Patient Reported Outcome (PRO) Among High-Grade Glioma Patients Receiving TTFields Treatment: A Two Center Observational Study

Study design: A two center, observational study. Introduction: Patient reported outcome (PRO) plays an increasingly important role in the evaluation of novel therapies for tumor patients. It has been shown that tumor treating fields (TTFields) in combination with standard therapy prolong survival in high-grade glioma (hgG) patients. But critics claim that TTFields significantly impacts patients' everyday life due to side effects and average daily time on therapy (18 h) in a patient population with very limited life expectancy and high symptom burden. However, very limited data exist on PRO for TTFields treatment. Methods: This two center, observational study describes PRO of 30 hgG patients receiving TTFields in combination with chemotherapy. We introduced a device-specific questionnaire (DSQ) addressing device-specific restrictions and impact on daily live after 2 months of therapy. Additionally following questionnaires were used: EORTC (European Organization for Research and Treatment of Cancer), QLQ-30 (Quality of life of cancer patients), QLQ BN20 (Quality of life brain cancer module), QLQ FA13 (Cancer-related fatigue), and SSUK-8 (social support). Results: Surveys have been completed by 91% of enrolled patients. EORTC QLQ-30 revealed better physical, emotional, and cognitive function than social and role function of study cohort. TTFields users reported frequently on positive social support and a low level of detrimental interactions. Seventy one percent of patients felt affected in daily life due to TTFields at least 2-3 times per week up to several times per day while maintaining high therapy compliance. Most frequent device-specific restrictions were duration of therapy (74%), size (66%), and weight (70%) of the device and changing time and bonding of the transducer arrays (66%, mean duration: 43.6 min). Restrictions on exercise of hobbies/work (63%/61%), body care (71%), and sexuality/relationship (64%) were most relevant. Seventy percent would recommend TTFields to others and 67% would reuse TTFields treatment again based on their current experience. Conclusion: The study shows that although TTFields treatment frequently affects everyday life in all aspects, therapy compliance was high and 67% of patients would reconsider TTFields for themselves. We propose that findings of PRO be taken into account for medical consultation about TTFields and in future device development to deliver high-value patient-centered care

Utilization of Epidural Electrodes as a Diagnostic Tool in Intractable Epilepsy—A Technical Note

The utilization of epidural electrodes in the preoperative evaluation of intractable epilepsy is a valuable but underrepresented tool. In recent years, we have adapted the use of cylindrical epidural 1-contact electrodes (1-CE) instead of Peg electrodes. 1-CEs are more versatile since their explantation is a possible bedside procedure. Here we report our experience with 1-CEs as well as associated technical nuances. This retrospective analysis included 56 patients with intractable epilepsy who underwent epidural electrode placement for presurgical evaluation at the Department of Neurosurgery at the Charité University Hospital from September 2011 to July 2021. The median age at surgery was 36.3 years (range: 18–87), with 30 (53.6%) female and 26 (46.4%) male patients. Overall, 507 electrodes were implanted: 93 Fo electrodes, 33 depth electrodes, and 381 epidural electrodes, with a mean total surgical time of 100.5 ± 38 min and 11.8 ± 5 min per electrode. There was a total number of 24 complications in 21 patients (8 Fo electrode dislocations, 6 CSF leaks, 6 epidural electrode dislocations or malfunction, 3 wound infections, and 2 hemorrhages); 11 of these required revision surgery. The relative electrode complication rates were 3/222 (1.4%) in Peg electrodes and 3/159 (1.9%) in 1-CE. In summary, epidural recording via 1-CE is technically feasible, harbours an acceptable complication rate, and adequately replaces Peg electrodes

Predictive MGMT status in a homogeneous cohort of IDH wildtype glioblastoma patients

