0000000000042896
AUTHOR
Alf Giese
Image-guided transcranial Doppler sonography for monitoring of vasospasm after subarachnoid hemorrhage.
Transcranial Doppler ultrasound (TCD) is a standard method for bedside vasospasm monitoring after subarachnoid hemorrhage (SAH). Image guidance has previously been shown to reduce intra- and interobserver variability of this method. The aim of the present study was to compare image-guided and conventional TCD in vasospasm monitoring after SAH.418 TCD exams of 24 consecutive SAH patients registered in a database were evaluated. Of these, 130 image-guided exams were identified which had been performed on the same day as conventional Doppler exams. These matched pairs were taken for statistical analysis. Data were tested statistically using the sign test applied at patient level to aggregated …
Strategies in Glioma-Surgery
1.1 Epidemiology and classification of gliomas Malignant glioma is one of the most feared diseases in the industrialized nations. About 77% of all malignant tumors within the central nervous system are gliomas. There are about 18.000 newly diagnosed cases annually within the USA (9/100.000 inhabitants per year) and the disease causes about 13.000 deaths each year. Statistically this is a higher loss of life-time than all other tumor-entities together (Schwartzbaum et al., 2006). About 45-50% of these gliomas are histologically classified as gliobalstoma multiforme (GBM) the most aggressive type of glioma which is classified as WHO grade IV (following the classification of Kleihues et al., 2…
Molecular pathway activation – New type of biomarkers for tumor morphology and personalized selection of target drugs
Anticancer target drugs (ATDs) specifically bind and inhibit molecular targets that play important roles in cancer development and progression, being deeply implicated in intracellular signaling pathways. To date, hundreds of different ATDs were approved for clinical use in the different countries. Compared to previous chemotherapy treatments, ATDs often demonstrate reduced side effects and increased efficiency, but also have higher costs. However, the efficiency of ATDs for the advanced stage tumors is still insufficient. Different ATDs have different mechanisms of action and are effective in different cohorts of patients. Personalized approaches are therefore needed to select the best ATD…
Microsurgical fenestration of perineural cysts to the thecal sac at the level of the distal dural sleeve
Background Surgery for symptomatic sacral perineural cysts remains an issue of discussion. Assuming micro-communications between the cyst and thecal sac resulting in a valve mechanism and trapping of CSF as a pathomechanism, microsurgical fenestration from the cyst to the thecal sac was performed to achieve free CSF communication. Methods In 13 consecutive patients (10 female, 3 male), MRI revealed sacral perineural cysts and excluded other pathologies. Micro-communication between the thecal sac and the cysts was shown by delayed contrast filling of the cysts on postmyelographic CT. Surgical fenestration achieved free CSF communication between the thecal sac and cysts in all patients. The p…
Oncobox, gene expression-based second opinion system for predicting response to treatment in advanced solid tumors.
e13143 Background: Anticancer Targeted Drugs (ATDs) specifically target one or a few types of tumor-related molecules in a cell. More than two hundred of ATDs were approved worldwide. They have different mechanisms of action and are effective for different cohorts of patients. However, many individual cases remain poorly responsive and it is of great importance to identify predictive markers of ATD efficacy. Our aim was to develop a platform enabling smart selection of the most efficient ATD therapies. Methods: We generated a second-opinion platform for clinical oncologists termed Oncobox. It is based on the analysis of gene expression profile of a cancer sample in comparison with the corr…
Automatic scanning of large tissue areas in neurosurgery using optical coherence tomography
Background With its high spatial and temporal resolution, optical coherence tomography (OCT) is an ideal modality for intra-operative imaging. One possible application is to detect tumour invaded tissue in neurosurgery, e.g. during complete resection of glioblastoma. Ideally, the whole resection cavity is scanned. However, OCT is limited to a small field of view (FOV) and scanning perpendicular to the tissue surface. Methods We present a new method to use OCT for scanning of the resection cavity during neurosurgical resection of brain tumours. The main challenges are creating a map of the cavity, scanning perpendicular to the surface and merging the three-dimensional (3D) data for intra-ope…
First multiphoton tomography of brain in man
We report on the first two-photon in vivo brain tissue imaging study in man. High resolution in vivo histology by multiphoton tomography (MPT) including two-photon FLIM was performed in the operation theatre during neurosurgery to evaluate the feasibility to detect label-free tumor borders with subcellular resolution. This feasibility study demonstrates, that MPT has the potential to identify tumor borders on a cellular level in nearly real-time.
