Fluorescence-Guided Neurosurgery

Fluorescence-Guided Neurosurgery

see 5 aminolevulinic acid fluorescence guided resection.

see Fluorescein sodium guided resection.

see Fluorescence guided surgery of glioma.

The first use of fluorescence for brain tumour surgery was in 1948 by G.E. Moore 1) using fluorescein sodium.

Achieving a maximal safe extent of resection during brain tumor surgery is the goal for improved patient prognosisFluorescence-guided neurosurgery using 5-aminolevulinic acid (5-ALA) induced Protoporphyrin IX has thereby become a valuable tool enabling a high frequency of complete resections and a prolonged progression free survival in glioblastoma patients.

Erkkilä et al., from the Center for Medical Physics and Biomedical Engineering, Medical University of Vienna, Advanced Development Microsurgery, Carl Zeiss Meditec AG, Christian Doppler Laboratory for Innovative Optical Imaging and Its Translation to Medicine, Medical University of Vienna, Institute of Neurology, Department of Neurosurgery, General Hospital and Medical University of Vienna, presented a widefield fluorescence lifetime imaging device with 250 mm working distance working under similar conditions like surgical microscopes based on a time-of-flight based dual tap CMOS camera. In contrast to intensity-based fluorescence imaging this method is invariant to light scattering and absorption while being sensitive to the molecular composition of the tissue. They evaluated the feasibility of lifetime imaging of Protoporphyrin IX using the system to analyze brain tumor phantoms and fresh 5-ALA labeled human tissue samples. The results demonstrate the potential of this lifetime sensing device to go beyond the limitation of current intensity-based fluorescence-guided neurosurgery 2).

Books

Fluorescence-Guided Neurosurgery: Neuro-oncology and Cerebrovascular Applications September 10, 2018 The definitive textbook on state-of-the-art fluorescence-guided neurosurgery

Advances in fluorescence-guided surgery (FGS) have resulted in a paradigm shift in neurosurgical approaches to neuro-oncological and cerebrovascular pathologies. Edited by two of the foremost authorities on the topic, Fluorescence-Guided Neurosurgery: Neuro-oncology and Cerebrovascular Applications encompasses the depth and breadth of this groundbreaking, still nascent technology. The book reflects significant contributions made by world renowned neurosurgeons Constantinos Hadjipanayis, Walter Stummer, and esteemed contributors on the growing uses of 5-aminolevulinic acid (5-ALA) and other FGS agents.

The European Medicine Agency approved 5-ALA in 2007, heralding the birth of FGS globally. In 2017, the U.S. Food and Drug Administration approved 5-ALA (Gleolan) as an imaging agent to facilitate realtime detection and visualization of malignant tissue during glioma surgery. In the two decades since Dr. Stummer’s initial description of 5-ALA FGS in a human patient, major strides have been made in its practical applications, leading to improved resection outcomes. As FGS is increasingly incorporated into neurosurgical practice, it holds promise for future innovations. Generously-illustrated and enhanced with online videos, this textbook is the definitive resource on the subject.

Key Features

The improved efficacy of 5-ALA for resecting high- and low-grade gliomas, recurrences, meningiomas, brain metastases, spinal cord tumors, pediatric brain tumors, and other adult tumors The future of fluorescence, including potentially powerful new fluorophores molecularly targeted specifically to tumors The use of the fluorescent agent indocyanine green (ICG) for brain tumors, cerebral aneurysms, AVMs, and cerebral vascularization Special topics such as fluorescein, illuminating tumor paint, confocal microscopy, Raman spectroscopy, and integrating FGS with intraoperative imaging and brain mapping This single accessible reference presents the current state-of-the-art on this emerging, exciting surgical technology. As such, it is a must-have for neurosurgical residents, fellows, and practicing neurosurgeons.

1)

Moore GE, Peyton WT, French LA, Walker WW (1948) The clinical use of fluorescein in neurosurgery; the localization of brain tumors. J Neurosurg 5:392–398
2)

Erkkilä MT, Bauer B, Hecker-Denschlag N, Madera Medina MJ, Leitgeb RA, Unterhuber A, Gesperger J, Roetzer T, Hauger C, Drexler W, Widhalm G, Andreana M. Widefield fluorescence lifetime imaging of protoporphyrin IX for fluorescence-guided neurosurgery: an ex vivo feasibility study. J Biophotonics. 2019 Jan 12. doi: 10.1002/jbio.201800378. [Epub ahead of print] PubMed PMID: 30636030.

5 aminolevulinic acid fluorescence guided resection of spinal tumor

Multiple studies have attempted to evaluate the utility of 5-ALA-aided resection of spinal neoplasms.

Wainwright et al., from the Westchester Medical CenterTohoku University Hospital, reviewed the existing literature on the use of 5-ALA and PpIXfluorescence as an aid to resection of primary and secondary spinal neoplasms by searching the PUBMED and EMBASE database for records up to March 2018. Data was abstracted from all studies describing spinal neurosurgical uses in the English language.

In the reviewed studies, the most useful fluorescence was observed in meningiomas, ependymomas, drop metastases from cerebral gliomas, and spinal hemangiopericytoma, which is consistent with applications in cerebral neoplasms.

The available literature is significantly limited by a lack of standardized methods for measurement and quantification of 5-ALA fluorescence. The results of the reviewed studies should guide future development of rational trial protocols for the use of 5-ALA guided resection in spinal neoplasms1).


Three hours before the induction of anesthesia, 5-ALA was administered to patients with different intra- and extradural spinal tumors. In all patients a neurosurgical resection or biopsy of the spinal tumor was performed under conventional white-light microscopy. During each surgery, the presence of Protoporphyrin IX fluorescence was additionally assessed using a modified neurosurgical microscope. At the end of an assumed gross-total resection (GTR) under white-light microscopy, a final inspection of the surgical cavity of fluorescing intramedullary tumors was performed to look for any remaining fluorescing foci. Histopathological tumor diagnosis was established according to the current WHO classification.

Fifty-two patients with 55 spinal tumors were included in this study. Resection was performed in 50 of 55 cases, whereas 5 of 55 cases underwent biopsy. Gross-total resection was achieved in 37 cases, STR in 5, and partial resection in 8 cases. Protoporphyrin IX fluorescence was visible in 30 (55%) of 55 cases, but not in 25 (45%) of 55 cases. Positive PpIX fluorescence was mainly detected in ependymomas (12 of 12), meningiomas (12 of 12), hemangiopericytomas (3 of 3), and in drop metastases of primary CNS tumors (2 of 2). In contrast, none of the neurinomas (8 of 8), carcinoma metastases (5 of 5), and primary spinal gliomas (3 of 3; 1 pilocytic astrocytoma, 1 WHO Grade II astrocytoma, 1 WHO Grade III anaplastic oligoastrocytoma) revealed PpIX fluorescence. It is notable that residual fluorescing tumor foci were detected and subsequently resected in 4 of 8 intramedullary ependymomas despite assumed GTR under white-light microscopy.

In this study, 5-ALA-PpIX fluorescence was observed in spinal tumors, especially ependymomas, meningiomas, hemangiopericytomas, and drop metastases of primary CNS tumors. In cases of intramedullary tumors, 5-ALA-induced PpIX fluorescence is a useful tool for the detection of potential residual tumor foci 2).


A study included 10 patients who underwent surgical resection of an intramedullary ependymoma. Nine patients were orally administered 5-ALA (20 mg/kg) 2 hours before the induction of anesthesia. 5-ALA fluorescence was visualized with an operating microscope. Tumors were removed in a standardized manner with electrophysiological monitoring. The extent of resection was evaluated on the basis of intraoperative findings and postoperative magnetic resonance imaging. Histopathological diagnosis was established according to World Health Organization 2007 criteria. Cell proliferation was assessed by Ki-67 labeling index.

5-ALA fluorescence was positive in 7 patients (6 grade II and 1 grade III) and negative in 2 patients (grade II). Intraoperative findings were dichotomized: Tumors covered by the cyst were easily separated from the normal parenchyma, whereas tumors without the cyst appeared to be continuous to the spinal cord. In these cases, 5-ALA fluorescence was especially valuable in delineating the ventral and cranial and caudal margins. Ki-67 labeling index was significantly higher in 5-ALA-positive cases compared with 5-ALA-negative cases. All patients improved neurologically or stabilized after surgery.

5-ALA fluorescence was useful for detecting tumor margins during surgery for intramedullary ependymoma. When combined with electrophysiological monitoring, fluorescence-guided resection could help to achieve maximum tumor resection safely 3).

References

1)

Wainwright JV, Endo T, Cooper JB, Tominaga T, Schmidt MH. The role of 5-aminolevulinic acid in spinal tumor surgery: a review. J Neurooncol. 2018 Dec 29. doi: 10.1007/s11060-018-03080-0. [Epub ahead of print] Review. PubMed PMID: 30594965.
2)

Millesi M, Kiesel B, Woehrer A, Hainfellner JA, Novak K, Martínez-Moreno M, Wolfsberger S, Knosp E, Widhalm G. Analysis of 5-aminolevulinic acid-induced fluorescence in 55 different spinal tumors. Neurosurg Focus. 2014 Feb;36(2):E11. doi: 10.3171/2013.12.FOCUS13485. PubMed PMID: 24484249.
3)

Inoue T, Endo T, Nagamatsu K, Watanabe M, Tominaga T. 5-aminolevulinic acid fluorescence-guided resection of intramedullary ependymoma: report of 9 cases. Neurosurgery. 2013 Jun;72(2 Suppl Operative):ons159-68; discussion ons168. doi: 10.1227/NEU.0b013e31827bc7a3. PubMed PMID: 23149963.