Methylation of the O(6)-Methylguanine-DNA methyltransferase (MGMT) promoter is predictive for treatment response in glioblastoma patients. However, precise predictive cutoff values to distinguish "MGMT methylated" from "MGMT unmethylated" patients remain highly debated in terms of pyrosequencing (PSQ) analysis. We retrospectively analyzed a clinically and molecularly very well-characterized cohort of 111 IDH wildtype glioblastoma patients, who underwent gross total tumor resection and received standard Stupp treatment. Detailed clinical parameters were obtained. Predictive cutoff values for MGMT promoter methylation were determined using ROC curve analysis and survival curve comparison using Log-rank (Mantel-Cox) test. MGMT status was analyzed using pyrosequencing (PSQ), semi-quantitative methylation specific PCR (sqMSP) and direct bisulfite sequencing (dBiSeq). Highly methylated (> 20%) MGMT correlated with significantly improved progression-free survival (PFS) and overall survival (OS) in our cohort. Median PFS was 7.2 months in the unmethylated group (UM, 20% mean methylation). Median OS was 13.4 months for UM, 17.9 months for LM and 29.93 months for HM. Within the LM group, correlation of PSQ and sqMSP or dBiSeq was only conclusive in 51.5% of our cases. ROC curve analysis revealed superior test precision for survival if additional sqMSP results were considered (AUC = 0.76) compared to PSQ (cutoff 10%) alone (AUC = 0.67). We therefore challenge the widely used, strict PSQ cutoff at 10% which might not fully reflect the clinical response to alkylating agents and suggest applying a second method for MGMT testing (e.g. MSP) to confirm PSQ results for patients with LM MGMT levels if therapeutically relevant

Reduction in wound healing complications and infection rate by lumbar CSF drainage after decompressive hemicraniectomy

Objective: Wound healing disorders and surgical site infections are the most frequently encountered complications after decompressive hemicraniectomy (DHC). Subgaleal CSF accumulation causes additional tension of the scalp flap and increases the risk of wound dehiscence, CSF fistula, and infection. Lumbar CSF drainage might relieve subgaleal CSF accumulation and is often used when a CSF fistula through the surgical wound appears. The aim of this study was to investigate if early prophylactic lumbar drainage might reduce the rate of postoperative wound revisions and infections after DHC. Methods: The authors retrospectively analyzed 104 consecutive patients who underwent DHC from January 2019 to May 2021. Before January 2020, patients did not receive lumbar drainage, whereas after January 2020, patients received lumbar drainage within 3 days after DHC for a median total of 4 (IQR 2-5) days if the first postoperative CT scan confirmed open basal cisterns. The primary endpoint was the rate of severe wound healing complications requiring surgical revision. Secondary endpoints were the rate of subgaleal CSF accumulations and hygromas as well as the rate of purulent wound infections and subdural empyema. Results: A total of 31 patients died during the acute phase; 34 patients with and 39 patients without lumbar drainage were included for the analysis of endpoints. The predominant underlying pathology was malignant hemispheric stroke (58.8% vs 66.7%) followed by traumatic brain injury (20.6% vs 23.1%). The rate of surgical wound revisions was significantly lower in the lumbar drainage group (5 [14.7%] vs 14 [35.9%], p = 0.04). A stepwise linear regression analysis was used to identify potential covariates associated with wound healing disorder and reduced them to lumbar drainage and BMI. One patient was subject to paradoxical herniation. However, the patient's symptoms rapidly resolved after lumbar drainage was discontinued, and he survived with only moderate deficits related to the primary disease. There was no significant difference in the rate of radiological herniation signs. The median lengths of stay in the ICU were similar, with 12 (IQR 9-23) days in the drainage group compared with 13 (IQR 11-23) days in the control group (p = 0.21). Conclusions: In patients after DHC and open basal cisterns on postoperative CT, lumbar drainage appears to be safe and reduces the rate of surgical wound revisions and intracranial infection after DHC while the risk for provoking paradoxical herniation is low early after surgery

MRI-Based Risk Assessment for Incomplete Resection of Brain Metastases

Recent studies demonstrated that gross total resection of brain metastases cannot always be achieved. Subtotal resection (STR) can result in an early recurrence and might affect patient survival. We initiated a prospective observational study to establish a MRI-based risk assessment for incomplete resection of brain metastases.Peer Reviewe

High-grade astrocytoma with piloid features (HGAP): the Charité experience with a new central nervous system tumor entity

