A glutamatergic biomarker panel enables differentiating Grade 4 gliomas/astrocytomas from brain metastases.

Background: The differentiation of high-grade glioma and brain tumors of an extracranial origin is eminent for the decision on subsequent treatment regimens. While in high-grade glioma, a surgical resection of the tumor mass is a fundamental part of current standard regimens, in brain metastasis, the burden of the primary tumor must be considered. However, without a cancer history, the differentiation remains challenging in the imaging. Hence, biopsies are common that may help to identify the tumor origin. An additional tool to support the differentiation may be of great help. For this purpose, we aimed to identify a biomarker panel based on the expression analysis of a small sample of tissue to support the pathological analysis of surgery resection specimens. Given that an aberrant glutamate signaling was identified to drive glioblastoma progression, we focused on glutamate receptors and key players of glutamate homeostasis. Methods: Based on surgically resected samples from 55 brain tumors, the expression of ionotropic and metabotropic glutamate receptors and key players of glutamate homeostasis were analyzed by RT-PCR. Subsequently, a receiver operating characteristic (ROC) analysis was performed to identify genes whose expression levels may be associated with either glioblastoma or brain metastasis. Results: Out of a total of 29 glutamatergic genes analyzed, nine genes presented a significantly different expression level between high-grade gliomas and brain metastases. Of those, seven were identified as potential biomarker candidates including genes encoding for AMPA receptors GRIA1, GRIA2, kainate receptors GRIK1 and GRIK4, metabotropic receptor GRM3, transaminase BCAT1 and the glutamine synthetase (encoded by GLUL). Overall, the biomarker panel achieved an accuracy of 88% (95% CI: 87.1, 90.8) in predicting the tumor entity. Gene expression data, however, could not discriminate between patients with seizures from those without. Conclusion: We have identified a panel of seven genes whose expression may serve as a biomarker panel to discriminate glioblastomas and brain metastases at the molecular level. After further validation, our biomarker signatures could be of great use in the decision making on subsequent treatment regimens after diagnosis.

Comparing tumor microRNA profiles of patients with long­ and short­term­surviving glioblastoma.

Glioblastoma is one of the most frequent primary brain tumors with a poor prognosis. Nevertheless, some patients show a prolonged survival. The aim of the present study was to compare the expression profiles of tumor derived microRNA (miR) of long­term survivors with those of short­term survivors in order to identify differentially expressed miRs as well as their target genes, which may elucidate mechanisms that play a role in varying tumor progression and, therefore, may influence survival. Formalin­fixed paraffin­embedded samples of 23 patients with glioblastoma were classified according to overall survival. Profiles of miR expression were determined using Nanostring technology. Expression levels of potential target genes of differentially expressed miRs were assessed using immunohistochemistry. MiR profiles of long­term survivors differed from those of short­term survivors. A total of three prominent differentially expressed miRs were highlighted: MiR­130b­3p, which is downregulated in long­term survivors, and miR­146b­5p and miR­148a­3p, which are upregulated in long­term survivors. Known tumor suppressor genes are among targets potentially affected by miR­130b­3p, whereas targets of miR­146b­5p and miR­148a­3p consist of several genes known to have a role in tumor invasion and aggressiveness. In conclusion, it was revealed that a type of miR­signature was associated with short­ and long­term survival, potentially serving as biomarker for disease progression and providing a base for further functional studies.

A red flag for diagnosing brain death: decompressive craniectomy of the posterior fossa.

