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New Hope in Brain Glioma Surgery: The Role of Intraoperative Ultrasound. A Review

New Hope in Brain Glioma Surgery: The Role of Intraoperative Ultrasound. A Review brain sciences Review New Hope in Brain Glioma Surgery: The Role of Intraoperative Ultrasound. A Review 1 2 3 1 , Maria Angela Pino , Alessia Imperato , Irene Musca , Rosario Maugeri *, 1 3 1 3 Giuseppe Roberto Giammalva , Gabriele Costantino , Francesca Graziano , Francesco Meli , 3 1 3 Natale Francaviglia , Domenico Gerardo Iacopino and Alessandro Villa Department of Experimental Biomedicine and Clinical Neurosciences, School of Medicine, Neurosurgical Clinic, AOUP “Paolo Giaccone”, 90100 Palermo, Italy; mariangelapino@live.it (M.A.P.); robertogiammalva@live.it (G.R.G.); francesca.graziano03@unipa.it (F.G.); gerardo.iacopino@gmail.com (D.G.I.) Division of Neurosurgery, IRCCS Neuromed, 86077 Pozzilli, Italy; alessia.imperato@gmail.com Division of Neurosurgery, ARNAS Civico Hospital, 90100 Palermo, Italy; irene.musca93@gmail.com (I.M.); gabcostantino@gmail.com (G.C.); melifra75@gmail.com (F.M.); francaviglianatale@gmail.com (N.F.); alessandrovilla83@gmail.com (A.V.) * Correspondence: rosario.maugeri1977@gmail.com; Tel.: +39-091-655-2391; Fax: +39-091-655-2393 Received: 17 October 2018; Accepted: 16 November 2018; Published: 19 November 2018 Abstract: Maximal safe resection represents the gold standard for surgery of malignant brain tumors. As regards gross-total resection, accurate localization and precise delineation of the tumor margins are required. Intraoperative diagnostic imaging (Intra-Operative Magnetic Resonance-IOMR, Intra-Operative Computed Tomography-IOCT, Intra-Operative Ultrasound-IOUS) and dyes (fluorescence) have become relevant in brain tumor surgery, allowing for a more radical and safer tumor resection. IOUS guidance for brain tumor surgery is accurate in distinguishing tumor from normal parenchyma, and it allows a real-time intraoperative visualization. We aim to evaluate the role of IOUS in gliomas surgery and to outline specific strategies to maximize its efficacy. We performed a literature research through the Pubmed database by selecting each article which was focused on the use of IOUS in brain tumor surgery, and in particular in glioma surgery, published in the last 15 years (from 2003 to 2018). We selected 39 papers concerning the use of IOUS in brain tumor surgery, including gliomas. IOUS exerts a notable attraction due to its low cost, minimal interruption of the operational flow, and lack of radiation exposure. Our literature review shows that increasing the use of ultrasound in brain tumors allows more radical resections, thus giving rise to increases in survival. Keywords: intraoperative ultrasound; IOUS; brain tumor; glioma surgery 1. Introduction Maximal safe resection represents the gold standard for surgery of malignant brain tumors: gross total resection of the tumor while preserving the surrounding functional brain tissue is the main goal, since it is associated with longer survival and better patient quality of life [1]. This is particularly true for gliomas, the most common primary malignant brain tumors whose pathogenesis is still unknown [2,3]. Concerning gross total resection, accurate localization and precise delineation of the tumor margins are required in order to avoid devastating lesions on nervous structures [4]. Frame-based and frameless stereotactic preoperative data-based techniques, also known as neuronavigation systems, are routinely used to help surgeons plan the site of craniotomy and identify critical neural structures. Brain Sci. 2018, 8, 202; doi:10.3390/brainsci8110202 www.mdpi.com/journal/brainsci Brain Sci. 2018, 8, 202 2 of 16 Unfortunately, these systems have inherent problems related to loss of accuracy resulting from unpredictable distortions, shifts, and deformations after craniotomy and tissue removal. Therefore, neuronavigation is not a true real-time system: the accuracy is maximal before the craniotomy and decreases significantly while progressing through surgical manipulation. It is due to two main factors: the first is “brain shift” caused by the effect of gravity on the brain, brain swelling, as well as the drainage of cerebrospinal fluid (CSF); the second factor is the deformation of brain parenchyma caused by surgical maneuvers and tumor removal [5]. Several surgical techniques and technological innovations have been recently introduced to help the surgeon achieve the maximal safe resection of the tumor while reducing the odds of post-operative complications [6,7]. Some examples are represented by the intraoperative use of neurophysiological monitoring and the use of the awake surgery technique. Moreover, in recent years, new methods, including intraoperative diagnostic imaging (Intra-Operative Magnetic Resonance-IOMR, Intra-Operative Computed Tomography-IOCT, Intra-Operative Ultrasound-IOUS) and dyes (fluorescence) have become relevant in neuro-oncological surgery, allowing for a more radical and safer tumor resection [8]. Some of these innovations, such as the IOMR, are expensive and not available in every neurosurgical centre. Therefore, in the last few years, great attention has been paid to the possible intraoperative use of ultrasound (IOUS) guidance for brain tumor surgery. IOUS is not a new technology, but it is accurate in distinguishing tumor from normal parenchyma, and allows a real-time intraoperative visualization. IOUS is cheap, easily repeatable, safe for the patient, potentially available in all neurosurgical centres. As early as in the 1970s, B-mode ultrasound (US) was introduced into the operating room. However, it was the development and application of real-time grey-scale US imaging technology that really provided an impetus to IOUS. The use of ultrasound to achieve maximally safe resection of brain tumors has been implemented since the 1980s [9]. In the pre-MR era, US (2-dimensional (2D) B-mode grey-scale US) imaging became a routinely-used adjunct in the neurosurgical operating room. With the introduction of MR imaging (MRI), an entirely new and vivid “image” of intracranial anatomy was unveiled. Neurosurgeons rapidly adopted MRI into routine clinical diagnostic practice. The development of stereotactic localization and navigation technology in the late 1980s ushered in the era of “computer-assisted surgery.” In 1992, Le Roux et al. noted that the majority of brain tumors, including low-grade gliomas, were visible with intraoperative ultrasound [10]. The Norwegian Group first employed IOUS in 1997, and demonstrated the utility of real-time intraoperative ultrasound to identify tumors and facilitate resection [11]. In the contemporary era, IOUS imaging is used in neuro-oncological surgery to investigate the spatiotemporal change of the tumor morphology during the operation. B-mode is the most commonly-used modality [12]. The solid part of the tumor appears hyperechogenic compared to the surrounding cerebral parenchyma, while cysts appear hypoechoic. The presence of blood or calcifications, which can often occur in the tumor mass, alters the echogenicity of the lesions; therefore, the procedure should be led by an experienced operator. Many authors described the ultrasonographic characteristics of some tumors by comparing them with conventional imaging studies, such as Computed Tomography (CT) and MR [13–17]. After the craniotomy is performed, the utility of ultrasound is evident in different phases of surgery. IOUS help to plan the opening of the dura and to centre the corticectomy. In the following phases, IOUS allows identification of the tumor margins, thus helping for a maximally radical resection. The main advantage of IOUS consists of obtaining a real-time scan: this can be repeated as many times as necessary, in order to overcome the errors produced by brain shift [18]. It also avoids the cost and the duration of other intraoperative techniques. Its main limitations are spatial resolution, width and orientation of the field of view (different from the standard orthogonal planes of CT and MRI), and scan quality, which are operator dependent. Even if US are widely adopted to evaluate cerebral blood flow through transcranial Doppler [19], Neurosurgeons are not confident with a technique that provides brain images oriented on infinite axis Brain Sci. 2018, 8, 202 3 of 16 (not only the standard axial, sagittal, and coronal plane), and the ability to “understand and interpret” anatomic details displayed on the screen requires significant training and experience. Since most neurosurgeons do not receive specific US training, and US is not yet a standard diagnostic and intraoperative tool for cerebral lesions, there is an inherent difficulty in interpreting IOUS imaging and in correctly setting up the machine; these two factors both lead to a longer learning curve. Real-time intraoperative fusion of preoperative MRI/CT scans and intraoperative ultrasounds is a highly desirable solution to overcome the above-mentioned limitations. Moreover, the greatest limitation of US is their limited ability to penetrate the skull; therefore, the most important application of IOUS in brain tumor surgery occurs after performing the craniotomy. Since IOUS has gained great popularity in recent years, the purpose of this study is to review the current literature to evaluate the role of IOUS in gliomas surgery and to outline specific strategies to maximize its efficacy. 