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Due to their delicate locations as well as aggressive and infiltrative behavior, malignant brain tumors remain a therapeutic challenge. Harnessing the efficacy and specificity of the T-cell response to counteract malignant brain tumor progression and recurrence, represents an attractive treatment option. With the tremendous advances in the current era of immunotherapy, ongoing studies aim to determine the best treatment strategies for mounting a tumor-specific immune response against malignant brain tumors. However, immunosuppression in the local tumor environment, molecular and cellular heterogeneity as well as a lack of suitable targets for tumor-specific vaccination impede the successful implementation of immunotherapeutic treatment strategies in neuro-oncology. In this review, we therefore discuss the role of T cell exhaustion, the genetic and antigenic landscape, potential pitfalls and ongoing efforts to overcome the individual challenges in order to elicit a tumor-specific T cell response.

Activating intra-tumor innate immunity might enhance tumor immune surveillance. Virotherapy is proposed to achieve tumor cell killing, while indirectly activating innate immunity. Here, we report that recombinant poliovirus therapy primarily mediates antitumor immunotherapy via direct infection of non-malignant tumor microenvironment (TME) cells, independent of malignant cell lysis. Relative to other innate immune agonists, virotherapy provokes selective, TBK1-IRF3 driven innate inflammation that is associated with sustained type-I/III interferon (IFN) release. Despite priming equivalent antitumor T cell quantities, MDA5-orchestrated TBK1-IRF3 signaling, but not NFκB-polarized TLR activation, culminates in polyfunctional and Th1-differentiated antitumor T cell phenotypes. Recombinant type-I IFN increases tumor-localized T cell function, but does not mediate durable antitumor immunotherapy without concomitant pattern recognition receptor (PRR) signaling. Thus, virus-induced MDA5-TBK1-IRF3 signaling in the TME provides PRR-contextualized IFN responses that elicit functional antitumor T cell immunity. TBK1-IRF3 innate signal transduction stimulates eventual function and differentiation of tumor-infiltrating T cells. Innate intratumoral immunity might be important in enhancing oncolytic tumor immunotherapy. Here, the authors show that recombinant poliovirus signalling through TBK-IRF3 enhances tumor-infiltrating T cell activity and multi-cytokine function.

Although clinically relevant, the detection rates of EpCAM positive CTCs in non-small cell lung cancer (NSCLC) are surprisingly low. To find new clinically informative markers for CTC detection in NSCLC, the expression of EGFR and HER3 was first analyzed in NSCLC tissue (n = 148). A positive EGFR and HER3 staining was observed in 52.3% and 82.7% of the primary tumors, and in 62.7% and 91.2% of brain metastases, respectively. Only 3.0% of the brain metastases samples were negative for both HER3 and EGFR proteins, indicating that the majority of metastases express these ERBB proteins, which were therefore chosen for CTC enrichment using magnetic cell-separation. Enrichment based on either EGFR or HER3 detected CTCs in 37.8% of the patients, while the combination of EGFR/HER3 enrichment with the EpCAM-based CellSearch technique detected a significantly higher number of 66.7% CTC-positive patients (Cohen’s kappa = −0.280) which underlines the existence of different CTC subpopulations in NSCLC. The malignant origin of keratin-positive/CD45-negative CTC clusters and single CTCs detected after EGFR/HER3 based enrichment was documented by the detection of NSCLC-associated mutations. In conclusion, EGFR and HER3 expression in metastasized NSCLC patients have considerable value for CTC isolation plus multiple markers can provide a novel liquid biopsy approach.

PurposeThis study sought to recognize differences in clinical disease manifestations of spondylodiscitis depending on the causative bacterial species.MethodsWe performed an evaluation of all spondylodiscitis cases in our clinic from 2013–2018. 211 patients were included, in whom a causative bacterial pathogen was identified in 80.6% (170/211). We collected the following data; disease complications, comorbidities, laboratory parameters, abscess occurrence, localization of the infection (cervical, thoracic, lumbar, disseminated), length of hospital stay and 30-day mortality rates depending on the causative bacterial species. Differences between bacterial detection in blood culture and intraoperative samples were also recorded.ResultsThe detection rate of bacterial pathogens through intraoperative sampling was 66.3% and could be increased by the results of the blood cultures to a total of 80.6% (n = 170/211). S. aureus was the most frequently detected pathogen in blood culture and intraoperative specimens and and was isolated in a higher percentage cervically than in other locations of the spine. Bacteremic S. aureus infections were associated with an increased mortality (31.4% vs. overall mortality of 13.7%, p = 0.001), more frequently developing complications, such as shock, pneumonia, and myocardial infarction. Comorbidities, abscesses, length of stay, sex, and laboratory parameters all showed no differences depending on the bacterial species.ConclusionBlood culture significantly improved the diagnostic yield, thus underscoring the need for a structured diagnostic approach. MSSA spondylodiscitis was associated with increased mortality and a higher incidence of complications.