PURPOSE: Brain death/death by neurologic criteria (BD/DNC) may be determined in many countries by a clinical examination that shows coma, brainstem areflexia, and apnea, provided the conditions causing reversible loss of brain function are excluded a priori. To date, accounts of recovery from BD/DNC in adults have been limited to noncompliance with guidelines. CLINICAL FEATURES: We report the case of a 72-yr-old man with a combined primary infratentorial (hemorrhagic) and secondary global (anoxic) brain lesion in whom decompressive craniectomy of the posterior fossa and six-hour therapeutic hypothermia (33-34°C) followed by 8-hour rewarming to ≥ 36°C were conducted. Thirteen hours later, clinical findings of brain function loss were documented in addition to guideline-compliant exclusion of reversible causes (arterial hypotension, intoxication, depressant drug effects, relevant metabolic or endocrine disequilibrium, chronic hypercapnia, neuromuscular disorders, and administration of a muscle relaxant). Since a primary infratentorial brain lesion was present, German guidelines required further ancillary testing. Doppler ultrasonography revealed some preserved cerebral circulation, and BD/DNC was not diagnosed. Approximately 24 hr after rewarming to ≥ 36°C, the patient exhibited respiratory efforts. He continued with assisted respiration until final asystole/apnea, without regaining additional brain function other than mild signs of hemispasticity. Follow-up computed tomography showed partial herniation of the cerebellum through the craniectomy gap of the posterior fossa, alleviating caudal brain stem compression. CONCLUSIONS: Therapeutic decompressive craniectomy of the posterior fossa may allow for delayed reversal of apnea. In these patients, proof of cerebral circulatory arrest should be mandatory for diagnosing BD/DNC.

RéSUMé: OBJECTIF: Dans de nombreux pays, la mort cérébrale / décès déterminé par des critères neurologiques (MC / DDN) peut être déterminée par un examen clinique qui montre le coma, l'aréflexie du tronc cérébral et l'apnée, sous réserve que les conditions causant une perte réversible de la fonction cérébrale soient exclues a priori. À ce jour, les comptes rendus décrivant un rétablissement après une MC / DDN chez les adultes ont été limités en raison d'un non-respect des lignes directrices. CARACTéRISTIQUES CLINIQUES: Nous rapportons le cas d'un homme de 72 ans atteint d'une lésion cérébrale sous-tentorielle primaire (hémorragique) et secondaire globale (anoxique) chez qui une craniectomie décompressive de la fosse postérieure et une hypothermie thérapeutique de six heures (33-34 °C), suivie d'un réchauffement de 8 heures à ≥ 36 °C, ont été réalisés. Treize heures plus tard, les résultats cliniques de la perte de la fonction cérébrale ont été documentés, en plus de l'exclusion conforme aux lignes directrices des causes réversibles (hypotension artérielle, intoxication, effets des médicaments dépresseurs, déséquilibre métabolique ou endocrinien pertinent, hypercapnie chronique, troubles neuromusculaires et administration d'un relaxant musculaire). Étant donné qu'une lésion cérébrale sous-tentorielle primaire était présente, les directives allemandes exigeaient la réalisation d'autres tests auxiliaires. L'échographie Doppler a révélé la préservation d'une certaine circulation cérébrale, et la MC / DDN n'a pas été diagnostiquée. Environ 24 heures après le réchauffement du patient à ≥ 36 °C, le patient a manifesté des efforts respiratoires. Il a continué à respirer avec assistance jusqu'à l'asystole / l'apnée finale, sans retrouver de fonction cérébrale supplémentaire autre que de légers signes d'hémispasticité. La tomodensitométrie de suivi a montré une hernie partielle du cervelet à travers l'espace de craniectomie de la fosse postérieure, soulageant la compression caudale du tronc cérébral. CONCLUSION: La craniectomie décompressive thérapeutique de la fosse postérieure peut permettre une inversion retardée de l'apnée. Chez ces patients, la preuve d'un arrêt circulatoire cérébral devrait être obligatoire pour diagnostiquer une MC / DDN.

The miR-183/96/182 cluster is upregulated in glioblastoma carrying EGFR amplification.