2. Literature Research and Findings We performed a literature research through the Pubmed database by selecting each article focused on the use of IOUS in brain tumor surgery, and in particular, in glioma surgery, published in the last 15 years (from 2003 to 2018). We performed a query using the following combinations of the Medical Subject Headings (MESH) terms: ultrasound, intraoperative ultrasound, intraoperative image guidance, glioma surgery, brain tumors surgery, high-grade glioma surgery, low-grade glioma surgery, alternating all these terms in various combinations. We included all the studies with information on the diagnosis, the extent of the resection, and the postoperative evaluation of the degree of resection by neuroimaging. We excluded all papers written in languages other than English and all studies with incomplete data. After the identification of all articles that met the inclusion criteria, and after removing duplicates, we selected 39 papers dealing with the use of IOUS in brain tumor surgery, including gliomas. Twenty-one studies were prospective and 18 were retrospectives. In particular, we focused on the usefulness of ultrasound in the surgery of cerebral gliomas. 2264 patients were included in our review: 1650 patients with a histologic diagnosis of brain glioma and 522 patients with a non-glial tumor. We did not find any information about the histological report of 94 patients [20]. We paid special attention to the evaluation of the postoperative extent of resection (EOR), and in particular, to the achievement of gross-total resection (GTR), defined as the absence of any residual enhancement on postoperative volumetric-enhanced MRI performed within 72 h after surgical resection. Another important point was the analysis we performed of the usefulness of IOUS used with or without other neuroimaging techniques. The results of our literature review are briefly summarized in Table 1 (see Section 3). 3. The Use of IOUS in Brain Glioma Surgery The use of IOUS seems to have significantly increased the GTR rate achieved in brain tumors/gliomas surgery. As regard intraoperative visualisation of the tumor and its residuals, the effectiveness of IOUS has been documented in a series of 192 HGG patients, in which the combination of neuronavigation and IOUS was also related to increased overall survival [21]. Erdogan et al. [22], in a prospective study of 32 patients, documented a good level of agreement between intraoperative ultrasonography and postoperative contrast-enhanced MRI in detecting tumor residue; they concluded that the IOUS produces results similar to those of MRI, and therefore, can be used to maximize tumor resection. Brain Sci. 2018, 8, 202 4 of 16 Regarding the reliability of intraoperative ultrasound images, the best 2-D ultrasound images are obtained with a linear array probe (linear array intra-operative ultrasound, lioUS) (Philips, Amsterdam, The Netherlands), which is quite large and difficult to manoeuvre into a scalp window. For this reason, in a series of 13 LGG patients, Coburger et al. [23] compared a conventional phased array probe (conventional intra-operative ultrasound, cioUS) (Philips, Amsterdam, The Netherlands) with a new, smaller linear array probe. They observed that the lioUS images significantly corresponded to the intra-operative MRI (iMRI), and that it was unlikely that the cioUS was less accurate. The sensitivity was very high in the evaluation of the tumor residue for iMRI (83%), followed by lioUS (79%). The sensitivity for cioUS was lower (21%). On the other hand, in a series of 15 HGG patients, lioUS showed a significantly higher detection rate for residual tumors than cioUS, allowing a GTR of 73.3% [24]. Moreover, the authors found that the images produced by lioUS have few artefacts, better definition, and a more accurate visualization of the residual tumor compared with cioUS. Lothes et al. [25] in a prospective study on 11 patients with low-grade glioma (LGG) compared intraoperative MRI with conventional low-frequency intraoperative ultrasound (cioUS) and high-frequency linear array intraoperative ultrasound (lioUS). They concluded that although iMRI remains the method of choice, lioUS has been shown to be beneficial in a combined setup. Evaluation of lioUS was significantly superior to cioUS in most indications except for subcortical lesion. Proceeding further, the implementation of 3-D US should overcome some limitations of the 2-D US by producing a volumetric image. 3-D US showed 71% sensitivity in detecting residual tumors during the resection of cerebellar lesions, in a series of 16 patients who underwent resection of intracerebral lesions. However, the sample was too small to be conclusive [26]. Unsgaard et al. [27], in a study of 28 patients, analysed data of a 3-D IOUS-based intraoperative imaging and navigation system, comparing its usefulness in brain glioma and metastasis surgery. The results indicated that 3D US images give a good delineation of both metastases and the solid part of gliomas, thus providing a reliable guidance in tumor surgery before starting the resection. In larger series, it has been demonstrated that the use of 3-D navigable intraoperative ultrasound system may allow the surgeon to reach a 67% GTR of brain tumors [28]. Serra et al. [29], in a retrospective study of 22 patients, demonstrated that high frequency ultrasound (hfioUS) allows accurate detection of the tumor and detailed discrimination between normal, pathological, and oedematous tissue in all 22 cases, obtaining a GTR of 95.5%. Sweeney et al. [30], in a retrospective review of 260 patients, have shown that the use of IOUS might help to achieve a more successful GTR (81%) in both adult and paediatric neurosurgical patients. Moreover, a combination of IOUS with other intraoperative imaging modalities (such as fluorescent tissue enhancement) provided further increases of GTR in high-grade glioma surgery. In our department, fluorescein sodium has been used as an adjunct in glioma resection since September 2015. We recently reported a resection >95% in 83% (n = 39) of patients who underwent fluorescence-guided surgery [31]. In recent years, our preliminary experience demonstrates that the combined use of fluorescence dyeing with B-mode ultrasonography and contrast-enhanced ultrasound (CEUS) techniques helps the surgeon recognize the boundary between normal brain parenchyma and tumor. In a technical note that is not yet published, we described the removal of high-grade gliomas under fluorescence dye, B-mode ultrasonoghraphy, and CEUS technique in five patients (3 males, 2 females; mean age 55.2 years, range 36–68 years) who underwent craniotomies for intra-axial lesions, which were suspected for high-grade gliomas on preoperative MRI. According to our experience, we confirm the utility of IOUS in the initial steps of surgery and the central role of fluorescence in achieving a GTR. Ultrasound-based neuronavigation provides intraoperative support in planning the craniotomy, localizing the lesion, choosing the best point for the corticectomy (especially if deep tumors), as well as for resection control checking the boundaries structures. On the other hand, fluorescence-guided surgery appears to be a surface phenomenon; it is very useful to identify and demarcate the tumoral tissue once it is sufficiently exposed; according to our opinion, fluorescein sodium appears to be more important in the latest steps of resection. In addition, we show the Brain Sci. 2018, 8, 202 5 of 16 effectiveness, safety, accuracy, and feasibility of ultrasound-based fluorescein-guided surgery, which is less time- and cost-consuming. With regards to the prognosis of patients undergoing surgery for brain gliomas, it has been demonstrated that IOUS improves the prevalence of GTR and significantly increases 1- and 2-year overall survival [32]. These results may be due