Johan Richter

Background: Quantitative MRI (qMRI) relaxometry holds potential for brain tumor identification beyond contrast enhancement on conventional images. However, clinical implementation is limited by long acquisition times, changing conditions between imaging and surgery, and lack of correlation with standard techniques. Purpose: To extend a methodology for multimodal data analysis to relaxometry data. To integrate relaxometry into the burr hole needle biopsy procedure with optical guidance, setup a workflow for multimodal data processing and analysis, and apply the methodology in a clinical setting. Methods: Multi-dimensional multi-echo relaxometry data (2x6 min) was acquired in addition to the clinical imaging protocol. Relaxation rate and proton density maps, as well as their differences were calculated before (R₁, R₂) and after gadolinium contrast-agent administration (R₁Gd, R₂Gd). Radiological volumes of interest (VOIs: tumor, edema, white matter, and biopsy) were defined on clinical images. Rate distribution changes were analyzed on three levels: the biopsied volume, along the needle trajectory (4x4x4 mm³ volumes), and VOIs. Increased R₁Gd and R₂Gd were compared to indications from 5-aminolevulinic acid-induced fluorescence and detailed neuropathological evaluation. Results: Neuropathological analysis confirmed seven glioblastoma, one lymphoma, and one non-tumorous diagnosis. Increased R₁Gd was found in all biopsied volumes, although tumorous volumes presented larger R₁Gd increase (3–9 times) compared to volumes dominated by necrotic or non-tumorous tissue. Along the trajectory, increased R₁Gd and R₂Gd were not tumor-specific, however, the greatest R₁Gd shifts were found in or adjacent to radiologically defined tumorous tissue. Increased relaxation rates corresponded to 82% and 45% (R₁Gd: φ = 0.35, R₂Gd: φ = 0.27) of fluorescence peaks. In the radiological VOIs, increased R₁Gd and R₂Gd were found in tumorous tissue, a slight right shift in edematous tissue, and negligible changes in white matter. Conclusion: Combined analysis suggests increased R₁Gd together with fluorescence peaks as a marker for tumor tissue. The presented multimodal approach provides a workflow toward clinical translation of relaxometry.

Background/Objectives: Primary brain tumors are difficult to identify intraoperatively due to their infiltrative character in the marginal zone. Several optical methods have been suggested. Of these, 5-ALA-induced fluorescence visualized through a microscope is the most common. The aim is to present an investigational probe-based optical system and its translation for clinical use, summarize previous studies, and give examples of clinical implementations during resection and burr hole biopsies. Methods: The FluoRa system combines 5-ALA fluorescence spectroscopy with laser Doppler flowmetry (LDF). Probe designs are available for brain tumor resection (hand-held probe) or burr hole needle biopsies (frame-based or navigated). The outer cannulas of biopsy needles are modified with an opening at the tip for simultaneous use with optical probes during insertion along the trajectory. An updated version of FluoRa is introduced and experimentally investigated. Results: Probe-based fluorescence spectroscopy has been successfully translated for clinical use and applied during brain tumor resection (n = 75) and burr hole needle biopsies (n = 47). Forward-looking optical measurements through the biopsy needle reduce the number of trajectories (28/27) compared to prior to insertion (28/20), at the same time that the target for tissue sampling can be identified in situ. Additionally, increased microcirculation is identified along the trajectory with LDF. This is accomplished with FluoRa. Conclusions: Intraoperative probe-based spectroscopic measurements quantify 5-ALA fluorescence and thus identify glioblastoma and lymphoma tissue in situ during resection and burr hole needle biopsies.

