Study protocol for a multicenter randomised controlled trial on the (cost)effectiveness of biopsy combined with same-session MR-guided LITT versus biopsy alone in patients with primary irresectable glioblastoma (EMITT trial).

BACKGROUND: Glioblastoma (GBM) is the most common primary, malignant brain tumour with a 5-year survival of 5%. If possible, a glioblastoma is resected and further treated with chemoradiation therapy (CRT), but resection is not feasible in about 30% of cases. Current standard of care in these cases is a biopsy followed by CRT. Magnetic resonance (MR) imaging-guided laser interstitial thermal therapy (LITT) has been suggested as a minimally invasive alternative when surgery is not feasible. However, high-quality evidence directly comparing LITT with standard of care is lacking, precluding any conclusions on (cost-)effectiveness. We therefore propose a multicenter randomized controlled study to assess the (cost-)effectiveness of MR-guided LITT as compared to current standard of care (EMITT trial). METHODS AND ANALYSIS: The EMITT trial will be a multicenter pragmatic randomized controlled trial in the Netherlands. Seven Dutch hospitals will participate in this study. In total 238 patients will be randomized with 1:1 allocation to receive either biopsy combined with same-session MR-guided LITT therapy followed by CRT or the current standard of care being biopsy followed by CRT. The primary outcomes will be health-related quality of life (HR-QoL) (non-inferiority) using EORTC QLQ-C30 + BN20 scores at 5 months after randomization and overall survival (superiority). Secondary outcomes comprise cost-effectiveness (healthcare and societal perspective) and HR-QoL of life over an 18-month time horizon, progression free survival, tumour response, disease specific survival, longitudinal effects, effects on adjuvant treatment, ablation percentage and complication rates. DISCUSSION: The EMITT trial will be the first RCT on the effectiveness of LITT in patients with glioblastoma as compared with current standard of care. Together with the Dutch Brain Tumour Patient association, we hypothesize that LITT may improve overall survival without substantially affecting patients' quality of life. TRIAL REGISTRATION: This trial is registered at ClinicalTrials.gov (NCT05318612).

MR-guided LITT therapy in patients with primary irresectable glioblastoma: a prospective, controlled pilot study.

PURPOSE: Laser interstitial thermal therapy (LITT) is increasingly being used in the treatment of brain tumors, whereas high-quality evidence of its effectiveness is lacking. This pilot examined the feasibility of conducting a randomized controlled trial (RCT) in patients with irresectable newly diagnosed glioblastoma (nGBM), and generated data on technical feasibility and safety. METHODS: We included patients with irresectable nGBM with KPS ≥ 70 and feasible trajectories to ablate ≥ 70% of the tumor volume. Patients were initially randomized to receive either biopsy combined with LITT or biopsy alone, followed by chemoradiation (CRT). Randomization was stopped after 9 patients as the feasibility endpoint with respect to willingness to be randomized was met. Main endpoints were feasibility of performing an RCT, technical feasibility of LITT and safety. Follow-up was 3 months. RESULTS: A total of 15 patients were included, of which 10 patients received a biopsy followed by LITT and 5 patients a biopsy. Most patients were able to complete the follow-up procedures (93% clinical, 86% questionnaires, 78% MRI). Patients were planned within 3 weeks after consultation (median 12 days, range 8-16) and no delay was observed in referring patients for CRT (median 37 days, range 28-61). Two CD ≥ 3 complications occurred in the LITT arm and none in the biopsy arm. CONCLUSION: An RCT to study the effectiveness of LITT in patients with an irresectable nGBM seems feasible with acceptable initial safety data. The findings from this pilot study helped to further refine the design of a larger full-scale multicenter RCT in the Netherlands. Protocol and study identifier: The current study is registered at clinicaltrials.gov (EMITT pilot study, NTR: NCT04596930).

Diagnostic accuracy of flat-panel computed tomography in assessing cerebral perfusion in comparison with perfusion computed tomography and perfusion magnetic resonance: a systematic review.