Glioblastoma (GBM) is a highly aggressive primary brain tumor that is largely refractory to treatment and, therefore, invariably relapses. GBM patients have a median overall survival of 15 months and, given this devastating prognosis, there is a high need for therapy improvement. One of the therapeutic approaches currently tested in GBM is chimeric antigen receptor (CAR)-T cell therapy. CAR-T cells are genetically altered T cells that are redirected to eliminate tumor cells in a highly specific manner. There are several challenges to CAR-T cell therapy in solid tumors such as GBM, including restricted trafficking and penetration of tumor tissue, a highly immunosuppressive tumor microenvironment (TME), as well as heterogeneous antigen expression and antigen loss. In addition, CAR-T cells have limitations concerning safety, toxicity, and the manufacturing process. To date, CAR-T cells directed against several target antigens in GBM including interleukin-13 receptor alpha 2 (IL-13Rα2), epidermal growth factor receptor variant III (EGFRvIII), human epidermal growth factor receptor 2 (HER2), and ephrin type-A receptor 2 (EphA2) have been tested in preclinical and clinical studies. These studies demonstrated that CAR-T cell therapy is a feasible option in GBM with at least transient responses and acceptable adverse effects. Further improvements in CAR-T cells regarding their efficacy, flexibility, and safety could render them a promising therapy option in GBM.

Background The incidence of brain metastases in breast cancer (BCBM) patients is increasing. These patients have a very poor prognosis, and therefore, identification of blood-based biomarkers, such as circulating tumor cells (CTCs), and understanding the genomic heterogeneity could help to personalize treatment options. Methods Both EpCAM-dependent (CellSearch® System) and EpCAM-independent Ficoll-based density centrifugation methods were used to detect CTCs from 57 BCBM patients. DNA from individual CTCs and corresponding primary tumors and brain metastases were analyzed by next-generation sequencing (NGS) in order to evaluate copy number aberrations and single nucleotide variations (SNVs). Results CTCs were detected after EpCAM-dependent enrichment in 47.7% of the patients (≥ 5 CTCs/7.5 ml blood in 20.5%). The CTC count was associated with ERBB2 status ( p  = 0.029) of the primary tumor as well as with the prevalence of bone metastases ( p  = 0.021). EpCAM-independent enrichment revealed CTCs in 32.6% of the patients, especially among triple-negative breast cancer (TNBC) patients (70.0%). A positive CTC status after enrichment of either method was significantly associated with decreased overall survival time ( p  < 0.05). Combining the results of both enrichment methods, 63.6% of the patients were classified as CTC positive. In three patients, the matched tumor tissue and single CTCs were analyzed by NGS showing chromosomal aberrations with a high genomic clonality and mutations in pathways potentially important in brain metastasis formation. Conclusion The detection of CTCs, regardless of the enrichment method, is of prognostic relevance in BCBM patients and in combination with molecular analysis of CTCs can help defining patients with higher risk of early relapse and suitability for targeted treatment.

Breast cancer is a significant global health burden, causing a substantial number of deaths. Systemic metastatic tumour cell dissemination is a major cause of poor outcomes. Understanding the mechanisms underlying metastasis is crucial for effective interventions. Changes in the extracellular matrix play a pivotal role in breast cancer metastasis. In this work, we present an advanced multimodal X-ray computed tomography, by combining Small-angle X-ray Scattering Tensor Tomography (SAXS-TT) and X-ray Fluorescence Computed Tomography (XRF-CT). This approach likely brings out valuable information about the breast cancer metastasis cascade. Initial results from its application on a breast cancer specimen reveal the collective influence of key molecules in the metastatic mechanism, identifying a strong correlation between zinc accumulation (associated with matrix metalloproteinases MMPs) and highly oriented collagen. MMPs trigger collagen alignment, facilitating breast cancer cell intravasation, while iron accumulation, linked to angiogenesis and vascular endothelial growth factor VEGF, supports cell proliferation and metastasis. Therefore, these findings highlight the potential of the advanced multimodal X-ray computed tomography approach and pave the way for in-depth investigation of breast cancer metastasis, which may guide the development of novel therapeutic approaches and enable personalised treatment strategies, ultimately improving patient outcomes in breast cancer management.