5 aminolevulinic acid fluorescence guided resection

Indications

5-ALA-based fluorescence guided surgery has been shown to be a safe and effective method to improve intraoperative visualization and resection of malignant gliomas. However, it remains ineffective in guiding the resection of lower-grade, non-enhancing, and deep-seated tumors, mainly because these tumors do not produce detectable fluorescence with conventional visualization technologies, namely, wide-field (WF) surgical microscope. The introduction of fluorescence guided resection (FGS) represents one of the most important advances in the neurosurgical treatment of brain tumors.

5 aminolevulinic acid fluorescence guided resection permits the intraoperative visualization of malignant glioma tissue and supports the neurosurgeon with real-time guidance for differentiating tumor from normal brain that is independent of neuronavigation and brain shift.

Wei et al., describe some of the main factors that limit the sensitivity and accuracy of conventional WF surgical microscopy, and then provide a survey of commercial and research prototypes being developed to address these challenges, along with their principles, advantages and disadvantages, as well as the current status of clinical translation for each technology. They also provide a neurosurgical perspective on how these visualization technologies might best be implemented for guiding glioma surgeries in the future

Detection of PpIX expression in low-grade gliomas and at the infiltrative margins of all gliomas has been achieved with high-sensitivity probe-based visualization techniques. Deep-tissue PpIX imaging of up to 5 mm has also been achieved using red-light illumination techniques. Spectroscopic approaches have enabled more accurate quantification of PpIX expression.

Advancements in visualization technologies have extended the sensitivity and accuracy of conventional WF surgical microscopy. These technologies will continue to be refined to further improve the extent of resection in glioma patients using 5-ALA-induced fluorescence 1).

The 5 aminolevulinic acid has been used in glioma surgery and recent studies applied in Sylvian and spinal meningiomas 2) 3).

see 5 aminolevulinic acid fluorescence guided resection of glioma

see 5 aminolevulinic acid fluorescence guided resection of intracranial meningioma

see 5 aminolevulinic acid fluorescence guided resection in children

see 5 aminolevulinic acid fluorescence guided resection and intraoperative monitoring

see 5 aminolevulinic acid fluorescence guided resection of high grade glioma.

see 5 aminolevulinic acid fluorescence guided resection of low grade glioma.

Meningeal sarcoma

First case published in the literature of meningeal sarcoma in a child in which intraoperative fluorescence with 5-ALA was used to achieve a complete resection 4).

Meningioma

Metabolic imaging tools such as 5-ALA fluorescence-guided resection and navigated FET-PET were helpful for the resection of complex-shaped, recurrent skull base meningioma. 5-ALA fluorescence was useful to dissect the adherent interface between tumor and brain. Furthermore, it helped to delineate tumor margins in the nasal cavity. FET-PET improved the assessment of bony and dural infiltration. We hypothesize that these imaging technologies may reduce recurrence rates through better visualization of tumor tissue that might be left unintentionally. This has to be verified in larger, prospective trials 5).

Tumor fluorescence can occur in benign meningiomas (WHO grade I) as well as in WHO grade II and WHO grade III meningiomas. Most of the reviewed studies report fluorescence of the main tumor mass with high sensitivity and specificity. However, different parts of the same tumor can present with a different fluorescent pattern (heterogenic fluorescence). Quantitative probe fluorescence can be superior, especially in meningiomas with difficult anatomical accessibility. However, only one study was able to consistently correlate resected tissue with histopathological results and nonspecific fluorescence of healthy brain tissue remains a confounder. The use of 5-ALA as a tool to guide resection of intracranial meningiomas remains experimental, especially in cases with tumor recurrence. The principle of intraoperative fluorescence as a real-time method to achieve complete resection is appealing, but the usefulness of 5-ALA is questionable. 5-ALA in intracranial meningioma surgery should only be used in a protocolled prospective and long-term study 6).

Spinal tumor

The application of 5-ALA has also been described in spinal tumors.

Three hours before the induction of anesthesia, 5-ALA was administered to patients with different intra- and extradural spinal tumors. In all patients a neurosurgical resection or biopsy of the spinal tumor was performed under conventional white-light microscopy. During each surgery, the presence of Protoporphyrin IX fluorescence was additionally assessed using a modified neurosurgical microscope. At the end of an assumed gross-total resection (GTR) under white-light microscopy, a final inspection of the surgical cavity of fluorescing intramedullary tumors was performed to look for any remaining fluorescing foci. Histopathological tumor diagnosis was established according to the current WHO classification.

Fifty-two patients with 55 spinal tumors were included in this study. Resection was performed in 50 of 55 cases, whereas 5 of 55 cases underwent biopsy. Gross-total resection was achieved in 37 cases, STR in 5, and partial resection in 8 cases. Protoporphyrin IX fluorescence was visible in 30 (55%) of 55 cases, but not in 25 (45%) of 55 cases. Positive PpIX fluorescence was mainly detected in ependymomas (12 of 12), meningiomas (12 of 12), hemangiopericytomas (3 of 3), and in drop metastases of primary CNS tumors (2 of 2). In contrast, none of the neurinomas (8 of 8), carcinoma metastases (5 of 5), and primary spinal gliomas (3 of 3; 1 pilocytic astrocytoma, 1 WHO Grade II astrocytoma, 1 WHO Grade III anaplastic oligoastrocytoma) revealed PpIX fluorescence. It is notable that residual fluorescing tumor foci were detected and subsequently resected in 4 of 8 intramedullary ependymomas despite assumed GTR under white-light microscopy.

In this study, 5-ALA-PpIX fluorescence was observed in spinal tumors, especially ependymomas, meningiomas, hemangiopericytomas, and drop metastases of primary CNS tumors. In cases of intramedullary tumors, 5-ALA-induced PpIX fluorescence is a useful tool for the detection of potential residual tumor foci 7).

Complications

Stummer et al. showed that 5–ALA guided resections carry a higher risk of post-operative neurological deterioration than conventional resections (26% vs 15%, respectively), even though the difference vanished within weeks 8).

Just as tumour tissue is often indiscernible from normal brain tissue, functionally critical tissues are indistinguishable from tissues with less clinically relevant functions.

Thus, knowing when to stop a resection due to proximity to areas of crucial neurological functions is of obvious and utmost importance. Detailed knowledge of the normal brain anatomy and distribution of function is not sufficient during glioma resection. Interindividual variability and functional relocation (i.e., plasticity) induced by the presence of an infiltrating tumour 9) requires an exact functional brain map at the site of surgery in order to spare areas involved in crucial (so-called eloquent) functions. Preoperative localisation of function, either with functional MRI (fMRI) or navigated transcranial magnetic stimulation (nTMS), provides an approximate map 10) 11).

Furthermore, intra-operative direct cortical and subcortical electrical stimulation (DCS) for functional analysis of the tissue in the tumour’s infiltration zone is required for accurate identification of areas that need to be spared in order to retain the patient’s functional integrity 12) 13). Motor evoked potentials (MEP) provide real-time information on the integrity of the primary motor cortex and the corticospinal tract 14). Direct cortical mapping and phase reversal identify the primary motor and sensory cortices. Subcortical mapping can estimate the distance to the pyramidal tract, acting as guidance close to functionally critical areas 15). When integrated into the existing surgical tools, continuous and dynamic mapping enables more extensive resection while simultaneously protecting motor function 16). Using these techniques and a detailed electrophysiological “Bern-concept”, a group achieved complete motor function protection in 96% of patients with high-risk motor eloquent tumours 17). Furthermore, localisation of cortical and subcortical regions relevant to language function is essential for speech preservation during resection of gliomas in proximity to presumed speech areas 18) and requires the patient to be awake during the brain mapping part of surgery. Similarly, intra-operative mapping of visual functions may contribute to increased resections while avoiding tissue essential for vision within the temporal and occipital lobes 19).

