Marcel Seiz-Rosenhagen

DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis

BACKGROUND The WHO classification of brain tumours describes 15 subtypes of meningioma. Nine of these subtypes are allotted to WHO grade I, and three each to grade II and grade III. Grading is based solely on histology, with an absence of molecular markers. Although the existing classification and grading approach is of prognostic value, it harbours shortcomings such as ill-defined parameters for subtypes and grading criteria prone to arbitrary judgment. In this study, we aimed for a comprehensive characterisation of the entire molecular genetic landscape of meningioma to identify biologically and clinically relevant subgroups. METHODS In this multicentre, retrospective analysis, we investigated genome-wide DNA methylation patterns of meningiomas from ten European academic neuro-oncology centres to identify distinct methylation classes of meningiomas. The methylation classes were further characterised by DNA copy number analysis, mutational profiling, and RNA sequencing. Methylation classes were analysed for progression-free survival outcomes by the Kaplan-Meier method. The DNA methylation-based and WHO classification schema were compared using the Brier prediction score, analysed in an independent cohort with WHO grading, progression-free survival, and disease-specific survival data available, collected at the Medical University Vienna (Vienna, Austria), assessing methylation patterns with an alternative methylation chip. FINDINGS We retrospectively collected 497 meningiomas along with 309 samples of other extra-axial skull tumours that might histologically mimic meningioma variants. Unsupervised clustering of DNA methylation data clearly segregated all meningiomas from other skull tumours. We generated genome-wide DNA methylation profiles from all 497 meningioma samples. DNA methylation profiling distinguished six distinct clinically relevant methylation classes associated with typical mutational, cytogenetic, and gene expression patterns. Compared with WHO grading, classification by individual and combined methylation classes more accurately identifies patients at high risk of disease progression in tumours with WHO grade I histology, and patients at lower risk of recurrence among WHO grade II tumours (p=0·0096) from the Brier prediction test). We validated this finding in our independent cohort of 140 patients with meningioma. INTERPRETATION DNA methylation-based meningioma classification captures clinically more homogenous groups and has a higher power for predicting tumour recurrence and prognosis than the WHO classification. The approach presented here is potentially very useful for stratifying meningioma patients to observation-only or adjuvant treatment groups. We consider methylation-based tumour classification highly relevant for the future diagnosis and treatment of meningioma. FUNDING German Cancer Aid, Else Kröner-Fresenius Foundation, and DKFZ/Heidelberg Institute of Personalized Oncology/Precision Oncology Program.

Methylation-based classification of benign and malignant peripheral nerve sheath tumors

AbstractThe vast majority of peripheral nerve sheath tumors derive from the Schwann cell lineage and comprise diverse histological entities ranging from benign schwannomas and neurofibromas to high-grade malignant peripheral nerve sheath tumors (MPNST), each with several variants. There is increasing evidence for methylation profiling being able to delineate biologically relevant tumor groups even within the same cellular lineage. Therefore, we used DNA methylation arrays for methylome- and chromosomal profile-based characterization of 171 peripheral nerve sheath tumors. We analyzed 28 conventional high-grade MPNST, three malignant Triton tumors, six low-grade MPNST, four epithelioid MPNST, 33 neurofibromas (15 dermal, 8 intraneural, 10 plexiform), six atypical neurofibromas, 43 schwannomas (including 5 NF2 and 5 schwannomatosis associated cases), 11 cellular schwannomas, 10 melanotic schwannomas, 7 neurofibroma/schwannoma hybrid tumors, 10 nerve sheath myxomas and 10 ganglioneuromas. Schwannomas formed different epigenomic subgroups including a vestibular schwannoma subgroup. Cellular schwannomas were not distinct from conventional schwannomas. Nerve sheath myxomas and neurofibroma/schwannoma hybrid tumors were most similar to schwannomas. Dermal, intraneural and plexiform neurofibromas as well as ganglioneuromas all showed distinct methylation profiles. Atypical neurofibromas and low-grade MPNST were indistinguishable with a common methylation profile and frequent losses of CDKN2A. Epigenomic analysis finds two groups of conventional high-grade MPNST sharing a frequent loss of neurofibromin. The larger of the two groups shows an additional loss of trimethylation of histone H3 at lysine 27 (H3K27me3). The smaller one retains H3K27me3 and is found in spinal locations. Sporadic MPNST with retained neurofibromin expression did not form an epigenetic group and most cases could be reclassified as cellular schwannomas or soft tissue sarcomas. Widespread immunohistochemical loss of H3K27me3 was exclusively seen in MPNST of the main methylation cluster, which defines it as an additional useful marker for the differentiation of cellular schwannoma and MPNST.

