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Fluorescence Guided Resection of Brain Tumors: Evaluation of a Hand-held Spectroscopic Probe
Linköping University, Department of Biomedical Engineering. Linköping University, Faculty of Science & Engineering. (MINT)
2017 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Malignant gliomas grow infiltrative in the brain and can therefore not be completely removed by neurosurgical means. However, for an optimized oncological treatment it has proven useful to resect as much as possible of tumor. The identification of the tumor in the marginal zone is difficult but crucial. Studies have shown that visualization of the specific enhancement of 5-aminolevulinic acid(5-ALA) in the tumor can help to maximize the resection. The Department of Biomedical Engineering, Linköping University, has developed an optical hand-held probe (HHP) to identify tumor tissue with a high sensitivity by means of fluorescence spectroscopy.

The technical design and the optical properties of the probe were gradually developed in a standard neurosurgical setting during resection of malignant gliomas. The device could easily be implemented in the operating room, meeting all requirements in terms of sterile handling and without interference of any kind with other equipment. The integration of the device in a navigation system and its use in combination with a blue light surgical microscope were simple. Measurements in 27 operations during resection of malignant gliomas were compared to results from biopsies from the same tumor locations. The equipment was tested as a stand-alone device (n = 180), integrated in a navigation system or in combination with the blue light microscope (n = 190). A ratiocal culated from the measurements enabled objective and comparable values for different tissue types, in correspondence with the findings from the histopathological examinations and in accordance with the navigation system as well as with the surgical microscope.The marginal zone was explored and tumor fluorescence could be identified beyond the fluorescence as seen through the microscope. A higher sensitivity of the HHP was confirmed; the specificity was lower.

The combined use of the HHP with a navigation system and with asurgical microscope was beneficial.

Abstract [sv]

Maligna hjärntumörer växer infiltrerande i hjärnan och kan därförinte helt avlägsnas genom kirurgiska operationer. För en optimerad behandling har det emellertid visat sig vara av värde att avlägsna såmycket som möjligt av tumörvävnaden. Identifiering av tumören i gränszonen är mycket svårt, men avgörande. Studier har visat att visualisering av den specifika laddningen av 5-aminolevulinsyra (5-ALA) i tumören kan bidra till att maximera resektionen. Institutionen för Medicinsk Teknik (IMT) på Linköpings universitet,har utvecklat en liten handhållen optisk prob (HHP) för att identifiera tumörvävnad med hög känslighet med hjälp avfluorescens-spektroskopi.

Den tekniska konstruktionen och de optiska egenskaperna hos proben utvecklades stegvis genom testning i flera neurokirurgiska operationer för resektion av maligna gliom. Utrustningen uppfyllde alla krav när det gällde steril hantering i operationssalen och kunde användas utan störningar av något slag med annan operationsutrustning. Integreringen i ett navigerings-system och användningen i kombination med ett kirurgiskt mikroskop för fluorescens-styrd kirurgi var oproblematiska. Mätningar under 27 operationer vid resektion av maligna gliom jämfördes med resultat från biopsier från samma tumörtagningsställen. Utrustningen testades såväl som en fristående enhet (n = 180) och som integrerad i ett navigationssystem eller i kombination med mikroskopet (n =190). En särskild kvot beräknad ur mätningarna möjliggjorde objektiva och jämförbara värden för olika vävnader, i överensstämmelse med resultaten från de vävnadspatologiska undersökningarna och i överensstämmelse med navigationssystemet såväl som med det kirurgiska mikroskopet.

Tumörernas gränszon undersöktes och tumörfluorescens kunde identifieras bortom fluorescensen som mikroskopet visade. En högre känslighet hos HHP bekräftades; specificiteten var lägre. Den kombinerade användningen av HHP med ett navigationssystem och med ett kirurgiskt mikroskop visade sig vara fördelaktig.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2017. , p. 77
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1581
National Category
Surgery Neurosciences Medical Laboratory and Measurements Technologies Other Medical Engineering
Identifiers
URN: urn:nbn:se:liu:diva-139793DOI: 10.3384/diss.diva-139793ISBN: 978-91-7685-475-4 (print)OAI: oai:DiVA.org:liu-139793DiVA, id: diva2:1133616
Public defence
2017-09-01, Hugo Theorell, ingång 7, Campus US, Linköping, 09:00 (English)
Opponent
Supervisors
Available from: 2017-08-16 Created: 2017-08-16 Last updated: 2019-10-28Bibliographically approved
List of papers
1. Evaluation of a Fiber-Optic Fluorescence Spectroscopy System to Assist Neurosurgical Tumor Resections
Open this publication in new window or tab >>Evaluation of a Fiber-Optic Fluorescence Spectroscopy System to Assist Neurosurgical Tumor Resections
Show others...
2007 (English)In: Novel Optical Instrumentation for Biomedical Applications III (Proceedings Volume) / [ed] Christian D. Depeursinge, Bellingham, Washington, USA: SPIE - International Society for Optical Engineering, 2007, Vol. 6631, p. 66310W-1-66310W-8Conference paper, Published paper (Other academic)
Abstract [en]