to the detection of residual tumors with high specificity by the use of IOUS, and hence, to the improvement of the resection rate [11]. In a series of 35 patients, Chacko et al. [33] reported that IOUS had a positive predictive value of 0.84, and Rygh et al. [34] showed similar results in a retrospective work of 19 high-grade glioma (HGG) (specificity and sensitivity of 95%). They reported a considerable decrease of specificity (up to 42%) during the resection, while the sensitivity remained as high as 87%. Nevertheless, after the resection, the sensitivity reaches a low value (26%), and the specificity has a value equal to 88%. Neuronavigation has undoubtedly provided great advantage in brain tumor surgery by improving surgical accuracy and safety. It is based on MRI or CT scans, which should be performed within 24 h prior to surgery. Unfortunately, after performing the craniotomy, changes in brain morphology may occur compared to preoperative examinations because of the brain shift [18], which can lead to inaccuracies of between 5 and 10 mm [35]. These changes also become even more important as the tumor is debulked. As some studies highlight, intraoperative ultrasound may allow us to overcome the limit of anatomic distortion due to brain shift and tumor debulking [36]. In this regard, in a series of 67 patients, Prada et al. demonstrated that brain shift distortion may be corrected by the fusion of images between intraoperative ultrasound and preoperative magnetic resonance using neuro-navigation systems [37,38]. They have concluded that intraoperative US imaging combined with neuro-navigator is reliable, accurate, and easy to use, allowing a continuous real-time feedback without interrupting surgery. With regards to tumor pathological characterisation, contrast-enhanced ultrasound (CEUS) is a valuable tool for visualizing vascularization patterns that often correlates with lesion histology. Prada et al. [39], in a series of 71 patients, found that intra-operative CEUS (iCEUS) allows for the characterization of different brain neoplasms. Furthermore, iCEUS shows afferent and efferent vessels and hyperperfused areas, thus possibly modifying the intraoperative surgical strategy. Arlt et al. [40], in a retrospective study of 50 patients, examined the advantages of using of contrast-enhanced and three-dimensional reconstructed ultra-sound (3D CEUS) in brain tumors. The authors found that three-dimensional CEUS is a useful intraoperative imaging tool, especially for brain glioma surgery. The results of our literature review are briefly summarized in Table 1. Brain Sci. 2018, 8, 202 6 of 16 Table 1. Summary of the reviewed literature. Author and Study Design N Pts Tumor Grade GTR Sen % Sp% Primary Endpoint Results Year The comparison between the IOUS findings and the post-op CT scan To evaluate the usefulness of findings in the 28 pts with intra-operative ultrasound (IOUS) in parenchymal tumors; 5 patients HGG (22) Chacko et al., Clinical Article the detection of residual tumor who had received prior radiation 35 LGG (11) 12/35 (34.29%) / / 2003 [33] (Prospective Study) compared with a postoperative and 2 inflammatory granulomas Others (2) computed tomogram and with were excluded from the analysis, histo-pathology. there was concordance between the IOUS findings and the post-op CT scan in 23 of 28 cases. Steno et al., Case Report 1 LGG (1) 97% / / / / 2012 [41] (Retrospective) 48/107 (45%) Vs. To examine if the introduction of 3D 34/45 (43%) Patient survival increased after Sæther et al., ultrasound and neuronavigation (i.e., Retrospective study 192 HGG (192) operated before / / introduction of intraoperative 2012 [21] the SonoWand®system) may have had the introduction ultrasound and neuronavigation. an impact on overall survival. of intraoperative ultrasound Correlation with postoperative To determine the inter-method MRI revealed a good level of HHG 15 (GBM (8) agreement between intraoperative agreement (9 cases with agreement Erdogan et al., Original article Anaplastic astrocytoma (4) ultrasono- graphy and postoperative 32 59.38% / / on positive residue and 19 cases 2005 [22] (Prospective Study) Oligodendroglioma (3)) contrast-enhanced magnetic resonance with agreement on negative Others (17) imaging (MRI) in detecting tumor residue, no agree- ment in four residue. cases) lioUS can be used as a safe and To evaluate the use of navigated lioUS precise tool for intracranial image Coburger et al., (linear array intraoperative guided resection control of GBM. Prospective study 15 HHG 15 (GBM) 73.3% / / 2014 [24] ultrasound) as a resection control in It shows a significant higher glioblastoma surgery. detection rate of residual tumor compared to conventional cioUS. To assess the practical utility of 3D The navigable 3D US system is a navigable US system and its impact on Clinical Article HGG (51) very useful intraoperative image Moiyadi et al., intraoperative decisions (retrospective 90 LGG (17) 67% guidance tool in neuro-oncology, 2013 [28] during cerebral glioma surgery and study) Others (22) often facilitating better and radical analyze the extent of resection resections. achieved in malignant gliomas. To test the feasibility of navigation based on ultrasound navigation only Neuronavigation based solely on HHG 6 (GBM) and analyze whether intraoperative intraoperative ultrasound is PeredoHarvey Original article LGG 3 imaging could substitute regular feasible and may increase surgical 18 85.6% / / et al., 2012 [42] (Prospective Study) (Oligodendroglioma) navigation for lesion localization for safety when preoperative Others 9 biopsies or resection and whether neuronavigational image is not intraoperative imaging in this system feasible or unavailable. allowed resection control. Brain Sci. 2018, 8, 202 7 of 16 Table 1. Cont. Author and Study Design N Pts Tumor Grade GTR Sen % Sp% Primary Endpoint Results Year The hfioUS probe allowed in this To demonstrate the utility of study a precise detection of the Original article intraoperative use of high frequency Serra et al., HGG 14 tumor and a de- tailed (Retrospective 22 95.5% / / ultra- sound (hfioUS) in maximizing 2012 [29] Others 8 discrimination between normal, study) the extent of resection (EOR) of patholog- ical and edematous intracerebral high-grade tumors. tissue in all 22 cases. To investigate the value of intraoperative sonography in The use of intraoperative Wang et al., HGG (79) improving the prevalence of total ultrasound improves the Prospective Study 137 81.8% / / 2012 [32] LGG (58) tumor resection and the survival time prevalence of total tumor resection of patients who underwent resection and the patient’s survival time. of cerebral gliomas. The IOUS is a very useful tool in Original Article 77 in 75 pts (one intraoperative localization and (retrospective pts was operated delineation of lesions and Moiyadi et al., 41 glial tumors To evaluate the utility of the IOUS in analysis of three times) (69 76% / / planning various stages of tumor 2011 [20] 36 others an objective manner. prospectively brain tumors and resection. It is easy, convenient, collected data) 8 spinal timors) reliable, widely available, and above all a cost-effective tool. To test if intraoperative 3-D 3-D ultrasound is especially Rohde et al., Prospective study 16 / 80.7% 71% 60% ultrasound likewise can be used for helpful for detection of overseen 2011 [26] resection control. brain tumor tissue. To evaluate resection grades and The study suggest that better clinical outcome in surgery of ultrasound facilitates better high-grade gliomas, operated with use surgery and also clearly Clinical article Solheim et al., of the SonoWand system. demonstrates that, in terms of (Retrospective 142 HGG 142 74.5% / / 2010 [43] To explore the impact of ultrasound surgical results, the selection of Study) image quality and relationships patients seems to be much more between patient selection and surgical important than the selection of results. surgical tools. This study shows that while ultrasound is highly accurate in delineating GBM before resection, To compare the ability of navigated 3D but it appears less accurate during Clinical Article ultrasound to distinguish tumor and Rygh et al., and after resection. During (Retrospective 19 HGG 19 76.9% 95% 95% normal brain tissue at the tumor 2008 [34] resection, there seems to be some Study) border zone in subsequent phases of overestimation of tumor, while resection. small tumor remnants and infiltrated tissue in the cavity wall is underestimated after resection. To prove the concept of 3D ultrasound with regard to technical effects and The introduction of 3D ultrasound human impact. This includes has increased the