Glioblastoma in the real-world setting: patterns of care and outcome in the Austrian population.

PURPOSE: We present results of a retrospective population-based investigation of patterns of care and outcome of glioblastoma patients in Austria. PATIENTS AND METHODS: In this nation-wide cooperative project, all Austrian glioblastoma patients newly diagnosed between 2014 and 2018 and registered in the ABTR-SANOnet database were included. Histological typing used criteria of the WHO classification of CNS tumors, 4th edition 2016. Patterns of care were assessed, and all patients were followed until the end of 2019. RESULTS: 1,420 adult glioblastoma cases were identified. 813 (57.3%) patients were male and 607 (42.7%) female. Median age at diagnosis was 64 years (range: 18-88). Median overall survival (OS) was 11.6 months in the total cohort and 10.9 months in patients with proven IDH-wildtype. Median OS in the patient group ≤ 65 years receiving postoperative standard of care therapy was 16.1 months. In the patient group > 65 years with postoperative therapy, median OS was 11.2 months. Follow-up ≥ 5 years identified 13/264 (4.9%) long-term survivors. Brain tumor surgery frequently was assisted by 5-aminolevulinic acid (5-ALA) fluorescence (up to 55%). Postoperative treatment was initiated around one month after surgery (median: 31 days) following standardized protocols in 1,041/1,420 (73.3%) cases. In 830 patients (58.5%), concomitant radiochemotherapy was started according to the established standard of care. Treatment in case of progressive disease was considerably variable. 170/1,420 patients (12.0%) underwent a second surgical procedure, 467 (33.0%) received systemic treatment after progression, and 173 (12.2%) were re-irradiated. CONCLUSION: Our data illustrate and confirm nation-wide translation of effective standard of care to Austrian glioblastoma patients in the recent past. In the case of progressive disease, highly variable therapeutic approaches were used, most frequently accompanied by anti-angiogenic therapy. Long-term survival was observed in a minor proportion of mostly younger patients who typically had gross total tumor resection, a favorable postoperative ECOG score, and standard of care therapy.

Beyond T cell toxicity - Intrathecal chemokine CXCL13 indicating B cell involvement in immune-related adverse events following checkpoint inhibition: A two-case series and literature review.

BACKGROUND AND PURPOSE: This study was undertaken to raise awareness of a role of B cells in immune checkpoint inhibitor (ICI)-associated neurological immune-related adverse events (nirAE). METHODS: A systematic literature review was made, with case observations of a melanoma and a non-small cell lung cancer (NSCLC) patient who developed ICI-associated nirAE with cerebrospinal fluid (CSF) findings indicating B cell involvement. RESULTS: Two patients receiving ipilimumab/nivolumab for melanoma and chemotherapy/pembrolizumab for NSCLC developed nirAE in the form of myocarditis/myositis/myasthenia gravis overlap syndrome (triple M) and cerebellitis plus longitudinal transverse myelitis (c-LETM), respectively. Intrathecal inflammation with chemokine C-X-C motif ligand (CXCL13) elevation was present in both patients; the triple M case had acetylcholine receptor antibodies, antititin reactivity, altered CD4/CD8 T cell ratio in blood, and depressed programmed death-1 (PD-1) expression on CSF T cells; the c-LETM case showed intrathecal antibody production and plasma cells. Both patients insufficiently responded to first-line treatment. The NSCLC case improved upon administration of B cell-depleting therapy with rituximab, whereas the melanoma patient died before escalation therapy was initiated. Literature research revealed one additional ICI-associated LETM case with intrathecal CXCL13 elevation, three cases with ICI-associated aquaporin-4 antibody neuromyelitis spectrum disorder, and evidence of B cell-mediated toxicity based on antibody-mediated immune pathologies in ICI-associated immune-related adverse events. CONCLUSIONS: The case observations highlight the plethora of uncertainties in diagnosis and treatment of ICI-associated nirAE, exemplify the heterogeneity of immune mechanisms involved, and suggest a role of B cells, which may be underdiagnosed. Intrathecal CXCL13 may serve as a biomarker of B cell involvement in nirAE, supported by intrathecal immunoglobulin synthesis, presence of plasma cells, and/or recruitment of cognate immune cells.

Radiomic features define risk and are linked to DNA methylation attributes in primary CNS lymphoma.