Rates of Upper Facet Joint Violation in Minimally Invasive Percutaneous and Open Instrumentation: A Comparative Cohort Study of Different Insertion Techniques.
Background Minimally invasive pedicle screw placement may have a higher incidence of violation of the superior cephalad unfused facet joint. Study Aims We investigated the incidence and risk factors of upper facet joint violation in percutaneous robot-assisted instrumentation versus percutaneous fluoroscopy-guided and open transpedicular instrumentation. Methods A retrospective study including all consecutive patients who underwent lumbar instrumentation, fusion, and decompression for spondylolisthetic stenosis and degenerative disk disease was conducted between January 2012 and January 2016. All operations were performed by the same surgeon; the patients were divided into three groups acc…
Diversity of Clinically Relevant Outcomes Resulting from Hypofractionated Radiation in Human Glioma Stem Cells Mirrors Distinct Patterns of Transcriptomic Changes
Hypofractionated radiotherapy is the mainstay of the current treatment for glioblastoma. However, the efficacy of radiotherapy is hindered by the high degree of radioresistance associated with glioma stem cells comprising a heterogeneous compartment of cell lineages differing in their phenotypic characteristics, molecular signatures, and biological responses to external signals. Reconstruction of radiation responses in glioma stem cells is necessary for understanding the biological and molecular determinants of glioblastoma radioresistance. To date, there is a paucity of information on the longitudinal outcomes of hypofractionated radiation in glioma stem cells. This study addresses long-te…
A novel minimally invasive, dorsolateral, tubular partial odontoidectomy and autologous bone augmentation to treat dens pseudarthrosis: cadaveric, 3D virtual simulation study and technical report.
OBJECTIVE The goal of this study was to demonstrate the clinical and technical nuances of a minimally invasive, dorsolateral, tubular approach for partial odontoidectomy, autologous bone augmentation, and temporary C1–2 fixation to treat dens pseudarthrosis. METHODS A cadaveric feasibility study, a 3D virtual reality reconstruction study, and the subsequent application of this approach in 2 clinical cases are reported. Eight procedures were completed in 4 human cadavers. A minimally invasive, dorsolateral, tubular approach for odontoidectomy was performed with the aid of a tubular retraction system, using a posterolateral incision and an oblique approach angle. Fluoroscopy and postprocedur…
EGFL7 enhances surface expression of integrin α5β1 to promote angiogenesis in malignant brain tumors
Abstract Glioblastoma (GBM) is a typically lethal type of brain tumor with a median survival of 15 months postdiagnosis. This negative prognosis prompted the exploration of alternative treatment options. In particular, the reliance of GBM on angiogenesis triggered the development of anti‐VEGF (vascular endothelial growth factor) blocking antibodies such as bevacizumab. Although its application in human GBM only increased progression‐free periods but did not improve overall survival, physicians and researchers still utilize this treatment option due to the lack of adequate alternatives. In an attempt to improve the efficacy of anti‐VEGF treatment, we explored the role of the egfl7 gene in ma…
Disparity between Inter-Patient Molecular Heterogeneity and Repertoires of Target Drugs Used for Different Types of Cancer in Clinical Oncology
Inter-patient molecular heterogeneity is the major declared driver of an expanding variety of anticancer drugs and personalizing their prescriptions. Here, we compared interpatient molecular heterogeneities of tumors and repertoires of drugs or their molecular targets currently in use in clinical oncology. We estimated molecular heterogeneity using genomic (whole exome sequencing) and transcriptomic (RNA sequencing) data for 4890 tumors taken from The Cancer Genome Atlas database. For thirteen major cancer types, we compared heterogeneities at the levels of mutations and gene expression with the repertoires of targeted therapeutics and their molecular targets accepted by the current guideli…
CD133 Expression Is Not Synonymous to Immunoreactivity for AC133 and Fluctuates throughout the Cell Cycle in Glioma Stem-Like Cells.