Glioblastoma (GBM) is one of the most frequent primary brain tumors. Limited therapeutic options and high recurrency rates lead to a dismal prognosis. One frequent, putative driver mutation is the genomic amplification of the oncogenic receptor tyrosine kinase EGFR. Often accompanied by variants like EGFRvIII, heterogenous expression and ligand independent signaling render this tumor subtype even more difficult to treat, as EGFR-directed therapeutics show only weak effects at best. So EGFR-amplified GBM is considered to have an even worse prognosis, and therefore, deeper understanding of molecular mechanisms and detection of potential targets for novel therapeutic strategies is urgently needed. In this study, we looked at the level of microRNAs (miRs), small non-coding RNAs frequently deregulated in cancer, both acting as oncogenes and tumor suppressors. Comparative analysis of GBM with and without EGFR amplification should give insight into the expression profiles of miRs, which are considered both as potential targets for directed therapies or as therapeutic reagents. Comparison of miR profiles of EGFR-amplified and EGFR-normal GBM revealed an upregulation of the miR-183/96/182 cluster, which is associated with oncogenic properties in several tumor entities. One prominent target of this miR cluster is FOXO1, a pro-apoptotic factor. By observing FOXO1 downregulation in EGFR-amplified tumors, we can see a significant correlation of EGFR amplification, miR-183/96/182 cluster upregulation, and repression of FOXO1. Although no significant difference in overall survival is shown, these data may contribute to the molecular understanding of this tumor subtype and offer potential targets for miR-based therapies.

A multicenter cohort study of early complications after cranioplasty: results of the German Cranial Reconstruction Registry.

OBJECTIVE: Cranioplasty (CP) is a crucial procedure after decompressive craniectomy and has a significant impact on neurological improvement. Although CP is considered a standard neurosurgical procedure, inconsistent data on surgery-related complications after CP are available. To address this topic, the authors analyzed 502 patients in a prospective multicenter database (German Cranial Reconstruction Registry) with regard to early surgery-related complications. METHODS: Early complications within 30 days, medical history, mortality rates, and neurological outcome at discharge according to the modified Rankin Scale (mRS) were evaluated. The primary endpoint was death or surgical revision within the first 30 days after CP. Independent factors for the occurrence of complications with or without surgical revision were identified using a logistic regression model. RESULTS: Traumatic brain injury (TBI) and ischemic stroke were the most common underlying diagnoses that required CP. In 230 patients (45.8%), an autologous bone flap was utilized for CP; the most common engineered materials were titanium (80 patients [15.9%]), polyetheretherketone (57 [11.4%]), and polymethylmethacrylate (57 [11.4%]). Surgical revision was necessary in 45 patients (9.0%), and the overall mortality rate was 0.8% (4 patients). The cause of death was related to ischemia in 2 patients, diffuse intraparenchymal hemorrhage in 1 patient, and cardiac complications in 1 patient. The most frequent causes of surgical revision were epidural hematoma (40.0% of all revisions), new hydrocephalus (22.0%), and subdural hematoma (13.3%). Preoperatively increased mRS score (OR 1.46, 95% CI 1.08-1.97, p = 0.014) and American Society of Anesthesiologists Physical Status Classification System score (OR 2.89, 95% CI 1.42-5.89, p = 0.003) were independent predictors of surgical revision. Ischemic stroke, as the underlying diagnosis, was associated with a minor rate of revisions compared with TBI (OR 0.18, 95% CI 0.06-0.57, p = 0.004). CONCLUSIONS: The authors have presented class II evidence-based data on surgery-related complications after CP and have identified specific preexisting risk factors. These results may provide additional guidance for optimized treatment of these patients.

Newly Diagnosed IDH-Wildtype Glioblastoma and Temporal Muscle Thickness: A Multicenter Analysis.