ICG videography facilitates interpretation of vascular supply and anatomical landmarks in intramedullary spinal lesions: two case reports.

Study Design. This is an illustration of two case reports. Objective. We present two cases where intradural indocyanine-green (ICG) videography facilitated interpretation of vascular supply patterns and anatomic landmarks in intramedullary spinal lesions. Summary of Background Data. ICG videography is a new, complimentary imaging method, that is routinely employed in the context of vascular neurosurgical procedures and has recently been described to facilitate localization of intradural spinal lesions before dural opening. Its role in the setting of intramedullary lesions is less well defined. Methods. Two cases are presented. The first patient (case 1) had a small, diffuse, intramedullary lesion of unknown etiology who was referred for additional work-up and surgery. The second patient had presented with progressive paraparesis and ataxia due to an extensive intradural lesion, and he was referred for resection of the tumor. Routine exposure of the spinal cord via (hemi-)laminectomy and durotomy was followed by ICG videography (injection of intravenous indocyanine green, visualization with operating microscope in combination with an additional fluorescent light source) to guide the surgical strategy. Results. In case 1, ICG videography helped to delineate the anatomic midline for optimization of myelotomy. In case 2, imaging was able to identify arterial feeders of the highly vascularized lesion and simplified safe removal of the lesion. Conclusion. ICG videography may represent a useful adjunct for optimization of surgical approach and strategy in intramedullary spinal tumors in selected cases. The anatomic midline can be safely identified in cases where usual landmarks are distorted, and better interpretation of supply patterns in highly vascularized lesions may increase safety of resection.

Cortical indocyanine green videography for quantification of acute hypoperfusion after subarachnoid hemorrhage: a feasibility study.

BACKGROUND: Acute neurological deficits after subarachnoid hemorrhage (SAH) correlate with outcome, and a phase of acute hypoperfusion was characterized recently. Indocyanine green (ICG) videography is an established intraoperative imaging technique with important descriptive potential. OBJECTIVE: To analyze whether ICG can be used to analyze and confirm perfusion changes early after SAH. METHODS: We prospectively enrolled 11 patients with acute SAH within the past 24 hours and 14 patients undergoing surgery for unruptured aneurysms. Cortical ICG videography was performed, and offline analysis included the arterial, parenchymal, and venous cortical compartment. Transit times, signal gradient, maximum of fluorescence intensity, and the area under the curve were calculated as surrogate markers for perfusion characteristics. RESULTS: Arterial, parenchymal, and venous transit times were comparable in both groups. The velocity of signal change in SAH patients was significantly lower in all 3 compartments (P < .001, P < .01, P < .001, respectively), as was the peak fluorescence intensity (P < .001). In SAH patients, fluorescence intensity did not vary between areas with and without diffuse cortical blood. Area under the curve analysis showed significantly lower values in SAH patients compared with the control group (P < .001). CONCLUSION: Cortical ICG videography and analysis are feasible during surgery. Patients early after SAH have a significantly lower velocity of signal change, lower peak of fluorescence intensity, and lower overall area under the curve, but similar transit times. This technique can be used to quantify perfusion alteration, in this case, acute SAH, and may be used as an adapted measurement tool for intraoperative therapy. ABBREVIATIONS: AImax, peak fluorescence intensity AUC, area under the curve CBF, cerebral blood flow CBV, cerebral blood volume HH, Hunt and Hess ICG, indocyanine green ICP, intracranial pressure MAP, mean arterial pressure mFS, modified Fisher Scale MTT, mean transit time ROI, region of interest TTP, time to peak

Immediate Titanium Mesh Implantation for Patients with Postcraniotomy Neurosurgical Site Infections: Safe and Aesthetic Alternative Procedure?

