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Background Supratentorial intraventricular tumors (SIVTs) are rare lesions of various entities characteristically presenting with hydrocephalus and often posing a surgical challenge due to their deep-seated localization. We aimed to elaborate on shunt dependency after tumor resection, clinical characteristics, and perioperative morbidity. Methods We retrospectively searched the institutional database for patients with supratentorial intraventricular tumors treated at the Department of Neurosurgery of the Ludwig-Maximilians-University in Munich, Germany, between 2014 and 2022. Results We identified 59 patients with over 20 different SIVT entities, most often subependymoma (8/59 patients, 14%). Mean age at diagnosis was 41 ± 3 years. Hydrocephalus and visual symptoms were observed in 37/59 (63%) and 10/59 (17%) patients, respectively. Microsurgical tumor resection was provided in 46/59 patients (78%) with complete resection in 33/46 patients (72%). Persistent postoperative neurological deficits were encountered in 3/46 patients (7%) and generally mild in nature. Complete tumor resection was associated with less permanent shunting in comparison to incomplete tumor resection, irrespective of tumor histology (6% versus 31%, p = 0.025). Stereotactic biopsy was utilized in 13/59 patients (22%), including 5 patients who received synchronous internal shunt implantation for symptomatic hydrocephalus. Median overall survival was not reached and did not differ between patients with or without open resection. Conclusions SIVT patients display a high risk of developing hydrocephalus and visual symptoms. Complete resection of SIVTs can often be achieved, preventing the need for long-term shunting. Stereotactic biopsy along with internal shunting represents an effective approach to establish diagnosis and ameliorate symptoms if resection cannot be safely performed. Due to the rather benign histology, the outcome appears excellent when adjuvant therapy is provided.

Background Terminology to describe extent of resection in glioblastoma is inconsistent across clinical trials. A surgical classification system was previously proposed based upon residual contrast-enhancing (CE) tumor. We aimed to (1) explore the prognostic utility of the classification system and (2) define how much removed non-CE tumor translates into a survival benefit. Methods The international RANO resect group retrospectively searched previously compiled databases from 7 neuro-oncological centers in the USA and Europe for patients with newly diagnosed glioblastoma per WHO 2021 classification. Clinical and volumetric information from pre- and postoperative MRI were collected. Results We collected 1,008 patients with newly diagnosed IDHwt glioblastoma. 744 IDHwt glioblastomas were treated with radiochemotherapy per EORTC-26981/22981 (TMZ/RT→TMZ) following surgery. Among these homogenously treated patients, lower absolute residual tumor volumes (in cm3) were favorably associated with outcome: patients with “maximal CE resection” (class 2) had superior outcome compared to patients with “submaximal CE resection” (class 3) or “biopsy” (class 4). Extensive resection of non-CE tumor (≤5 cm3 residual non-CE tumor) was associated with better survival among patients with complete CE resection, thus defining class 1 (“supramaximal CE resection”). The prognostic value of the resection classes was retained on multivariate analysis when adjusting for molecular and clinical markers. Conclusions The proposed “RANO categories for extent of resection in glioblastoma” are highly prognostic and may serve for stratification within clinical trials. Removal of non-CE tumor beyond the CE tumor borders may translate into additional survival benefit, providing a rationale to explicitly denominate such “supramaximal CE resection.”

In newly diagnosed IDH-wildtype glioblastoma, the frequency and prognostic relevance of tumor regrowth between resection and the initiation of adjuvant radiochemotherapy are unclear. In this retrospective single-center study we included 64 consecutive cases, for whom magnetic resonance imaging (MRI) was available for both the volumetric assessment of the extent of resection immediately after surgery as well as the volumetric target delineation before the initiation of adjuvant radiochemotherapy (time interval: 15.5 ± 1.9 days). Overall, a median new contrast-enhancement volume was seen in 21/64 individuals (33%, 1.5 ± 1.5 cm3), and new non-contrast lesion volume in 18/64 patients (28%, 5.0 ± 2.3 cm3). A multidisciplinary in-depth review revealed that new contrast-enhancement was either due to (I) the progression of contrast-enhancing tumor remnants in 6/21 patients or (II) distant contrast-enhancing foci or breakdown of the blood–brain barrier in previously non-contrast-enhancing tumor remnants in 5/21 patients, whereas it was unspecific or due to ischemia in 10/21 patients. For non-contrast-enhancing lesions, three of eighteen had progression of non-contrast-enhancing tumor remnants and fifteen of eighteen had unspecific changes or changes due to ischemia. There was no significant association between findings consistent with tumor regrowth and a less favorable outcome (overall survival: 14 vs. 19 months; p = 0.423). These findings support the rationale that analysis of the postsurgical remaining tumor-volume for prognostic stratification should be carried out on immediate postoperative MRI (