BACKGROUND: Reduced temporal muscle thickness (TMT) has been discussed as a prognostic marker in IDH-wildtype glioblastoma. This retrospective multicenter study was designed to investigate whether TMT is an independent prognostic marker in newly diagnosed glioblastoma. METHODS: TMT was retrospectively measured in 335 patients with newly diagnosed glioblastoma between 1 January 2014 and 31 December 2019 at the University Hospitals of Leipzig and Rostock. The cohort was dichotomized by TMT and tested for association with overall survival (OS) after 12 months by multivariate proportional hazard calculation. RESULTS: TMT of 7.0 mm or more was associated with increased OS (46.3 ± 3.9% versus 36.6 ± 3.9%, p > 0.001). However, the sub-groups showed significant epidemiological differences. In multivariate proportional hazard calculation, patient age (HR 1.01; p = 0.004), MGMT promoter status (HR 0.76; p = 0.002), EOR (HR 0.61), adjuvant irradiation (HR 0.24) and adjuvant chemotherapy (HR 0.40; all p < 0.001) were independent prognostic markers for OS. However, KPS (HR 1.00, p = 0.31), BMI (HR 0.98, p = 0.11) and TMT (HR 1.06; p = 0.07) were not significantly associated with OS. CONCLUSION: TMT has not appeared as a statistically independent prognostic marker in this cohort of patients with newly diagnosed IDH-wildtype glioblastoma.

Correlation between Kir4.1 expression and barium-sensitive currents in rat and human glioma cell lines.

Gliomas are the most common primary brain tumors and often become apparent through symptomatic epileptic seizures. Glial cells express the inwardly rectifying K+ channel Kir4.1 playing a major role in K+ buffering, and are presumably involved in facilitating epileptic hyperexcitability. We therefore aimed to investigate the molecular and functional expression of Kir4.1 channels in cultured rat and human glioma cells. Quantitative PCR showed reduced expression of Kir4.1 in rat C6 and F98 cells as compared to control. In human U-87MG cells and in patient-derived low-passage glioblastoma cultures, Kir4.1 expression was also reduced as compared to autopsy controls. Testing Kir4.1 function using whole-cell patch-clamp experiments on rat C6 and two human low-passage glioblastoma cell lines (HROG38 and HROG05), we found a significantly depolarized resting membrane potential (RMP) in HROG05 (-29 ± 2 mV, n = 11) compared to C6 (-71 ± 1 mV, n = 12, P < 0.05) and HROG38 (-60 ± 2 mV, n = 12, P < 0.05). Sustained K+ inward or outward currents were sensitive to Ba2+ added to the bath solution in HROG38 and C6 cells, but not in HROG05 cells, consistent with RMP depolarization. While immunocytochemistry confirmed Kir4.1 in all three cell lines including HROG05, we found that aquaporin-4 and Kir5.1 were also significantly reduced suggesting that the Ba2+-sensitive K+ current is generally impaired in glioma tissue. In summary, we demonstrated that glioma cells differentially express functional inwardly rectifying K+ channels suggesting that impaired K+ buffering in cells lacking functional Ba2+-sensitive K+ currents may be a risk factor for increased excitability and thereby contribute to the differential epileptogenicity of gliomas.

[Skull and cervical spine fractures]. / Frakturen von Kopf und Halswirbelsäule.

BACKGROUND: Injuries of the skull and the cervical spine are common trauma sequelae and prompt diagnosis is of utmost importance to prevent neurologic complications. OBJECTIVES: The different imaging modalities for the diagnosis of skull and cervical spine fractures are presented and discussed in the context of the current literature. MATERIALS AND METHODS: Common fractures of the skull and cervical spine and their classification systems are described. Indications for imaging are discussed within the context of the literature. RESULTS: Fractures of the head can affect the cranial vault, the base of the skull, and the petrous bone. Injuries to the dura are associated with an open craniocerebral trauma. Fractures of the cervical spine can be subdivided into fractures of the craniocervical junction and subaxial fractures. CONCLUSIONS: The imaging modality of choice in the acute setting is computed tomography (CT). Skull fractures can be differentiated into open and closed craniocerebral traumas and accompanying intracranial trauma sequelae must be recognized. In the case of petrous bone fractures, attention must always be paid to the middle and inner ear structures. In cervical spine fractures, decisive is whether the fracture is stable or unstable and whether there has been an accompanying injury to the myelon.