A transmembrane protein CD133 has been implicated as a marker of stem-like glioma cells and predictor for therapeutic response in malignant brain tumours. CD133 expression is commonly evaluated by using antibodies specific for the AC133 epitope located in one of the extracellular domains of membrane-bound CD133. There is conflicting evidence regarding the significance of the AC133 epitope as a marker for identifying stem-like glioma cells and predicting the degree of malignancy in glioma cells. The reasons for discrepant results between different studies addressing the role of CD133/AC133 in gliomas are unclear. A possible source for controversies about CD133/AC133 is the widespread assumpt…
Clinical use of RNA sequencing and oncobox analytics to predict personalized targeted therapeutic efficacy.
e13676 Background: Analysis of mutation profiles in cancer patients does not provide clinical benefits in 80-90% of cases in the US (Marquart et al., 2018). Gene expression analysis potentially complements standard detection of clinically relevant mutations. Methods: 239 adult late-stage cancer patients. RNA gene expression sequencing completed on solid tumor samples using FFPE blocks. Patient mRNA profiles were analyzed using Oncobox bioinformatics, prioritizing target drugs according to their personalized predicted efficacy. Summary reports were provided to oncologists and resulting treatment selection and outcomes were assessed. Results: As of February 2020, feedback was received from p…
Evaluation of robot-guided minimally invasive implantation of 2067 pedicle screws
ObjectiveRecent studies have investigated the role of spinal image guidance for pedicle screw placement. Many authors have observed an elevated placement accuracy and overall improvement of outcome measures. This study assessed a bi-institutional experience following introduction of the Renaissance miniature robot for spinal image guidance in Europe.MethodsThe medical records and radiographs of all patients who underwent robot-guided implantation of spinal instrumentation using the novel system (between October 2011 and March 2015 in Mainz and February 2014 and February 2016 in Regensburg) were reviewed to determine the efficacy and safety of the newly introduced robotic system. Screw posit…
Detection of intracranial circulatory arrest in brain death using cranial CT-angiography.
Background and purpose Computed tomographic-angiography (CT-A) is becoming more accepted in detecting intracranial circulatory arrest in brain death (BD). An international consensus about the use and the parameters of this technique is currently not established. We examined intracranial contrast enhancement in CT-A after clinically confirmed BD, compared the results with electroencephalography (EEG) and Transcranial Doppler Ultrasonography (TCD) findings and developed a commonly applicable CT-A protocol. Methods Prospective, monocentric study between April 2008 and October 2011. EEG, TCD and CT-A were performed in 63 patients aged between 18 and 88 years (mean, 55 years) who fulfilled clini…
Evaluation of a Completely Robotized Neurosurgical Operating Microscope
BACKGROUND Operating microscopes are essential for most neurosurgical procedures. Modern robot-assisted controls offer new possibilities, combining the advantages of conventional and automated systems. OBJECTIVE We evaluated the prototype of a completely robotized operating microscope with an integrated optical coherence tomography module. METHODS A standard operating microscope was fitted with motors and control instruments, with the manual control mode and balance preserved. In the robot mode, the microscope was steered by a remote control that could be fixed to a surgical instrument. External encoders and accelerometers tracked microscope movements. The microscope was additionally fitted…
Image guidance to improve reliability and data integrity of transcranial Doppler sonography.