Purpose: High-grade astrocytoma with piloid features (HGAP) is a recently described brain tumor entity defined by a specific DNA methylation profile. HGAP has been proposed to be integrated in the upcoming World Health Organization classification of central nervous system tumors expected in 2021. In this series, we present the first single-center experience with this new entity. Methods: During 2017 and 2020, six HGAP were identified. Clinical course, surgical procedure, histopathology, genome-wide DNA methylation analysis, imaging, and adjuvant therapy were collected. Results: Tumors were localized in the brain stem (n = 1), cerebellar peduncle (n = 1), diencephalon (n = 1), mesencephalon (n = 1), cerebrum (n = 1) and the thoracic spinal cord (n = 2). The lesions typically presented as T1w hypo- to isointense and T2w hyperintense with inhomogeneous contrast enhancement on MRI. All patients underwent initial surgical intervention. Three patients received adjuvant radiochemotherapy, and one patient adjuvant radiotherapy alone. Four patients died of disease, with an overall survival of 1.8, 9.1, 14.8 and 18.1 months. One patient was alive at the time of last follow-up, 14.6 months after surgery, and one patient was lost to follow-up. Apart from one tumor, the lesions did not present with high grade histology, however patients showed poor clinical outcomes. Conclusions: Here, we provide detailed clinical, neuroradiological, histological, and molecular pathological information which might aid in clinical decision making until larger case series are published. With the exception of one case, the tumors did not present with high-grade histology but patients still showed short intervals between diagnosis and tumor progression or death even after extensive multimodal therapy

Effectiveness of Immune Checkpoint Inhibition vs Chemotherapy in Combination With Radiation Therapy Among Patients With Non–Small Cell Lung Cancer and Brain Metastasis Undergoing Neurosurgical Resection

Importance: Patients with brain metastases from non-small cell lung cancer (NSCLC) have regularly been excluded from prospective clinical trials that include therapy with immune checkpoint inhibitors (ICIs). Clinical data demonstrating benefit with ICIs, specifically following neurosurgical brain metastasis resection, are scarce. Objective: To evaluate and compare the association of radiation therapy with ICIs vs classic therapy involving radiation therapy and chemotherapy regarding overall survival in a cohort of patients who underwent NSCLC brain metastasis resection. Design, setting and participants: This single-center 1:1 propensity-matched comparative effectiveness study at the largest neurosurgical clinic in Germany included individuals who had undergone craniotomy with brain metastasis resection from January 2010 to December 2021 with histologically confirmed NSCLC. Of 1690 patients with lung cancer and brain metastasis, 480 were included in the study. Key exclusion criteria were small-cell lung cancer, lack of tumor cells by means of histopathological analysis on brain metastasis resection, and patients who underwent biopsy without tumor resection. The association of overall survival with treatment with radiation therapy and chemotherapy vs radiation therapy and ICI was evaluated. Exposures: Radiation therapy and chemotherapy vs radiation therapy and ICI following craniotomy and microsurgical brain metastasis resection. Main outcomes and measures: Median overall survival. Results: From the whole cohort of patients with NSCLC (N = 384). 215 (56%) were male and 169 (44%) were female. The median (IQR) age was 64 (57-72) years. The 2 cohorts of interest included 108 patients (31%) with radiation therapy and chemotherapy and 63 patients (16%) with radiation therapy and ICI following neurosurgical metastasis removal (before matching). Median (IQR) follow-up time for the total cohort was 47.9 (28.2-70.1) months with 89 patients (23%) being censored and 295 (77%) dead at the end of follow-up in December 2021. After covariate equalization using propensity score matching (62 patients per group), patients receiving radiation therapy and chemotherapy after neurosurgery had significantly lower overall survival (11.8 months; 95% CI; 9.1-15.2) compared with patients with radiation therapy and ICIs (23.0 months; 95% CI; 20.3-53.8) (P < .001). Conclusions and relevance: Patients with NSCLC brain metastases undergoing neurosurgical resection had longer overall survival when treated with radiation therapy and ICIs following neurosurgery compared with those receiving platinum-based chemotherapy and radiation. Radiation and systemic immunotherapy should be regularly evaluated as a treatment option for these patients

