Molecular tumor analysis and liquid biopsy: a feasibility investigation analyzing circulating tumor DNA in patients with central nervous system lymphomas.

BACKGROUND: Central nervous system lymphomas (CNSL) is a devastating disease. Currently, a confirmatory biopsy is required prior to treatment. OBJECTIVE: Our investigation aims to prove the feasibility of a minimally-invasive diagnostic approach for the molecular characterization of CNSL. METHODS: Tissue biopsies from 6 patients with suspected CNSL were analyzed using a 649gene next-generation sequencing (NGS) tumor panel (tumor vs. reference tissue (EDTA-blood)). The individual somatic mutation pattern was used as a basis for the digital PCR analyzing circulating tumor DNA (ctDNA) from plasma and cerebrospinal fluid (CSF) samples, identifying one selected tumor mutation during this first step of the feasibility investigation. RESULTS: NGS-analysis of biopsy tissue revealed a specific somatic mutation pattern in all confirmed lymphoma samples (n = 5, NGS-sensitivity 100%) and none in the sample identified as normal brain tissue (NGS-specificity 100%). cfDNA-extraction was dependent on the extraction-kit used and feasible in 3 samples, in all of which somatic mutations were detectable (100%). Analysis of CSF-derived cfDNA was superior to plasma-derived cfDNA and routine microscopic analysis (lymphoma cells: n = 2, 40%). One patient showed a divergent molecular pattern, typical of Burkitt-Lymphoma (HIV+, serologic evidence of EBV-infection). Lumbar puncture was tolerated without complications, whereas biopsy caused 3 hemorrhages. CONCLUSIONS: Our investigation provides evidence that analysis of cfDNA in central nervous system tumors is feasible using the described protocol. Molecular characterization of CNSL could be achieved by analysis of CSF-derived cfDNA. Knowledge of a tumor's specific mutation pattern may allow initiation of targeted therapies, treatment surveillance and could lead to minimally-invasive diagnostics in the future.

Endoscopic surgery for tumors of the pineal region via a paramedian infratentorial supracerebellar keyhole approach (PISKA).

The tumors of the pineal region represent a significant challenge in terms of patient selection and surgical approach. Traditional surgical options were commonly used to approach this area causing considerable surgical morbidity and mortality. We report for the first time on a series of endoscopic procedures for lesions of the pineal region performed via an infratentorial supracerebellar keyhole approach (PISKA) in the prone position using endoscope-assisted and endoscope-controlled technique. A single-institution series of 11 consecutive patients (five male and six female patients [11 total cases]; mean age 21 years, range 1-75 years) treated via the endoscope-assisted and endoscope-controlled PISKA for a pathological entity in the pineal region was retrospectively reviewed. The mean follow-up time was 24 months. The endoscopic PISKA was successfully used to approach a variety of pineal lesions, including pineocytoma (three patients), pineal cysts (four patients), germinoma, lipoma, medulloblastoma, and glioblastoma (one patient each). Gross total resection was achieved in ten cases and subtotal resection in one case. The mean preoperative tumor volumes were approximately 2 × 2 cm. Five patients developed postoperatively transient Parinaud's syndrome. One patient underwent surgical revision for cerebrospinal fluid leak. There was no mortality. Ten patients had an uneventful postoperative course with restitutio ad integrum after a mean follow-up duration of 13.5 months. The endoscopically PISKA is a safe and effective minimally invasive approach that enables endoscopic treatment of different lesions of the pineal region with comparable results to standard microsurgical technique but less morbidity.

Comparison of navigated transcranial magnetic stimulation and functional magnetic resonance imaging for preoperative mapping in rolandic tumor surgery.

Navigated transcranial magnetic stimulation (nTMS) is a novel tool for preoperative functional mapping. It detects eloquent cortical areas directly, comparable to intraoperative direct cortical stimulation (DCS). The aim of this study was to evaluate the advantage of nTMS in comparison with functional magnetic resonance imaging (fMRI) in the clinical setting. Special focus was placed on accuracy of motor cortex localization in patients with rolandic lesions. Thirty consecutive patients were enrolled in the study. All patients received an fMRI and nTMS examination preoperatively. Feasibility of the technique and spatial resolution of upper and lower extremity cortical mapping were compared with fMRI. Consistency of preoperative mapping with intraoperative DCS was assessed via the neuronavigation system. nTMS was feasible in all 30 patients. fMRI was impossible in 7 out of 30 patients with special clinical conditions, pediatric patients, central vascular lesions, or compliance issues. The mean accuracy to localize motor cortex of nTMS was higher than in fMRI. In the subgroup of intrinsic tumors, nTMS produced statistically significant higher accuracy scores of the lower extremity localization than fMRI. fMRI failed to localize hand or leg areas in 6 out of 23 cases. Using nTMS, a preoperative localization of the central sulcus was possible in all patients. Verification of nTMS motor cortex localization with DCS was achieved in all cases. The fMRI localization of the hand area proved to be postcentral in one case. nTMS has fewer restrictions for preoperative functional mapping than fMRI and requires only a limited level of compliance. nTMS scores higher on the accuracy scale than fMRI. nTMS represents a highly valuable supplement for the preoperative functional planning in the clinical routine.

Incidence of symptomatic hemorrhage after stereotactic electrode placement.