value of measurement of fusion accuracy, the neuronavigation substantially, Lindner et al., Original Article HGG 9 23 77% / / extent of tumor resection and the making it possible to update 2006 [36] (Prospective Study) Others 14 suitability for detection and capture of several times during surgery and intraoperative brain shift as well as a minimize the problem of brain protocol of operative handling as shift. described by different neurosurgeons. Brain Sci. 2018, 8, 202 8 of 16 Table 1. Cont. Author and Study Design N Pts Tumor Grade GTR Sen % Sp% Primary Endpoint Results Year The reliability of IOUS depends on tumor type. It is beneficial to use IOUS for the resection of To evaluate intra-operative ultrasound Renner et al., HGG 22 metastases and a few high-grade Prospective Study 36 76.2% / / (IOUS) as a tool of resection control 2005 [44] Others 14 gliomas. Concerning the after brain tumor surgery. volumetric accuracy, the value of IOUS is worse than its value of navigation and resection control. Low-grade Low-grade astrocytoma: astrocytoma: 72% 100% To investigate whether the images Reformatted images from 3D US Anaplastic Anaplastic from the 3D US imaging system HGG 15 volumes give a good delineation of Unsgaard et al., Clinical Article astrocytoma: astrocytoma: provide the surgeon with sufficient 28 LGG 7 76.6% metastases and the solid part of 2005 [27] (Prospective Study) 86% 75% information to do a safe delineation of Others 6 gliomas before starting the Glioblastoma: Glioblastoma: the margins of gliomas and metastases resection. 88% 56% during the operation. Metastasis: Metastasis: 100% 100% During surgery performed on To investigate whether (IOUS) helped relapsed, irradiated, high-grade the surgeon navigate towards the gliomas, IOUS provided a reliable tumor as seen in preoperative method of navigating towards the Mursc et al., Original Article 25 HGG 25 / / / magnetic resonance imaging and core of the tumor. At the borders, 2017 [45] (Prospective Study) whether IOUS was able to distinguish it did not reliably distinguish between tumor margins and the between remnants or tumor-free surrounding tissue. tissue, but hypoechoic areas seldom contained tumor tissue. The use of IOUS might help achieve a more successful GTR in To expand on results from the both adult and pediatric previous study in order to provide neurosurgical patients and might Clinical Article Glioma 50.8% Glioma 100% Sweeney et al., HGG 110 more evidence on the usage of IOUS in improve surgical outcomes. (Retrospective 260 81% Metastatic Metastatic 2018 [30] Others 150 the determination of gross-total It might be useful to study the review) tumors 47.4% tumors 100% resection (GTR) in both adult and combined efficacy of IOUS and pediatric patients with brain tumors. intraoperative fluorescence imaging in achieving a higher GTR rate in invasive CNS tumor cases. IOUS was a valuable tool in localizing lesions, selecting the proper approach, con- trolling the Original Article Sun et al, 2007 Gliomas 68 To evaluate the value of IOUS extent of resection and displaying (Retrospective 110 / / / [46] Others 42 in neurological operations. the distribution of vasculature. Study) IOUS can provide more reliable safe guard for minimally invasive neurosurgery. Brain Sci. 2018, 8, 202 9 of 16 Table 1. Cont. Author and Study Design N Pts Tumor Grade GTR Sen % Sp% Primary Endpoint Results Year The use of IOUS may play an important role in achieving a Clinical Article HGG 5 To evaluate the correlation of extent of greater extent of resection by Smith et al., 61.1% (Retrospective 62 LGG 34 71% resection between IOUS and providing real-time information on 2016 [47] Review) Others 23 postoperative MRI. tumor volume and location in the setting of brain shift throughout the course of an operation. To evaluate the ideal application and Although iMRI remains the typical interactions of intraoperative imaging method of choice, lioUS MRI (iMRI), conventional has shown to be beneficial in a Lothes et al., Original Article low-frequency intraoperative 11 LGG 11 / / / combined setup. Evaluation of 2016 [25] (Prospective Study) ultrasound (cioUS), and lioUS was significantly superior to high-frequency linear array cioUS in most indications except intraoperative ultrasound (lioUS) to for subcortical lesions. optimize surgical workflow. Combining awake surgery with 3DUS is feasible and beneficial. It To emphasize the convenience and does not entail any additional Original Article Moiyadi et al., HGG 17 feasibility of the use of navigable surgical workflow modification or (Retrospective 22 78% / / 2017 [48] LGG 5 three-dimensional US with awake patient discomfort. This combined Study) surgery for gliomas. modality intraoperative monitoring can be beneficial for eloquent region tumors. Integration of probabilistic fiber tracking and navigated ultrasonography into To assess whether the combined use of intraoperative neuro-navigation navigated ultrasonography with the facilitated anatomic orientation Original Article integration of FMRIB Software Library Rueckriegel et al., during glioma resection. (Retrospective 11 / 27.27% / / based probabilistic fiber tracking into 2016 [49] Combination with navigated Study) neuronavigations technically feasible ultrasonography provided a and achievable in the preoperative three-dimensional estimation of and intraoperative workflow. intra-operative brain shift and, therefore, improved the reliability of neuronavigation. CEUS is extremely specific in the identification of residual tumor. To assess the capability of The ability of CEUS to distinguish contrast-enhanced ultrasound (CEUS) between tumor and artifacts or Prada et al., to identify residual tumor mass during normal brain on B-mode is based Prospective study 10 HGG 10 / / / 2016 [50] glioblastoma multiforme (GBM) on its capacity to show the surgery, to increase the extent of vascularization degree. Therefore, resection. CEUS can play a decisive role in the process of maximizing GBM resection. Brain Sci. 2018, 8, 202 10 of 16 Table 1. Cont. Author and Study Design N Pts Tumor Grade GTR Sen % Sp% Primary Endpoint Results Year Intraoperative US should be considered as a really valuable tool To evaluate the role of intraoperative in guiding the surgeon’s LGG 14 US imaging Prada et al., hands in brain lesion removal, Prospective Study 58 HGG 27 / / / Associated whit conventional 2015 [38] providing real-time feedback and Others 17 neuronavigation in brain tumor allowing the operator to modify surgery. the surgical strategy based on the real intraoperative situation. iCEUS adds valuable anatomic and biological information such as To evaluate and describe different vascularization, microcirculation, brain pathologies by means of and tissue perfusion dynamic, intraoperative contrast-enhanced which will possibly provide ultrasound further insights into the pathology Prospective Study LGG 16 (iCEUS) compared with preliminary of brain tumors. It might help the Prada et al., (in an off -label 71 HGG 37 / / / baseline US and preoperative MRI. surgeon to tailor the approach to 2014 [39] setting) Others 18 This technique, being dynamic and the lesion, highlighting the lesion, continuous, allows a real-time direct clarifying between tumor and view of the vascularization and flow edematous brain tissue, and distribution patterns of different types showing afferent and efferent of neurosurgical lesions. vessels and hyperperfused areas, thus possibly modifying the intraoperative surgical strategy. CEUS is a fast, safe, dynamic, To perform the first characterization of real-time, and economic tool that Prospective Study Prada et al., LGG 22 cerebral glioma using CEUS and to might be helpful during surgery in (in an off -label 69 / / / 2014 [51] HGG 47 possibly achieve an intraoperative differentiating malignant and setting) differentiation of different gliomas. benign gliomas and refining surgical strategy. Intraoperative US imaging combined with neuro-navigator To demonstrate the usefulness of US represents a major innovation in Prada et al., intraoperative use in conjunction with Prospective study 67 / / / / neurosurgery; it is reliable, 2014 [37] the navigation system as a guiding accurate, easy to use, permitting a tool in brain tumor surgery. continuous real-time feedback without interrupting surgery. US was highly sensitive in detecting all types of pathology, was safe and precise in planning trajectories to intraparenchymal Original Artile HGG 62 HGG 46.77% To assess the utility of routine use of lesions and was accurate in Policicchio et al., (Retrospective 162 LGG 9 LGG 55.56% / / iUS during various types of checking extent of resection in 2018 [52] Review) Others 91 Metastases 86.67% intracranial surgery. more than 80% of cases. iUS is a versatile and feasible tool; it could improve safety and its use may be considered in routine intracranial surgery. Brain Sci. 2018, 8, 202 11 of 16 Table 1. Cont. Author and Study Design N Pts Tumor Grade GTR Sen % Sp% Primary Endpoint Results Year Intraoperative ultrasound is an 34 (15 pts excellent tool in localizing low To evaluate the importance of Petridis et al., ultrasound was grade gliomas intraoperatively. It Retrospective Study LGG 34 17.6% / / intraoperative diagnostic ultrasound 2015 [53] used and in 19 is an inexpensive, real time for localization of low-grade gliomas. not). neuronavigational tool, which overcomes brain shift. To analyze the impact of OS and PFS were longer in patients intraoperative resection control Original article that had a GTR using ioUS (either Neidert et al., modalities on over- all survival (OS) (Retrospective 76 HGG 76 / / / ioUS alone or ioUS in combination 2016 [54] and progression-free survival (PFS) Study) with ioMRI) compared to those following gross total resection (GTR) patients without ioUS. of glioblastoma. The results of this study demonstrate that 3D ultrasound To evaluate the effectiveness of can be effectively used as a 111 HGG 75 Navigated 3D ultrasound as a novel stand-alone navigation modality Moiyadi et al., Retrospective Study (81 with US, LGG 12 53% / / intraoperative imaging adjunct during the resection of brain 2016 [55] 30without US) Others 24 permitting quick real-time updates to tumors. The ability to provide facilitate tumor resection repeated, high-quality intraoperative updates is useful for guiding resection. iCEUS has potential for safe, real-time, dynamic contrast-based imaging for routine use in neurooncological surgery and image-guided biopsy. ICEUS To provide further clinical data on the eliminates the effect of anatomical HGG 1 versatile application of Intraoperative Lekht et al., distortions associated with Retrospective Study 5 LGG 1 / / / contrast-enhanced ultrasound 2016 [56] standard neuronavigation and Others 3 (iCEUS) through a technical note and provides quantitative perfusion illustrative case series. data in real time, which may hold major implications for intraoperative diagnosis, tissue differentiation, and quantification of extent of resection. To evaluate the usefulness of the use US monitoring with SMI images in of the latest innovative imaging the gray scale mode is a pioneering Case Report HGG 5 Ishikawa et al., technique for detecting very low-flow monitoring technique to recognize (Retrospective 15 LGG 2 / / / 2017 [57] components, Superb Microvascular tumor vessels and tumor margins Study) Others 8 Imaging (SMI), with US during brain and to differentiate tumor from tumor surgery surrounding healthy tissue. To assess histopathological basis of All of the assessed established imaging results of intraoperative imaging techniques detect Coburger et al., magnetic resonance imaging (iMRI), infiltrating tumor only to a certain Prospective Study 33 HGG 33 / 80% 100% 2017 [58] 5-aminolevulinic acid (5-ALA), and extent. Only 5-ALA showed a linear array intraoperative significant correlation with ultrasound (lioUS). histopathological findings. Brain Sci. 2018, 8, 202 12 of 16 Table 1. Cont. Author and Study Design N Pts Tumor Grade GTR Sen % Sp% Primary Endpoint Results Year Intraoperative resection control in To evaluate LGGs using the accuracy of linear array ultrasound lioUS reaches a degree of accuracy Coburger et al., Clinical Article in comparison to close to iMRI. Test results of lioUS 13 LGG 13 / 79% 67% 2015 [23] (Prospective Study) conventional intraoperative are superior to cioUS. cioUS often ultrasound (cioUS) and intraoperative fails to discriminate solid tumors high-field MRI (iMRI). from “normal” brain tissue during resection control. Tumor detection using a lioUS is significantly superior to cioUS. Overall test Original Article To evaluate sensitivity and specificity performance in lioUS is Coburger et al., (prospective 20 HGG 20 / 76% 58% of lioUS to detect residual tumor comparable with results of iMRI, 2015 [59] non-randomized in patients harboring a glioblastoma. while, the latter has a higher study) specificity and a significantly lower sensitivity in comparison with lioUS. To investigate the value of Intraoperative CEUS could intraoperative contrast enhanced help in determining boundary of ultrasound (CEUS) for evaluating the peritumoral brain edema of Cheng et al., Clinical Study HGG 50 88 / / / grade of glioma and the correlation glioma. Intraoperative CEUS 2016 [60] (Prospective Study) LGG 38 between microvessel density (MVD) parameters in cerebral gliomas and vascular endothelial growth factor could indirectly reflect the (VEGF). information of MVD and VEGF. Three-dimensional CEUS is a reliable intraoperative imaging modality and could improve imaging quality. Ninety percent of To examine contrast-enhanced and the high-grade gliomas (HGG, three-dimensional reconstructed ultra- glioblastoma and astrocytoma sound (3D CEUS) in brain tumor grade III) showed high contrast HGG 23 surgery regarding the up-take of uptake with an improved imaging Arlt et al., Clinical Article 50 LGG 6 GBM: 62% / / contrast agent pre- and post-tumor quality in more than 50%. Gross 2016 [40] (Prospective Study) Others 21 resection, imaging quality and in total resection and incomplete comparison, with postoperative resection of glioblastoma were magnetic resonance imaging in adequately highlighted by 3D different tumor entities. CEUS intraoperatively. The application of US contrast agent could be a helpful imaging tool, especially for resection control in glioblastoma surgery. Brain Sci. 2018, 8, 202 13 of 16 4. Conclusions The main objective in brain tumor surgery is to obtain a radical resection with minimal morbidity, as radical removal has been demonstrated to be a main factor affecting overall survival. The advent of neuronavigation has certainly brought significant advantages in brain tumor surgery, allowing identification of the lesion and its margins during the resection, but there is the great limitation of anatomic distortion after craniotomy. Intraoperative ultrasound has allowed us to overcome this limit. Furthermore, IOUS exerts a notable attraction due to the low cost, minimal interruption of the operative flow, and lack of radiation exposure. In experienced hands, sonographic features can help differentiate low-grade gliomas, which can exhibit calcifications and mild hyperechogenicity from high-grade gliomas, which can show necrotic degeneration [61]. Our literature review shows that the increasing use of ultrasound in brain tumors may allow more radical resections, thereby increasing overall survival. The studies analysed in our review show a great correlation between postoperative MRI and intraoperative ultrasound, especially for gliomas and metastases. Moreover, the lioUS appears to provide higher quality images compared to the cioUS, particularly concerning the visualization of the tumor residual. Contrast-enhanced ultrasound (CEUS) allows for the evaluation of the tumor vasculature, thus suggesting the histological diagnosis. In conclusion, the combined use of IOUS and neuronavigation may facilitate tumor removal, enhancing more radical resection, and thus improving patient overall survival and quality of life. Author Contributions: Conceptualization, M.A.P. and A.V.; Methodology, R.M.; Validation, R.M., D.G.I. and N.F.; Formal Analysis, G.R.G.; Investigation, I.M.; Data Curation, G.C., F.M. and A.I.; Writing-Original Draft Preparation, M.A.P.; Writing-Review & Editing, G.R.G., F.G., A.V.; Supervision, R.M.; Project Administration, D.G.I., N.F. Funding: This research received no external funding. Conflicts of Interest: The authors declare no conflict of interest. References 1. Giammalva, G.R.; Iacopino, D.G.; Azzarello, G.; Gaggiotti, C.; Graziano, F.; Gulì, C.; Pino, M.; Maugeri, R. End-of-Life Care in High-Grade Glioma Patients. The Palliative and Supportive Perspective. Brain Sci. 2018, 8, 125. [CrossRef] [PubMed] 2. La Torre, D.; Maugeri, R.; Angileri, F.F.; Pezzino, G.; Conti, A.; Cardali, S.M.; Calisto, A.; Sciarrone, G.; Misefari, A.; Germanò, A.; et al. Human leukocyte antigen frequency in human high-grade gliomas: A case-control study in Sicily. Neurosurgery 2009, 64, 1082–1088. 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Abstract