Background: The prognostic roles of clinical and laboratory markers have been exploited to model risk in patients with primary CNS lymphoma, but these approaches do not fully explain the observed variation in outcome. To date, neuroimaging or molecular information is not used. The aim of this study was to determine the utility of radiomic features to capture clinically relevant phenotypes, and to link those to molecular profiles for enhanced risk stratification. Methods: In this retrospective study, we investigated 133 patients across 9 sites in Austria (2005-2018) and an external validation site in South Korea (44 patients, 2013-2016). We used T1-weighted contrast-enhanced MRI and an L1-norm regularized Cox proportional hazard model to derive a radiomic risk score. We integrated radiomic features with DNA methylation profiles using machine learning-based prediction, and validated the most relevant biological associations in tissues and cell lines. Results: The radiomic risk score, consisting of 20 mostly textural features, was a strong and independent predictor of survival (multivariate hazard ratio = 6.56 [3.64-11.81]) that remained valid in the external validation cohort. Radiomic features captured gene regulatory differences such as in BCL6 binding activity, which was put forth as testable treatment target for a subset of patients. Conclusions: The radiomic risk score was a robust and complementary predictor of survival and reflected characteristics in underlying DNA methylation patterns. Leveraging imaging phenotypes to assess risk and inform epigenetic treatment targets provides a concept on which to advance prognostic modeling and precision therapy for this aggressive cancer.

Non-convulsive status epilepticus with right arm apraxia: A case report.

Non-convulsive SE (NCSE) is characterized by altered consciousness with or without slight motor manifestations or other phenomena such as aphasia, sensory, auditory, emotional, gustatory or other symptoms. A 69-year-old right-handed man developed the sudden onset of apraxia in his right arm. On admission, the patient was alert and well oriented. In his past medical history, an intracerebral hematoma (ICH) in the left temporo-parietal area was noted occurred five years before the current admission. An electroencephalography (EEG) showed rhythmic theta-delta activity with fluctuating frequency between 1.5 and 5 Hz in the left centro-parieto-temporal area, which promptly responded to the intravenous injection of 2 mg clonazepam and 1000 mg levetiracetam. Apraxia resolved completely and the EEG demonstrated intermittent non-rhythmic delta-theta slowing in the left temporo-parietal area. A cranial CT scan showed residual cystic encephalomalacia in the left temporo-parietal area due to the previous ICH. An MRI exhibited an old parenchymal defect in the left temporo-parietal area with a residual hemosiderin rim on the susceptibility weighted imaging (SWI) and no diffusion restriction on the diffusion weighted image (DWI). NCSE presented with right arm apraxia in our patient with a post-hemorrhagic residual parenchymal defect in the left temporo-parietal area.

Increasing use of immunotherapy and prolonged survival among younger patients with primary CNS lymphoma: a population-based study.

Background: Primary CNS lymphoma is a highly aggressive and rare type of extranodal non-Hodgkin lymphoma. Although, new therapeutic approaches have led to improved survival, the management of the disease poses a challenge, practice patterns vary across institutions and countries, and remain ill-defined for vulnerable patient subgroups. Material and Methods: Using information from the Austrian Brain Tumor Registry we followed a population-based cohort of 189 patients newly diagnosed from 2005 to 2010 through various lines of treatment until death or last follow-up (12-31-2016). Prognostic factors and treatment-related data were integrated in a comprehensive survival analysis including conditional survival estimates. Results: We find variable patterns of first-line treatment with increasing use of rituximab and high-dose methotrexate (HDMTX)-based poly-chemotherapy after 2007, paralleled by an increase in median overall survival restricted to patients aged below 70 years. In the entire cohort, 5-year overall survival was 24.4% while 5-year conditional survival increased with every year postdiagnosis. Conclusion: In conclusion, we show that the use of poly-chemotherapy and immunotherapy has disseminated to community practice to a fair extent and survival has increased over time at least in younger patients. Annually increasing conditional survival rates provide clinicians with an adequate and encouraging prognostic measure.

Multifocal motor neuropathy in Austria: a nationwide survey of clinical features and response to treatment.

BACKGROUND AND OBJECTIVES: Multifocal motor neuropathy (MMN) is a rare neuropathy and detailed descriptions of larger patient cohorts are scarce. The objective of this study was to evaluate epidemiological, clinical, and laboratory features of MMN patients and their response to treatment in Austria and to compare these data with those from the literature. METHODS: Anonymized demographic and clinical data about MMN patients until 31.12.2017 were collected from registered Austrian neurologists. Exploratory statistics on clinical and laboratory features as well as treatment regimens and responses were performed. RESULTS: 57 Patients with MMN were identified, resulting in a prevalence of 0.65/100.000. Mean age of onset was 44.1 ± 13.1 years, the diagnostic delay 5.5 ± 8.4 years. In 77% of patients, symptom onset was in the upper limbs, and in 92%, it occurred in distal muscles. Proximal onset was never observed in the lower limbs. At the final follow-up, the majority of patients had atrophy (88%) in affected regions. Definite motor conduction blocks (CB) were found in 54 patients. Anti-GM1-IgM antibodies were present in 43%. Treatment with intravenous immunoglobulins improved muscle strength and INCAT score initially, but at last follow-up, both scores deteriorated to values before treatment. DISCUSSION: The findings of the present study corroborate the previous findings in MMN. Onset typically occurs in the upper limbs and mostly distal, CBs are found in the majority of cases, while anti-GM1-IgM antibodies are detected in only approximately 40%. Our study underlines that the initial good response to treatment fades over time.

