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Institute
Purpose: In patients with pyogenic spondylodiscitis, surgery is considered the treatment of choice to conduct proper debridement, stabilise the spine and avoid extended bed rest, which in turn is a risk factor for complications such as deep vein thrombosis and pulmonary embolism. Methods: We conducted a retrospective clinical study with analysis of a group of 99 patients who had undergone treatment for pyogenic discitis at our institution between June 2012 and August 2017. Included parameters were age, sex, disease pattern, the presence of deep vein thrombosis, resuscitation, in-hospital mortality, present anticoagulation, preexisting comorbidities, tobacco abuse, body mass index, microbiological germ detection and laboratory results. Results: Among the analysed cohort, 12% of the treated patients for pyogenic spondylodiscitis suffered from a radiologically confirmed pulmonary embolism. Coronary heart disease (p < 0.01), female sex (p < 0.01), anticoagulation at admission (p < 0.01) and non-O blood type (p < 0.001) were associated with development of pulmonary embolism. Pulmonary embolism was significantly associated with resuscitation (p < 0.005) and deep vein thrombosis (p < 0.001). Neurosurgery was not associated with increased risk for pulmonary embolism compared to conservative-treated patients (p > 0.05). Conclusion: Surgery for pyogenic spondylodiscitis was not associated with an elevated risk of pulmonary embolism in our analysis. However, we describe several risk factors for pulmonary embolism in this vulnerable cohort. Prospective studies are necessary to improve prevention and postoperative management in patients with pyogenic spondylodiscitis.
Glioblastoma (GBM) is a cancer type with high thrombogenic potential and GBM patients are therefore at a particularly high risk for thrombotic events. To date, only limited data on anticoagulation management after pulmonary embolism (PE) in GBM is available and the sporadic use of DOACs remains off-label. A retrospective cohort analysis of patients with GBM and postoperative, thoracic CT scan confirmed PE was performed. Clinical course, follow-up at 6 and 12 months and the overall survival (OS) were evaluated using medical charts and neuroradiological data. Out of 584 GBM patients, 8% suffered from postoperative PE. Out of these, 30% received direct oral anticoagulants (DOACs) and 70% low-molecular-weight heparin (LMWH) for therapeutic anticoagulation. There was no significant difference in major intracranial hemorrhage (ICH), re-thrombosis, or re-embolism between the two cohorts. Although statistically non-significant, a tendency to reduced mRS at 6 and 12 months was observed in the LMWH cohort. Furthermore, patients receiving DOACs had a statistical benefit in OS. In our analysis, DOACs showed a satisfactory safety profile in terms of major ICH, re-thrombosis, and re-embolism compared to LMWH in GBM patients with postoperative PE. Prospective, randomized trials are urgent to evaluate DOACs for therapeutic anticoagulation in GBM patients with PE.
Linking epigenetic signature and metabolic phenotype in IDH mutant and IDH wildtype diffuse glioma
(2020)
Aims: Changes in metabolism are known to contribute to tumour phenotypes. If and how metabolic alterations in brain tumours contribute to patient outcome is still poorly understood. Epigenetics impact metabolism and mitochondrial function. The aim of this study is a characterisation of metabolic features in molecular subgroups of isocitrate dehydrogenase mutant (IDHmut) and isocitrate dehydrogenase wildtype (IDHwt) gliomas. Methods: We employed DNA methylation pattern analyses with a special focus on metabolic genes, large-scale metabolism panel immunohistochemistry (IHC), qPCR-based determination of mitochondrial DNA copy number and immune cell content using IHC and deconvolution of DNA methylation data. We analysed molecularly characterised gliomas (n = 57) for in depth DNA methylation, a cohort of primary and recurrent gliomas (n = 22) for mitochondrial copy number and validated these results in a large glioma cohort (n = 293). Finally, we investigated the potential of metabolic markers in Bevacizumab (Bev)-treated gliomas (n = 29). Results: DNA methylation patterns of metabolic genes successfully distinguished the molecular subtypes of IDHmut and IDHwt gliomas. Promoter methylation of lactate dehydrogenase A negatively correlated with protein expression and was associated with IDHmut gliomas. Mitochondrial DNA copy number was increased in IDHmut tumours and did not change in recurrent tumours. Hierarchical clustering based on metabolism panel IHC revealed distinct subclasses of IDHmut and IDHwt gliomas with an impact on patient outcome. Further quantification of these markers allowed for the prediction of survival under anti-angiogenic therapy. Conclusion: A mitochondrial signature was associated with increased survival in all analyses, which could indicate tumour subgroups with specific metabolic vulnerabilities.