brain sciences Review New Hope in Brain Glioma Surgery: The Role of Intraoperative Ultrasound. A Review 1 2 3 1 , Maria Angela Pino , Alessia Imperato , Irene Musca , Rosario Maugeri *, 1 3 1 3 Giuseppe Roberto Giammalva , Gabriele Costantino , Francesca Graziano , Francesco Meli , 3 1 3 Natale Francaviglia , Domenico Gerardo Iacopino and Alessandro Villa Department of Experimental Biomedicine and Clinical Neurosciences, School of Medicine, Neurosurgical Clinic, AOUP “Paolo Giaccone”, 90100 Palermo, Italy; mariangelapino@live.it (M.A.P.); robertogiammalva@live.it (G.R.G.); francesca.graziano03@unipa.it (F.G.); gerardo.iacopino@gmail.com (D.G.I.) Division of Neurosurgery, IRCCS Neuromed, 86077 Pozzilli, Italy; alessia.imperato@gmail.com Division of Neurosurgery, ARNAS Civico Hospital, 90100 Palermo, Italy; irene.musca93@gmail.com (I.M.); gabcostantino@gmail.com (G.C.); melifra75@gmail.com (F.M.); francaviglianatale@gmail.com (N.F.); alessandrovilla83@gmail.com (A.V.) * Correspondence: rosario.maugeri1977@gmail.com; Tel.: +39-091-655-2391; Fax: +39-091-655-2393 Received: 17 October 2018; Accepted: 16 November 2018; Published: 19 November 2018 Abstract: Maximal safe resection represents the gold standard for surgery of malignant brain tumors. As regards gross-total resection, accurate localization and precise delineation of the tumor margins are required. Intraoperative diagnostic imaging (Intra-Operative Magnetic Resonance-IOMR, Intra-Operative Computed Tomography-IOCT, Intra-Operative Ultrasound-IOUS) and dyes (fluorescence) have become relevant in brain tumor surgery, allowing for a more radical and safer tumor resection. IOUS guidance for brain tumor surgery is accurate in distinguishing tumor from normal parenchyma, and it allows a real-time intraoperative visualization. We aim to evaluate the role of IOUS in gliomas surgery and to outline specific strategies to maximize its efficacy. We performed a literature research through the Pubmed database by selecting each article which was focused on the use of IOUS in brain tumor surgery, and in particular in glioma surgery, published in the last 15 years (from 2003 to 2018). We selected 39 papers concerning the use of IOUS in brain tumor surgery, including gliomas. IOUS exerts a notable attraction due to its low cost, minimal interruption of the operational flow, and lack of radiation exposure. Our literature review shows that increasing the use of ultrasound in brain tumors allows more radical resections, thus giving rise to increases in survival. Keywords: intraoperative ultrasound; IOUS; brain tumor; glioma surgery 1. Introduction Maximal safe resection represents the gold standard for surgery of malignant brain tumors: gross total resection of the tumor while preserving the surrounding functional brain tissue is the main goal, since it is associated with longer survival and better patient quality of life [1]. This is particularly true for gliomas, the most common primary malignant brain tumors whose pathogenesis is still unknown [2,3]. Concerning gross total resection, accurate localization and precise delineation of the tumor margins are required in order to avoid devastating lesions on nervous structures [4]. Frame-based and frameless stereotactic preoperative data-based techniques, also known as neuronavigation systems, are routinely used to help surgeons plan the site of craniotomy and identify critical neural structures. Brain Sci. 2018, 8, 202; doi:10.3390/brainsci8110202 www.mdpi.com/journal/brainsci Brain Sci. 2018, 8, 202 2 of 16 Unfortunately, these systems have inherent problems related to loss of accuracy resulting from unpredictable distortions, shifts, and deformations after craniotomy and tissue removal. Therefore, neuronavigation is not a true real-time system: the accuracy is maximal before the craniotomy and decreases significantly while progressing through surgical manipulation. It is due to two main factors: the first is “brain shift” caused by the effect of gravity on the brain, brain swelling, as well as the drainage of cerebrospinal fluid (CSF); the second factor is the deformation of brain parenchyma caused by surgical maneuvers and tumor removal [5]. Several surgical techniques and technological innovations have been recently introduced to help the surgeon achieve the maximal safe resection of the tumor while reducing the odds of post-operative complications [6,7]. Some examples are represented by the intraoperative use of neurophysiological monitoring and the use of the awake surgery technique. Moreover, in recent years, new methods, including intraoperative diagnostic imaging (Intra-Operative Magnetic Resonance-IOMR, Intra-Operative Computed Tomography-IOCT, Intra-Operative Ultrasound-IOUS) and dyes (fluorescence) have become relevant in neuro-oncological surgery, allowing for a more radical and safer tumor resection [8]. Some of these innovations, such as the IOMR, are expensive and not available in every neurosurgical centre. Therefore, in the last few years, great attention has been paid to the possible intraoperative use of ultrasound (IOUS) guidance for brain tumor surgery. IOUS is not a new technology, but it is accurate in distinguishing tumor from normal parenchyma, and allows a real-time intraoperative visualization. IOUS is cheap, easily repeatable, safe for the patient, potentially available in all neurosurgical centres. As early as in the 1970s, B-mode ultrasound (US) was introduced into the operating room. However, it was the development and application of real-time grey-scale US imaging technology that really provided an impetus to IOUS. The use of ultrasound to achieve maximally safe resection of brain tumors has been implemented since the 1980s [9]. In the pre-MR era, US (2-dimensional (2D) B-mode grey-scale US) imaging became a routinely-used adjunct in the neurosurgical operating room. With the introduction of MR imaging (MRI), an entirely new and vivid “image” of intracranial anatomy was unveiled. Neurosurgeons rapidly adopted MRI into routine clinical diagnostic practice. The development of stereotactic localization and navigation technology in the late 1980s ushered in the era of “computer-assisted surgery.” In 1992, Le Roux et al. noted that the majority of brain tumors, including low-grade gliomas, were visible with intraoperative ultrasound [10]. The Norwegian Group first employed IOUS in 1997, and demonstrated the utility of real-time intraoperative ultrasound to identify tumors and facilitate resection [11]. In the contemporary era, IOUS imaging is used in neuro-oncological surgery to investigate the spatiotemporal change of the tumor morphology during the operation. B-mode is the most commonly-used modality [12]. The solid part of the tumor appears hyperechogenic compared to the surrounding cerebral parenchyma, while cysts appear hypoechoic. The presence of blood or calcifications, which can often occur in the tumor mass, alters the echogenicity of the lesions; therefore, the procedure should be led by an experienced operator. Many authors described the ultrasonographic characteristics of some tumors by comparing them with conventional imaging studies, such as Computed Tomography (CT) and MR [13–17]. After the craniotomy is performed, the utility of ultrasound is evident in different phases of surgery. IOUS help to plan the opening of the dura and to centre the corticectomy. In the following phases, IOUS allows identification of the tumor margins, thus helping for a maximally radical resection. The main advantage of IOUS consists of obtaining a real-time scan: this can be repeated as many times as necessary, in order to overcome the errors produced by brain shift [18]. It also avoids the cost and the duration of other intraoperative techniques. Its main limitations are spatial resolution, width and orientation of the field of view (different from the standard orthogonal planes of CT and MRI), and scan quality, which are operator dependent. Even if US are widely adopted to evaluate cerebral blood flow through transcranial Doppler [19], Neurosurgeons are not confident with a technique that provides brain images oriented on infinite axis Brain Sci. 2018, 8, 202 3 of 16 (not only the standard axial, sagittal, and coronal plane), and the ability to “understand and interpret” anatomic details displayed on the screen requires significant training and experience. Since most neurosurgeons do not receive specific US training, and US is not yet a standard diagnostic and intraoperative tool for cerebral lesions, there is an inherent difficulty in interpreting IOUS imaging and in correctly setting up the machine; these two factors both lead to a longer learning curve. Real-time intraoperative fusion of preoperative MRI/CT scans and intraoperative ultrasounds is a highly desirable solution to overcome the above-mentioned limitations. Moreover, the greatest limitation of US is their limited ability to penetrate the skull; therefore, the most important application of IOUS in brain tumor surgery occurs after performing the craniotomy. Since IOUS has gained great popularity in recent years, the purpose of this study is to review the current literature to evaluate the role of IOUS in gliomas surgery and to outline specific strategies to maximize its efficacy. 