Introduction The cIMPACT-NOW update 6 first introduced glioblastoma diagnosis based on the combination of IDH-wildtype (IDHwt) status and TERT promotor mutation (pTERTmut). In glioblastoma as defined by histopathology according to the WHO 2016 classification, MGMT promotor status is associated with outcome. Whether this is also true in glioblastoma defined by molecular markers is yet unclear. Methods We searched the institutional database for patients with: (1) glioblastoma defined by histopathology; and (2) IDHwt astrocytoma with pTERTmut. MGMT promotor methylation was analysed using methylation-specific PCR and Sanger sequencing of CpG sites within the MGMT promotor region. Results We identified 224 patients with glioblastoma diagnosed based on histopathology, and 54 patients with IDHwt astrocytoma with pTERTmut (19 astrocytomas WHO grade II and 38 astrocytomas WHO grade III). There was no difference in the number of MGMT methylated tumors between the two cohorts as determined per PCR, and also neither the number nor the pattern of methylated CpG sites differed as determined per Sanger sequencing. Progression-free (PFS) and overall survival (OS) was similar between the two cohorts when treated with radio- or chemotherapy. In both cohorts, higher numbers of methylated CpG sites were associated with favourable outcome. Conclusions Extent and pattern of methylated CpG sites are similar in glioblastoma and IDHwt astrocytoma with pTERTmut. In both tumor entities, higher numbers of methylated CpG sites appear associated with more favourable outcome. Evaluation in larger prospective cohorts is warranted.

BACKGROUND Lung cancer patients are at a high risk for brain metastases, and affected patients frequently succumb to their intracranial disease. Chimeric Antigen Receptor (CAR) T-cells emerged as a powerful cell-based immunotherapy for hematological malignancies; however, it remains unclear whether CAR T-cells represent a viable therapeutic avenue for brain metastases. METHODS A fully immunocompetent, orthotopic cerebral metastasis model was established in mice by combining a chronic cranial window with repetitive intracerebral two-photon laser scanning microscopy. This approach enabled the in vivo-characterization of fluorescent CAR T-cells and tumor cells on a single-cell level over weeks. Intraparenchymal injection of EpCAM-expressing Lewis lung carcinoma cells was performed, and EpCAM-directed CAR T-cells (EpCAMCAR T-cells) were injected into the adjacent brain parenchyma after brain tumor formation. RESULTS All mice had visible tumor take with rapidly growing lesions following intracranial tumor cell injection. In mice treated with EpCAMCAR T-cells, we observed substantial CAR T-cell accumulation within the tumor compared to controls treated with undirected T-cells. This was paralleled by lower velocities of EpCAMCAR T-cells, characterizing antitumor cytotoxicity due to ‘immune cell’-‘tumor cell’ contacts. Consequently, treatment with EpCAMCAR T-cells resulted in reduced tumorous growth as determined per in vivo-microscopy (median tumor area on day 10: 1.8 versus 10.8 mm2; p=0.001) and immunohistochemistry of excised brains. However, the number of intratumoral EpCAMCAR T-cells within the tumor markedly decreased during the observation period, pointing towards insufficient persistence. Accordingly, survival was prolonged in mice receiving EpCAMCAR T-cells but long-lasting remission was rare (median survival: 15 versus 13 days; p=0.012). No CNS-specific or systemic toxicities of EpCAMCAR T-cells were encountered. CONCLUSION Our findings indicate that EpCAMCAR T-cells injected into the cerebral parenchyma may safely induce relevant anti-tumor effects in brain metastases from lung cancer. Strategies improving the CAR T-cell persistence within brain metastases are warranted to further boost the therapeutic success.