[Vertebroplasty and kyphoplasty : A critical statement]. / Vertebroplastie und Kyphoplastie : Eine kritische Stellungnahme.

BACKGROUND: Despite optimal drug-conservative therapy, a relevant percentage of patients with vertebral compression fractures (WKF) do not experience any relevant improvement in their pain symptoms. Vertebroplasty (VP) and kyphoplasty (KP) are described in the literature as percutaneous interventional procedures for the treatment of WKF. OBJECTIVE: Assessment of the effectiveness of the VP and KP in the treatment of WKF and discussion of the procedures in the context of the current literature. MATERIAL AND METHODS: Presentation of the fundamentals of VP and KP and their further developments. Description of indications and contraindications. Discussion of the current literature and recommendations of the individual professional associations. RESULTS: In patients with vertebral compression fractures, VP or KP of the affected vertebral body leads to a pain reduction in more than 90% of cases. Clinically relevant complications occur in less than 1% of interventions. CONCLUSION: VP and KP are a safe and effective method for treating painful WKF. Optimal patient selection improves the clinical outcome.

Volumetric assessment of glioblastoma and its predictive value for survival.

BACKGROUND: The objective of this study was to evaluate the morphology of glioblastoma on structural pretreatment magnetic resonance imaging (MRI), defining imaging prognostic factors. METHOD: We conducted a retrospective analysis of MR images from 114 patients harboring a primary glioblastoma, derived from two neurosurgical departments. Tumor segmentation was carried out in a semi-automated fashion. Tumor compartments comprised contrast-enhancing volume (CEV+), perifocal hyperintensity on fluid-attenuated inversion recovery (FLAIR) images (FLAIR+) excluding CEV+, and a non-enhancing area within the CEV+ lesion (CEV-). Additionally, two ratios were calculated from these volumes, the edema-tumor ratio (ETR) and necrosis-tumor ratio (NTR). All patients received surgical resection, followed by concomitant radiation and chemotherapy. RESULTS: Tumor segmentation revealed the strongest correlation between the CEV+ volume and the CEV-, presenting intratumoral necrosis (p < 0.001). The relation between the tumor surrounding the FLAIR+ area and the CEV+ volume and the ETR is inversely correlated (p = 0.001). The most important prognostic factor in multivariable analysis was NTR (HR 2.63, p = 0.016). The cut-off value in our cohort for NTR was 0.33, equivalent to a decrease in survival if the necrotic core of the tumor (CEV-) accounts for more than 33% of the tumor mass itself (CEV+). CONCLUSIONS: Our data emphasizes the importance of the necrosis-tumor ratio as a biomarker in glioblastoma imaging, rather than single tumor compartment volumes. NTR can help to identify a subset of tumors with a higher resistance to therapy and a dismal prognosis.

Association Between Tumor Compartment Volumes, the Incidence of Pretreatment Seizures, and Statin-Mediated Protective Effects in Glioblastoma.

BACKGROUND: Seizures are a common initial symptom of malignant brain tumors such as glioblastoma (GBM). However, why some of these tumors are epileptogenic and others never trigger seizures remains controversial. OBJECTIVE: To identify potential clinical and radiological features of epileptogenic tumors and the effect of initial seizures on survival. METHODS: The analyzed patient cohort was retrospectively compiled (bicentric), only isocitrate dehydrogenase wild-type GBMs were included. Volumetric assessment was performed on pretreatment magnetic resonance imaging with the aid of a semi-automated 3D measurement (tumor, necrosis, and edema volume). Two ratios were calculated, reflecting the proportion of peritumoral edema and necrosis (NTR) toward the tumor volume. For overall survival analyses, only patients after a surgical resection (residual tumor volume <2 cm3) followed by standard radiation and chemotherapy were included. RESULTS: Pretreatment seizures occurred in 33% of cases (n = 224), younger patients (≤60 yr) were predominantly affected (P = .022). All measured volumes were inversely correlated with the onset of seizures (P = .001). In multivariate analyses, the total tumor volume and the NTR were considerably smaller within epileptogenic GBMs (P = .050, P = .019, respectively). A positive statin intake was associated with significantly lesser seizure (P = .007, odds ratio 4.94). Neither the occurrence of seizures nor the intake of statins had an impact on OS (P = .357, P = .507, respectively). CONCLUSION: The size and amount of necrosis was significantly smaller in epileptogenic GBMs, maybe owed to the fact that these tumors were clinically detected at an earlier stage of their growth. Furthermore, the intake of statins was associated with a decreased occurrence of pretreatment seizures.