References

1) Wei L, Roberts DW, Sanai N, Liu JTC. Visualization technologies for 5-ALA-based fluorescence-guided surgeries. J Neurooncol. 2018 Dec 15. doi: 10.1007/s11060-018-03077-9. [Epub ahead of print] Review. PubMed PMID: 30554344.2) Chae MP, Song SW, Park SH, Park CK. Experience with 5- aminolevulinic Acid in fluorescence-guided resection of a deep sylvian meningioma. J Korean Neurosurg Soc. 2012;52:558–60.3) Stummer W, Novotny A, Stepp H, Goetz C, Bise K, Reulen HJ. Fluorescence-guided resection of glioblastoma multiforme by using 5-aminolevulinic acid-induced porphyrins: A prospective study in 52 consecutive patients. J Neurosurg. 2000;93:1003–13.4) Bernal García LM, Cabezudo Artero JM, Royano Sánchez M, Marcelo Zamorano MB, López Macías M. Fluorescence-guided resection with 5-aminolevulinic acid of meningeal sarcoma in a child. Childs Nerv Syst. 2015 Apr 12. [Epub ahead of print] PubMed PMID: 25863951.5) Cornelius JF, Slotty PJ, Stoffels G, Galldiks N, Langen KJ, Steiger HJ. 5-Aminolevulinic Acid and (18)F-FET-PET as Metabolic Imaging Tools for Surgery of a Recurrent Skull Base Meningioma. J Neurol Surg B Skull Base. 2013 Aug;74(4):211-6. doi: 10.1055/s-0033-1342918. Epub 2013 Apr 1. PubMed PMID: 24436914.6) Motekallemi A, Jeltema HR, Metzemaekers JD, van Dam GM, Crane LM, Groen RJ. The current status of 5-ALA fluorescence-guided resection of intracranial meningiomas-a critical review. Neurosurg Rev. 2015 Mar 5. [Epub ahead of print] PubMed PMID: 25736455.7) Millesi M, Kiesel B, Woehrer A, Hainfellner JA, Novak K, Martínez-Moreno M, Wolfsberger S, Knosp E, Widhalm G. Analysis of 5-aminolevulinic acid-induced fluorescence in 55 different spinal tumors. Neurosurg Focus. 2014 Feb;36(2):E11. doi: 10.3171/2013.12.FOCUS13485. PubMed PMID: 24484249.8) Stummer W1, Tonn JC, Mehdorn HM, Nestler U, Franz K, Goetz C, et al. ALA-Glioma Study Group. Counterbalancing risks and gains from extended resections in malignant glioma surgery: a supplemental analysis from the randomized 5–aminolevulinic acid glioma resection study. J Neurosurg. 2011;114(3):613–23. doi: 10.3171/2010.39) Ojemann G, Ojemann J, Lettich E, Berger M. Cortical language localization in left, dominant hemisphere. An electrical stimulation mapping investigation in 117 patients. J Neurosurg. 1989;71(3):316–26.10) Seghier ML, Lazeyras F, Pegna AJ, Annoni JM, Zimine I, Mayer E, et al. Variability of fMRI activation during a phonological and semantic language task in healthy subjects. Hum Brain Mapp. 2004;23(3):140–55.11) Krieg SM, Shiban E, Buchmann N, Gempt J, Foerschler A, Meyer B, et al. Utility of presurgical navigated transcranial magnetic brain stimulation for the resection of tumors in eloquent motor areas. J Neurosurg. 2012;116(5):994–1001. doi: 10.3171/2011.12.JNS11152412) , 18) Duffau H, Capelle L, Sichez N, Denvil D, Lopes M, Sichez JP, et al. Intraoperative mapping of the subcortical language pathways using direct stimulations. An anatomo-functional study. Brain. 2002;125(1):199–214.13) Duffau H, Capelle L, Denvil D, Sichez N, Gatignol P, Taillandier L, et al. Usefulness of intraoperative electrical subcortical mapping during surgery for low-grade gliomas located within eloquent brain regions: functional results in a consecutive series of 103 patients. J Neurosurg. 2003;98(4):764–78.14) Seidel K, Beck J, Stieglitz L, Schucht P, Raabe A. The warning-sign hierarchy between quantitative subcortical motor mapping and continuous motor evoked potential monitoring during resection of supratentorial brain tumors. J Neurosurg. 2013;118(2):287–96.15) Seidel K, Beck J, Stieglitz L, Schucht P, Raabe A. Low Threshold Monopolar Motor Mapping for Resection of Primary Motor Cortex Tumors. Neurosurgery. 2012;71(1):104–14.16) Raabe A, Beck J, Schucht P, Seidel K. Continuous dynamic mapping of the corticospinal tract during surgery of motor eloquent brain tumors: evaluation of a new method. J Neurosurg. 2014;120(5)1015–24. doi: 10.3171/2014.1.JNS13909.17) Schucht P, Seidel K. Beck J, Murek M, Jilch A, Wiest R, et al. Intraoperative monopolar mapping during 5-ALA-guided resections of glioblastomas adjacent to motor eloquent areas: evaluation of resection rates and neurological outcome. Neurosurg Focus. 2014;27(6):E16.19) Gras-Combe G, Moritz-Gasser S, Herbet G, Duffau H. Intraoperative subcortical electrical mapping of optic radiations in awake surgery for glioma involving visual pathways. J Neurosurg. 2012;117(3):466–73.

Fluorescence-Guided Neurosurgery: Neuro-oncology and Cerebrovascular Applications

The definitive textbook on state-of-the-art fluorescence-guided neurosurgery

Advances in fluorescence-guided surgery (FGS) have resulted in a paradigm shift in neurosurgical approaches to neuro-oncological and cerebrovascular pathologies. Edited by two of the foremost authorities on the topic, Fluorescence-Guided Neurosurgery: Neuro-oncology and Cerebrovascular Applications encompasses the depth and breadth of this groundbreaking, still nascent technology. The book reflects significant contributions made by world renowned neurosurgeons Constantinos Hadjipanayis, Walter Stummer, and esteemed contributors on the growing uses of 5-aminolevulinic acid (5-ALA) and other FGS agents.

The European Medicine Agency approved 5-ALA in 2007, heralding the birth of FGS globally. In 2017, the U.S. Food and Drug Administration approved 5-ALA (Gleolan) as an imaging agent to facilitate realtime detection and visualization of malignant tissue during glioma surgery. In the two decades since Dr. Stummer’s initial description of 5-ALA FGS in a human patient, major strides have been made in its practical applications, leading to improved resection outcomes. As FGS is increasingly incorporated into neurosurgical practice, it holds promise for future innovations. Generously-illustrated and enhanced with online videos, this textbook is the definitive resource on the subject.

Key Features

  • The improved efficacy of 5-ALA for resecting high- and low-grade gliomas, recurrences, meningiomas, brain metastases, spinal cord tumors, pediatric brain tumors, and other adult tumors
  • The future of fluorescence, including potentially powerful new fluorophores molecularly targeted specifically to tumors
  • The use of the fluorescent agent indocyanine green (ICG) for brain tumors, cerebral aneurysms, AVMs, and cerebral vascularization
  • Special topics such as fluorescein, illuminating tumor paint, confocal microscopy, Raman spectroscopy, and integrating FGS with intraoperative imaging and brain mapping

This single accessible reference presents the current state-of-the-art on this emerging, exciting surgical technology. As such, it is a must-have for neurosurgical residents, fellows, and practicing neurosurgeons.

 

 

UpToDate: Fluorescence guided surgery of glioma

Fluorescence guided surgery of glioma

It must be remembered that intraoperative visualization of fluorescence depends on the sensitivity of both the microscope filters and the cameraused 1).


The use of the optical contrast agent sodium fluorescein (NaFl) to guide resection of gliomas has been under investigation for decades. Although this imaging strategy assumes the agent remains confined to the vasculature except in regions of blood brain barrier (BBB) disruption, clinical studies have reported significant NaFl signal in normal brain tissue, limiting tumor-to-normal contrast. A possible explanation arises from earlier studies, which reported that NaFl exists in both pure and protein-bound forms in the blood, the former being small enough to cross the BBB.

A study of Folaron et al. from the Thayer School of Engineering and Department of Surgery Geisel School of Medicine, Dartmouth College, Hanover; and Section of Neurosurgery, and Norris Cotton Cancer Center, Dartmouth Hitchcock Medical CenterLebanonNew Hampshire, aimed to elucidate the kinetic binding behavior of NaFl in circulating blood and its effect on NaFl accumulation in brain tissue and tumor contrast. Additionally, they examined the blood and tissue kinetics, as well as tumor uptake, of a pegylated form of fluorescein selected as a potential optical analog of gadolinium-based MRI contrast agents.

Cohorts of mice were administered one of the following doses/forms of NaFl: 1) high human equivalent dose (HED) of NaFl, 2) low HED of NaFl, or 3) pegylated form of fluorescein. In each cohort, groups of animals were euthanized 15, 30, 60, and 120 minutes after administration for ex vivo analysis of fluorescein fluorescence. Using gel electrophoresis and fluorescence imaging of blood and brain specimens, the authors quantified the temporal kinetics of bound NaFl, unbound NaFl, and pegylated fluorescein in the blood and normal brain tissue. Finally, they compared tumor-to-normal contrast for NaFl and pegylated-fluorescein in U251 glioma xenografts.

Administration of NaFl resulted in the presence of unbound and protein-bound NaFl in the circulation, with unbound NaFl constituting up to 70% of the signal. While protein-bound NaFl was undetectable in brain tissue, unbound NaFl was observed throughout the brain. The observed behavior was time and dose dependent. The pegylated form of fluorescein showed minimal uptake in brain tissue and improved tumor-to-normal contrast by 38%.

Unbound NaFl in the blood crosses the BBB, limiting the achievable tumor-to-normal contrast and undermining the inherent advantage of tumor imaging in the brain. Dosing and incubation time should be considered carefully for NaFl-based fluorescence-guided surgery (FGS) of glioma. A pegylated form of fluorescein showed more favorable normal tissue kinetics that translated to higher tumor-to-normal contrast. These results warrant further development of pegylated-fluorescein for FGS of glioma 2).


Senders et al., systematically review all clinically tested fluorescent agents for application in FGS for glioma and all preclinically tested agents with the potential for FGS for glioma.

They searched the PubMed and Embase databases for all potentially relevant studies through March 2016.

They assessed fluorescent agents by the following outcomes: rate of gross total resection (GTR), overall and progression free survival, sensitivity and specificity in discriminating tumor and healthy brain tissue, tumor-to-normal ratio of fluorescent signal, and incidence of adverse events.