The highly malignant brain tumor, glioblastoma multiforme, is difficult to totally resect without aid due to its infiltrative way of growing and its morphological similarities to surrounding functioning brain under direct vision in the operating field. The need for an inexpensive and robust real-time visualizing system for resection guiding in neurosurgery has been formulated by research groups all over the world. The main goal is to develop a system that helps the neurosurgeon to make decisions during the surgical procedure. A compact fiber optic system using fluorescence spectroscopy has been developed for guiding neurosurgical resections. The system is based on a high power light emitting diode at 395 nm and a spectrometer. A fiber bundle arrangement is used to guide the excitation light and fluorescence light between the instrument and the tissue target. The system is controlled through a computer interface and software package especially developed for the application. This robust and simple instrument has been evaluated in vivo both on healthy skin but also during a neurosurgical resection procedure. Before surgery the patient received orally a low dose of 5-aminolevulinic acid, converted to the fluorescence tumor marker protoporphyrin IX in the malignant cells. Preliminary results indicate that PpIX fluorescence and brain tissue autofluorescence can be recorded with the help of the developed system intraoperatively during resection of glioblastoma multiforme.

Place, publisher, year, edition, pages
Bellingham, Washington, USA: SPIE - International Society for Optical Engineering, 2007
Series
Proceedings of SPIE - International Society for Optical Engineering, ISSN 0277-786X ; Vol. 6631
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-38407 (URN)10.1117/12.728546 (DOI)44225 (Local ID)9780819467751 (ISBN)44225 (Archive number)44225 (OAI)
Conference
Novel optical instrumentation for biomedical applications III : 17-19 June 2007, Munich, Germany
Available from: 2009-10-10 Created: 2009-10-10 Last updated: 2018-03-23Bibliographically approved
2. Optical Touch Pointer for Fluorescence Guided Glioblastoma Resection Using 5-Aminolevulinic Acid
Open this publication in new window or tab >>Optical Touch Pointer for Fluorescence Guided Glioblastoma Resection Using 5-Aminolevulinic Acid
2010 (English)In: Lasers in Surgery and Medicine, ISSN 0196-8092, E-ISSN 1096-9101, Vol. 42, no 1, p. 9-14Article in journal (Refereed) Published
Abstract [en]

Background and Objective

Total tumor resection in patients with glioblastoma multiforme (GBM) is difficult to achieve due to the tumor's infiltrative way of growing and morphological similarity to the surrounding functioning brain tissue. The diagnosis is usually subjectively performed using a surgical microscope. The objective of this study was to develop and evaluate a hand-held optical touch pointer using a fluorescence spectroscopy system to quantitatively distinguish healthy from malignant brain tissue intraoperatively.

Study Design/Materials and Methods

A fluorescence spectroscopy system with pulsed modulation was designed considering optimum energy delivery to the tissue, minimal photobleaching of PpIX and omission of the ambient light background in the operating room (OR). 5-Aminolevulinic acid (5-ALA) of 5 mg/kg body weight was given to the patients with a presumed GBM prior to surgery. During the surgery a laser pulse at 405 nm was delivered to the tissue. PpIX in glioblastoma tumor cells assigned with peaks at 635 and 704 nm was detected using a fiber optical probe.

Results/Conclusion

By using the pulsed fluorescence spectroscopy, PpIX fluorescence is quantitatively detected in the GBM. An effective suppression of low power lamp background from the recorded spectra in addition to a significant reduction of high power surgical lights is achieved.