PURPOSE: Flat-panel computed tomography (FP-CT) is increasingly available in angiographic rooms and hybrid OR's. Considering its easy access, cerebral imaging using FP-CT is an appealing modality for intra-procedural applications. The purpose of this systematic review is to assess the diagnostic accuracy of FP-CT compared with perfusion computed tomography (CTP) and perfusion magnetic resonance (MRP) in cerebral perfusion imaging. METHODS: We performed a systematic literature search in the Cochrane Library, MEDLINE, Embase, and Web of Science up to June 2019 for studies directly comparing FP-CT with either CTP or MRP in vivo. Methodological quality was assessed using the QUADAS-2 tool. Data on diagnostic accuracy was extracted and pooled if possible. RESULTS: We found 11 studies comparing FP-CT with CTP and 5 studies comparing FP-CT with MRP. Most articles were pilot or feasibility studies, focusing on scanning and contrast protocols. All patients studied showed signs of cerebrovascular disease. Half of the studies were animal trials. Quality assessment showed unclear to high risks of bias and low concerns regarding applicability. Five studies reported on diagnostic accuracy; FP-CT shows good sensitivity (range 0.84-1.00) and moderate specificity (range 0.63-0.88) in detecting cerebral blood volume (CBV) lesions. CONCLUSIONS: Even though FP-CT provides similar CBV values and reconstructed blood volume maps as CTP in cerebrovascular disease, additional studies are required in order to reliably compare its diagnostic accuracy with cerebral perfusion imaging.

Armored brain in a young girl with a syndromal hydrocephalus.

The authors present a case of a young girl affected by a syndromal hydrocephalus who developed a bilateral ossified chronic subdural hematoma with the typical radiological appearance of "the armored brain". Bilateral calcified chronic subdural hematoma is a rare complication of ventriculoperitoneal shunt. There is controversy in the treatment, but most published literature discourages a surgical intervention to remove the calcifications.

Phantom and in vivo accuracy of frameless optical navigation in stereotactic laser interstitial thermal therapy.

OBJECTIVE: Targeting accuracy presents a key factor in achieving maximal safe ablation in laser interstitial thermal therapy (LITT). The VarioGuide system has proven precise for brain biopsies, but data showing its accuracy in combination with LITT are limited. The aim of this study was to determine the phantom and in vivo accuracy of LITT probe placement using the VarioGuide system and to evaluate the effect of targeting error on maximum possible ablation volume. METHODS: Stereotactic LITT probe placement was performed using the VarioGuide system in 3 phantom skulls. The same system was used in 10 patients treated with LITT, for which data were retrospectively analyzed. Target point error (TPE), target depth deviation (TDD), target lateral deviation (TLD), and angular deviation (AD) were derived from intraprocedural MRI scans of both the phantom and in vivo trajectories. In vivo, the effect of targeting error on the maximum reachable ablation was calculated as the difference between the planned maximal achievable tumor ablation (PTA) and the actual maximal achievable tumor ablation (ATA). RESULTS: In total, 24 phantom and 16 in vivo trajectories were analyzed. In the phantom setting, the median TPE was 3.3 mm and median AD was 1.9°. Targeting accuracy significantly decreased for longer trajectories and those less perpendicular to the skull. In patients, the authors observed a comparable median TPE of 4.0 mm but significantly higher AD of 3.2°. In vivo, targeting inaccuracy resulted in a median decrease in maximum achievable ablation volume of 6% as compared to the planned trajectory. CONCLUSIONS: The authors' study indicates that utilizing the VarioGuide system in combination with LITT yields an average targeting error as large as 4 mm, which was smaller for shorter and straighter trajectories. In patients, targeting inaccuracy resulted in a median 6% decrease of the planned tumor ablation volume. These are important factors that should be considered in optimal case planning and patient selection in LITT.

Stereotactic laser ablation in neuro-oncology - A survey among European neurosurgeons.

Introduction: In the last decades, the application of stereotactic laser ablation (SLA) for the treatment of intracranial tumours has been growing, even though comparative trials are lacking. Our aim was to investigate the familiarity with SLA of neurosurgeons in Europe and their opinion regarding potential neuro-oncological indications. Furthermore, we investigated treatment preferences and variability for three exemplar neuro-oncological cases and willingness to refer for SLA. Material and methods: A 26-questions survey was mailed to members of the EANS neuro-oncology section. We presented three clinical cases of respectively deep-seated glioblastoma, recurrent metastasis and recurrent glioblastoma. Descriptive statistics was applied to report results. Results: 110 respondents completed all questions. Recurrent glioblastoma and recurrent metastases were regarded as the most feasible indications for SLA (chosen by 69% and 58% of the respondents) followed by newly diagnosed high-grade gliomas (31%). Seventy percent of respondents would refer patients for SLA. The majority of respondents would consider SLA as a treatment option for all three presented cases: 79% for the deep-seated glioblastoma case, 65% for the recurrent metastasis case and 76% for the recurrent glioblastoma case. Among respondents who wouldn't consider SLA, preference for standard treatment and lack of clinical evidence were reported as the main reasons. Conclusions: Most of respondents considered SLA as a treatment option for recurrent glioblastoma, recurrent metastases and newly diagnosed deep-seated glioblastoma. At the moment the current evidence to support such a treatment is very low. Comparative prospective trials are needed to support the use of SLA and determine proper indications.