BACKGROUND Surgical site infection (SSI) is one of the main complications after craniotomy. The incidence is up to 11% in the literature. The established procedure is debridement, removal of the bone flap, and delayed cranioplasty. Delayed cranioplasty has several disadvantages. A promising approach is the immediate titanium mesh implantation at the time of wound revision. We report our experience with this technique regarding outcome measured by reinfection rates and patient satisfaction. METHODS Patients treated in our department from January 2013 to October 2014 with SSI after craniotomy for brain tumor, trauma, or vascular pathologies were prospectively collected. In all these patients, immediate titanium mesh implantation after bone flap removal was performed. Primary outcome parameters were the reinfection rate and patient satisfaction via self-designed questionnaires in a follow-up period >3 months. RESULTS Twenty-four patients were included within the study period. Main risk factors causing SSI were previous steroid medication (62.5%), cranial radiation therapy (42%), cerebrospinal fluid fistula after initial surgery (12.5%), and diabetes mellitus (25%). The follow-up was >3 months after titanium mesh cranioplasty (mean 4.6 months; range 3-6 months). No recurrent infection was detected in the study group. In 2 cases, reoperation was necessary. The returning questionnaires showed a high satisfaction rate with the cosmetic result. CONCLUSIONS Our small series seems to confirm that immediate titanium mesh implantation for patients with postcraniotomy SSI is a cost-effective, safe, and cosmetically suitable alternative to delayed cranioplasty in selected patients without hydrocephalus or persistent cerebrospinal fluid fistula.

The GNAQ in the haystack: intramedullary meningeal melanocytoma of intermediate grade at T9–10 in a 58-year-old woman

Meningeal melanocytomas are rare tumors. They are derived from leptomeningeal melanocytes and predominantly occur along the spine and the posterior fossa. Here, the authors report a case of intramedullary melanocytoma of intermediate grade in a 58-year-old female patient who was initially misdiagnosed with malignant melanoma until mutational analyses of a panel of genes associated with melanotic tumors led to reclassification.

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.

Intraoperative Radiotherapy in Newly Diagnosed Glioblastoma (INTRAGO): An Open-Label, Dose-Escalation Phase I/II Trial

BACKGROUND The median time to recurrence of glioblastoma (GB) following multimodal treatment is ∼7 mo. Nearly all cancers recur locally, suggesting that augmenting local treatments may improve outcomes. OBJECTIVE To investigate whether intraoperative radiotherapy (IORT) to the resection cavity is safe and effective. METHODS INTRAGO was a phase I/II trial to evaluate the safety and tolerability of IORT with 20 to 40 Gy of low-energy photons in addition to standard radiochemotherapy (ClinicalTrials.gov ID, NCT02685605). The primary endpoint was safety as per occurrence of dose-limiting toxicities. Secondary endpoints were progression-free survival (PFS) and overall survival (OS). We also performed an exploratory analysis of the local PFS (L-PFS), defined as recurrence within 1 cm of the treated margin. RESULTS Fifteen patients were treated at 3 dose levels. Of these, 13 underwent incomplete resection, 6 had unresected satellites, and 3 did not receive per-protocol treatment (PPT). The MGMT promoter was unmethylated in 10 patients. The median follow-up was 13.8 mo. The majority of grade 3 to 5 adverse events were deemed unrelated to IORT. Five cases of radionecrosis were observed, 2 were classified as grade 3 events. Other grade 3 events judged related to radiotherapy (external-beam radiotherapy and/or IORT) were wound dehiscence (n = 1), CSF leakage (n = 1), cyst formation (n = 1). No IORT-related deaths occurred. The median PFS was 11.2 mo (95% confidence interval [CI]: 5.4-17.0) for all patients and 11.3 mo (95% CI: 10.9-11.6) for those receiving PPT. The median L-PFS was 14.3 mo (95% CI: 8.4-20.2) for all patients and 17.8 mo (95% CI: 9.7-25.9) for those receiving PPT. The median OS was 16.2 mo (95% CI: 11.1-21.4) for all patients and 17.8 mo (95% CI: 13.9-21.7) for those receiving PPT. CONCLUSION These data suggest that IORT is associated with manageable toxicity. Considering the limitations of a 15-patient phase I/II trial, further studies aimed at assessing an outcome benefit are warranted.

