibrillation patients, the impact of CKD on periprocedural complications and the outcome after an interventional left atrial appendage closure (LAAC) is unclear. The present study, therefore, aimed to investigate whether CKD influences the procedure's effectiveness and safety. METHODS: LAARGE is a prospective, non-randomised registry. LAAC was conducted with different standard commercial devices, and the follow-up period was one year. CKD was defined by an eGFR < 60 mL/min/1.73 m2, and subgroups were further analysed (i.e. eGFR < 15, 15-29, and 30-59 mL/min/1.73 m2, respectively). RESULTS: Two hundred ninety-nine of 623 patients (48.0%) revealed a CKD. The prevalence of cardiovascular comorbidity, CHA2DS2-VASc score (4.9 vs. 4.2), and HAS-BLED score (4.3 vs. 3.5) was significantly higher in CKD patients (each p < 0.001). Implantation success was similarly high across all GFR groups (97.9%). Periprocedural MACCE (0.7 vs. 0.3%), and other major complications (4.7 vs. 3.7%) were comparably infrequent. Survival free of stroke was significantly lower among CKD patients within 1 year (82.0 vs. 93.0%; p < 0.001; consistent after adjustment for confounding factors), without significant accentuation in advanced CKD (i.e. eGFR < 30 mL/min/1.73 m2; p > 0.05 vs. eGFR 30-59 mL/min/1.73 m2). Non-fatal strokes were absolutely infrequent during follow-up (0 vs. 1.1%). Severe non-fatal bleedings were observed only among CKD patients (1.4 vs. 0%; p = 0.021). CONCLUSIONS: Despite an increased cardiovascular risk profile of CKD patients, device implantation was safe, and LAAC was associated with effective stroke prevention across all CKD stages.

Measuring Dispersion and Serial Dependence in Ordinal Time Series Based on the Cumulative Paired ϕ-Entropy.

The family of cumulative paired ϕ-entropies offers a wide variety of ordinal dispersion measures, covering many well-known dispersion measures as a special case. After a comprehensive analysis of this family of entropies, we consider the corresponding sample versions and derive their asymptotic distributions for stationary ordinal time series data. Based on an investigation of their asymptotic bias, we propose a family of signed serial dependence measures, which can be understood as weighted types of Cohen's κ, with the weights being related to the actual choice of ϕ. Again, the asymptotic distribution of the corresponding sample κϕ is derived and applied to test for serial dependence in ordinal time series. Using numerical computations and simulations, the practical relevance of the dispersion and dependence measures is investigated. We conclude with an environmental data example, where the novel ϕ-entropy-related measures are applied to an ordinal time series on the daily level of air quality.

Regime-Switching Discrete ARMA Models for Categorical Time Series.

For the modeling of categorical time series, both nominal or ordinal time series, an extension of the basic discrete autoregressive moving-average (ARMA) models is proposed. It uses an observation-driven regime-switching mechanism, leading to the family of RS-DARMA models. After having discussed the stochastic properties of RS-DARMA models in general, we focus on the particular case of the first-order RS-DAR model. This RS-DAR ( 1 ) model constitutes a parsimoniously parameterized type of Markov chain, which has an easy-to-interpret data-generating mechanism and may also handle negative forms of serial dependence. Approaches for model fitting are elaborated on, and they are illustrated by two real-data examples: the modeling of a nominal sequence from biology, and of an ordinal time series regarding cloudiness. For future research, one might use the RS-DAR ( 1 ) model for constructing parsimonious advanced models, and one might adapt techniques for smoother regime transitions.

Comparison in Patients < 75 Years of Age - Versus - Those > 75 Years on One-year-Events With Atrial Fibrillation and Left Atrial Appendage Occluder (From the Prospective Multicenter German LAARGE Registry).