2. Literature Research and Findings We performed a literature research through the Pubmed database by selecting each article focused on the use of IOUS in brain tumor surgery, and in particular, in glioma surgery, published in the last 15 years (from 2003 to 2018). We performed a query using the following combinations of the Medical Subject Headings (MESH) terms: ultrasound, intraoperative ultrasound, intraoperative image guidance, glioma surgery, brain tumors surgery, high-grade glioma surgery, low-grade glioma surgery, alternating all these terms in various combinations. We included all the studies with information on the diagnosis, the extent of the resection, and the postoperative evaluation of the degree of resection by neuroimaging. We excluded all papers written in languages other than English and all studies with incomplete data. After the identification of all articles that met the inclusion criteria, and after removing duplicates, we selected 39 papers dealing with the use of IOUS in brain tumor surgery, including gliomas. Twenty-one studies were prospective and 18 were retrospectives. In particular, we focused on the usefulness of ultrasound in the surgery of cerebral gliomas. 2264 patients were included in our review: 1650 patients with a histologic diagnosis of brain glioma and 522 patients with a non-glial tumor. We did not find any information about the histological report of 94 patients [20]. We paid special attention to the evaluation of the postoperative extent of resection (EOR), and in particular, to the achievement of gross-total resection (GTR), defined as the absence of any residual enhancement on postoperative volumetric-enhanced MRI performed within 72 h after surgical resection. Another important point was the analysis we performed of the usefulness of IOUS used with or without other neuroimaging techniques. The results of our literature review are briefly summarized in Table 1 (see Section 3). 3. The Use of IOUS in Brain Glioma Surgery The use of IOUS seems to have significantly increased the GTR rate achieved in brain tumors/gliomas surgery. As regard intraoperative visualisation of the tumor and its residuals, the effectiveness of IOUS has been documented in a series of 192 HGG patients, in which the combination of neuronavigation and IOUS was also related to increased overall survival [21]. Erdogan et al. [22], in a prospective study of 32 patients, documented a good level of agreement between intraoperative ultrasonography and postoperative contrast-enhanced MRI in detecting tumor residue; they concluded that the IOUS produces results similar to those of MRI, and therefore, can be used to maximize tumor resection. Brain Sci. 2018, 8, 202 4 of 16 Regarding the reliability of intraoperative ultrasound images, the best 2-D ultrasound images are obtained with a linear array probe (linear array intra-operative ultrasound, lioUS) (Philips, Amsterdam, The Netherlands), which is quite large and difficult to manoeuvre into a scalp window. For this reason, in a series of 13 LGG patients, Coburger et al. [23] compared a conventional phased array probe (conventional intra-operative ultrasound, cioUS) (Philips, Amsterdam, The Netherlands) with a new, smaller linear array probe. They observed that the lioUS images significantly corresponded to the intra-operative MRI (iMRI), and that it was unlikely that the cioUS was less accurate. The sensitivity was very high in the evaluation of the tumor residue for iMRI (83%), followed by lioUS (79%). The sensitivity for cioUS was lower (21%). On the other hand, in a series of 15 HGG patients, lioUS showed a significantly higher detection rate for residual tumors than cioUS, allowing a GTR of 73.3% [24]. Moreover, the authors found that the images produced by lioUS have few artefacts, better definition, and a more accurate visualization of the residual tumor compared with cioUS. Lothes et al. [25] in a prospective study on 11 patients with low-grade glioma (LGG) compared intraoperative MRI with conventional low-frequency intraoperative ultrasound (cioUS) and high-frequency linear array intraoperative ultrasound (lioUS). They concluded that although iMRI remains the method of choice, lioUS has been shown to be beneficial in a combined setup. Evaluation of lioUS was significantly superior to cioUS in most indications except for subcortical lesion. Proceeding further, the implementation of 3-D US should overcome some limitations of the 2-D US by producing a volumetric image. 3-D US showed 71% sensitivity in detecting residual tumors during the resection of cerebellar lesions, in a series of 16 patients who underwent resection of intracerebral lesions. However, the sample was too small to be conclusive [26]. Unsgaard et al. [27], in a study of 28 patients, analysed data of a 3-D IOUS-based intraoperative imaging and navigation system, comparing its usefulness in brain glioma and metastasis surgery. The results indicated that 3D US images give a good delineation of both metastases and the solid part of gliomas, thus providing a reliable guidance in tumor surgery before starting the resection. In larger series, it has been demonstrated that the use of 3-D navigable intraoperative ultrasound system may allow the surgeon to reach a 67% GTR of brain tumors [28]. Serra et al. [29], in a retrospective study of 22 patients, demonstrated that high frequency ultrasound (hfioUS) allows accurate detection of the tumor and detailed discrimination between normal, pathological, and oedematous tissue in all 22 cases, obtaining a GTR of 95.5%. Sweeney et al. [30], in a retrospective review of 260 patients, have shown that the use of IOUS might help to achieve a more successful GTR (81%) in both adult and paediatric neurosurgical patients. Moreover, a combination of IOUS with other intraoperative imaging modalities (such as fluorescent tissue enhancement) provided further increases of GTR in high-grade glioma surgery. In our department, fluorescein sodium has been used as an adjunct in glioma resection since September 2015. We recently reported a resection >95% in 83% (n = 39) of patients who underwent fluorescence-guided surgery [31]. In recent years, our preliminary experience demonstrates that the combined use of fluorescence dyeing with B-mode ultrasonography and contrast-enhanced ultrasound (CEUS) techniques helps the surgeon recognize the boundary between normal brain parenchyma and tumor. In a technical note that is not yet published, we described the removal of high-grade gliomas under fluorescence dye, B-mode ultrasonoghraphy, and CEUS technique in five patients (3 males, 2 females; mean age 55.2 years, range 36–68 years) who underwent craniotomies for intra-axial lesions, which were suspected for high-grade gliomas on preoperative MRI. According to our experience, we confirm the utility of IOUS in the initial steps of surgery and the central role of fluorescence in achieving a GTR. Ultrasound-based neuronavigation provides intraoperative support in planning the craniotomy, localizing the lesion, choosing the best point for the corticectomy (especially if deep tumors), as well as for resection control checking the boundaries structures. On the other hand, fluorescence-guided surgery appears to be a surface phenomenon; it is very useful to identify and demarcate the tumoral tissue once it is sufficiently exposed; according to our opinion, fluorescein sodium appears to be more important in the latest steps of resection. In addition, we show the Brain Sci. 2018, 8, 202 5 of 16 effectiveness, safety, accuracy, and feasibility of ultrasound-based fluorescein-guided surgery, which is less time- and cost-consuming. With regards to the prognosis of patients undergoing surgery for brain gliomas, it has been demonstrated that IOUS improves the prevalence of GTR and significantly increases 1- and 2-year overall survival [32]. These results may be due to the detection of residual tumors with high specificity by the use of IOUS, and hence, to the improvement of the resection rate [11]. In a series of 35 patients, Chacko et al. [33] reported that IOUS had a positive predictive value of 0.84, and Rygh et al. [34] showed similar results in a retrospective work of 19 high-grade glioma (HGG) (specificity and sensitivity of 95%). They reported a considerable decrease of specificity (up to 42%) during the