In IDH-wildtype glioblastomas which meet the histopathological or molecular diagnosis criteria, it remains unclear whether the presence of TERT promotor mutations provides additional prognostic information. Based on a multicenter cohort of 466 IDH-wildtype glioblastomas (including 396 with and 70 patients without TERT promotor mutations), we found that TERT promotor mutations were neither associated with progression-free survival nor overall survival. This held true in various treatment-based or molecular subgroups. This argues against standardized analysis for TERT promotor mutation status for the purpose of prognostic or therapeutic relevance in newly diagnosed IDH-wildtype glioblastoma that otherwise meets the histopathological and molecular diagnosis criteria.

BACKGROUND Terminology to describe extent of resection in glioblastoma is inconsistent across clinical trials. A surgical classification system was previously proposed based upon residual contrast-enhancing (CE) tumor. We aimed to (I) explore the prognostic utility of the classification system and (II) define how much removed non-CE tumor translates into a survival benefit. METHODS The international RANO resect group retrospectively searched the databases from seven neuro-oncological centers in the USA and Europe for patients with newly diagnosed glioblastoma per WHO 2021 classification. Clinical and volumetric information from pre- and post-operative MRI were collected. RESULTS We collected 1021 patients with newly diagnosed glioblastoma, including 1008 IDHwt patients. 744 IDHwt glioblastomas were treated with radiochemotherapy per EORTC 26981/22981 (TMZ/RT→TMZ) following surgery. Among such homogenously treated patients, lower absolute residual tumor volumes (in cm3) were favorably associated with outcome: patients with ‘maximal CE resection’ (class 2) had superior outcome compared to patients with ‘submaximal CE resection’ (class 3) or ‘biopsy’ (class 4) (median OS: 19 versus 15 versus 10 months; p=0.001). Extensive resection of non-CE tumor (≤ 5 cm3 residual non-CE tumor) provided an additional survival benefit in patients with complete CE resection, thus defining class 1 (‘supramaximal CE resection’) (median OS: 24 versus 19 months; p=0.008). The prognostic value of the resection classes was retained on multivariate analysis when adjusting for molecular and clinical markers including MGMT promotor status. Relative tumor reduction (in percentage) was not prognostic for outcome on multivariate analysis, and inter-rater agreement for CE and non-CE tumor on post-operative MRI was sufficient. CONCLUSION The proposed “RANO categories for extent of resection in glioblastoma” are highly prognostic and may serve for stratification of clinical trials. Removal of non-CE tumor beyond the CE tumor borders translates into additional survival benefit, providing a rationale to explicitly denominate such a ‘supramaximal CE resection’.

BACKGROUND Intraventricular tumors (IVTs) are rare lesions of various entities, which pose a surgical challenge. We aimed to elaborate on surgical approaches and outcomes, postoperative morbidity, and elucidate whether preoperative hydrocephalus necessitates shunting despite surgical resection. METHODS We retrospectively searched the institutional database for patients with supratentorial intraventricular tumours that were treated in the Department of Neurosurgery of the Ludwig-Maximilians-University Munich, Germany between 2014 and 2022. RESULTS We identified 59 patients with supratentorial intraventricular tumors comprising over 15 different tumor entities, most often subependymoma (8/59 patients, 14%). Median age at diagnosis was 41.4 years (range 0-86 years) with 31 male patients (53%) and 28 female patients (48%). Microsurgical tumor resection was completed in 46/59 patients (78%) with incomplete tumor resection (≥ 1ml postoperative tumor volume) in 13/46 patients (28%) and complete tumor resection (< 1ml postoperative tumor volume) in 33/46 patients (72%). In cases where neurosurgical tumor resection was not feasible, stereotactic biopsy was provided in 13/59 patients (22%), often combined with stereotactic internal shunt implantation (5/59 patients, 8%). Mean follow-up was 24 months; median overall survival was not reached. Postoperative persistent hydrocephalus necessitating ventriculoperitoneal shunt placement was rare (5/59 patients, 8%). Ventriculocisternostomy was performed in one patient. New postoperative focal neurological deficits – mostly transient – were encountered in 16/59 patients (27%) at discharge with mild to moderate permanent focal neurological deficits at 3 months in 3/59 patients (5%). CONCLUSION Complete resection of IVT can often be achieved and forms the basis for favourable outcome. Permanent neurological deficits are rare, and hydrocephalus can almost always be alleviated which prevents the need for long-term shunting. If microsurgical resection is not feasible, stereotactic biopsy along with internal shunting represents an effective approach to establish diagnosis and ameliorate symptoms.