Place, publisher, year, edition, pages
Wiley-Blackwell, 2010
Keywords
background light suppression • fluorescence spectroscopy • glioblastoma multiforme • intraoperative
National Category
Engineering and Technology
Identifiers
urn:nbn:se:liu:diva-53946 (URN)10.1002/lsm.20868 (DOI)
Available from: 2010-02-15 Created: 2010-02-15 Last updated: 2017-12-12Bibliographically approved
3. Fluorescence Spectroscopy Measurements in Ultrasonic Navigated Resection of Malignant Brain Tumors
Open this publication in new window or tab >>Fluorescence Spectroscopy Measurements in Ultrasonic Navigated Resection of Malignant Brain Tumors
2011 (English)In: Lasers in Surgery and Medicine, ISSN 0196-8092, E-ISSN 1096-9101, Vol. 43, no 1, p. 8-14Article in journal (Refereed) Published
Abstract [en]

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.

Keywords
5-amino-levulin acid (5-ALA);fluorescence-guided resection (FGR);glioblastoma multiforme;optical touch pointer (OTP);protoporphyrin IX (PpIX) fluorescence;ultrasound navigation
National Category
Medical Laboratory and Measurements Technologies
Identifiers
urn:nbn:se:liu:diva-64689 (URN)10.1002/lsm.21022 (DOI)000286440300002 ()
Available from: 2011-02-01 Created: 2011-02-01 Last updated: 2017-12-11Bibliographically approved
4. Combination of Hand-Held Probe and Microscopy for Fluorescence Guided Surgery in the Brain Tumor Marginal Zone
Open this publication in new window or tab >>Combination of Hand-Held Probe and Microscopy for Fluorescence Guided Surgery in the Brain Tumor Marginal Zone
2017 (English)In: Photodiagnosis and Photodynamic Therapy, ISSN 1572-1000, Vol. 18, p. 185-192Article in journal (Refereed) Published
Abstract [en]

Background

Visualization of the tumor is crucial for differentiating malignant tissue from healthy brain during surgery, especially in the tumor marginal zone. The aim of the study was to introduce a fluorescence spectroscopy-based hand-held probe (HHF-probe) for tumor identification in combination with the fluorescence guided resection surgical microscope (FGR-microscope), and evaluate them in terms of diagnostic performance and practical aspects of fluorescence detection.

Material and Methods

Eighteen operations were performed on 16 patients with suspected high-grade glioma. The HHF-probe and the FGR-microscope were used for detection of protoporphyrin (PpIX) fluorescence induced by 5-aminolevulinic acid (5-ALA) and evaluated against histopathological analysis and visual grading done through the FGR-microscope by the surgeon. A ratio of PpIX fluorescence intensity to the autofluorescence intensity (fluorescence ratio) was used to quantify the spectra detected by the probe.

Results

Fluorescence ratio medians (range 0 – 40) measured by the probe were related to the intensity of the fluorescence in the FGR-microscope, categorized as “none” (0.3, n = 131), “weak” (1.6, n = 34) and “strong” (5.4, n = 28). Of 131 “none” points in the FGR-microscope, 88 (67%) exhibited fluorescence with the HHF-probe. For the tumor marginal zone, the area under the receiver operator characteristics (ROC) curve was 0.49 for the FGR-microscope and 0.65 for the HHF-probe.

Conclusions

The probe was integrated in the established routine of tumor resection using the FGR-microscope. The HHF-probe was superior to the FGR-microscope in sensitivity; it detected tumor remnants after debulking under the FGR-microscope. The combination of the HHF-probe and the FGR-microscope was beneficial especially in the tumor marginal zone.

Place, publisher, year, edition, pages
Amsterdam: Elsevier, 2017
Keywords
High-grade glioma, Fluorescence guided resection (FGR), 5-Aminolaevulinic acid (5-ALA), Fluorescence spectroscopy, Protoporphyrin (PpIX)
National Category
Medical Engineering
Identifiers
urn:nbn:se:liu:diva-134849 (URN)10.1016/j.pdpdt.2017.01.188 (DOI)000404315000028 ()28223144 (PubMedID)
Note

Funding agencies: Swedish Governmental Agency for Innovation Systems (Vinnova); Swedish Foundation for Strategic Research (SSF); Swedish Research Council (VR) [311-2006-7661, 523-2013-2735]; NovaMedTech; Swedish Childhood Cancer Foundation [MT 2013-0043]; ALF Grants Region

Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2019-10-14Bibliographically approved

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