The search strategy resulted in 2155 articles that were screened by titles and abstracts. After full-text screening, 105 articles fulfilled the inclusion criteria evaluating the following fluorescent agents: 5 aminolevulinic acid (5-ALA) (44 studies, including three randomized control trials), fluorescein(11), indocyanine green (five), hypericin (two), 5-aminofluorescein-human serum albumin (one), endogenous fluorophores (nine) and fluorescent agents in a pre-clinical testing phase (30). Three meta-analyses were also identified.

5-ALA is the only fluorescent agent that has been tested in a randomized controlled trial and results in an improvement of GTR and progression-free survival in high-grade gliomas. Observational cohort studies and case series suggest similar outcomes for FGS using fluorescein. Molecular targeting agents (e.g., fluorophore/nanoparticle labeled with anti-EGFR antibodies) are still in the pre-clinical phase, but offer promising results and may be valuable future alternatives. 3).


Mounting evidence suggests that a more extensive surgical resection is associated with an improved life expectancy for both low grade glioma and high grade glioma patients. However, radiographically complete resections are not often achieved in many cases because of the lack of sensitivityand specificity of current neurosurgical guidance techniques at the margins of diffuse infiltrative gliomas. Intraoperative fluorescence imaging offers the potential to improve the extent of resection and to investigate the possible benefits of resecting beyond the radiographic margins.

Liu et al., in 2014 provided a review of wide-field and high-resolution fluorescence-imaging strategies that are being developed for neurosurgical guidance, with a focus on emerging imaging technologies and clinically viable contrast agents. The strengths and weaknesses of these approaches will be discussed, as well as issues that are being addressed to translate these technologies into the standard of care 4).


322 patients aged 23-73 years with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomly assigned to 20 mg/kg bodyweight 5-aminolevulinic acid for fluorescence-guided resection (n=161) or to conventional microsurgery with white light (n=161). The primary endpoints were the number of patients without contrast-enhancing tumour on early MRI (ie, that obtained within 72 h after surgery) and 6-month progression-free survival as assessed by MRI. Secondary endpoints were volume of residual tumour on postoperative MRI, overall survival, neurological deficit, and toxic effects. We report the results of an interim analysis with 270 patients in the full-analysis population (139 assigned 5-aminolevulinic acid, 131 assigned white light), which excluded patients with ineligible histological and radiological findings as assessed by central reviewers who were masked as to treatment allocation; the interim analysis resulted in termination of the study as defined by the protocol. Primary and secondary endpoints were analysed by intention to treat in the full-analysis population. The study is registered at http://www.clinicaltrials.gov as NCT00241670.

FINDINGS: Median follow-up was 35.4 months (95% CI 1.0-56.7). Contrast-enhancing tumour was resected completely in 90 (65%) of 139 patients assigned 5-aminolevulinic acid compared with 47 (36%) of 131 assigned white light (difference between groups 29% [95% CI 17-40], p<0.0001). Patients allocated 5-aminolevulinic acid had higher 6-month progression free survival than did those allocated white light (41.0% [32.8-49.2] vs 21.1% [14.0-28.2]; difference between groups 19.9% [9.1-30.7], p=0.0003, Z test). Groups did not differ in the frequency of severe adverse events or adverse events in any organ system class reported within 7 days after surgery.

INTERPRETATION: Tumour fluorescence derived from 5-aminolevulinic acid enables more complete resections of contrast-enhancing tumour, leading to improved progression-free survival in patients with malignant glioma 5).

References

1)

Moiyadi A, Syed P, Srivastava S. Fluorescence-guided surgery of malignant gliomas based on 5-aminolevulinic acid: paradigm shifts but not a panacea. Nat Rev Cancer. 2014 Feb;14(2):146. doi: 10.1038/nrc3566-c1. PubMed PMID: 24457418.
2)

Folaron M, Strawbridge R, Samkoe KS, Filan C, Roberts DW, Davis SC. Elucidating the kinetics of sodium fluorescein for fluorescence-guided surgery of glioma. J Neurosurg. 2018 Sep 7:1-11. doi: 10.3171/2018.4.JNS172644. [Epub ahead of print] PubMed PMID: 30192200.
3)

Senders JT, Muskens IS, Schnoor R, Karhade AV, Cote DJ, Smith TR, Broekman ML. Agents for fluorescence-guided glioma surgery: a systematic review of preclinical and clinical results. Acta Neurochir (Wien). 2017 Jan;159(1):151-167. doi: 10.1007/s00701-016-3028-5. Review. PubMed PMID: 27878374; PubMed Central PMCID: PMC5177668.
4)

Liu JT, Meza D, Sanai N. Trends in fluorescence image-guided surgery for gliomas. Neurosurgery. 2014 Jul;75(1):61-71. doi: 10.1227/NEU.0000000000000344. Review. PubMed PMID: 24618801; PubMed Central PMCID: PMC4062574.
5)

Stummer W, Pichlmeier U, Meinel T, Wiestler OD, Zanella F, Reulen HJ; ALA-Glioma Study Group. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 2006 May;7(5):392-401. PubMed PMID: 16648043.

Update: 5 aminolevulinic acid fluorescence guided resection of high grade glioma

5 aminolevulinic acid fluorescence guided resection of high grade glioma

J.Sales-Llopis
Neurosurgery Service, Alicante University General Hospital, Alicante Institute for Health and Biomedical Research (ISABIAL – FISABIO Foundation), Alicante, Spain.
Fluorescence guided resection (FGR) in high grade glioma aims at increasing complete resections and, thus, local control. This technique uses 5 aminolevulinic acid (5-ALA), a natural intermediate substance in the heme-porphyrin biosynthesis pathway, and a protoporphyrin IX (PpIX) precursor. PpIX is fluorescent under blue light exposure 1).

Doses

The highest visible and measurable fluorescence was yielded by 20 mg/kg. No fluorescence was elicited at 0.2 mg/kg. Increasing 5-ALA doses did not result in proportional increases in tissue fluorescence or PPIX accumulation in plasma, indicating that doses higher than 20 mg/kg will not elicit useful increases in fluorescence 2).

History

In 2000 Stummer et al published that Five-aminolevulinic acid (5-ALA)-derived fluorescence was approved for fluorescence-guided resections of malignant gliomas, relying on selective synthesis and accumulation of protoporphyrin IX (PPIX) within malignant glioma cells 3).
In 2006 Stummer et al., published that tumour fluorescence derived from 5 aminolevulinic acid enables more complete resections of contrast-enhancing tumour, leading to improved progression-free survival in patients with malignant glioma 4).
The positive predictive value (PPV) of utilizing the most robust ALA fluorescence intensity (lava-like orange) as a predictor of tumor presence is high. However, the negative predictive value (NPV) of utilizing the absence of fluorescence as an indicator of no tumor is poor. ALA intensity is a strong predictor for degree of tumor cellularity for the most fluorescent areas but less so for lower ALA intensities. Even in the absence of tumor cells, reactive changes may lead to ALA fluorescence 5).


Many studies have shown that the ratio of gross total resections was higher if the fluorescence technique was used. The fluorescence signal intensity is correlated to the cell density and the PpIX concentration. The current method has a very high specificity but still lower sensitivity, particularly regarding the zones with poor tumoral infiltration 6).
PpIX fluorescence was also identified as a novel marker for intraoperative detection of anaplastic foci in nonenhancing gliomas that ensures a precise histopathological diagnosis and optimal patient treatment. Furthermore, 5 prospective studies have confirmed that PpIX fluorescence is able to identify residual tumor tissue after assumed maximal resection of malignant gliomas with conventional white-light microscopy. Because intraoperative detection of malignant glioma tissue is significantly improved by 5-ALA FGS, high rates of complete tumor resections are achieved, especially in combination with intraoperative monitoring and mapping 7).
In the future, chemotherapy with new anticancer agents, immunotherapy, and new methods of radiotherapy and gene therapy will be developed; however, ALA will play a key role in malignant glioma treatment before the development of these new treatments 8).

Limitations

Visual assessment of PpIX fluorescence is subjective and limited by the distorting effects of light attenuation and tissue autofluorescence 9).


Resection of reactive tissue without active recurrent tumor after multimodal treatment for glioblastoma is frequently associated with solid or vague 5-AIF. Therefore, neurosurgeons should remain cautious when attempting to employ intraoperative 5-ALA induced fluorescence (5-AIF) to discriminate radiation- and chemotherapy-induced tissue changes from true disease progression. Nevertheless, 5-AIF-guided resection remains a valid tool in the neurosurgical treatment of recurrent gliomas 10).
The resection cavity underestimates the volume of resected tissue and 5-ALA complete resections go significantly beyond the volume of pre-operative contrast-enhancing tumor bulk on MRI, indicating that 5-ALA also stains MRI non-enhancing tumor tissue. Use of 5-ALA may thus enable extension of coalescent tumor resection beyond radiologically evident tumor. The impact of this more extended resection method on time to progression and overall survival has not been determined, and potentially puts adjacent and functionally intact tissue at risk 11).

Systematic reviews

In 2013 based on available literature, there was level of evidence 2 that 5-ALA-guided surgery is more effective than conventional neuronavigation-guided surgery in increasing diagnostic accuracy and extent of tumor resection, enhancing quality of life, or prolonging survival in patients with high-grade malignant gliomas 12).