Left atrial appendage closure (LAAC) is an alternative to oral anticoagulation therapy in patients with non-valvular atrial fibrillation for the prevention of embolic stroke and systemic embolism. Although elderly patients (>75 years) have both higher ischemic and bleeding risk as compared with younger patients, they benefit from optimal anticoagulation. The subanalysis aimed to assess the indications, the safety, efficacy, and 1-year outcomes of interventional LAAC in elderly patients (≥ 75 years) compared with younger (< 75 years) patients in clinical practice. We analyzed data from the prospective Left-Atrium-Appendage Occluder Registry Germany. A total of 638 patients were included in the registry, 402 (63%) were aged ≥ 75 years. Compared with younger subjects, patients aged ≥75 were more likely to have higher CHA2DS2-VASC and HAS-BLED scores. Procedural success rate was high und similar in both groups (97.6%). Periprocedural adverse events were not statistically significant in groups (11.9% in <75 years vs 12.9% in ≥75 years; p = 0.80). At 1 year follow-up, all-cause mortality was higher in patients aged ≥75 compared withwith younger group (13.0% vs 7.8 %,p = 0.04), mainly due to non-cardiovascular causes (10.6% vs 6.0%). No significant differences in major bleeding, stroke, systemic embolism were observed. In conclusion, LAAC is feasible and safe in patients with AF at high stroke risk and with contraindications for OAC and should be considered as candidates for LAA closure. Elderly patients often present these characteristics and could benefit from this novel therapy.

WATCHMAN versus ACP or Amulet devices for left atrial appendage occlusion: a sub-analysis of the multicentre LAARGE registry.

AIMS: Several left atrial appendage (LAA) closure systems are available. Due to differences in device design, the results of specific occluders derived from trials cannot simply be generalised to all devices. The present analysis sought to assess two contemporary LAA closure devices in clinical practice. METHODS AND RESULTS: The work represents a non-randomised sub-analysis of the prospective, multicentre, Left-Atrium-Appendage Occluder Register - GErmany (LAARGE) registry. The WATCHMAN (group 1) and the AMPLATZER Cardiac Plug (ACP) or Amulet occluder (group 2) were assessed. A total of 641 patients at 38 centres were enrolled. Of these, 278 (43%) and 340 (53%) patients received the WATCHMAN and ACP/Amulet occluder, respectively. High technical success was achieved with a slight difference between the groups (96% in group 1 vs 99% in group 2; p=0.007). Procedural safety did not differ (98% in group 1 vs 97% in group 2; p=0.55). The Kaplan-Meier estimated one-year composite of death or stroke was 12.0% and 12.9%, respectively (p=0.79). CONCLUSIONS: Both the WATCHMAN and the ACP/Amulet occluder provide excellent procedural results with comparable implantation success and no differences with respect to procedural safety and long-term effectiveness.

RADIANCE - Radiochemotherapy with or without Durvalumab in the treatment of anal squamous cell carcinoma: A randomized multicenter phase II trial.

PURPOSE: Anal squamous cell carcinomas (ASCC) are increasing in frequency across the developed world. The 3-year disease-free survival (DFS) in patients with locally-advanced disease is approximately 60% after primary radiochemotherapy (RCT). There is a strong rationale for combining immunotherapy with RCT in patients with ASCC due to its association with human papilloma virus (HPV) infection. METHODS/DESIGN: RADIANCE is an investigator initiated, prospective, multicenter, randomized phase II trial testing the addition of Durvalumab, a PD-L1 immune checkpoint inhibitor, to standard RCT in 178 patients with locally advanced ASCC (T2 ≥ 4 cm Nany, cT3-4 and/or cN+). In the control arm, patients will be treated with standard mitomycin C (MMC)/5-fluorouracil (5-FU)-based RCT. Intensity-modulated radiotherapy (IMRT) will be applied as follows: PTV_A (primary tumor) T1-T2 < 4 cm N+: 28 × 1.9 Gy = 53.2 Gy; or T2 ≥ 4 cm, T3-4 Nany: 31 × 1.9 Gy = 58.9 Gy; PTV_N (involved node): 28 × 1.8 Gy = 50.4 Gy ; and PTV_Elec (elective node): 28 × 1.43 Gy = 40.0 Gy over a period of 5,5-6 weeks. Concomitant chemotherapy will be administered using MMC with 5-FU during weeks 1 and 5 of radiotherapy (MMC 12 mg/m2, day 1 [maximum single dose 20 mg]; 5-FU 1000 mg/m2 days 1-4 and 29-32). In the experimental arm, Durvalmab (1500 mg absolute dose, intravenously) will be combined with the same RCT as in the control arm. Immunotherapy with Durvalumab will start 14 days before initiation of standard RCT, administered every four weeks (q4w) thereafter for a total of twelve doses. The primary endpoint is disease-free survival (DFS) after 3 years. DISCUSSION: As ASCC is considered an immunogenically "hot" tumor due to its association with HPV infection, the combination of RCT with Durvalumab may improve tumor control and long-term clinical outcome in this patient collective compared to RCT alone.

