Genetically modified T cells expressing chimeric antigen receptors (CARs) so far have mostly failed in the treatment of solid tumors owing to a number of limitations, including an immunosuppressive tumor microenvironment and insufficient CAR T cell activation and persistence. Next-generation approaches using CAR T cells that secrete transgenic immunomodulatory cytokines upon CAR signaling, known as TRUCKs (“T cells redirected for universal cytokine-mediated killing”), are currently being explored. As TRUCKs were engineered by the transduction of T cells with two separate vectors, we developed a lentiviral modular “all-in-one” vector system that combines constitutive CAR expression and inducible nuclear factor of activated T cells (NFAT)-driven transgene expression for more efficient production of TRUCKs. Activation of the GD2-specific CAR via GD2+ target cells induced NFAT promoter-driven cytokine release in primary human T cells, and indicated a tight linkage of CAR-specific activation and transgene expression that was further improved by a modified NFATsyn promoter. As proof-of-concept, we showed that T cells containing the “all-in-one” vector system secrete the immunomodulatory cytokines interleukin (IL)12 or IL18 upon co-cultivation with primary human GD2+ tumor cells, resulting in enhanced effector cell properties and increased monocyte recruitment. This highlights the potential of our system to simplify application of TRUCK-modified T cells in solid tumor therapy.

Brain metastases have been considered the most common structural neurological complication of systemic cancer. Due to poor prognosis they influence the survival rate as well as the quality of life of the patients. The treatment of cerebral metastasis depends on the patients' situation and the decisions of the treating physicians. The early awareness of a probable metastasis from GI to the brain will have a great influence on treatment outcomes as well as the survival rate and the quality-of-life of the patients.

BACKGROUND High-resolution vessel wall imaging plays an increasingly important role in assessing the risk of aneurysm rupture. OBJECTIVE To introduce an approach toward the validation of the wall enhancement as a direct surrogate parameter for aneurysm stability. METHODS A total of 19 patients harboring 22 incidental intracranial aneurysms were enrolled in this study. The aneurysms were dichotomized according to their aneurysm-to-pituitary stalk contrast ratio using a cutoff value of 0.5 (nonenhancing < 0.5; enhancing ≥ 0.5). We evaluated the association of aneurysm wall enhancement with morphological characteristics, hemodynamic features, and inflammatory chemokines directly measured inside the aneurysm. RESULTS Differences in plasma concentration of chemokines and inflammatory molecules, morphological, and hemodynamic parameters were analyzed using the Welch test or Mann-Whitney U test. The concentration ΔIL-10 in the lumen of intracranial aneurysms with low wall enhancement was significantly increased compared to aneurysms with strong aneurysm wall enhancement (P = .014). The analysis of morphological and hemodynamic parameters showed significantly increased values for aneurysm volume (P = .03), aneurysm area (P = .044), maximal diameter (P = .049), and nonsphericity index (P = .021) for intracranial aneurysms with strong aneurysm wall enhancement. None of the hemodynamic parameters reached statistical significance; however, the total viscous shear force computed over the region of low wall shear stress showed a strong tendency toward significance (P = .053). CONCLUSION Aneurysmal wall enhancement shows strong associations with decreased intrasaccular IL-10 and established morphological indicators of aneurysm instability.

The present work explores optical coherence tomography (OCT) as a suitable in vivo neuroimaging modality of the subarachnoid space (SAS). Patients ( n = 26) with frontolateral craniotomy were recruited. The temporal and frontal arachnoid mater and adjacent anatomical structures were scanned using microscope-integrated three-dimensional OCT, (iOCT). Analysis revealed a detailed depiction of the SAS (76.9%) with delineation of the internal microanatomical structures such as the arachnoid barrier cell membrane (ABCM; 96.2%), trabecular system (50.2%), internal blood vessels (96.2%), pia mater (26.9%) and the brain cortex (96.2%). Orthogonal distance measuring was possible. The SAS showed a mean depth of 570 µm frontotemporal. The ABCM showed a mean depth of 74 µm frontotemporal. These results indicate that OCT provides a dynamic, non-invasive tool for real-time imaging of the SAS and adjacent anatomical structures at micrometer spatial resolution. Further studies are necessary to evaluate the value of OCT during microsurgical procedures.

Introduction: A multitude of approaches have been postulated for assessing the risk of intracranial aneurysm rupture. However, the amount of potential predictive factors is not applicable in clinical practice and they are rejected in favor of the more practical PHASES score. For the subgroup of multiple intracranial aneurysms (MIAs), the PHASES score might severely underestimate the rupture risk, as only the aneurysm with the largest diameter is considered for risk evaluation. Methods: In this study, we investigated 38 patients harboring a total number of 87 MIAs with respect to their morphological and hemodynamical characteristics. For the determination of the best suited parameters regarding their predictive power for aneurysm rupture, we conducted three phases of statistical evaluation. The statistical analysis aimed to identify parameters that differ significantly between ruptured and unruptured aneurysms, show smallest possible correlations among each other and have a high impact on rupture risk prediction. Results: Significant differences between ruptured and unruptured aneurysms were found in 16 out of 49 parameters. The lowest correlation were found for gamma, aspect ratio (AR1), aneurysm maximal relative residence time (Aneurysm_RRT_max) and aneurysm mean relative residence time. The data-driven parameter selection yielded a significant correlation of only two parameters (AR1 and the Aneurysm_RRT_max) with rupture state (area under curve = 0.75). Conclusion: A high number of established morphological and hemodynamical parameters seem to have no or only low effect on prediction of aneurysm rupture in patients with MIAs. For best possible rupture risk assessment of patients with MIAs, only the morphological parameter AR1 and the hemodynamical parameter Aneurysm_RRT_max need to be included in the prediction model.