Barone et al., in a Cochrane Database Systematic Review published in 2014, that there is low to very low quality evidence (according to GRADE criteria) that image guided surgery using iMRI, 5-ALA or DTI-neuronavigation increases the proportion of patients with high grade glioma that have a complete tumour resection on post-operative MRI. There is a theoretical concern that maximising the extent of resection may lead to more frequent adverse events but this was poorly reported in the included studies. Effects of image guided surgery on survival quality of life (QoL) are unclear. Further research, including studies of ultrasound guided surgery, is needed 13).


In 2015, a literature review produced 503 potential publications; only 20 of these fulfilled the inclusion criteria of this analysis, including a total of 565 patients treated with 5-ALA-FIGR reporting on its outcomes and 800 histological samples reporting 5-ALA-FIGR sensitivity and specificity.
The mean gross total resection (GTR) rate was 75.4% (95% CI: 67.4-83.5, p<0.001). The mean time to tumor progression (TTP) was 8.1 months (95% CI: 4.7-12, p<0.001). The mean overall survival gain reported was 6.2 months (95% CI: -1-13, p<0.001). The specificity was 88.9% (95% CI: 83.9-93.9, p<0.001) and the sensitivity was 82.6% (95% CI: 73.9-91.9, p<0.001).
5-ALA-FIGR in GBM is highly sensitive and specific, and imparts significant benefits to patients in terms of improved GTR and TTP 14).

Alternatives

CLR1501 (green) and CLR1502 (near infrared) are novel tumor-selective fluorescent agents for discriminating tumor from normal brain 15).

Case series

2017

Data of 47 consecutive patients with HGG have been collected in our study (25 males, 22 females; mean age: 60.3 years, range: 27-86 years). Fluorescein (5 mg/kg of body weight) was injected intravenously right after the induction of general anesthesia. A YELLOW 560 filter was used on an OPMI Pentero 900 microscope (Carl Zeiss Meditec, Oberkochen, Germany) to complete a microsurgical tumor removal. Glioma resection and quality of life were evaluated preoperative and postoperatively.
Gross total resection (GTR) was achieved in 53.2% (n = 25) of patients. A subtotal resection (STR) (>95%) was achieved in 29.8% (n = 14), while a partial resection (PR) (<95%) was obtained in 17% (n = 8) of patients. Overall, in 83% (n = 39) of patients who underwent fluorescence-guided surgery the resection rate achieved was >95%. No adverse effects correlated to fluorescein have been recorded.
Fluorescein seems to be safe and effective in the resection of HGGs, allowing a high rate of gross total removal of contrast enhanced areas 16).

2016

Thirty-two patients received fluorescein sodium (3 mg/kg) intravenously prior to resection. Fluorescence was intraoperatively visualized using a Zeiss Pentero surgical microscope equipped with a YELLOW 560 filter. Stereotactically localized biopsy specimens were acquired from CE and NCE regions based on preoperative MRI in conjunction with neuronavigation. The fluorescence intensity of these specimens was subjectively classified in real time with subsequent quantitative image analysis, histopathological evaluation of localized biopsy specimens, and radiological volumetric assessment of the extent of resection. RESULTS Bright fluorescence was observed in all GBMs and localized to the CE regions and portions of the NCE margins of the tumors, thus serving as a visual guide during resection. Gross-total resection (GTR) was achieved in 84% of the patients with an average resected volume of 95%, and this rate was higher among patients for whom GTR was the surgical goal (GTR achieved in 93.1% of patients, average resected volume of 99.7%). Intraoperative fluorescein staining correlated with histopathological alteration in both CE and NCE regions, with positive predictive values by subjective fluorescence evaluation greater than 96% in NCE regions.
Intraoperative administration of fluorescein provides an easily visualized marker for glioma pathology in both CE and NCE regions of GBM. These findings support the use of fluorescein as a microsurgical adjunct for guiding GBM resection to facilitate safe maximal removal 17).


A single-center, prospective, single-arm, open-label Phase II clinical trial of ALA fluorescence-guided resection of high-grade gliomas (Grade III and IV) was held over a 43-month period (August 2010 to February 2014). ALA was administered at a dose of 20 mg/kg body weight. Intraoperative biopsies from resection cavities were collected. The biopsies were graded on a 4-point scale (0 to 3) based on ALA fluorescence intensity by the surgeon and independently based on tumor cellularity by a neuropathologist. The primary outcome of interest was the correlation of ALA fluorescence intensity to tumor cellularity. The secondary outcome of interest was ALA adverse events. Sensitivities, specificities, positive predictive values (PPVs), negative predictive values (NPVs), and Spearman correlation coefficients were calculated. RESULTS A total of 211 biopsies from 59 patients were included. Mean age was 53.3 years and 59.5% were male. The majority of biopsies were glioblastoma (GBM) (79.7%). Slightly more than half (52.5%) of all tumors were recurrent. ALA intensity of 3 correlated with presence of tumor 97.4% (PPV) of the time. However, absence of ALA fluorescence (intensity 0) correlated with the absence of tumor only 37.7% (NPV) of the time. For all tumor types, GBM, Grade III gliomas, and recurrent tumors, ALA intensity 3 correlated strongly with cellularity Grade 3; Spearman correlation coefficients ® were 0.65, 0.66, 0.65, and 0.62, respectively. The specificity and PPV of ALA intensity 3 correlating with cellularity Grade 3 ranged from 95% to 100% and 86% to 100%, respectively. In biopsies without tumor (cellularity Grade 0), 35.4% still demonstrated ALA fluorescence. Of those biopsies, 90.9% contained abnormal brain tissue, characterized by reactive astrocytes, scattered atypical cells, or inflammation, and 8.1% had normal brain. In nonfluorescent (ALA intensity 0) biopsies, 62.3% had tumor cells present. The ALA-associated complication rate among the study cohort was 3.4%.
The PPV of utilizing the most robust ALA fluorescence intensity (lava-like orange) as a predictor of tumor presence is high. However, the NPV of utilizing the absence of fluorescence as an indicator of no tumor is poor. ALA intensity is a strong predictor for degree of tumor cellularity for the most fluorescent areas but less so for lower ALA intensities. Even in the absence of tumor cells, reactive changes may lead to ALA fluorescence18).

2015

58 patients with high grade gliomas (°III and °IV) were included. 10 of 63 tumors (15.9 %) failed to fluoresce intraoperatively of which nine (90 %) had been adjuvantly treated prior to recurrence, as were 46 of the 53 fluorescing tumors (86.8 %). Non-fluorescing tumors were IDH mutated significantly more often (p = 0.005). 30 tumors (47.6 %) were located eloquently. 51 (80.9 %) patients showed no new neurologic deficits postoperatively. 13 patients (20.6 %) showed no signs of recurrence at their latest follow up. Eight patients were lost to follow up. Overall survival was significantly longer in the 5-ALA group (p = 0.025). Fluorescence-guided surgery in recurrent gliomas is safe and allows for a good surgical and neurological outcome in a difficult surgical environment, especially when used in combination with neuronavigation and intraoperative ultrasound to prevent over-resection. Adjuvant therapy did not significantly influence fluorescing properties 19).

2014

Clinical and surgical data from patients affected by HGG who underwent surgery guided by 5-ALA fluorescence between June 2011 and February 2014 were retrospectively evaluated. Surgical outcome was evaluated by assessing the resection rate as gross total resection (GTR) > 98% and GTR > 90%. We finally stratified data for recurrent surgery, tumor location, tumor size, and tumor grade (IV versus III grade sec. WHO).
94 patients were finally enrolled. Overall GTR > 98% and GTR > 90% was achieved in 93% and 100% of patients. Extent of resection (GTR > 98%) was dependent on tumor location, tumor grade (P < 0.05), and tumor size (P < 0.05). In 43% of patients the boundaries of fluorescent tissue exceeded those of tumoral tissue detected by neuronavigation, more frequently in larger (57%) (P < 0.01) and recurrent (60%) tumors.
5-ALA fluorescence in HGG surgery enables a GTR in 100% of cases even if selection of patients remains a main bias. Recurrent surgery, and location, size, and tumor grade can predict both the surgical outcome and the intraoperative findings 20).


Schucht et al., prospectively studied 72 consecutive patients who underwent 5-ALA-guided surgery for a glioblastoma adjacent to the corticospinal tract (CST; < 10 mm) with continuous dynamic monopolar motor mapping (short-train interstimulus interval 4.0 msec, pulse duration 500 μsec) coupled to an acoustic motor evoked potential (MEP) alarm. The extent of resection was determined based on early (< 48 hours) postoperative MRI findings. Motor function was assessed 1 day after surgery, at discharge, and at 3 months.
Five patients were excluded because of nonadherence to protocol; thus, 67 patients were evaluated. The lowest motor threshold reached during individual surgery was as follows (motor threshold, number of patients): > 20 mA, n = 8; 11-20 mA, n = 13; 6-10 mA, n = 10; 4-5 mA, n = 13; and 1-3 mA, n = 23. Motor deterioration at postsurgical Day 1 and at discharge occurred in 30% (n = 20) and 10% (n = 7) of patients, respectively. At 3 months, 3 patients (4%) had a persisting postoperative motor deficit, 2 caused by vascular injury and 1 by mechanical injury. The rates of intra- and postoperative seizures were 1% and 0%, respectively. Complete resection of enhancing tumor was achieved in 73% of patients (49/67) despite proximity to the CST.
A rather high rate of CRET can be achieved in glioblastomas in motor eloquent areas via a combination of 5-ALA for tumor identification and intraoperative mapping for distinguishing between presumed and actual motor eloquent tissues. Continuous dynamic mapping was found to be a very ergonomic technique that localizes the motor tissue early and reliably 21).