Extensive Leptomeningeal Intracranial and Spinal Metastases in a Patient with a Supratentorial Glioblastoma Multiforme, IDH-Wildtype.

BACKGROUND: Glioblastoma multiforme (GBM) is usually characterized by diffuse, infiltrative growth and local tumor progression. Extensive leptomeningeal metastases are rarely observed. It is unclear which GBMs are prone to this specific growth pattern and progression, and standardized salvage treatment protocols are unavailable. CASE DESCRIPTION: In a 45-year-old man without focal neurologic deficit, a right temporal GBM, IDH-wildtype (biomarkers MGMT promoter methylation negative, Ki-67 proliferation rate 70%) was diagnosed. Gross tumor resection followed by concomitant and adjuvant radiotherapy and chemotherapy with temozolomide was performed. Routine follow-up imaging 8 months later showed a right parietal meningeal tumor. Resection confirmed a distant GBM, and next-generation sequencing revealed high tumor mutational burden, high-frequency microsatellite instability, and a pharmacologically targetable KIT mutation. Complete neuraxis imaging revealed multiple contrast-enhancing tumors in the craniocervical junction and levels C7, Th8-Th11, and S1. The craniocervical tumors and the cervical spine from C1-C2 were irradiated as palliative care, and second-line combined chemotherapy and antiangiogenic therapy with irinotecan and bevacizumab was initiated, which was later changed to an immune-checkpoint blockade with pembrolizumab in combination with bevacizumab owing to tumor progression. Tumor growth was slowed, but the patient eventually developed a progressive paraparesis. Subsequent KIT-targeting tyrosine kinase inhibitor therapy with imatinib was administered for a short time. The patient died 13.8 months after initial diagnosis. CONCLUSIONS: High-risk genetic profiles for GBMs prone to develop extensive leptomeningeal metastases need to be identified. Guidelines on preemptive, complete neuraxis imaging in certain patients with GBM as well as treatment guidelines need to be developed.

The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space.

Glioblastoma is characterized by widespread genetic and transcriptional heterogeneity, yet little is known about the role of the epigenome in glioblastoma disease progression. Here, we present genome-scale maps of DNA methylation in matched primary and recurring glioblastoma tumors, using data from a highly annotated clinical cohort that was selected through a national patient registry. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected FFPE samples, and we validate bisulfite sequencing as a multipurpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional characteristics of the profiled tumor samples. On the basis of these data, we identified subtle differences between primary and recurring tumors, links between DNA methylation and the tumor microenvironment, and an association of epigenetic tumor heterogeneity with patient survival. In summary, this study establishes an open resource for dissecting DNA methylation heterogeneity in a genetically diverse and heterogeneous cancer, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology for a national cohort, thereby leveraging existing samples and data collected as part of routine clinical practice.

Diagnostic challenges in vacuolar myelopathy: a didactic case report.

INTRODUCTION: Because of the diagnostic complexity and potential pitfalls in interpreting test results, HIV-vacuolar myelopathy (HIVM) is far more often diagnosed postmortem than in vivo. In the era of highly active antiretroviral therapy (HAART), the topic of neuro-AIDS has become increasingly important. This case report covers some of the diagnostic problems encountered in vacuolar myelopathy based on magnetic resonance imaging (MRI) fiber-tracking pictures of the spine in a patient with HIVM, including a 1-year follow-up. CASE PRESENTATION: A 49-year-old man felt progressive weakness, and difficulties while walking, and he suffered from incomplete voiding. A week before admission, follicles appeared on the right side of his neck and shoulder. His medical history included a chronic HIV infection treated with HAART and a B-cell lymphoma in complete remission after chemotherapy. The initial exam revealed thoracic hyposensitivity level distal to dermatome Th9, spastic paraparesis of the lower limbs and herpes zoster infection in dermatome C3/C4. A lesion of the thoracic myelon could be ruled out in the MRI scan, chemotherapy-induced polyneuropathy was stable, and no acute opportunistic infection of the CNS was found. HIV load in cerebrospinal fluid (CSF) was markedly elevated. An HIV-associated vacuolar myelopathy was diagnosed, revealing the HIV itself as etiology. DISCUSSION: A negative or unspecific MRI scan excludes possible other causes, but by no means rules out HIV-related myelopathy. Furthermore, peripheral and central viral load should always be assessed to avoid missing a possible 'CSF HIV-escape'.