Left atrial appendage closure in patients with a reduced left ventricular ejection fraction: results from the multicenter German LAARGE registry.

BACKGROUND: Interventional left atrial appendage closure (LAAC) effectively prevents thromboembolic events in atrial fibrillation patients. Impaired left ventricular ejection fraction (LVEF) increases not only the thromboembolic risk but also the complication rates of cardiac interventions. The LAAC procedure's benefit in patients with an impaired LVEF, therefore, has yet to be investigated. METHODS: LAARGE is a prospective, non-randomized registry depicting the clinical reality of LAAC in Germany. Procedure was conducted with different standard commercial devices, and follow-up period was one year. In the sense of an as-treated analysis, patients with started procedure and documented LVEF were selected from the whole database. RESULTS: 619 patients from 37 centers were categorized into one of three groups: LVEF > 55% (56%), 36-55% (36%), and ≤ 35% (8%). Prevalence of cardiovascular comorbidity increased with LVEF reduction (p < 0.001 for trend). CHA2DS2-VASc score was 4.3, 4.8, and 5.1 (p < 0.001), and HAS-BLED score was 3.7, 4.1, and 4.2 (p < 0.001). Implantation success was consistently high (97.9%), rates of intra-hospital MACCE (0.5%), and other major complications (4.2%) were low (each p = NS). Kaplan-Meier estimation showed a decrease in survival free of stroke with LVEF reduction during one-year follow-up (89.3 vs. 87.0 vs. 79.8%; p = 0.067), a trend which was no longer evident after adjustment for relevant confounding factors. Rates of non-fatal strokes (0.4 vs. 1.1 vs. 0%) and severe bleedings (0.7 vs. 0.0 vs. 3.1%) were consistently low across all groups (each p = NS). CONCLUSIONS: LVEF reduction neither influenced the procedural success nor the effectiveness and safety of stroke prevention by LAAC. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02230748.

Long-Term Experience of Chemoradiotherapy Combined with Deep Regional Hyperthermia for Organ Preservation in High-Risk Bladder Cancer (Ta, Tis, T1, T2).