Schucht et al., selected 13 patients who had received a complete resection according to intraoperative 5-ALA induced fluorescence and CRET according to post-operative T1 contrast-enhanced MRI. The volumes of pre-operative contrast enhancing tissue, post-operative resection cavity and resected tissue were determined through shift-corrected volumetric analysis.
The mean resection cavity (29 cm(3)) was marginally smaller than the pre-operative contrast-enhancing tumor (39 cm(3), p = 0.32). However, the mean overall resection volume (84 cm(3)) was significantly larger than the pre-operative contrast-enhancing tumor (39 cm(3), p = 0.0087). This yields a mean volume of resected 5-ALA positive, but radiological non-enhancing tissue of 45 cm(3). The mean calculated rim of resected tissue surpassed pre-operative tumor diameter by 6 mm (range 0-10 mm).
Results of the current study imply that (i) the resection cavity underestimates the volume of resected tissue and (ii) 5-ALA complete resections go significantly beyond the volume of pre-operative contrast-enhancing tumor bulk on MRI, indicating that 5-ALA also stains MRI non-enhancing tumor tissue. Use of 5-ALA may thus enable extension of coalescent tumor resection beyond radiologically evident tumor. The impact of this more extended resection method on time to progression and overall survival has not been determined, and potentially puts adjacent and functionally intact tissue at risk 22).

2013

A retrospective review found 118 consecutive patients with high-grade gliomas operated on with the use of fluorescence-guided surgery with 5-aminolevulinic acid. Within that series, the 52 patients with newly diagnosed GBM and complete resection of enhancing tumor (CRET) in early MRI were selected for analysis. They studied the influence of residual fluorescence in the surgical field on overall survival and neurological complication rate. Multivariate analysis included potential relevant factors: age, Karnofsky Performance Scale, O-methylguanine methyltransferase methylation promoter status, tumor eloquent location, preoperative tumor volume, and adjuvant therapy.
The median overall survival was 27.0 months (confidence interval = 22.4-31.6) in patients with nonresidual fluorescence (n = 25) and 17.5 months (confidence interval = 12.5-22.5) for the group with residual fluorescence (n = 27) (P = .015). The influence of residual fluorescence was maintained in the multivariate analysis with all covariables, hazard ratio = 2.5 (P = .041). The neurological complication rate was 18.5% in patients with nonresidual fluorescence and 8% for the group with residual fluorescence (P = .267).
GBM patients with CRET in early MRI and no fluorescent residual tissue had longer overall survival than patients with CRET and residual fluorescent tissue 23).

2012

One hundred three consecutive patients underwent resection of glioblastoma from August 2008 to November 2010. Eligibility for CRET was based on the initial magnetic resonance imaging assessed by 2 reviewers. The primary end point was the number of patients with CRET and GTR. Secondary end points were volume of residual contrast-enhancing tissue and new postoperative neurological deficits.
Fifty-three patients were eligible for GTR/CRET (n = 43 newly diagnosed glioblastoma, n = 10 recurrent); 13 additional patients received surgery for GTR/CRET-ineligible glioblastoma. GTR was achieved in 96% of patients (n = 51, no residual enhancement >0.175 cm); CRET was achieved in 89% (n = 47, no residual enhancement). Postoperatively, 2 patients experienced worsening of preoperative hemianopia, 1 patient had a new mild hemiparesis, and another patient sustained sensory deficits.
Using 5-aminolevulinic acid imaging and intraoperative mapping/monitoring together leads to a high rate of CRET and an increased rate of GTR compared with the literature without increasing the rate of permanent morbidity. The combination of safety and resection-enhancing intraoperative technologies was likely to be the major drivers for this high rate of CRET/GTR 24).

2006

322 patients aged 23-73 years with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomly assigned to 20 mg/kg bodyweight 5-aminolevulinic acid for fluorescence-guided resection (n=161) or to conventional microsurgery with white light (n=161). The primary endpoints were the number of patients without contrast-enhancing tumour on early MRI (ie, that obtained within 72 h after surgery) and 6-month progression-free survival as assessed by MRI. Secondary endpoints were volume of residual tumour on postoperative MRI, overall survival, neurological deficit, and toxic effects. We report the results of an interim analysis with 270 patients in the full-analysis population (139 assigned 5-aminolevulinic acid, 131 assigned white light), which excluded patients with ineligible histological and radiological findings as assessed by central reviewers who were masked as to treatment allocation; the interim analysis resulted in termination of the study as defined by the protocol. Primary and secondary endpoints were analysed by intention to treat in the full-analysis population. The study is registered at http://www.clinicaltrials.gov as NCT00241670.
Median follow-up was 35.4 months (95% CI 1.0-56.7). Contrast-enhancing tumour was resected completely in 90 (65%) of 139 patients assigned 5-aminolevulinic acid compared with 47 (36%) of 131 assigned white light (difference between groups 29% [95% CI 17-40], p<0.0001). Patients allocated 5-aminolevulinic acid had higher 6-month progression free survival than did those allocated white light (41.0% [32.8-49.2] vs 21.1% [14.0-28.2]; difference between groups 19.9% [9.1-30.7], p=0.0003, Z test). Groups did not differ in the frequency of severe adverse events or adverse events in any organ system class reported within 7 days after surgery.
Tumour fluorescence derived from 5-aminolevulinic acid enables more complete resections of contrast-enhancing tumour, leading to improved progression-free survival in patients with malignant glioma 25).

2000

Fifty-two consecutive patients with GBM received oral doses of 5-ALA (20 mg/kg body weight) 3 hours before induction of anesthesia. Intraoperatively, tumor fluorescence was visualized using a modified operating microscope. Fluorescing tissue was removed whenever it was considered safely possible. Residual enhancement on early postoperative MR imaging was quantified and related to each patient’s characteristics to determine which factors influenced resection. Survival was analyzed using the Kaplan-Meier method and multivariate analysis was performed in which the Karnofsky Performance Scale (KPS) score, residual fluorescence, patient age, and residual enhancement on MR images were considered. Intraoperatively, two fluorescence qualities were perceived: solid fluorescence generally reflected coalescent tumor, whereas vague fluorescence mostly corresponded to infiltrative tumor. Complete resection of contrast-enhancing tumor was accomplished in 33 patients (63%). Residual intraoperative tissue fluorescence left unresected for safety reasons predicted residual enhancement on MR images in 18 of the 19 remaining patients. Age, residual solid fluorescence, and absence of contrast enhancement in MR imaging were independent explanatory factors for survival, whereas the KPS score was significant only in univariate analysis. No perioperative deaths and one case of permanent morbidity were encountered.
The observations in this study indicate the usefulness of 5-ALA-induced tumor fluorescence for guiding tumor resection. The completeness of resection, as determined intraoperatively from residual tissue fluorescence, was related to postoperative MR imaging findings and to survival in patients suffering from GBM 26).
1)

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Impact of intraoperative MRI-guided resection on resection and survival in patient with gliomas: a meta-analysis.

Implementation of intraoperative magnetic resonance imaging (iMRI) has been shown to optimize the extent of resection and safety of brain tumor surgery. In addition, iMRI can help account for the phenomenon of brain shift and can help to detect complications earlier than routine postoperative imaging, which can potentially improve patient outcome.
Intraoperative MRI is considered the gold standard among all intraoperative imaging technologies currently available. Its main indication is in the intraoperative detection of residual disease during tumour resections.
It allows real-time image-guided excision of brain tumors, especially gliomas and pituitary adenomas.
Intraoperative magnetic resonance imaging (iMRI) is an effective and proven tool in transsphenoidal endoscopic surgery. However, image interpretation is not always easy and can be hindered by the presence of blood, tumor remains or the displacement of surrounding structures.
Jiménez et al present a novel technique based on using intrasellar ballons to reduce these difficulties and facilitate the surgeon’s intraoperative assessment by iMRI.

Noise of unknown origin

Low magnetic field iMRI devices may produce low-quality images due to nonideal imaging conditions in the operating room and additional noise of unknown origin.
Unbiased nonlocal means filter for iMRI de-noising proved very useful for image quality enhancement and assistance in the interpretation of iMR images 1).
The higher signal-to-noise ratio offered by 3 Tesla (T) iMRI compared with lower field strength systems is particularly advantageous.
To maximize efficiency, iMRI sequences can be tailored to particular types of tumors and procedures, including nonenhancing brain tumor surgery, enhancing brain tumor surgery, transsphenoidal pituitary tumor surgery, and laser ablation. Unique imaging findings on iMRI include the presence of surgically induced enhancement, which can be a potential confounder for residual enhancing tumor, and hyperacute hemorrhage, which tends to have intermediate signal on T1-weighted sequences and high signal on T2-weighted sequences due to the presence of oxyhemoglobin. MR compatibility and radiofrequency shielding pose particularly stringent technical constraints at 3T and influence the design and usage of the surgical suite with iMRI 2).

Language

Intraoperative magnetic resonance imaging (iMRI) and functional neuronavigation may help maximize tumor resection, minimize language deficits in patients with gliomas involving language areas, and improve survival time for patients with glioblastomas 3).