Brain metastases frequently occur in lung cancer and dramatically limit prognosis of affected patients. The influence of tumor-associated macrophages and microglia (TAM/M) and their receptor CX3CR1 on different steps of brain metastasis formation from lung cancer is poorly characterized. We established a syngeneic orthotopic cerebral metastasis model in mice by combining a chronic cranial window with repetitive intravital 2-photon laser scanning microscopy. This allowed in vivo tracking of fluorescence-expressing tumor cells and TAM/M on a single-cell level over weeks. Intracarotid injection of red tdTomato-fluorescent Lewis lung carcinoma cell was performed in transgenic mice either proficient or deficient for CX3CR1. After intracarotid cell injection, intravascular tumor cells extravasated into the brain parenchyma and formed micro- and mature macrometastases. We observed potential phagocytosis of extravasated tumor cells by TAM/M. However, during later steps of metastasis formation, these anti-tumor effects diminished and were paralleled by TAM/M accumulation and activation. Although CX3CR1 deficiency resulted in a lower number of extravasated tumor cells, progression of these extravasated cells into micro metastases was more efficient. Overall, this resulted in a comparable number of mature macrometastases in CX3CR1-deficient and -proficient mice. Our findings indicate that unspecific inhibition of CX3CR1 might not be a suitable therapeutic option to prevent dissemination of lung cancer cells to the brain. Given the close interaction between TAM/M and tumor cells during metastasis formation, other therapeutic approaches targeting TAM/M function may warrant further evaluation. The herein established orthotopic mouse model may be a useful tool to evaluate such concepts in vivo.

Glioblastoma is the most common malignant primary brain tumor and is associated with a poor prognosis even after multimodal therapy. Chimeric antigen receptor (CAR) T cells have emerged as a promising therapeutic avenue in glioblastoma. CARs incorporate antigen-recognition moieties that endow autologous T cells with specificity against antigens expressed on glioblastoma (e.g., interleukin [IL]–13Rα2, epidermal growth factor receptor variant III [EGFRvIII], and human epidermal growth factor receptor 2 [HER2]). Compelling antitumor effects of such therapy have been shown in murine glioblastoma models. In humans, 5 phase I/II studies on IL-13Rα2-, EGFRvIII-, and HER2-directed CAR T cells for the treatment of glioblastoma have been published suggesting an acceptable safety profile. However, antitumor effects fell short of expectations in these initial clinical studies. Tumor heterogeneity, antigen loss, and the immunosuppressive tumor microenvironment are among the most important factors to limit the efficacy of CAR T-cell therapy in glioblastoma. Novel target antigens, modification of CAR T-cell design, the combination of CAR T-cell therapy with other therapeutic approaches, but also the use of CAR natural killer cells or CAR macrophages may optimize antitumor effects. Numerous clinical trials studying such approaches are ongoing, as well as several preclinical studies. With an increasing understanding of immune-escape mechanisms of glioblastoma and novel manufacturing techniques for CARs, CAR T cells may provide clinically relevant activity in glioblastoma. This review focuses on the use of CAR T cells in glioblastoma, but also introduces the basic structure, mechanisms of action, and relevant side effects of CAR T cells.