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of chemoradiotherapy (RCT) combined with regional deep hyperthermia (RHT) of high-risk bladder cancer after transurethral resection of bladder tumor (TUR-BT). MATERIALS AND METHODS: Between 1982 and 2016, 369 patients with pTa, pTis, pT1, and pT2 cN0-1 cM0 bladder cancer were treated with a multimodal treatment after TUR-BT. All patients received radiotherapy (RT) of the bladder and regional lymph nodes. RCT was administered to 215 patients, RCT + RHT was administered to 79 patients, and RT was used in 75 patients. Treatment response was evaluated 4-6 weeks after treatment with TUR-BT. RESULTS: Complete response (CR) overall was 83% (290/351), and in treatment groups was RT 68% (45/66), RCT 86% (178/208), and RCT + RHT 87% (67/77). CR was significantly improved by concurrent RCT compared with RT (odds ratio [OR], 2.32; 95% confidence interval [CI], 1.05-5.12; p = .037), less influenced by hyperthermia (OR, 2.56; 95% CI, 0.88-8.00; p = .092). Overall survival (OS) after RCT was superior to RT (hazard ratio [HR], 0.7; 95% CI, 0.50-0.99; p = .045). Five-year OS from unadjusted Kaplan-Meier estimates was RCT 64% versus RT 45%. Additional RHT increased 5-year OS to 87% (HR, 0.32; 95% CI, 0.18-0.58; p = .0001). RCT + RHT compared with RCT showed a significantly better bladder-preservation rate (HR, 0.13; 95% CI, 0.03-0.56; p = .006). Median follow-up was 71 months. The median number of RHT sessions was five. CONCLUSION: The multimodal treatment consisted of a maximal TUR-BT followed by RT; concomitant platinum-based chemotherapy combined with RHT in patients with high-grade bladder cancer improves local control, bladder-preservation rate, and OS. It offers a promising alternative to surgical therapies like radical cystectomy. IMPLICATIONS FOR PRACTICE: Radical cystectomy with appropriate lymph node dissection has long represented the standard of care for muscle-invasive bladder cancer in medically fit patients, despite many centers reporting excellent long-term results for bladder preserving strategies. This retrospective analysis compares different therapeutic modalities in bladder-preservation therapy. The results of this study show that multimodal treatment consisting of maximal transurethral resection of bladder tumor followed by radiotherapy, concomitant platinum-based chemotherapy combined with regional deep hyperthermia in patients with Ta, Tis, T1-2 bladder carcinomas improves local control, bladder-preservation rate, and survival. More importantly, these findings offer a promising alternative to surgical therapies like radical cystectomy. The authors hope that, in the future, closer collaboration between urologists and radiotherapists will further improve treatments and therapies for the benefit of patients.

Phase Ib evaluation of a self-adjuvanted protamine formulated mRNA-based active cancer immunotherapy, BI1361849 (CV9202), combined with local radiation treatment in patients with stage IV non-small cell lung cancer.

BACKGROUND: Preclinical studies demonstrate synergism between cancer immunotherapy and local radiation, enhancing anti-tumor effects and promoting immune responses. BI1361849 (CV9202) is an active cancer immunotherapeutic comprising protamine-formulated, sequence-optimized mRNA encoding six non-small cell lung cancer (NSCLC)-associated antigens (NY-ESO-1, MAGE-C1, MAGE-C2, survivin, 5T4, and MUC-1), intended to induce targeted immune responses. METHODS: We describe a phase Ib clinical trial evaluating treatment with BI1361849 combined with local radiation in 26 stage IV NSCLC patients with partial response (PR)/stable disease (SD) after standard first-line therapy. Patients were stratified into three strata (1: non-squamous NSCLC, no epidermal growth factor receptor (EGFR) mutation, PR/SD after ≥4 cycles of platinum- and pemetrexed-based treatment [n = 16]; 2: squamous NSCLC, PR/SD after ≥4 cycles of platinum-based and non-platinum compound treatment [n = 8]; 3: non-squamous NSCLC, EGFR mutation, PR/SD after ≥3 and ≤ 6 months EGFR-tyrosine kinase inhibitor (TKI) treatment [n = 2]). Patients received intradermal BI1361849, local radiation (4 × 5 Gy), then BI1361849 until disease progression. Strata 1 and 3 also had maintenance pemetrexed or continued EGFR-TKI therapy, respectively. The primary endpoint was evaluation of safety; secondary objectives included assessment of clinical efficacy (every 6 weeks during treatment) and of immune response (on Days 1 [baseline], 19 and 61). RESULTS: Study treatment was well tolerated; injection site reactions and flu-like symptoms were the most common BI1361849-related adverse events. Three patients had grade 3 BI1361849-related adverse events (fatigue, pyrexia); there was one grade 3 radiation-related event (dysphagia). In comparison to baseline, immunomonitoring revealed increased BI1361849 antigen-specific immune responses in the majority of patients (84%), whereby antigen-specific antibody levels were increased in 80% and functional T cells in 40% of patients, and involvement of multiple antigen specificities was evident in 52% of patients. One patient had a partial response in combination with pemetrexed maintenance, and 46.2% achieved stable disease as best overall response. Best overall response was SD in 57.7% for target lesions. CONCLUSION: The results support further investigation of mRNA-based immunotherapy in NSCLC including combinations with immune checkpoint inhibitors. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01915524 .