Recently, the conserved intracellular digestion mechanism ‘autophagy’ has been considered to be involved in early tumorigenesis and its blockade proposed as an alternative treatment approach. However, there is an ongoing debate about whether blocking autophagy has positive or negative effects in tumor cells. Since there is only poor data about the clinico-pathological relevance of autophagy in gliomas in vivo, we first established a cell culture based platform for the in vivo detection of the autophago-lysosomal components. We then investigated key autophagosomal (LC3B, p62, BAG3, Beclin1) and lysosomal (CTSB, LAMP2) molecules in 350 gliomas using immunohistochemistry, immunofluorescence, immunoblotting and qPCR. Autophagy was induced pharmacologically or by altering oxygen and nutrient levels. Our results show that autophagy is enhanced in astrocytomas as compared to normal CNS tissue, but largely independent from the WHO grade and patient survival. A strong upregulation of LC3B, p62, LAMP2 and CTSB was detected in perinecrotic areas in glioblastomas suggesting micro-environmental changes as a driver of autophagy induction in gliomas. Furthermore, glucose restriction induced autophagy in a concentration-dependent manner while hypoxia or amino acid starvation had considerably lesser effects. Apoptosis and autophagy were separately induced in glioma cells both in vitro and in vivo. In conclusion, our findings indicate that autophagy in gliomas is rather driven by micro-environmental changes than by primary glioma-intrinsic features thus challenging the concept of exploitation of the autophago-lysosomal network (ALN) as a treatment approach in gliomas.
Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti‐angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin‐2 (Ang‐2) as a potential target in both naive and bevacizumab‐treated glioblastoma. Ang‐2 expression was absent in normal human brain endothelium, while the highest Ang‐2 levels were observed in bevacizumab‐treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang‐2, whereas the combined inhibition of VEGF and Ang‐2 leads to extended survival, decreased vascular permeability, depletion of tumor‐associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206+ (M2‐like) macrophages were identified as potential novel targets following anti‐angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang‐2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang‐2 may potentially overcome resistance to bevacizumab therapy.
Immunohistochemical assessment of phosphorylated mTORC1-pathway proteins in human brain tumors
(2015)
Background: Current pathological diagnostics include the analysis of (epi-)genetic alterations as well as oncogenic pathways. Deregulated mammalian target of rapamycin complex 1 (mTORC1) signaling has been implicated in a variety of cancers including malignant gliomas and is considered a promising target in cancer treatment. Monitoring of mTORC1 activity before and during inhibitor therapy is essential. The aim of our study is to provide a recommendation and report on pitfalls in the use of phospho-specific antibodies against mTORC1-targets phospho-RPS6 (Ser235/236; Ser240/244) and phospho-4EBP1 (Thr37/46) in formalin fixed, paraffin embedded material.
Methods and findings: Primary, established cell lines and brain tumor tissue from routine diagnostics were assessed by immunocyto-, immunohistochemistry, immunofluorescent stainings and immunoblotting. For validation of results, immunoblotting experiments were performed. mTORC-pathway activation was pharmacologically inhibited by torin2 and rapamycin. Torin2 treatment led to a strong reduction of signal intensity and frequency of all tested antibodies. In contrast phospho-4EBP1 did not show considerable reduction in staining intensity after rapamycin treatment, while immunocytochemistry with both phospho-RPS6-specific antibodies showed a reduced signal compared to controls. Staining intensity of both phospho-RPS6-specific antibodies did not show considerable decrease in stability in a timeline from 0–230 minutes without tissue fixation, however we observed a strong decrease of staining intensity in phospho-4EBP1 after 30 minutes. Detection of phospho-signals was strongly dependent on tissue size and fixation gradient. mTORC1-signaling was significantly induced in glioblastomas although not restricted to cancer cells but also detectable in non-neoplastic cells.
Conclusion: Here we provide a recommendation for phospho-specific immunohistochemistry for patient-orientated therapy decisions and monitoring treatment response.
Posterior fossa tumor surgery is challenging due to the proximity and exposure of cerebellar structures. A favorable operative approach is unknown. Following lesions to the dentato–rubro–olivary-pathway, a neurodegenerative disease called hypertrophic olivary degeneration (HOD) can occur. This study for the first time demonstrates that paravermal trans-cerebellar approaches are associated with a significantly higher likelihood of HOD on MRI when compared to other approaches. This finding can well be attributed to dentate nucleus (DN) injury. Furthermore, cerebellar mutism syndrome (CMS) was discussed in the literature to be correlated with HOD due to a functional overlap of pathways involved. We found no such correlation in this study, but HOD was shown to be a reliable indicator for surgical disruption of efferent cerebellar pathways involving the DN. Henceforth, neurosurgeons should consider more midline or lateral approaches in posterior fossa surgery to spare the DN whenever feasible, and focus on cerebellar functional anatomy in their preoperative planning.