PurposeSurgical intervention with intercorporal stabilisation in spinal infections is increasingly needed. Our aim was to compare titanium and polyetheretherketon (PEEK) cages according to their adhesion characteristics of different bacteria species in vitro. MethodsPlates made from PEEK, polished titanium (Ti), two-surface-titanium (TiMe) (n = 2–3) and original PEEK and porous trabecular structured titanium (TiLi) interbody cages (n = 4) were inoculated in different bacterial solutions, S.aureus (MSSA, MRSA), S.epidermidis and E.coli. Growth characteristics were analysed. Biofilms and bacteria were visualised using confocal- and electron microscopy.ResultsQuantitative adherence of MSSA, MRSA, S.epidermidis and E.coli to Ti, TiMe and PEEK plates were different, with polished titanium being mainly advantageous over PEEK and TiMe with significantly less counts of colony forming units (CFU) for MRSA after 56 h compared to TiMe and at 72 h compared to PEEK (p = 0.04 and p = 0.005). For MSSA, more adherent bacteria were detected on PEEK than on TiMe at 32 h (p = 0.02). For PEEK and TiLi cages, significant differences were found after 8 and 72 h for S.epidermidis (p = 0.02 and p = 0.008) and after 72 h for MSSA (p = 0.002) with higher bacterial counts on PEEK, whereas E.coli showed more CFU on TiLi than PEEK (p = 0.05). Electron microscopy demonstrated enhanced adhesion in transition areas.ConclusionFor S.epidermidis, MSSA and MRSA PEEK cages showed a higher adherence in terms of CFU count, whereas for E.coli PEEK seemed to be advantageous. Electron microscopic visualisation shows that bacteria did not adhere at the titanium mesh structure, but at the border zones of polished material to rougher parts.

Study Design Retrospective cohort study. Objective Cavernous malformations (CMs) and hemangioblastomas (HBs) of the spinal cord exhibit distinct differences in histopathology but similarities in the neurological course. The aim of our study was to analyze the clinical differences between the vascular pathologies and a benign tumor of the spinal cord in a perioperative situation. Methods We performed a retrospective analysis of patients who had undergone surgery for lesions in the spinal cord between 1984 and 2015. Patients were screened for CMs and HBs as the primary inclusion criteria. General patient information, surgical data, and disease-specific data were collected from the records. Cooper–Epstein scores for clinical symptoms were evaluated preoperatively, at discharge, and at the 6-month follow-up. Results A total of 112 patients were included, of which 46 had been diagnosed with CMs and 66 with HBs. Patients with CMs often demonstrated more preoperative neurological deterioration compared to those with HBs (P < .05); accordingly, in took longer to diagnose HBs. Complete resection was possible for 96.8% of all patients with CMs and 90% of those with HBs. At the 6-month follow-up, patients with HBs more often presented with persisting neurologic impairment of the upper extremities compared to the CM patients (P < .001). Conclusion CMs and HBs of the spinal cord have similarities but also exhibit significant differences in neurological presentation and perioperative course. Surgical therapy is the treatment of choice for symptomatic lesions, and complete surgical resection is possible in the majority of cases for both entities. Neurologic outcomes are usually favorable, although patients with HBs retain neurologic deficits more often.

Key Points Cancer cells leaving the immunosuppressive microenvironment of the primary tumour become vulnerable to immune surveillance and require mechanisms of escape from immune-mediated elimination if they are to form metastases Circulating tumour cells (CTCs) and disseminated tumour cells (DTCs) are often detectable in the peripheral blood and bone marrow, respectively, of patients with any of a range of different malignancies CTCs and DTCs exploit a large variety of immune-escape mechanisms, including alterations in the expression of MHC molecules, NK-cell ligands, FAS, FAS ligand (FASL), and immune-checkpoint molecules, such as CD47 and programmed cell death 1 ligand 1 (PD-L1) CTC homing to distant organs can be supported by direct interactions with immune cells during the process of extravasation, and by the effects of inflammatory cytokines in the target organ Future studies must address the important question of how the immune system shapes the molecular composition of CTCs and DTCs during cancer dormancy and metastatic progression To form metastases, cancer cells must leave the immunosuppressive tumour microenvironment and traffic, predominantly in the circulation, to new tissue sites, where they must then expand. During this process, the tumour cells are open to attack by the immune system. This Review highlights the possible mechanisms used by circulating tumour cells in the blood and disseminated tumour cells in other tissues to evade, escape, or subvert the immune system in order to survive and form metastatic lesions. Metastatic spread of tumour cells is the main cause of cancer-related deaths. Understanding the mechanisms of tumour-cell dissemination has, therefore, become an important focus for cancer research. In patients with cancer, disseminated cancer cells are often detectable in the peripheral blood as circulating tumour cells (CTCs) and in the bone marrow or lymph nodes as disseminated tumour cells (DTCs). The identification and characterization of CTCs and DTCs has yielded important insights into the mechanisms of metastasis, resulting in a better understanding of the molecular alterations and profiles underlying drug resistance. Given the expanding role of immunotherapies in the treatment of cancer, interactions between tumour cells and immune cells are the subject of intense research. Theoretically, cancer cells that exit the primary tumour site — leaving the protection of the typically immunosuppressive tumour microenvironment — will be more vulnerable to attack by immune effector cells; thus, the survival of tumour cells after dissemination might be the 'Achilles' heel' of metastatic progression. In this Review, we discuss findings relating to the interactions of CTCs and DTCs with the immune system, in the context of cancer immuno-editing, evasion from immune surveillance, and formation of metastases.