Clinical implementation of a 3D4K-exoscope (Orbeye) in microneurosurgery

Exoscopic surgery promises alleviation of physical strain, improved intraoperative visualization and facilitation of the clinical workflow. In this prospective observational study, we investigate the clinical usability of a novel 3D4K-exoscope in routine neurosurgical interventions. Questionnaires on the use of the exoscope were carried out. Exemplary cases were additionally video-documented. All participating neurosurgeons (n = 10) received initial device training. Changing to a conventional microscope was possible at all times. A linear mixed model was used to analyse the impact of time on the switchover rate. For further analysis, we dichotomized the surgeons in a frequent (n = 1) and an infrequent (n = 9) user group. A one-sample Wilcoxon signed rank test was used to evaluate, if the number of surgeries differed between the two groups. Thirty-nine operations were included. No intraoperative complications occurred. In 69.2% of the procedures, the surgeon switched to the conventional microscope. While during the first half of the study the conversion rate was 90%, it decreased to 52.6% in the second half (p = 0.003). The number of interventions between the frequent and the infrequent user group differed significantly (p = 0.007). Main reasons for switching to ocular-based surgery were impaired hand-eye coordination and poor depth perception. The exoscope investigated in this study can be easily integrated in established neurosurgical workflows. Surgical ergonomics improved compared to standard microsurgical setups. Excellent image quality and precise control of the camera added to overall user satisfaction. For experienced surgeons, the incentive to switch from ocular-based to exoscopic surgery greatly varies

Opportunities and Alternatives of Modern Radiation Oncology and Surgery for the Management of Resectable Brain Metastases.

Postsurgical radiotherapy (RT) has been early proven to prevent local tumor recurrence, initially performed with whole brain RT (WBRT). Subsequent to disadvantageous cognitive sequalae for the patient and the broad distribution of modern linear accelerators, focal irradiation of the tumor has omitted WBRT in most cases. In many studies, the effectiveness of local RT of the resection cavity, either as single-fraction stereotactic radiosurgery (SRS) or hypo-fractionated stereotactic RT (hFSRT), has been demonstrated to be effective and safe. However, whereas prospective high-level incidence is still lacking on which dose and fractionation scheme is the best choice for the patient, further ablative techniques have come into play. Neoadjuvant SRS (N-SRS) prior to resection combines straightforward target delineation with an accelerated post-surgical phase, allowing an earlier start of systemic treatment or rehabilitation as indicated. In addition, low-energy intraoperative RT (IORT) on the surgical bed has been introduced as another alternative to external beam RT, offering sterilization of the cavity surface with steep dose gradients towards the healthy brain. This consensus paper summarizes current local treatment strategies for resectable brain metastases regarding available data and patient-centered decision-making

Molecular characterisation of sporadic endolymphatic sac tumours and comparison to von Hippel–Lindau disease‐related tumours

Aims: Although inactivation of the von Hippel-Lindau gene (VHL) on chromosome 3p25 is considered to be the major cause of hereditary endolymphatic sac tumours (ELSTs), the genetic background of sporadic ELST is largely unknown. The aim of this study was to determine the prevalence of VHL mutations in sporadic ELSTs and compare their characteristics to VHL-disease-related tumours. Methods: Genetic and epigenetic alterations were compared between 11 sporadic and 11 VHL-disease-related ELSTs by targeted sequencing and DNA methylation analysis. Results: VHL mutations and small deletions detected by targeted deep sequencing were identified in 9/11 sporadic ELSTs (82%). No other cancer-related genetic pathway was altered except for TERT promoter mutations in two sporadic ELST and one VHL-disease-related ELST (15%). Loss of heterozygosity of chromosome 3 was found in 6/10 (60%) VHL-disease-related and 10/11 (91%) sporadic ELSTs resulting in biallelic VHL inactivation in 8/10 (73%) sporadic ELSTs. DNA methylation profiling did not reveal differences between sporadic and VHL-disease-related ELSTs but reliably distinguished ELST from morphological mimics of the cerebellopontine angle. VHL patients were significantly younger at disease onset compared to sporadic ELSTs (29 vs. 52 years, p < 0.0001, Fisher's exact test). VHL-disease status was not associated with an increased risk of recurrence, but the presence of clear cells was found to be associated with shorter progression-free survival (p = 0.0002, log-rank test). Conclusion: Biallelic inactivation of VHL is the main mechanism underlying ELSTs, but unknown mechanisms beyond VHL may rarely be involved in the pathogenesis of sporadic ELSTs