Brain metastases are the most common intracranial tumor in adults and are associated with poor patient prognosis and median survival of only a few months. Treatment options for brain metastasis patients remain limited and largely depend on surgical resection, radio- and/or chemotherapy. The development and pre-clinical testing of novel therapeutic strategies require reliable experimental models and diagnostic tools that closely mimic technologies that are used in the clinic and reflect histopathological and biochemical changes that distinguish tumor progression from therapeutic response. In this study, we sought to test the applicability of magnetic resonance (MR) spectroscopy in combination with MR imaging to closely monitor therapeutic efficacy in a breast-to-brain metastasis model. Given the importance of radiotherapy as the standard of care for the majority of brain metastases patients, we chose to monitor the post-irradiation response by magnetic resonance spectroscopy (MRS) in combination with MR imaging (MRI) using a 7 Tesla small animal scanner. Radiation was applied as whole brain radiotherapy (WBRT) using the image-guided Small Animal Radiation Research Platform (SARRP). Here we describe alterations in different metabolites, including creatine and N-acetylaspartate, that are characteristic for brain metastases progression and lactate, which indicates hypoxia, while choline levels remained stable. Radiotherapy resulted in normalization of metabolite levels indicating tumor stasis or regression in response to treatment. Our data indicate that the use of MR spectroscopy in addition to MRI represents a valuable tool to closely monitor not only volumetrical but also metabolic changes during tumor progression and to evaluate therapeutic efficacy of intervention strategies. Adapting the analytical technology in brain metastasis models to those used in clinical settings will increase the translational significance of experimental evaluation and thus contribute to the advancement of pre-clinical assessment of novel therapeutic strategies to improve treatment options for brain metastases patients.

In patients with atrial fibrillation, catheter ablation is suggested to reduce the mortality rate and is thus frequently performed. However, peri- and postprocedural thromboembolic complications as well as high recurrence rates of atrial fibrillation limit its advantages and require concomitant anticoagulation. With the advent of novel oral anticoagulants (NOACs), fixed dosing without routine laboratory monitoring became feasible. Nevertheless, several factors are associated with either an overdose or an insufficient drug activity of NOACs. We report on a patient with atrial fibrillation undergoing catheter ablation and cardioversion suffering from ischemic stroke despite being under oral anticoagulation. It turned out that the drug activity of the NOACs used was repeatedly insufficient in spite of regular intake and adequate dosing. In sum, drug activity controls should be taken into consideration in patients with thrombotic events despite oral anticoagulation with NOACs.

Brain metastases represent the most common intracranial tumor in adults associated with poor prognosis and median survival of only a few months. Despite current success in the development of targeted or immuno-therapies against different cancer entities, those strategies are ineffective against brain metastases. Hence, treatment options for brain metastasis patients largely remain limited to surgical resection and radio- and/or chemotherapy. This paucity can in part be attributed to the immune-privileged status of the brain where the blood brain-barrier restricts the entry of blood-borne immune cells. However, recent insights into the immune landscape of primary brain cancers indicate that tumor progression leads to an infiltration of blood-borne immune cells into the brain. We employ a comprehensive set of experimental brain metastasis models to characterize the immune landscape of brain metastases from different primary cancer entities at distinct disease stages and in response to radiotherapy. Our data indicate that brain metastases induce massive infiltration of myeloid and lymphoid cell populations into the central nervous system. This leads to the establishment of a dynamic and highly complex tumor microenvironment that affects tumor progression and therapy response. Fractionated whole-brain radiotherapy leads to enhanced infiltration of blood-borne myeloid and lymphoid cells. Transcriptome analysis of brain-resident and recruited myeloid cells indicate a switch from a proinflammatory towards an immune-suppressive environment at advanced disease stages. Importantly, radiotherapy was found to induce gene signatures that are associated with proinflammatory innate immune responses that could revert the establishment of an immune-suppressive environment. Consequently, radiotherapy might sensitize brain metastases towards immuno-therapies. Our goal is to identify pathways or molecular targets that are induced by radiotherapy in the tumor microenvironment to overcome resistance against immuno-therapy. In this project, we seek to test strategies to maintain or induce proinflammatory immune responses for improved targeted or immuno-therapies against brain metastasis. Citation Format: Michael Schulz, Katja Niesel, Anna Salamero Boix, Woon Hyung Chae, Birgitta Michels, Alexander Schaeffer, Maja Strecker, Tijna Alekseeva, Stefan Stein, Henner Farin, Franz Roedel, Patrick Harter, Karlheinz Plate, and Lisa Sevenich. Effects of ionizing radiation on brain metastasis-associated inflammation and its implication for immunotherapy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr A111.