Correlation of Ki-67 Index with Volumetric Segmentation and its Value as a Prognostic Marker in Glioblastoma.

OBJECTIVE: Previous research has shown a strong correlation between the Ki-67 proliferation index and grade of malignancy in astrocytoma. Ki-67 has also shown encouraging results as a prognostic marker for patients' overall survival (OS). We focus on whether the index is linked to the appearance of glioblastoma on pretreatment magnetic resonance imaging (MRI) or to OS. METHODS: In our retrospective study, only isocitrate dehydrogenase IDH wild-type glioblastoma was included (n = 152). Ki-67 index was quantified via immunohistochemistry. On all pretreatment MRI, tumor compartments (tumor, necrosis, and edema) were volumetrically assessed. An OS subpopulation was filtered from the total cohort (residual tumor volume ≤2 cm3). In addition, a propensity score matching was executed. RESULTS: All volumetric assessed tumor volumes correlated with each other (P ≤ 0.011), although the Ki-67 index showed no correlation with any of the measured volumes. Concerning the OS, a cutoff value of 20% for the Ki-67 index showed a significant influence on patients' OS in multivariate analysis (P = 0.043). CONCLUSIONS: The unique appearance of every glioblastoma on MRI seems to be independent of the Ki-67 index. Furthermore, the Ki-67 index did show a distinct prognostic value for OS within our cohort at a cutoff value of 20% for Ki-67.

Validation of a Novel Clinical Score: The Rostock Functional and Cosmetic Cranioplasty Score.

With a rising number of cranioplasty (CP) procedures and an increasing percentage of patients with a good clinical outcome and prolonged survival after CP, looking at the functional and aesthetic outcome of these patients becomes more and more important. The aim of our study was to evaluate a novel score, combining functional and cosmetics aspects after CP, created at our institution: the Rostock Functional and Cosmetic Cranioplasty (RFCC-) Score. A total of 27 patients were enrolled, representing all indications for a secondary CP after decompressive craniectomy or extended temporal trephination with a complete separation of the temporalis muscle. Besides the clinical evaluation, five different already established clinical rating systems were tested and compared with our score. For reasons of objectivity, the score was also tested against the patient's own rating. Our findings showed that the RFCC-Score, derived from a health professional, is superior to other scoring systems, which only display a facet of the functional state of the patient. Our score is objective and independent of a disposition for a depression of the patient. It can be obtained without the need of a verbal communication, making it applicable for nearly all patients after CP. The score is time-saving, clearly arranged, and reliable, which are inevitable requirements for the comparing and evaluation of different surgical techniques and associated complications of CP.

Volumetric quantification of glioblastoma: experiences with different measurement techniques and impact on survival.

The potential impact of different radiological features of glioblastoma multiforme (GBM) on overall survival (OS) like tumor volume, peritumoral edema (PTE), necrosis volume, necrosis-tumor ratio (NTR) and edema-tumor ratio (ETR) is still very controversial. To determine the influence of volumetric data on OS und to compare different measuring techniques described in literature. We prospectively evaluated preoperative MR images from 30 patients harboring a primary supratentorial GBM. All patients received gross-total tumor resection followed by standard radiation and chemotherapy (temozolomide). By 3D semi-automated segmentation, we measured tumor volume, necrosis volume, PTE, postoperative residual tumor volume and calculated ETR, NTR and the extent of resection. After critical review of the existing literature we compared alternative measuring techniques with the gold standard of 3D segmentation. Statistical analysis showed a significant impact of the preoperative tumor and necrosis volumes on OS (p = 0.041, respectively p = 0.039). Furthermore, NTR also showed a significant association with OS (p = 0.005). Comparison of previously described measuring techniques and scorings with our results showed that no other technique is reliable and accurate enough as a predictive tool. The critical review of previously published studies revealed mainly inaccurate measurement techniques and patient selection as potential reasons for inconsistent results. Preoperatively measured necrosis volume and NTR are the most important radiological features of GBM with a strong influence on OS. No other measuring techniques are specific enough and comparable with 3D segmentation.