Study Protocol: Early Stereotactic Gamma Knife Radiosurgery to Residual Tumor After Surgery of Newly Diagnosed Glioblastoma (Gamma-GBM)

BACKGROUND Glioblastoma (GBM) is the most common malignant brain tumor in adult patients. Tumor recurrence commonly occurs around the resection cavity, especially after subtotal resection (STR). Consequently, the extent of resection correlates with overall survival (OS), suggesting that depletion of postoperative tumor remnants will improve outcome. OBJECTIVE To assess safety and efficacy of adding stereotactic radiosurgery (SRS) to the standard treatment of GBM in patients with postoperative residual tumor. METHODS Gamma-GBM is a single center, open-label, prospective, single arm, phase II study that includes patients with newly diagnosed GBM (intraoperative via frozen sections) who underwent STR (residual tumor will be identified by native and contrast enhanced T1-weighted magnetic resonance imaging scans). All patients will receive SRS with 15 Gy (prescribed to the 50% isodose enclosing all areas of residual tumor) early (within 24-72 h) after surgery. Thereafter, all patients undergo standard-of-care therapy for GBM (radiochemotherapy with 60 Gy external beam radiotherapy [EBRT] plus concomitant temozolomide and 6 cycles of adjuvant temozolomide chemotherapy). The primary outcome is median progression-free survival, secondary outcomes are median OS, occurrence of radiation induced acute (<3 wk), early delayed (<3 mo), and late (>3 mo post-SRS) neurotoxicity and incidence of symptomatic radionecrosis. EXPECTED OUTCOMES We expect to detect efficacy and safety signals by the immediate application of SRS to standard-of-care therapy in newly diagnosed GBM. DISCUSSION Early postoperative SRS to areas of residual tumor could bridge the therapeutic gap between surgery and adjuvant therapies.

Neuro-Endocrine Recovery After Pituitary Apoplexy: Prolactin as a Predictive Factor

OBJECTIVE Pituitary apoplexy is a serious medical complication of a pre-existing pituitary adenoma characterized by a variety of clinical symptoms ranging from mild headache to neurologically impaired and finally comatose patients. Management options are surgery or conservative treatment (e. g., with dexamethasone). Surgery is commonly performed in case of severe acute neurological and visual symptoms. However, prospective studies demonstrating a benefit of surgery over conservative treatment in terms of visual, neurological and even endocrine outcomes are lacking. Decision making is still controversial, and recommendations for surgery are based on low evidence grades and focus on visual impairment. Endocrine function and especially markers identifying patients with potential for pituitary recovery after surgery are not well described in the literature. PATIENTS AND DESIGN We analysed data from 24 patients (m:f/16:8) with a median age of 64 yrs (38 to 83yrs) that underwent surgery for pituitary apoplexy regardless of time from symptom onset. Apoplexies were necrotic in 14 cases and haemorrhagic in 10 cases. RESULTS Preoperatively, 7 patients (29.2%) showed complete anterior pituitary insufficiency, 16 patients (66.6%) had partial anterior pituitary insufficiency and one patient (4.17%) had normal pituitary functions. Persistent panhypopituitarism was found in 7 patients (29.2%), whereas an overall improvement of pituitary function was noted in 13 (57.1%) patients. Preoperative prolactin (PRL) levels were significantly associated with recovery of endocrine functions, whereas specifically all patients with preoperative PRL levels of at least 8.8 ng/ml recovered partially or fully. Time to surgery (0-7 days vs. 1-4 weeks vs.>4 weeks) was not significantly associated with outcome. CONCLUSIONS Our data emphasize that normal and high preoperative PRL levels are associated with better endocrine outcome after surgery. We conclude that patients benefit from surgical intervention even after delayed diagnosis with the serum PRL levels is being a valid biomarker for clinical decision making.