Background: The inclusion of immune checkpoint inhibitors (ICIs) in therapeutic algorithms has led to significant survival benefits in patients with various metastatic cancers. Concurrently, an increasing number of neurological immune related adverse events (IRAE) has been observed. In this retrospective analysis, we examine the ICI-induced incidence of cerebral pseudoprogression and propose a classification system.
Methods: We screened our hospital information system to identify patients with any in-house ICI treatment for any tumor disease during the years 2007-2019. All patients with cerebral MR imaging (cMRI) of sufficient diagnostic quality were included. cMRIs were retrospectively analyzed according to immunotherapy response assessment for neuro-oncology (iRANO) criteria.
Results: We identified 12 cases of cerebral pseudoprogression in 123 patients treated with ICIs and sufficient MRI. These patients were receiving ICI therapy for lung cancer (n=5), malignant melanoma (n=4), glioblastoma (n=1), hepatocellular carcinoma (n=1) or lymphoma (n=1) when cerebral pseudoprogression was detected. Median time from the start of ICI treatment to pseudoprogression was 5 months. All but one patient developed neurological symptoms. Three different patterns of cerebral pseudoprogression could be distinguished: new or increasing contrast-enhancing lesions, new or increasing T2 predominant lesions and cerebral vasculitis type pattern.
Conclusion: Cerebral pseudoprogression followed three distinct patterns and was detectable in 3.2% of all patients during ICI treatment and in 9.75% of the patients with sufficient brain imaging follow up. The fact that all but one of the affected patients developed neurological symptoms, which would be classified as progressive disease according to iRANO criteria, mandates vigilance in the diagnosis and treatment of ICI-induced cerebral lesions.
(1) Background: A lesion within the dentato-rubro-olivary pathway (DROP) in the posterior fossa can cause secondary neurodegeneration of the inferior olivary nucleus: so-called hypertrophic olivary degeneration (HOD). The clinical syndrome of HOD occurs slowly over months and may be overlooked in progressive neuro-oncological diseases. Posterior fossa tumors are often located near these strategic structures. The goal of this study was to analyze the systematics of HOD occurrence in neuro-oncological patients.
(2) Methods: The neuroradiological database of the university healthcare center was scanned for HOD-related terms from 2010 to 2019. After excluding patients with other causes of HOD, 12 datasets from neuro-oncological patients were analyzed under predetermined criteria.
(3) Results: Patients received multimodal tumor treatments including neurosurgery, radiotherapy, and chemotherapy. HOD occurred both unilaterally (left n = 4; right n = 5) and bilaterally (n = 3). Though the mass effect of posterior fossa tumors had already affected strategic structures of the DROP, none of the patients showed signs of HOD on MRI until therapeutic measures including neurosurgery affecting the DROP were applied. HOD was visible on MRI within a median of 6 months after the neurosurgical intervention. In 67%, the presumed underlying surgical lesion in the DROP lay in the contralateral dentate nucleus.
(4) Conclusion: In a selected cohort of neuro-oncological patients, therapeutic lesions within the DROP were associated with HOD occurrence.
Background: Glioblastoma (GBM) is a cancer type with high thrombogenic potential and GBM patients are therefore at a particularly high risk for thrombotic events. To date only limited data on anticoagulation management after pulmonary embolism (PE) in GBM is available and the sporadic use of DOACs remains off-label.
Methods: A retrospective cohort analysis of patients with GBM and postoperative, thoracic CT-scan confirmed, PE was performed. Clinical course, follow-up at 6 and 12 months and the overall survival (OS) were evaluated using medical charts and neuroradiological data.
Results: Out of 584 GBM patients, 8% suffered from postoperative PE. Out of theses, 30% received direct oral anticoagulants (DOACs) and 70% low-molecular-weight heparin (LMWH) for therapeutic anticoagulation. There was no significant difference in major intracranial hemorrhage (ICH), re-thrombosis or re-embolism between the two cohorts. Although statistically non-significant, a tendency to reduced mRS at 6- and 12 months was observed in the LMWH cohort. Furthermore, patients receiving DOACs had a statistical benefit in OS.
Conclusion: In our analysis DOACs showed a satisfactory safety profile in terms of major ICH, re-thrombosis and re-embolism compared to LMWH in GBM patients with postoperative PE. Prospective, randomized trials are urgent to evaluate DOACs for therapeutic anticoagulation in GBM patients with PE.