Background Brain metastases represent a common complication of lung cancer and dramatically limit prognosis in affected patients. The influence of tumor-associated macrophages and microglia (TAM/M) and their receptor CX3CR1 on different steps of brain metastasis formation from lung cancer is poorly characterized, but might be of therapeutic relevance. Methods We established an orthotopic cerebral metastasis model using CX3CR1-proficient (CX3CR1GFP/wt) and -deficient (CX3CR1GFP/GFP) mice with green-fluorescent TAM/M. A cranial window was prepared, and intracarotid injection of red-fluorescent Lewis Lung Carcinoma-cells (tdtLLC) was performed two weeks later. Formation of brain metastases was followed by repetitive two-photon laser scanning microscopy. Results After intracarotid injection, intravascular tumor cells extravasated into the cerebral parenchyma and eventually formed micrometastases (≤50 cells) and mature macrometastases (>50 cells). We observed phagocytosis of extravasated tumor cells by TAM/M during early steps of metastatic growth. Notably, these anti-tumor effects of TAM/M diminished during later steps of metastasis formation and were accompanied by TAM/M accumulation and activation. CX3CR1-deficiency resulted in a lower number of extravasated tumor cells, and only a small number of TAM/M were visualized during early steps of metastasis formation (extravasation, formation of micrometastases) in such mice. In contrast, progression of extravasated tumor cells into micrometastases was more frequently found in CX3CR1-deficient mice. Overall, these mechanisms resulted in a comparable number of mature macrometastases between CX3CR1-deficient and -proficient mice. Conclusion Our findings indicate that unspecific inhibition of CX3CR1 might not be a suitable therapeutic approach to prevent cerebral dissemination of lung cancer cells. Given the close interaction between TAM/M and tumour cells during metastasis formation, other therapeutic approaches targeting TAM/M function warrant evaluation. Such concepts might be evaluated in vivo using the herein established orthotopic mouse model.

Mitochondrial dysfunctions mark a critical step in many central nervous system (CNS) pathologies, including multiple sclerosis (MS). Such dysfunctions lead to depolarization of mitochondrial membranes and imbalanced redox homeostasis. In this context, reactive oxygen species (ROS) are potentially deleterious but can also act as an important signaling step for cellular maintenance. The transcription factor nuclear factor (erythroid-derived 2)-like 2 (Nrf2), the key regulator in the cellular oxidative stress-response, induces a battery of genes involved in repair and regeneration. Here, we investigated the relevance of Nrf2 signaling for the prevention of cellular damage caused by dysfunctional mitochondria. We employed sodium azide (SA) as mitochondrial inhibitor on oligodendroglial OliNeu cells in vitro, and the cuprizone model with wild type and GFAP-Cre+::Keap1loxP/loxP mice to induce mitochondrial defects. The importance of Nrf2 for cellular functions and survival after SA treatment was elucidated by in vitro knockdown experiments with shRNA directed against Nrf2 and its inhibitor Keap1 as well as by methysticin treatment. Metabolic activity, cytotoxicity, and depolarization of the mitochondrial membrane were analyzed after SA treatment. The expression of Nrf2 target genes as well as endoplasmic reticulum stress response genes was additionally measured by real-time PCR (in vitro) and PCR gene arrays (in vivo). Treatment of OliNeu cells with SA resulted in significant depolarization of the mitochondrial membrane, decreased metabolic activity, and increased cytotoxicity. This was partly counteracted in Nrf2-hyperactivated cells and intensified in Nrf2-knockdown cells. Our studies demonstrate a key role of Nrf2 in maintaining cellular functions and survival in the context of mitochondrial dysfunction.

The extent of remyelination in multiple sclerosis lesions is often incomplete. Injury to oligodendrocyte progenitor cells can be a contributing factor for such incomplete remyelination. The precise mechanisms underlying insufficient repair remain to be defined, but oxidative stress appears to be involved. Here, we used immortalized oligodendrocyte cell lines as model systems to investigate a causal relation of oxidative stress and endoplasmic reticulum stress signaling cascades. OLN93 and OliNeu cells were subjected to chemical hypoxia by blocking the respiratory chain at various levels. Mitochondrial membrane potential and oxidative stress levels were quantified by flow cytometry. Endoplasmic reticulum stress was monitored by the expression induction of activating transcription factor 3 and 4 (Atf3, Atf4), DNA damage-inducible transcript 3 protein (Ddit3), and glucose-regulated protein 94. Lentiviral silencing of nuclear factor (erythroid-derived 2)-like 2 or kelch-like ECH-associated protein 1 was applied to study the relevance of NRF2 for endoplasmic reticulum stress responses. We demonstrate that inhibition of the respiratory chain induces oxidative stress in cultured oligodendrocytes which is paralleled by the expression induction of distinct mediators of the endoplasmic reticulum stress response, namely Atf3, Atf4, and Ddit3. Atf3 and Ddit3 expression induction is potentiated in kelch-like ECH-associated protein 1-deficient cells and absent in cells lacking the oxidative stress-related transcription factor NRF2. This study provides strong evidence that oxidative stress in oligodendrocytes activates endoplasmic reticulum stress response in a NRF2-dependent manner and, in consequence, might regulate oligodendrocyte degeneration in multiple sclerosis and other neurological disorders.