Metaanalysis

The Medline, PubMed, Cochrane, Google Scholar databases were searched until September 26th, 2015 Randomized controlled trials (RCTs), two-arm prospective studies, retrospective studies in patients with glioblastoma/glioma who had received surgical treatment were included.
The primary outcome measures were the extent of tumor resection and tumor size reduction for using iMRI-guided or conventional neuronavigation-guided neurosurgery. Secondary outcomes included impact of surgery on the 6-month progression-free survival (PFS) and 12-month overall survival (OS) rates and surgical duration were also studied.
They found that iMRI was associated with greater rate of gross total resection (rGTR) compared with conventional neuronavigation procedures (3.16, 95% confidence interval [CI] 2.07-4.83, P < 0.001). We found no difference between the two neuronavigation approaches in extent of resection (EOR), tumor size reduction, or time required for surgery (P values ≥0.065). Intraoperative MRI was associated with a higher rate of progression-free survival (PFS) compared with conventional neuronavigation (odds ratio, 1.84; 95% CI of 1.15 to 2.95; P = 0.012), but the rate of overall survival (OS) between groups was similar (P = 0.799). Limitations of the study included the fact that data from non-RCTs were used, the small study population, and heterogeneity of outcomes across studies.
The findings indicate that iMRI more frequently resulted in more complete resections leading to improved PFS in patients with malignant gliomas 4).

Case series

2015

In 300 consecutive patients, three sequential groups (groups A, B, C; n=100 each) were compared with respect to time management, complications and technical difficulties to assess improvement in these parameters with experience.
Raheja et al observed a reduction in the number of technical difficulties (p<0.001), time to induction (p<0.001) and total anesthesia time (p=0.007) in sequential groups. IOMRI was performed for neuronavigation guidance (n=252) and intraoperative validation of extent of resection (EOR; n=67). Performing IOMRI increased the EOR over and beyond the primary surgical attempt in 20.5% (29/141) and 18% (11/61) of patients undergoing glioma and pituitary surgery, respectively. Overall, EOR improved in 59.7% of patients undergoing IOMRI (40/67). Intraoperative tractography and real time navigation using re-uploaded IOMRI images (accounting for brain shift) helps in intraoperative planning to reduce complications. IOMRI is an asset to neurosurgeons, helping to augment the EOR, especially in glioma and pituitary surgery, with no significant increase in morbidity to the patient 5).

2013

Brell et al. retrospectively reviewed the first 21 patients operated on the aid of this technology. Maximal safe resection was the surgical goal in all cases. Surgeries were performed using conventional instrumentation and the required assistance in each case.
The mean number of intraoperative studies was 2.3 per procedure (range: 2 to 4). Intraoperative studies proved that the surgical goal had been achieved in 15 patients (71.4%), and detected residual tumour in 6 cases (28.5%). After comparing the last intraoperative image and the postoperative study, 2 cases (9.5%) were considered as “false negatives”.
Intraoperative MRI is a safe, reliable and useful tool for guided resection of brain tumours. Low-field devices provide images of sufficient quality at a lower cost; therefore their universalisation seems feasible 6).

Case reports

Giordano et al. describe two explicative cases including the setup, positioning, and the complete workflow of the surgical approach with intraoperative imaging. Even if the configuration of iopMRI equipment was originally designed for cranial surgery, they have demonstrated the feasibility of cervical intramedullary glioma resection with the aid of high-field iopMRI. This tool was extremely useful to evaluate the extent of tumor removal and to obtain a higher resection rate, but still need some enhancement in the configuration of the headrest coil and surgical table to allow better patient positioning 7).

1) Mizukuchi T, Fujii M, Hayashi Y, Tsuzaka M. Usability of unbiased nonlocal means for de-noising intraoperative magnetic resonance images in neurosurgery. Int J Comput Assist Radiol Surg. 2014 Jan 7. [Epub ahead of print] PubMed PMID: 24395699.
2) Ginat DT, Swearingen B, Curry W, Cahill D, Madsen J, Schaefer PW. 3 Tesla intraoperative MRI for brain tumor surgery. J Magn Reson Imaging. 2014 Jun;39(6):1357-65. PubMed PMID: 24921066.
3) Zhang J, Chen X, Zhao Y, Wang F, Li F, Xu B. Impact of intraoperative magnetic resonance imaging and functional neuronavigation on surgical outcome in patients with gliomas involving language areas. Neurosurg Rev. 2015 Apr;38(2):319-30. doi: 10.1007/s10143-014-0585-z. Epub 2014 Dec 19. PubMed PMID: 25519766.
4) Li P, Qian R, Niu C, Fu X. Impact of intraoperative MRI-guided resection on resection and survival in patient with gliomas: a meta-analysis. Curr Med Res Opin. 2016 Dec 23:1-28. doi: 10.1080/03007995.2016.1275935. [Epub ahead of print] PubMed PMID: 28008781.
5) Raheja A, Tandon V, Suri A, Sarat Chandra P, Kale SS, Garg A, Pandey RM, Kalaivani M, Mahapatra AK, Sharma BS. Initial experience of using high field strength intraoperative MRI for neurosurgical procedures. J Clin Neurosci. 2015 Aug;22(8):1326-31. doi: 10.1016/j.jocn.2015.02.027. Epub 2015 Jun 12. PubMed PMID: 26077939.
6) Brell M, Roldán P, González E, Llinàs P, Ibáñez J. [First intraoperative magnetic resonance imaging in a Spanish hospital of the public healthcare system: initial experience, feasibility and difficulties in our environment]. Neurocirugia (Astur). 2013 Jan-Feb;24(1):11-21. doi: 10.1016/j.neucir.2012.07.003. Epub 2012 Nov 13. Spanish. PubMed PMID: 23154131.
7) Giordano M, Gerganov VM, Metwali H, Fahlbusch R, Samii A, Samii M, Bertalanffy H. Feasibility of cervical intramedullary diffuse glioma resection using intraoperative magnetic resonance imaging. Neurosurg Rev. 2013 Nov 15. [Epub ahead of print] PubMed PMID: 24233260.

New Book: Image-Guided Stereotactic Radiosurgery

Image-Guided Stereotactic Radiosurgery: High-Precision, Non-invasive Treatment of Solid Tumors
By Harun Badakhshi

Image-Guided Stereotactic Radiosurgery: High-Precision, Non-invasive Treatment of Solid Tumors

List Price:$109.00
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This book provides the reader with a detailed update on the use of stereotactic radiosurgery (SRS) in patients with lesions of the brain and other parts of the body. The aim is not simply to explain the application of SRS and document its value with reference to the author’s own clinical experiences and other published evidence, but also to contextualize the technology within a new strategic concept of cancer care. When embedded within an appropriate conceptual framework, technology becomes pivotal in changing therapeutic strategies. A new paradigm that is increasingly impacting on clinical practice is the oligometastatic state, on the basis that long-term survival might be achieved in patients with a low volume and number of metastatic lesions. This book accordingly addresses the value of SRS in patients with oligometastases of solid tumors to the brain, lung, spine, and liver. In addition, it examines the use of SRS in patients with diverse brain lesions, early-stage stage lung cancer, liver cancer, and early-stage prostate cancer. Readers will be persuaded that SRS, using cutting-edge imaging technologies to deliver precisely targeted radiation therapy, represents an exciting non-invasive procedure that holds great promise for the present and the future of cancer care.


Dr Harun Badakhshi is Chief Physician and chairman of clinical radiation oncology at Ernst von Bergmann Medical Center, an academic teaching hospital of Humboldt University Berlin. He also serves as senior lecturer / assoc. professor at Charité School of Medicine Humboldt University Berlin, and is holding various functions in regional and European organizations and societies that are related to cancer research and education. He has previously worked as vice chairman of radiation oncology at University Hospital Charité.
His research interest is primarily in neurooncology, lung and breast cancer, and metastases research. A focus of his research lies, especially, in studying effects of image-guided high precision radiotherapy for benign and malignant tumors, as well in investigations about curative potentials for cancer with oligometastases.
He has published about 50 original peer-reviewed research papers to date and many reviews on different aspects of medicine, including prevention, education, health economics. He serves as a reviewer for more than 10 specialized journals, and as an appraiser for regional medical organizations and physician chamber.

Product Details

  • Published on: 2016-07-27
  • Original language: English
  • Number of items: 1
  • Dimensions: .0″ h x .0″ w x .0″ l, .0 pounds
  • Binding: Hardcover
  • 271 pages

Book: Image-Guided Hypofractionated Stereotactic Radiosurgery: A Practical Approach to Guide Treatment of Brain and Spine Tumors

Image-Guided Hypofractionated Stereotactic Radiosurgery: A Practical Approach to Guide Treatment of Brain and Spine Tumors

Image-Guided Hypofractionated Stereotactic Radiosurgery: A Practical Approach to Guide Treatment of Brain and Spine Tumors

List Price:$259.95
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The recent development of hypofractionated stereotactic radiation therapy (SRT), which calls for one to five fractions of high-dose radiation to be administered using special equipment, has resulted in the need for education on practice guidelines.
Image-Guided Hypofractionated Stereotactic Radiosurgery: A Practical Approach to Guide Treatment of Brain and Spine Tumors offers comprehensive, how-to guidance on hypofractionated SRT for brain and spine metastases, glioma, benign tumors, and other tumor types. Presenting the state of the art of the technology and practice, this book:

  • Discusses the pros and cons of hypofractionated SRT compared to single-fraction radiosurgery, providing a deeper understanding of radiosurgery and radiobiology
  • Explains the toxicity and adverse effects of hypofractionated SRT, aiding practitioners in communicating the risks and benefits of treatment and in obtaining their patients’ consent
  • Outlines the current standards for safe practice, including checklists for implementation

Comprised of chapters authored by well-recognized experts in the radiation, oncology, and neurosurgery communities, Image-Guided Hypofractionated Stereotactic Radiosurgery: A Practical Approach to Guide Treatment of Brain and Spine Tumors delivers a level of technological and clinical detail not available in journal papers.