Effect of 10 different polymorphisms on preoperative volumetric characteristics of glioblastoma multiforme.

There is a distinct diversity between the appearance of every glioblastoma multiforme (GBM) on pretreatment magnetic resonance imaging (MRI) with a potential impact on clinical outcome and survival of the patients. The object of this study was to determine the impact of 10 different single nucleotide polymorphisms (SNPs) on various volumetric parameters in patients harboring a GBM. We prospectively analyzed 20 steroid-naïve adult patients who had been treated for newly diagnosed GBM. The volumetry was performed using MRI with the help of a semiautomated quantitative software measuring contrast enhancing tumor volume including necrosis, central necrosis alone and peritumoral edema (PTE). We calculated ratios between the tumor volume and edema (ETR), respectively necrosis (NTR). SNP analysis was done using genomic DNA extracted from peripheral blood genotyped via PCR and sequencing. There was a strong correlation between tumor volume and PTE (p < 0.001), necrosis (p < 0.001) and NTR (p = 0.003). Age and sex had no influence on volumetric data. The Aquaporin 4-31G > A SNP had a significant influence on the ETR (p = 0.042) by decreasing the measured edema compared with the tumor volume. The Interleukin 8-251A > T SNP was significantly correlated with an increased tumor (p = 0.048), PTE (p = 0.033) and necrosis volume (p = 0.028). We found two SNPs with a distinct impact on pretreatment tumor characteristics, presenting a potential explanation for the individual diversity of GBM appearance on MRI and influence on survival.

German Cranial Reconstruction Registry (GCRR): protocol for a prospective, multicentre, open registry.

INTRODUCTION: Owing to increasing numbers of decompressive craniectomies in patients with malignant middle cerebral artery infarction, cranioplastic surgery becomes more relevant. However, the current literature mainly consists of retrospective single-centre (evidence class III) studies. This leads to a wide variability of technical approaches and clinical outcomes. To improve our knowledge about the key elements of cranioplasty, which may help optimising clinical treatment and long-term outcome, a prospective multicentre registry across Germany, Austria and Switzerland will be established. METHODS: All patients undergoing cranioplastic surgery in participating centres will be invited to join the registry. Technical methods, materials, medical history, adverse events and clinical outcome measures, including modified Rankin scale and EQ-5D, will be assessed at several time points. Patients will be accessible to inclusion either at initial decompressive surgery or when cranioplasty is planned. Scheduled monitoring will be carried out at time of inclusion and subsequently at time of discharge, if any readmission is necessary, and at follow-up presentation. Cosmetic results and patient satisfaction will also be assessed. Collected data will be managed and statistically analysed by an independent biometric institute. The primary endpoint will be mortality, need for operative revision and neurological status at 3 months following cranioplasty. ETHICS AND DISSEMINATION: Ethics approval was obtained at all participating centres. The registry will provide reliable prospective evidence on surgical techniques, used materials, adverse events and functional outcome, to optimise patient treatment. We expect this study to give new insights in the treatment of skull defects and to provide a basis for future evidence-based therapy regarding cranioplastic surgery. TRIAL REGISTRATION NUMBER: This trial is indexed in the German Clinical Trials Register (DRKS-ID: DRKS00007931). The Universal Trial Number (UTN) is U1111-1168-7425.