Circulating monocytes and tumor-associated macrophages express recombined immunoglobulins in glioblastoma patients

Background: Glioblastoma is the most common and malignant brain tumor in adults. Glioblastoma is usually fatal 12–15 months after diagnosis and the current possibilities in therapy are mostly only palliative. Therefore, new forms of diagnosis and therapy are urgently needed. Since tumor-associated macrophages are key players in tumor progression and survival there is large potential in investigating their immunological characteristics in glioblastoma patients. Recent evidence shows the expression of variable immunoglobulins and TCRαβ in subpopulations of monocytes, in vitro polarized macrophages and macrophages in the tumor microenvironment. We set out to investigate the immunoglobulin sequences of circulating monocytes and tumor-associated macrophages from glioblastoma patients to evaluate their potential as novel diagnostic or therapeutic targets. Results: We routinely find consistent expression of immunoglobulins in tumor-associated macrophages (TAM) and circulating monocytes from all glioblastoma patients analyzed in this study. However, the immunoglobulin repertoires of circulating monocytes and TAM are generally more restricted compared to B cells. Furthermore, the immunoglobulin expression in the macrophage populations negatively correlates with the tumor volume. Interestingly, the comparison of somatic mutations, V-chain usage, CDR3-length and the distribution of used heavy chain genes on the locus of chromosome 14 of the immunoglobulins from myeloid to B cells revealed virtually no differences. Conclusions: The investigation of the immunoglobulin repertoires from TAM and circulating monocytes in glioblastoma-patients revealed a negative correlation to the tumor volume, which could not be detected in the immunoglobulin repertoires of the patients’ B lymphocytes. Furthermore, the immunoglobulin repertoires of monocytes were more diverse than the repertoires of the macrophages in the tumor microenvironment from the same patients suggesting a tumor-specific immune response which could be advantageous for the use as diagnostic or therapeutic target

DNA methylation-based classification of central nervous system tumours.

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology

MR angiography follow-up 10 years after cryptogenic nonperimesencephalic subarachnoid hemorrhage.

OBJECTIVES:Long-term magnetic resonance angiography (MRA) follow-up studies regarding cryptogenic nonperimesencephalic subarachnoid hemorrhage (nSAH) are scarce. This single-centre study identified all patients with angiographically verified cryptogenic nSAH from 1998 to 2007: The two main objectives were to prospectively assess the incidence of de novo aneurysm with 3.0-MRI years after cryptogenic nSAH in patients without evidence for further hemorrhage, and retrospectively assess patient demographics and outcome. METHODS:From prospectively maintained report databases all patients with angiographically verified cryptogenic nSAH were identified. 21 of 29 patients received high-resolution 3T-MRI including time-of-flight and contrast-enhanced angiography, 10.2 ± 2.8 years after cryptogenic nSAH. MRA follow-up imaging was compared with initial digital subtraction angiography (DSA) and CT/MRA. Post-hemorrhage images were related to current MRI with reference to persistent lesions resulting from delayed cerebral ischemia (DCI) and post-hemorrhagic siderosis. Patient-based objectives were retrospectively abstracted from clinical databases. RESULTS:29 patients were identified with cryptogenic nSAH, 17 (59%) were male. Mean age at time of hemorrhage was 52.9 ± 14.4 years (range 4 - 74 years). 21 persons were available for long-term follow-up. In these, there were 213.5 person years of MRI-follow-up. No de novo aneurysm was detected. Mean modified Rankin Scale (mRS) during discharge was 1.28. Post-hemorrhage radiographic vasospasm was found in three patients (10.3%); DCI-related lesions occurred in one patient (3.4%). Five patients (17.2%) needed temporary external ventricular drainage; long-term CSF shunt dependency was necessary only in one patient (3.4%). Initial DSA retrospectively showed a 2 x 2 mm aneurysm of the right distal ICA in one patient, which remained stable. Post-hemorrhage siderosis was detected 8.1 years after the initial bleeding in one patient (4.8%). CONCLUSION:Patients with cryptogenic nSAH have favourable outcomes and do not exhibit higher risks for de novo aneurysms. Therefore the need for long-term follow up after cryptogenic nSAH is questionable

Clinical details of patients with cryptogenic nonperimesencephalic subarachnoid hemorrhage.

<p>1 = male, 2 = female, tEVD = need of an temporary external ventricular drainage, lSD = long term shunt dependency, rVS = radiographic vasospasm, DCI = delayed cerebral ischemia, mRS = mean Rankin scale, mHS = mean hospital stay <i>(day)</i>, mICUS = mean intensive care unit stay (day), FU yrs = follow-up years, AA = aneurysm,° = follow-up data missing</p><p>Clinical details of patients with cryptogenic nonperimesencephalic subarachnoid hemorrhage.</p

Initial and follow-up digital subtraction angiography of a 44-year-old female patient (Table 1, #21) 8 years after bleeding.

<p><i>A</i> Right ICA angiogram (lateral view) obtained in 2005 depicting a 2 x 2 mm aneurysm of the right distal ICA <i>(arrow)</i>, which was not initially detected. <i>B</i> Pre-operative angiogram of the right ICA (lateral view) in 2013; since 2005 the morphology and extension of the distal ICA aneurysm remained stable <i>(arrow)</i>. ICA = internal carotid artery.</p

MRI follow-up eight years after nonperimesencephalic subarachnoid hemorrhage of a 73-year-old male patient (Table 1, #17).

<p>Post-hemorrhagic sulcal siderosis is indicated by arrows. <i>A-D</i> show no residuals after bleeding. <i>E</i> shows sulcal siderosis on the parietal and occipital left hemisphere. <i>F</i> depicts no aneurysm in TOF-angiography. Sequences: <i>A</i> = T2 TIRM weighted, <i>B</i> = T1-TIRM weighted, <i>C</i> = diffusion-weighted, <i>D</i> = T2 weighted, <i>E</i> = T2* weighted, <i>F</i> = time-of-flight-angiography.</p

MRI follow-up six years after nonperimesencephalic subarachnoid hemorrhage of a 59-year-old male patient (Table 1, #15).

<p>DCI-related lesions are indicated by arrows. <i>A-E</i> show bilateral chronic liquor-isointense areas with surrounding gliosis and no diffusion restriction, nor hemosiderin residues. <i>F</i> depicts no aneurysm in TOF-angiography. <i>Sequences</i>: <i>A =</i> T2 TIRM weighted, <i>B</i> = T1-TIRM weighted, <i>C</i> = diffusion-weighted, <i>D</i> = T2 weighted, <i>E</i> = T2* weighted, <i>F</i> = time-of-flight-angiography.</p