Product Details

  • Published on: 2016-05-02
  • Original language: English
  • Number of items: 1
  • Dimensions: 10.00″ h x 7.01″ w x .0″ l, .0 pounds
  • Binding: Hardcover
  • 376 pages

Editorial Reviews

Review
“… a caregiver’s roadmap for a panoply of common clinical scenarios encountered in radiosurgical care of patients with cancer. … An awareness of how much this book can help in very practical terms is a good first step to helping your patients.”
―Jonathan P.S. Knisely, MD, Department of Radiation Medicine, Center for Advanced Medicine, Northwell Health, Lake Success, New York, USA
“… a pragmatic approach to the emerging use of image-guided hypofractionated stereotactic radiosurgery for brain and spinal tumors. Each clinical chapter has a very useful checklist specific to brain and spinal indications, which facilitates implementation of the concepts.”
―John H. Suh, MD, Department of Radiation Oncology, Brain Tumor Institute, Cleveland Clinic Foundation, Ohio, USA
“… a much-needed overview of focal hypofractionated stereotactic radiosurgery for brain and spine tumors. The authors are experts, and as a result this book represents a most comprehensive, practical, and authoritative guide for practitioners.”
―David A. Larson, MD, Professor, Departments of Radiation Oncology and Neurological Surgery, University of California, San Francisco, USA
“From brain metastases to spinal metastases to high-grade gliomas to benign brain tumors, there are pearls of wisdom here to help practicing neurosurgical oncologists and radiation oncologists take the best care of their patients. A must read!”
―James T. Rutka, MD, PhD, RS McLaughlin Professor and Chair, Department of Surgery, University of Toronto, Ontario, Canada
“… a comprehensive discussion of radiosurgery biology, imaging, techniques, and management of value for both single-session and hypofractionated approaches.”
―Douglas Kondziolka, MD, Professor and Director, Center for Advanced Radiosurgery, NYU Langone Medical Center, New York City, New York, USA
“… includes a wealth of treatment opportunities to further improve upon efficient, effective, and safer opportunities for our patients.”
―Helen A. Shih, MD, Chief, CNS and Eye Services, Department of Radiation Oncology, and Associate Medical Director, Francis H. Burr Proton Therapy Center, Massachusetts General Hospital, Boston, USA
“Expert practitioners document the state of the art of this new discipline of neurosurgery and radiation oncology.”
―John R. Adler, Jr., MD, Dorothy and TK Chan Professor Emeritus, Stanford University, California, USA
“… provides an invaluable guide through the technical tricks and traps, and beyond into safe practice.”
―Anthony L. Zietman, MD, Jenot W. and William U. Shipley Professor of Radiation Oncology, Harvard Medical School, and Associate Director, Radiation Oncology Residency Program, Massachusetts General Hospital, Boston, USA
“This book is packed with expert perspectives on both single and hypofractionated radiosurgery for brain and spine, presenting state-of-the-art techniques in this emerging field.”
―Ian Paddick, National Hospital for Neurology and Neurosurgery, Queen Square, London, UK
“… covers the relevant indications for hypofractionated radiosurgery and helps readers understand the basic principles in this fast-evolving field in radiation medicine.”
―Alex Muacevic, MD, Professor, University of Munich, and Director, Cyberknife Center Munich, Germany
About the Author
Arjun Sahgal, MD (chief editor), is a leader in the field of high-precision stereotactic radiation to the brain and spine. After training at the University of Toronto, Ontario, Canada, in radiation oncology, he completed a fellowship at the University of California, San Francisco, in brain and spine radiosurgery with Dr. David Larson. Since then he has been recognized as a national and international clinical expert and research leader in radiosurgery. His main focus is on developing spine stereotactic body radiotherapy as an effective therapy for patients with spinal tumors. He has published numerous book chapters on the subject and more than 200 peer-reviewed papers in high-impact journals, including Journal of Clinical Oncology and The Lancet Oncology. He has edited or written several books specific to research on brain and bone metastases and is an editorial board member for several journals. He was chairman of the International Stereotactic Radiosurgery Society meeting (June 2013) and was a board member for the Brain Tumour Foundation of Canada and the International Stereotactic Radiosurgery Society. He has been invited to speak at several international meetings, has been a visiting professor at various universities, and leads several research groups. His further research activities involve integrating MRI into radiotherapy delivery, combining novel pharmacologic therapies with radiosurgery, and MRI-guided focused ultrasound.
Simon S. Lo, MD, is professor of radiation oncology at Case Western Reserve University, Cleveland, Ohio, and director of radiosurgery services and neurologic radiation oncology at University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Cleveland, Ohio. Dr. Lo graduated from the Faculty of Medicine of The Chinese University of Hong Kong and did his residency in clinical oncology (Royal College of Radiologists, UK curriculum) at Queen Elizabeth Hospital, Hong Kong. He subsequently completed a residency in radiation oncology at the University of Minnesota, Minneapolis, and also received a grant from the American College of Radiation Oncology for a gastrointestinal radiation oncology fellowship at the Mayo Clinic (Minnesota). He was a visiting resident at Princess Margaret Hospital, University of Toronto, Ontario, Canada. He is currently chair of the American College of Radiology Appropriateness Criteria Expert Panel in Bone Metastasis and is the radiation oncology track co-chair for a Radiological Society of North America (RSNA) refresher course. He is an expert in brain and spinal tumors, stereotactic radiosurgery, and stereotactic body radiotherapy (SBRT). He has published more than 135 peer-reviewed papers, more than 50 book chapters, and three textbooks, including a comprehensive textbook in SBRT (27,000 downloads in 32 months). He has given lectures on SBRT to the American Society for Radiation Oncology (ASTRO), RSNA, the Radiosurgery Society, the International Stereotactic Radiosurgery Society, and the American Thoracic Society conferences and in multiple U.S. and international academic centers. He was also a member of both the ASTRO bone and brain metastases taskforces and contributed to the ASTRO guidelines for bone and brain metastases. He is on the editorial boards of multiple oncology journals and is a reviewer for The Lancet, The Lancet Oncology, Nature Reviews Clinical Oncology, Journal of Clinical Oncology, Radiotherapy & Oncology, andInternational Journal of Radiation Oncology: Biology and Physics. His areas of research are in brain tumors, stereotactic radiosurgery, radiobiological modeling for ablative radiotherapy, SBRT for lung, liver, and spinal tumors, and toxicities associated with SBRT.
Lijun Ma, PhD, is professor in residence of radiation oncology physics and director of the Physics Residency Program at the University of California, San Francisco. Dr. Ma has served in American Association of Physicists in Medicine on multiple task groups and working groups. He currently co-chairs the normal tissue complication probability spine subcommittee and serves on the editorial board of Medical Physics. He is board certified by the American Board of Medical Physics and is a member of the American College of Radiology. He has been active professionally in the International Society of Stereotactic Radiosurgery and has served on its executive board. Dr. Ma has published more than 100 papers and more than 20 book chapters, and is a holder of three international patents.
Jason P. Sheehan, MD, graduated with highest distinction in bachelors of chemical engineering at the University of Virginia, Charlottesville, Virginia, where he subsequently earned a master of science in biomedical engineering and a doctorate in biological physics. He earned his medical degree from the University of Virginia and completed his neurosurgical residency at the University of Virginia along with fellowships in stereotactic and functional neurosurgery at the University of Pittsburgh and microsurgery at the Auckland Medical Center in New Zealand. After his neurosurgical training, he joined the faculty of the University of Virginia’s Department of Neurological Surgery. He currently serves as the Harrison Distinguished Professor of Neurological Surgery. He is also the vice chairman of academic affairs, associate director of the residency program, and director of stereotactic radiosurgery. Dr. Sheehan’s research effort focuses on translational and clinical studies for minimally invasive intracranial and spinal surgery. He has published more than 300 papers and has served as the editor for several books. He has received the National Brain Tumor Foundation’s Translational Research Award, the Young Neurosurgeon Award from the World Federation of Neurological Surgeons, the Integra Award, the Synthes Skull Base Award, and the Crutchfield Gage Research Award. He serves on the editorial boards of Neurosurgery, Journal of Neurosurgery, Journal of Neuro-Oncology, and the Journal of Radiosurgery and SBRT. He is a member of the American Association of Neurological Surgeons (AANS), the Congress of Neurological Surgeons (CNS), the Society for Neuro-Oncology, the Society of Pituitary Surgeons, the American Society of Therapeutic Radiology and Oncology, the International Stereotactic Radiosurgery Society, and the Neurosurgical Society of the Virginias. He serves on the executive committee for the AANS/CNS section on tumors and is chair of the radiosurgery committee for the AANS/CNS section on tumors. He is listed in Best Doctors of America.
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