Abstract Background Principles and accuracy of image-guided transcranial Doppler (IG TCD) sonography have been published recently. However, it remains open whether combination of image guidance and TCD offers an additional clinical advantage. This study scores the accuracy of conventional TCD examinations and investigates the potential improvement of TCD data integrity and reliability regarding the additional use of IG. Methods Conventional TCD was performed by a group of experienced investigators, who were blinded to images of a navigation system tracking the Doppler probe, whereas an independent observer documented the TCD findings, acquired by the investigators, due to saving spatial dat…
Image-Guided Transcranial Doppler Ultrasound for Monitoring Posthemorrhagic Vasospasms of Infratentorial Arteries: A Feasibility Study
Background A considerable number of patients with subarachnoid hemorrhage (SAH) develop vasospasms of the infratentorial arteries. Transcranial Doppler sonography (TCD) is used to screen for vasospasm. In this study, we used a technical modification that combines TCD with an image guidance device that the operator can use to navigate to the ultrasonic window and to predefined intracranial vascular targets. Our aim was to analyze the feasibility, spatial precision, and spatial reproducibility of serial image-guided TCD of infratentorial and—for comparison—supratentorial arteries in the clinical setting of monitoring for vasospasm after SAH. Methods The study included 10 SAH patients, who eac…
Algorithmically deduced FREM2 molecular pathway is a potent grade and survival biomarker of human gliomas
Gliomas are the most common malignant brain tumors with high mortality rates. Recently we showed that the FREM2 gene has a role in glioblastoma progression. Here we reconstructed the FREM2 molecular pathway using the human interactome model. We assessed the biomarker capacity of FREM2 expression and its pathway as the overall survival (OS) and progression-free survival (PFS) biomarkers. To this end, we used three literature and one experimental RNA sequencing datasets collectively covering 566 glioblastomas (GBM) and 1097 low-grade gliomas (LGG). The activation level of deduced FREM2 pathway showed strong biomarker characteristics and significantly outperformed the FREM2 expression level it…
Interface transition checklists in spinal surgery
Issue Recently, quality tools have been promoted to improve patient safety and process efficiency in healthcare. While surgeons primarily focused on surgical issues, like infection rates or implant design, we introduced pre-admission and preoperative checklists in the early 2000s. Initial assessment To assess the efficiency of these tools in a neurosurgical department, we performed a survey of all spinal instrumentation patients operated in 2011 ( n = 147). The results revealed several problems. Choice of solution We consequently redesigned the checklists accompanied by flanking measures, such as written and online accessible standards. Furthermore, the staff was trained to use the update…
MGMT promoter methylation status and prognosis of patients with primary or recurrent glioblastoma treated with carmustine wafers
The prognostic role of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation in glioblastoma patients treated with carmustine (BCNU) wafer implantation is unclear. Here, we report on a retrospective study of 47 patients with either newly diagnosed (30 patients) or recurrent (17 patients) glioblastoma (WHO grade IV) treated with BCNU (bis-chloroethylnitrosourea) wafers. Thirteen of the newly diagnosed patients received local BCNU and irradiation only (first-line BCNU), while 17 patients additionally received concomitant and adjuvant temozolomide (TMZ) radiochemotherapy (first-line BCNU + TMZ). Of the 17 patients treated for recurrent glioblastoma (second-line BCNU), 16 had rec…
Video-Assisted Navigation for Adjustment of Image-Guidance Accuracy to Slight Brain Shift
Background Information supplied by an image-guidance system can be superimposed on the operating microscope oculars or on a screen, generating augmented reality. Recently, the outline of a patient's head and skull, injected in the oculars of a standard operating microscope, has been used to check the registration accuracy of image guidance. Objective To propose the use of the brain surface relief and superficial vessels for real-time intraoperative visualization and image-guidance accuracy and for intraoperative adjustment for brain shift. Methods A commercially available image-guidance system and a standard operating microscope were used. Segmentation of the brain surface and cortical bloo…
Autostereoscopic Three-Dimensional Neuronavigation to the Sella: Technical Note.
