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.
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.
Purpose
This study sought to recognize differences in clinical disease manifestations of spondylodiscitis depending on the causative bacterial species.
Methods
We 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.
Results
The 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.
Conclusion
Blood 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.
Knowledge on immune and stromal cells in medulloblastoma microenvironment is still limited as previous work was frequently restricted by low sample size and the lack of molecular subgroup ...information. We characterized 10 microenvironment cell populations as well as
from gene expression in 1422 brain tumors and 763 medulloblastomas. All in all, medulloblastomas showed low expression of immune markers. Still, there were substantial differences with a clustering of medulloblastoma subgroups according to their microenvironment profile. Specifically, SHH medulloblastomas displayed strong signatures of fibroblasts, T cells and macrophages, while markers of cytotoxic lymphocytes were enriched in Group 4 tumors.
gene expression appeared to be relatively high in single SHH and WNT cases but was undetectable by immunohistochemistry. In addition, two diverse immuno-stromal patterns were identified, indicating distinct types of local tumor immunosuppression, which were primarily controlled by either macrophage and regulatory T cell-mediated mechanisms or immunosuppressive cytokines and checkpoints, respectively. None of the immune cell signatures had an independent prognostic value in the present dataset after multiple testing correction. These results suggest a mild, but subgroup-specific infiltration of immune cells in medulloblastoma.
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.
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.
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).
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.
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.
Purpose
Surgical 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.
Methods
Plates 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.
Results
Quantitative 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.
Conclusion
For
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.
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