BACKGROUND Brain metastases dramatically limit prognosis of lung cancer patients. Unlike systemic disease, brain metastases from lung cancer poorly respond to checkpoint-inhibition therapy. Targeting the immunosuppressive tumor-associated macrophages and microglia (TAM/M) and their receptor CSF1R may increase efficacy of checkpoint-inhibitors. METHODS Cranial windows were prepared in fully immunocompetent, transgenic CX3CR1GFP/wt-mice with green-fluorescent TAM/M. Intracranial injection of red-fluorescent Lewis Lung Carcinoma-cells was performed, and mice received one of the following three treatments: PD1-inhibition only (n = 8); PD1-inhibition combined with an anti-CSF1R-antibody (exhibiting limited blood-brain-barrier permeability under physiologic conditions, n = 8); or PD1-inhibition combined with a small molecular CSF1R-inhibitor (exhibiting high blood-brain-barrier permeability, n = 7). Tumor growth and TAM/M were followed by repetitive two-photon laser-scanning-microscopy over weeks. RESULTS Following intracranial injection, metastases were detected in all three treatment groups within eight days. In mice receiving PD1-inhibition only, metastases showed exponential growth which was paralleled by intra- and peritumoral accumulation of TAM/M. Treatment with an anti-CSF1R-antibody resulted in significantly lower numbers of intratumoral TAM/M given increased tumoral blood-brain-barrier permeability, but did not substantially affect peritumoral TAM/M or TAM/M localized in the healthy contralateral hemisphere. In contrast, treatment with a small molecular CSF1R-inhibitor not only reduced the number of intratumoral TAM/M, but also of peritumoral and contralateral TAM/M. Compared to PD1-inhibition only, the addition of either an anti-CSF1R-antibody or a small molecular CSF1R-inhibitor resulted in decreased tumor growth (tumor size on day 12: 8.3 mm2 (PD1-inhibition only) versus 0.9 mm2 (PD1-inhibition + anti-CSF1R-antibody) versus 2.5 mm2 (PD1-inhibition + small molecular CSF1R-inhibitor)) (p = 0.01). The beneficial effects of the small molecular CSF1R-inhibitor in reducing tumor growth were similar to those of the anti-CSF1R-antibody. CONCLUSION Targeting intratumoral TAM/M using CSF1-inhibition may increase the efficacy of checkpoint-inhibition therapy for cerebral lung cancer metastases. This approach warrants further evaluation in preclinical and clinical studies.

INTRODUCTION The cIMPACT-NOW update 6 introduced glioblastoma diagnosis based on the combination of IDH-wildtype (IDHwt) status and TERT promotor mutation (pTERTmut). In glioblastoma as defined by histopathology according to the WHO 2016 classification, MGMT promotor status is associated with outcome. Whether this is also true in glioblastoma defined by molecular markers is yet unclear. METHODS We searched the institutional database for patients with: 1.) glioblastoma defined by histopathology; and 2.) IDHwt astrocytoma with pTERTmut. MGMT promotor methylation was analysed using methylation-specific PCR and Sanger sequencing of CpG sites within the MGMT promotor region. RESULTS We identified 224 patients with glioblastoma diagnosed based on histopathology, and 71 patients with IDHwt astrocytoma with pTERTmut (32 astrocytomas WHO grade II and 39 astrocytomas WHO grade III). There was no difference in the number of MGMT methylated tumors between the two groups as determined per PCR, and also neither the number nor the pattern of methylated CpG sites differed as determined per Sanger sequencing. Progression-free (PFS) and overall survival (OS) was similar between the two groups. Surgery was associated with improved overall survival in IDHwt astrocytoma with pTERTmut. In patients treated with radiochemotherapy or radiotherapy, higher numbers of methylated CpG sites were associated with favourable outcome in both groups. CONCLUSION Extent and pattern of methylated CpG sites are similar in glioblastoma and IDHwt astrocytoma with pTERTmut. In both groups, higher numbers of methylated CpG sites are associated with favourable outcome when radio/chemotherapy is administered. Surgery may form the basis for favourable outcome.