Background A drawback of conventional neuronavigation is the necessity of focusing on two-dimensional images in 3 planes at the same time to determine one's position in the operating field. A solution would be to merge the images into a single three-dimensional (3D) image that mirrors the actual anatomy. The introduction of holographic glassless 3D monitors paved the way to 3D navigation. We present our experience with 3D neuronavigation as exemplified by navigation to and within the sella. Methods Operative planning was conducted with a navigation system using cranial computed tomography and magnetic resonance imaging. The image data sets were processed by the prototype Clariti 3D system t…
Predictive chromosomal clusters of synchronous and metachronous brain metastases in clear cell renal cell carcinoma
Synchronous (early) and metachronous (late) brain metastasis (BM) events of sporadic clear cell renal cell carcinoma (ccRCC) (n = 148) were retrospectively analyzed using comparative genomic hybridization (CGH). Using oncogenetic tree models and cluster analyses, chromosomal imbalances related to recurrence-free survival until BM (RFS-BM) were analyzed. Losses at 9p and 9q appeared to be hallmarks of metachronous BM events, whereas an absence of detectable chromosomal changes at 3p was often associated with synchronous BM events. Correspondingly, k-means clustering showed that cluster 1 cases generally exhibited low copy number chromosomal changes that did not involve 3p. Cluster 2 cases ha…
Use of a clinicoradiological score to determine the presurgical diagnosis of autoimmune hypophysitis in a teenage girl.
The distinction between autoimmune hypophysitis and other non–hormone secreting pituitary masses is often difficult to determine with certainty without pituitary biopsy and pathological examination. To aid in this distinction, the authors recently published a clinicoradiological scoring system, which they used in the case of a 15-year-old girl presented here. The patient presented with headache, visual field defects, polydipsia, and polyuria, and she was found to have secondary hypogonadism and hypoadrenalism. Magnetic resonance imaging showed a pituitary mass of approximately 2 cm in diameter. Application of the clinicoradiological parameters gave a score of −6, which favored a diagnosis o…
RNA-sequencing and bioinformatic analysis to pre-assess sensitivity to targeted therapeutics in recurrent glioblastoma.
e13533 Background: This study developed molecular guided tools for individualized selection of chemotherapeutics for recurrent glioblastoma (rGB). A consortium involving clinical neurooncologists, molecular biologists and bioinformaticians identified gene expression patterns in rGB and quantitatively analyzed pathways involved in response to FDA approved oncodrugs. Methods: From2016 to 2018 biopsies from GB were collected using a multisampling approach. Biopsy material was used to isolate glioma stem-like cells and examined by RNA-sequencing. RNA-seq results were subjected to differential expression (DE) analysis and Oncobox analysis – a bioinformatic tool for quantitative pathway activati…
Binostril versus mononostril approaches in endoscopic transsphenoidal pituitary surgery: clinical evaluation and cadaver study.
OBJECTIVE Over the past 2 decades, endoscopy has become an integral part of the surgical repertoire for skull base procedures. The present clinical evaluation and cadaver study compare binostril and mononostril endoscopic transnasal approaches and the surgical techniques involved. METHODS Forty patients with pituitary adenomas were treated with either binostril or mononostril endoscopic surgery. Neurosurgical, endocrinological, ophthalmological, and neuroradiological examinations were performed. Ten cadaver specimens were prepared, and surgical aspects of the preparation and neuroradiological examination were documented. RESULTS In the clinical evaluation, 0° optics were optimal in the nas…
Blurring the boundaries between frame-based and frameless stereotaxy: feasibility study for brain biopsies performed with the use of a head-mounted robot.
OBJECT Frame-based stereotactic interventions are considered the gold standard for brain biopsies, but they have limitations with regard to flexibility and patient comfort because of the bulky head ring attached to the patient. Frameless image guidance systems that use scalp fiducial markers offer more flexibility and patient comfort but provide less stability and accuracy during drilling and biopsy needle positioning. Head-mounted robot-guided biopsies could provide the advantages of these 2 techniques without the downsides. The goal of this study was to evaluate the feasibility and safety of a robotic guidance device, affixed to the patient’s skull through a small mounting platform, for …
Case of multifocal glioblastoma with four fusion transcripts of ALK, FGFR2, NTRK2, and NTRK3 genes stresses the need for tumor tissue multisampling for transcriptomic analysis
Glioblastoma multiforme (GBM) is the most malignant brain tumor with patient mortality rate close to 100%, 5-yr survival rate of ∼5%, and a median survival of 14 mo. GBMs have notorious histomorphologic and molecular heterogeneities thus giving hope for development of future personalized therapies. We describe here a case of a 48-yr-old male patient with three-nodular GBM. To address the question of intratumoral molecular heterogeneity, a comparative analysis of gene expression was performed by using multiple samples collected from different tumor sites with the aid of intraoperative magnetic resonance imaging (MRI). Sixteen GBM biosamples from parietal, temporal, and temporo-polar localiza…
Intratumoral Heterogeneity and Longitudinal Changes in Gene Expression Predict Differential Drug Sensitivity in Newly Diagnosed and Recurrent Glioblastoma.
