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.

Two patients with primary intraspinal primitive neuroectodermal tumour are presented. In a 32-year-old man, the tumour evolved intradurally from a sacral nerve root. Despite repeated surgery and radiochemotherapy, the patient suffered multiple intraspinal tumour relapses and intracranial seedings, and died 29 months after the first diagnosis. In a 17-year-old male adolescent, the tumour was located in the lumbar epidural space, extending into the paraspinal muscles. Following resection and radiochemotherapy, the patient is free from disease 23 months after the initial presentation. The clinical, radiological, histopathological and cytogenetic findings of both patients are presented and the relevant literature is reviewed. Particular attention is given to the histogenetic relationship between peripheral primitive neuroectodermal tumour and Ewing's sarcoma.

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 the DNA methylation dynamics in matched primary and recurring glioblastoma tumors, based on a national population registry and a comprehensively annotated clinical cohort. We demonstrate the feasibility of DNA methylation mapping in a large set of routinely collected formalin-fixed paraffin-embedded (FFPE) samples, and we validate bisulfite sequencing as a multi-purpose assay that allowed us to infer a range of different genetic, epigenetic, and transcriptional tumor characteristics. Based on these data, we identified characteristic 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 provides a resource for dissecting DNA methylation heterogeneity in genetically diverse and heterogeneous tumors, and it demonstrates the feasibility of integrating epigenomics, radiology, and digital pathology in a representative national cohort, leveraging samples and data collected as part of routine clinical practice.

The aim of this study was to determine the value, advantages and limitations of ultrasound-guided fine-needle aspiration biopsy (US-FNAB) in an endemic goitre area. US-FNAB was performed on all outpatients who presented with hypoechoic and/or hypofunctional and/or growing nodules. A total of 4518 US-FNABs were performed and 718 patients from this series underwent surgery. Cytological results of the primarily performed US-FNAB of these patients were compared retrospectively with the histological results. US-FNAB results were grouped as (1) non-malignant (n = 303), (2) non-malignant follicular proliferation (n = 177), (3) malignancy cannot be ruled out (n = 133), (4) malignant (n = 61), (5) inadequate (n = 34), and (6) sampling error; biopsy of a non-malignant nodule (n = 10). Nodules as small as 5 mm in diameter could be biopsied, gaining representative material. US-FNAB found a malignant or suspicious cytology in 65 out of 87 cases with malignant histology (74.71%). Diagnosis of early tumour stages was often possible: 12 of 18 thyroid carcinomas biopsied and smaller than 10 mm in diameter had malignant or suspicious cytology (groups 3 and 4). US-FNAB was performed incorrectly within non-malignant nodules in ten patients (1.39%) with multinodular goitre (ten papillary carcinomas, nine smaller than 10 mm). Regarding the cytology of groups 1 and 2 as benign and those of groups 3 and 4 as malignant, US-FNAB performance was as follows: sensitivity 87.84%, specificity 78.50%, negative predictive values 98.13%, positive predictive values 33.51% and accuracy 79.53%. Biopsies with inadequate material were obtained in 4.73% of all biopsies. No major adverse effects occurred. Re-biopsies in 61 cases did not alter the cytological outcome in those cases where adequate material was obtained. US-FNAB is a valuable method in the pre-operative assessment of thyroid nodules in order to select patients for surgery, as malignancy can often be detected even in early tumour stages. However, even with ultrasonographic guidance, the minimal tumour size detectable by US-FNAB is around 5 mm. The cytological interpretation in cases with regression and microfollicular proliferation also sets limits on the method. However, patients with non-malignant cytologies can be followed up safely by sonography due to the high NPV of US-FNAB as long as thyroid nodules do not become larger. Re-biopsies seem to be of limited value as long as adequate material was obtained by US-FNAB.

Background:Unlike malignant primary central nervous system (CNS) tumours outcome data on non-malignant CNS tumours are scarce. For patients diagnosed from 1996 to 2002 5-year relative survival of only 85.0% has been reported. We investigated this rate in a contemporary patient cohort to update information on survival.Methods:We followed a cohort of 3983 cases within the Austrian Brain Tumour Registry. All patients were newly diagnosed from 2005 to 2010 with a histologically confirmed non-malignant CNS tumour. Vital status, cause of death, and population life tables were obtained by 31 December 2011 to calculate relative survival.Results:Overall 5-year relative survival was 96.1% (95% CI 95.1–97.1%), being significantly lower in tumours of borderline (90.2%, 87.2–92.7%) than benign behaviour (97.4%, 96.3–98.3%). Benign tumour survival ranged from 86.8 for neurofibroma to 99.7% for Schwannoma; for borderline tumours survival rates varied from 83.2 for haemangiopericytoma to 98.4% for myxopapillary ependymoma. Cause of death was directly attributed to the CNS tumour in 39.6%, followed by other cancer (20.4%) and cardiovascular disease (15.8%).Conclusion:The overall excess mortality in patients with non-malignant CNS tumours is 5.5%, indicating a significant improvement in survival over the last decade. Still, the remaining adverse impact on survival underpins the importance of systematic registration of these tumours.