Brain tumor needle biopsies are performed to retrieve tissue samples for neuropathological analysis. Although preoperative images guide the procedure, there are risks of hemorrhage and sampling of non-tumor tissue. This study aimed to develop and evaluate a method for frameless one-insertion needle biopsies with in situ optical guidance and present a processing pipeline for combined postoperative analysis of optical, MRI, and neuropathological data. An optical system for quantified feedback on tissue microcirculation, gray–whiteness, and the presence of a tumor (protoporphyrin IX (PpIX) accumulation) with a one-insertion optical probe was integrated into a needle biopsy kit that was used for frameless neuronavigation. In Python, a pipeline for signal processing, image registration, and coordinate transformation was set up. The Euclidian distances between the pre- and postoperative coordinates were calculated. The proposed workflow was evaluated on static references, a phantom, and three patients with suspected high-grade gliomas. In total, six biopsy samples that overlapped with the region of the highest PpIX peak without increased microcirculation were taken. The samples were confirmed as being tumorous and postoperative imaging was used to define the biopsy locations. A 2.5 ± 1.2 mm difference between the pre- and postoperative coordinates was found. Optical guidance in frameless brain tumor biopsies could offer benefits such as quantified in situ indication of high-grade tumor tissue and indications of increased blood flow along the needle trajectory before the tissue is removed. Additionally, postoperative visualization enables the combined analysis of MRI, optical, and neuropathological data.

BACKGROUND: Accurate stereotactic biopsies of brain tumors are imperative for diagnosis and tailoring of the therapy. Repetitive needle insertions enhance risks of brain lesioning, hemorrhage, and complications due to prolonged procedure. OBJECTIVE: To investigate clinical benefits of a combined 5-aminolaevulinic acid (5-ALA) fluorescence and laser Doppler flowmetry system for the detection of malignant brain tumor and blood vessels in stereotactic biopsies. METHODS: Planning of targets and trajectories was followed by optical measurements in 20 patients, using the Leksell Stereotactic System and a manual insertion device. Fluorescence spectra, microvascular blood flow, and tissue grayness were recorded each millimeter along the paths. Biopsies were taken at preplanned positions. The diagnoses were compared with the fluorescence signals. The recordings were plotted against measurement positions and compared. Sites indicating a risk of hemorrhage were counted as well as the time for the procedures. RESULTS: Signals were recorded along 28 trajectories, and 78 biopsies were collected. The final diagnosis showed 17 glioblastomas, 2 lymphomas, and 1 astrocytoma grade III. Fluorescence was seen along 23 of the paths with 4 having the peak of 5-ALA fluorescence 3 mm or more from the precalculated target. There was increased microcirculation in 40 of 905 measured positions. The measurement time for each trajectory was 5 to 10 min. CONCLUSION: The probe provided direct feedback of increased blood flow along the trajectory and of malignant tissue in the vicinity of the target. The method can increase the precision and the safety of the biopsy procedure and reduce time.

Background and Objective: Glioblastoma multiforme is a highly malignant primary brain tumor. It has no border but at best a marginal zone, however, invisible to the surgeon. An optical touch pointer (OTP) enabling differentiation of healthy and tumor tissue by means of fiber‐optic fluorescence spectroscopy has been developed. In combination with an ultrasonic navigation system, the OTP may be used for demarcation of resectable tumor tissue. The aim of the study was to evaluate the clinical performance of OTP during surgery of malignant brain tumors.Study Design/Materials and Methods: Nine patients were operated on with the standard surgical procedure, including white light microscopy and navigation. A total of 5 mg/kg bodyweight of 5‐amino‐levulin acid was orally administrated before surgery. The OTP was calibrated into the ultrasound‐based navigation system and measurements were performed in tumor core and along the tumor border. The ratio between the protoporphyrin IX fluorescence at 635 nm and the autofluorescence was used for quantifications of data. Biopsies (n = 20), ultrasound images (n = 30), and visual inspection (n = 180) were compared to the fluorescence ratio.Results/Conclusion: Healthy and tumor tissue could be identified and differentiated with the OTP (P < 0.001). The fluorescence ratio in average was 0 outside the tumor and low in the gliotic edema zone around the tumor. It increased in the marginal zone and was highest in the solid tumor tissue. In the necrotic tissue, in the center of the tumor, the ratio in average was 0. The OTP can be used in combination with ultrasound‐based navigation and may help to determine whether to resect otherwise not identifiable tissue. Lasers Surg. Med. 43:8–14, 2011.