Simple Summary Primary or secondary central nervous system (CNS) lymphoma is frequently associated with a poor prognosis. CAR T-cells are being established as a relevant treatment approach in hematological B-cell malignancies. Unfortunately, most clinical studies on chimeric antigen-receptor (CAR) T-cells have excluded patients with CNS involvement but several clinical trials on CAR T-cell therapy in CNS lymphoma patients are currently ongoing. Preclinical and preliminary clinical data suggest an overall acceptable safety profile and considerable anti-tumor effects might be extrapolated for CAR T-cell therapy in CNS lymphoma. Abstract Primary CNS lymphomas (PCNSL) represent a group of extranodal non-Hodgkin lymphomas and secondary CNS lymphomas refer to secondary involvement of the neuroaxis by systemic disease. CNS lymphomas are associated with limited prognosis even after aggressive multimodal therapy. Chimeric antigen receptor (CAR) T-cells have proven as a promising therapeutic avenue in hematological B-cell malignancies including diffuse large B-cell lymphoma, B-cell acute lymphoblastic leukemia, and mantle-cell lymphoma. CARs endow an autologous T-cell population with MHC-unrestricted effectivity against tumor target antigens such as the pan B-cell marker CD19. In PCNSL, compelling and long-lasting anti-tumor effects of such therapy have been shown in murine immunocompromised models. In clinical studies on CAR T-cells for CNS lymphoma, only limited data are available and often include both patients with PCNSL but also patients with secondary CNS lymphoma. Several clinical trials on CAR T-cell therapy for primary and secondary CNS lymphoma are currently ongoing. Extrapolated from the available preliminary data, an overall acceptable safety profile with considerable anti-tumor effects might be expected. Whether these beneficial anti-tumor effects are as long-lasting as in animal models is currently in doubt; and the immunosuppressive tumor microenvironment of the brain may be among the most pivotal factors limiting efficacy of CAR T-cell therapy in CNS lymphoma. Based on an increasing understanding of CAR T-cell interactions with the tumor cells as well as the cerebral tissue, modifications of CAR design or the combination of CAR T-cell therapy with other therapeutic approaches may aid to release the full therapeutic efficiency of CAR T-cells. CAR T-cells may therefore emerge as a novel treatment strategy in primary and secondary CNS lymphoma.

Widespread inflammatory lesions within the central nervous system grey and white matter are major hallmarks of multiple sclerosis. The development of full-blown demyelinating multiple sclerosis lesions might be preceded by preactive lesions which are characterized by focal microglia activation in close spatial relation to apoptotic oligodendrocytes. In this study, we investigated the expression of signaling molecules of oligodendrocytes that might be involved in initial microglia activation during preactive lesion formation. Sodium azide was used to trigger mitochondrial impairment and cellular stress in oligodendroglial cells in vitro. Among various chemokines and cytokines, IL6 was identified as a possible oligodendroglial cell-derived signaling molecule in response to cellular stress. Relevance of this finding for lesion development was further explored in the cuprizone model by applying short-term cuprizone feeding (2–4 days) on male C57BL/6 mice and subsequent analysis of gene expression, in situ hybridization and histology. Additionally, we analyzed the possible signaling of stressed oligodendroglial cells in vitro as well as in the cuprizone mouse model. In vitro, conditioned medium of stressed oligodendroglial cells triggered the activation of microglia cells. In cuprizone-fed animals, IL6 expression in oligodendrocytes was found in close vicinity of activated microglia cells. Taken together, our data support the view that stressed oligodendrocytes have the potential to activate microglia cells through a specific cocktail of chemokines and cytokines among IL6. Further studies will have to identify the temporal activation pattern of these signaling molecules, their cellular sources, and impact on neuroinflammation.