OBJECT: Intracranial hemorrhage (ICH) is the most significant complication associated with the placement of stereotactic intracerebral electrodes. Previous reports have suggested that hypertension and the use of microelectrode recording (MER) are risk factors for cerebral hemorrhage. The authors evaluated the incidence of symptomatic ICH in a large cohort of patients with various diseases treated with stereotactic electrode placement. They examined the effect of comorbidities on the risk of ICH and independently assessed the risks associated with age, sex, use of MER, diagnosis, target location, hypertension, and previous use of anticoagulant medications. The authors also evaluated the effect of hemorrhage on length of hospital stay and discharge disposition. METHODS: Between 1991 and 2005, 567 electrodes were placed by two neurosurgeons during 337 procedures in 259 patients. Deep brain stimulation (DBS) was performed in 167 procedures, radiofrequency lesioning (RFL) of subcortical structures in 74, and depth electrodes were used in 96 procedures in patients with epilepsy. Electrodes were grouped according to target, patient diagnosis, use of MER, patient history of hypertension, and patient prior use of anticoagulant medication (stopped 10 days before surgery). The Charlson Comorbidity Index (CCI) was used to evaluate the effect of comorbidities. The CCI score, patient age, length of hospital stay, and discharge status were continuous variables. Symptomatic hemorrhages were grouped as transient or leading to permanent neurological deficits. RESULTS: The risk of hemorrhage leading to permanent neurological deficits in this study was 0.7%, and the risk of symptomatic hemorrhage was 1.2%. A patient history of hypertension was the most significant factor associated with hemorrhage (p = 0.007). Older age, male sex, and a diagnosis of Parkinson disease (PD) were also significantly associated with hemorrhage (p = 0.01, 0.04, 0.007, respectively). High CCI scores, specific target locations, and prior use of anticoagulant therapy were not associated with an increased risk of hemorrhage. The use of MER was not found to be correlated with an increased hemorrhage rate (p = 0.34); however, the number of hemorrhages in the patients who underwent DBS was insufficient to draw definitive conclusions. The mean length of stay for the DBS, RFL, and depth electrode patient groups was 2.9, 2.6, and 11.0 days, respectively. For patients who received DBS and RFL, the mean duration of hospitalization in cases of symptomatic hemorrhage was 8.2 days compared with 2.7 days in those without hemorrhaging (p < 0.0001). Three of the seven patients with symptomatic hemorrhages were discharged home. CONCLUSIONS: The placement of stereotactic electrodes is generally safe, with a symptomatic hemorrhage rate of 1.2%, and a 0.7% rate of permanent neurological deficit. Consistent with prior reports, this study confirms that hypertension is a significant risk factor for hemorrhage. Age, male sex, and diagnosis of PD were also significant risk factors. Patients with symptomatic hemorrhage had longer hospital stays and were less likely to be discharged home.

Supraorbital Keyhole Approach to the Skull Base: Evaluation of Complications Related to CSF Fistulas and Opened Frontal Sinus.

AIM: Cerebrospinal fluid (CSF) rhinorrhea due to a breach in the frontal sinus (FS) presents one of the main postoperative complications of the supraorbital keyhole approach. The goal of this study was to further analyze the actual surgical morbidity and potential risk for patients due to an opened FS after a surgery via a supraorbital craniotomy and compare the results with data published in the current literature. METHODS AND PATIENTS: A total of 350 consecutive patients who underwent surgeries via the supraorbital keyhole approach for various lesions were included in this retrospective study. Information on clinical history, neurologic symptoms, surgical approach, and postoperative complications was obtained retrospectively by a review of the patients' charts, the radiologic reports, and a thorough review of pre- and postoperative cranial computed tomography (CCT) imaging. RESULTS: The frequency of CSF rhinorrhea after this type of craniotomy in the literature is reported to range between 0% and 9.1%. In this study, analysis of postoperative CCT scans revealed that 88 patients (25.1%) showed a radiographic breach of the FS. Only 8 of these patients (2.3%) developed a CSF leak with rhinorrhea postoperatively. In all cases conservative treatment with lumbar drainage failed, and therefore a surgical revision for permanent closure was required. Only one patient (0.3%) with a CSF leak also developed meningitis. CONCLUSION: Inadvertent opening of the FS during the supraorbital craniotomy is a common surgery-related morbidity; however, the risk for the patient to develop a potentially dangerous meningitis was found to be minimal.

First preoperative functional mapping via navigated transcranial magnetic stimulation in a 3-year-old boy.

Preoperative functional mapping in children younger than 5 years old remains a challenge. Awake functional MRI (fMRI) is usually not an option for these patients. Except for a description of passive fMRI in sedated patients and magnetoencephalography, no other noninvasive mapping method has been reported as a preoperative diagnostic tool in children. Therefore, invasive intraoperative direct cortical stimulation remains the method of choice. To the authors' knowledge, this is the first case of a young child undergoing preoperative functional motor cortex mapping with the aid of navigated transcranial magnetic stimulation (nTMS). In this 3-year-old boy with a rolandic ganglioglioma, awake preoperative mapping was performed using nTMS. A precise location of Broca area 4 could be established. The surgical approach was planned according to the preoperative findings. Intraoperative direct cortical stimulation verified the location of the nTMS hotspots, and complete resection of the precentral tumor was achieved. Navigated TMS is a precise tool for preoperative motor cortex mapping and is feasible even in very young pediatric patients. In children for whom performing the fMRI motor paradigm is challenging, nTMS is the only available option for functional mapping.