Between-hospital variation in time to glioblastoma surgery: a report from the Quality Registry Neuro Surgery in the Netherlands.

OBJECTIVE: Patients with glioblastoma are often scheduled for urgent elective surgery. Currently, the impact of the waiting period until glioblastoma surgery is undetermined. In this national quality registry study, the authors determined the wait times until surgery for patients with glioblastoma, the risk factors associated with wait times, and the risk-standardized variation in time to surgery between Dutch hospitals. The associations between time to surgery and patient outcomes were also explored. METHODS: Data from all 4589 patients who underwent first-time glioblastoma surgery between 2014 and 2019 in the Netherlands were collected by 13 hospitals in the Quality Registry Neuro Surgery. Time to surgery comprised 1) the time from first MR scan to surgery (MTS), and 2) the time from first neurosurgical consultation to surgery (CTS). Long MTS was defined as more than 21 days and long CTS as more than 14 days. Potential risk factors were analyzed in multivariable logistic regression models. The standardized rate of long time to surgery was analyzed using funnel plots. Patient outcomes including Karnofsky Performance Scale (KPS) score change, complications, and survival were analyzed by multivariable logistic regression and proportional hazards models. RESULTS: The median overall MTS and CTS were 18 and 9 days, respectively. Overall, 2576 patients (56%) had an MTS within 3 weeks and 3069 (67%) had a CTS within 2 weeks. Long MTS was significantly associated with older age, higher preoperative KPS score, higher American Society of Anesthesiologists comorbidity class, season, lower hospital case volume, university affiliation, and resection. Long CTS was significantly associated with higher baseline KPS score, university affiliation, resection, more recent year of treatment, and season. In funnel plots, considerable practice variation was observed between hospitals in patients with long times to surgery. Fewer patients with KPS score improvement were observed after a long time until resection. Long CTS was associated with longer survival. Complications and KPS score decline were not associated with time to surgery. CONCLUSIONS: Considerable between-hospital variation among Dutch hospitals was observed in the time to glioblastoma surgery. A long time to resection impeded KPS score improvement, and therefore, patients who may improve should be identified for more urgent resection. Longer survival was observed in patients selected for longer time until surgery after neurosurgical consultation (CTS).

Laser Interstitial Thermal Therapy in Patients with Newly Diagnosed Glioblastoma: A Systematic Review.

BACKGROUND: Laser interstitial thermal therapy (LITT) is a minimal invasive neurosurgical technique for the treatment of brain tumors. Results of LITT have been reported in a case series of patients with deep seated and/or recurrent glioblastoma or cerebral metastases. With this review we aim to summarize the currently available evidence regarding safety and effectiveness of LITT in patients with newly diagnosed glioblastoma (nGBM). METHODS: A literature search was performed using electronic databases (PubMed and Embase). Papers were assessed for the methodological quality using the Risk Of Bias In Non- randomised Studies - of Interventions (ROBINS-I) tool, and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) was used to assess the quality of the evidence. RESULTS: We identified 835 papers of which only 11 articles were eligible for our review. All papers suffered from serious or critical risk of bias, and the quality of evidence was graded as very low according to the GRADE criteria. None of the studies was randomized and reporting of confounders and other parameters was poor. Median overall survival (OS) ranged from 4.1 to 32 months and progression free survival (PFS) from 2 to 31 months. The mean complication rate was 33.7%. No quality of life or cost-effectiveness data were reported. CONCLUSIONS: Due to the low quality of the studies, it is not possible to draw firm conclusions regarding the (cost) effectiveness of LITT in patients with newly diagnosed glioblastoma. The low quality of evidence shows the need for a well-designed prospective multicenter randomized controlled trial.

Atlanto axial rotatory dislocation in adults: a rare complication of an epileptic seizure--case report.

Atlanto Axial Rotatory Dislocations (AARDs) are a heterogeneous group of post-traumatic pathologies typical of the pediatric age, and rare in adults. We describe the case of a 34-year-old woman, developing Atlanto Axial Rotatory Fixation (AARF) after a generalized tonic-clonic epileptic seizure, an extremely rare traumatic cause never described in literature. AARF was detected only 1 month after the accident and nonsurgical treatment was attempted at the beginning. The patient underwent surgery only 2 months after the accident. The best treatment should be conservative reduction within 1 month; when it is not possible, it is advisable to perform surgery as soon as possible. C1-C2 fixation with Harm's technique is the gold standard for fixed luxations. Delay of treatment makes intraoperative reduction more difficult and increase the establishment of the chronic permanent change of neck muscles and ligaments.