Background: Inevitable recurrence after radiochemotherapy is the major problem in the treatment of glioblastoma, the most prevalent type of adult brain malignancy. Glioblastomas are notorious for a high degree of intratumor heterogeneity manifest through a diversity of cell types and molecular patterns. The current paradigm of understanding glioblastoma recurrence is that cytotoxic therapy fails to target effectively glioma stem cells. Recent advances indicate that therapy-driven molecular evolution is a fundamental trait associated with glioblastoma recurrence. There is a growing body of evidence indicating that intratumor heterogeneity, longitudinal changes in molecular biomarkers and spe…
Assessing psychological and supportive care needs in glioma patients - feasibility study on the use of the Supportive Care Needs Survey Short Form (SCNS-SF34-G) and the Supportive Care Needs Survey Screening Tool (SCNS-ST9) in clinical practice
Neuro-oncological patients experience high symptom and psychosocial burden. The aim was to test feasibility and practicability of the Supportive Care Needs Survey Short Form (SCNS-SF34-G) and the SCNS-Screening Tool (SCNS-ST9) to assess supportive care needs of neuro-oncological patients in clinical routine. A total of 173 patients, most with a primary diagnosis of high-grade glioma (81%), were assessed first using SCNS-SF34-G in comparison to two well-established patient-reported outcome measures, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQC30 + QLQ-BN20) and Distress Thermometer (DT). In a follow-up assessment, SCNS-ST9 was used …
Evaluation of efficacy and biocompatibility of a novel semisynthetic collagen matrix as a dural onlay graft in a large animal model
Background Semisynthetic collagen matrices are promising duraplasty grafts with low risk of cerebrospinal fluid (CSF) fistulas, good tissue integration and minor foreign body reaction. The present study investigates the efficacy and biocompatibility of a novel semisynthetic bilayered collagen matrix (BCM, B. Braun Aesculap) as dural onlay graft for duraplasty. Methods Thirty-four pigs underwent osteoclastic trepanation, excision of the dura, and placement of a cortical defect, followed by duraplasty using BCM, Suturable DuraGen™ (Integra Neuroscience), or periosteum. CSF tightness and intraoperative handling of the grafts were evaluated. Pigs were sacrificed after 1 and 6 months for histolo…
Three-dimensional Cross-Platform Planning for Complex Spinal Procedures
STUDY DESIGN A feasibility study. OBJECTIVE To develop a method based on the DICOM standard which transfers complex 3-dimensional (3D) trajectories and objects from external planning software to any navigation system for planning and intraoperative guidance of complex spinal procedures. SUMMARY OF BACKGROUND DATA There have been many reports about navigation systems with embedded planning solutions but only few on how to transfer planning data generated in external software. MATERIALS AND METHODS Patients computerized tomography and/or magnetic resonance volume data sets of the affected spinal segments were imported to Amira software, reconstructed to 3D images and fused with magnetic reson…
RNA sequencing for research and diagnostics in clinical oncology.
Molecular diagnostics is becoming one of the major drivers of personalized oncology. With hundreds of different approved anticancer drugs and regimens of their administration, selecting the proper treatment for a patient is at least nontrivial task. This is especially sound for the cases of recurrent and metastatic cancers where the standard lines of therapy failed. Recent trials demonstrated that mutation assays have a strong limitation in personalized selection of therapeutics, consequently, most of the drugs cannot be ranked and only a small percentage of patients can benefit from the screening. Other approaches are, therefore, needed to address a problem of finding proper targeted thera…