resection, while the sensitivity remained as high as 87%. Nevertheless, after the resection, the sensitivity reaches a low value (26%), and the specificity has a value equal to 88%. Neuronavigation has undoubtedly provided great advantage in brain tumor surgery by improving surgical accuracy and safety. It is based on MRI or CT scans, which should be performed within 24 h prior to surgery. Unfortunately, after performing the craniotomy, changes in brain morphology may occur compared to preoperative examinations because of the brain shift [18], which can lead to inaccuracies of between 5 and 10 mm [35]. These changes also become even more important as the tumor is debulked. As some studies highlight, intraoperative ultrasound may allow us to overcome the limit of anatomic distortion due to brain shift and tumor debulking [36]. In this regard, in a series of 67 patients, Prada et al. demonstrated that brain shift distortion may be corrected by the fusion of images between intraoperative ultrasound and preoperative magnetic resonance using neuro-navigation systems [37,38]. They have concluded that intraoperative US imaging combined with neuro-navigator is reliable, accurate, and easy to use, allowing a continuous real-time feedback without interrupting surgery. With regards to tumor pathological characterisation, contrast-enhanced ultrasound (CEUS) is a valuable tool for visualizing vascularization patterns that often correlates with lesion histology. Prada et al. [39], in a series of 71 patients, found that intra-operative CEUS (iCEUS) allows for the characterization of different brain neoplasms. Furthermore, iCEUS shows afferent and efferent vessels and hyperperfused areas, thus possibly modifying the intraoperative surgical strategy. Arlt et al. [40], in a retrospective study of 50 patients, examined the advantages of using of contrast-enhanced and three-dimensional reconstructed ultra-sound (3D CEUS) in brain tumors. The authors found that three-dimensional CEUS is a useful intraoperative imaging tool, especially for brain glioma surgery. The results of our literature review are briefly summarized in Table 1. Brain Sci. 2018, 8, 202 6 of 16 Table 1. Summary of the reviewed literature. Author and Study Design N Pts Tumor Grade GTR Sen % Sp% Primary Endpoint Results Year The comparison between the IOUS findings and the post-op CT scan To evaluate the usefulness of findings in the 28 pts with intra-operative ultrasound (IOUS) in parenchymal tumors; 5 patients HGG (22) Chacko et al., Clinical Article the detection of residual tumor who had received prior radiation 35 LGG (11) 12/35 (34.29%) / / 2003 [33] (Prospective Study) compared with a postoperative and 2 inflammatory granulomas Others (2) computed tomogram and with were excluded from the analysis, histo-pathology. there was concordance between the IOUS findings and the post-op CT scan in 23 of 28 cases. Steno et al., Case Report 1 LGG (1) 97% / / / / 2012 [41] (Retrospective) 48/107 (45%) Vs. To examine if the introduction of 3D 34/45 (43%) Patient survival increased after Sæther et al., ultrasound and neuronavigation (i.e., Retrospective study 192 HGG (192) operated before / / introduction of intraoperative 2012 [21] the SonoWand®system) may have had the introduction ultrasound and neuronavigation. an impact on overall survival. of intraoperative ultrasound Correlation with postoperative To determine the inter-method MRI revealed a good level of HHG 15 (GBM (8) agreement between intraoperative agreement (9 cases with agreement Erdogan et al., Original article Anaplastic astrocytoma (4) ultrasono- graphy and postoperative 32 59.38% / / on positive residue and 19 cases 2005 [22] (Prospective Study) Oligodendroglioma (3)) contrast-enhanced magnetic resonance with agreement on negative Others (17) imaging (MRI) in detecting tumor residue, no agree- ment in four residue. cases) lioUS can be used as a safe and To evaluate the use of navigated lioUS precise tool for intracranial image Coburger et al., (linear array intraoperative guided resection control of GBM. Prospective study 15 HHG 15 (GBM) 73.3% / / 2014 [24] ultrasound) as a resection control in It shows a significant higher glioblastoma surgery. detection rate of residual tumor compared to conventional cioUS. To assess the practical utility of 3D The navigable 3D US system is a navigable US system and its impact on Clinical Article HGG (51) very useful intraoperative image Moiyadi et al., intraoperative decisions (retrospective 90 LGG (17) 67% guidance tool in neuro-oncology, 2013 [28] during cerebral glioma surgery and study) Others (22) often facilitating better and radical analyze the extent of resection resections. achieved in malignant gliomas. To test the feasibility of navigation based on ultrasound navigation only Neuronavigation based solely on HHG 6 (GBM) and analyze whether intraoperative intraoperative ultrasound is PeredoHarvey Original article LGG 3 imaging could substitute regular feasible and may increase surgical 18 85.6% / / et al., 2012 [42] (Prospective Study) (Oligodendroglioma) navigation for lesion localization for safety when preoperative Others 9 biopsies or resection and whether neuronavigational image is not intraoperative imaging in this system feasible or unavailable. allowed resection control. Brain Sci. 2018, 8, 202 7 of 16 Table 1. Cont. Author and Study Design N Pts Tumor Grade GTR Sen % Sp% Primary Endpoint Results Year The hfioUS probe allowed in this To demonstrate the utility of study a precise detection of the Original article intraoperative use of high frequency Serra et al., HGG 14 tumor and a de- tailed (Retrospective 22 95.5% / / ultra- sound (hfioUS) in maximizing 2012 [29] Others 8 discrimination between normal, study) the extent of resection (EOR) of patholog- ical and edematous intracerebral high-grade tumors. tissue in all 22 cases. To investigate the value of intraoperative sonography in The use of intraoperative Wang et al., HGG (79) improving the prevalence of total ultrasound improves the Prospective Study 137 81.8% / / 2012 [32] LGG (58) tumor resection and the survival time prevalence of total tumor resection of patients who underwent resection and the patient’s survival time. of cerebral gliomas. The IOUS is a very useful tool in Original Article 77 in 75 pts (one intraoperative localization and (retrospective pts was operated delineation of lesions and Moiyadi et al., 41 glial tumors To evaluate the utility of the IOUS in analysis of three times) (69 76% / / planning various stages of tumor 2011 [20] 36 others an objective manner. prospectively brain tumors and resection. It is easy, convenient, collected data) 8 spinal timors) reliable, widely available, and above all a cost-effective tool. To test if intraoperative 3-D 3-D ultrasound is especially Rohde et al., Prospective study 16 / 80.7% 71% 60% ultrasound likewise can be used for helpful for detection of overseen 2011 [26] resection control. brain tumor tissue. To evaluate resection grades and The study suggest that better clinical outcome in surgery of ultrasound facilitates better high-grade gliomas, operated with use surgery and also clearly Clinical article Solheim et al., of the SonoWand system. demonstrates that, in terms of (Retrospective 142 HGG 142 74.5% / / 2010 [43] To explore the impact of ultrasound surgical results, the selection of Study) image quality and relationships patients seems to be much more between patient selection and surgical important than the selection of results. surgical tools. This study shows that while ultrasound is highly accurate in delineating GBM before resection, To compare the ability of navigated 3D but it appears less accurate during Clinical Article ultrasound to distinguish tumor and Rygh et al., and after resection. During (Retrospective 19 HGG 19 76.9% 95% 95% normal brain tissue at the tumor 2008 [34] resection, there seems to be some Study) border zone in subsequent phases of overestimation of tumor, while resection. small tumor remnants and infiltrated tissue in the cavity wall is underestimated after resection. To prove the concept of 3D ultrasound with regard to technical effects and The introduction of 3D ultrasound human impact. This includes has increased the value of measurement of fusion accuracy, the neuronavigation substantially, Lindner et al., Original Article HGG 9 23 77% / / extent of tumor resection and the making it possible to update 2006 [36] (Prospective Study) Others 14 suitability for detection and capture of several times during surgery and intraoperative brain shift as well as a minimize the problem of brain protocol of operative handling as shift. described by different neurosurgeons. Brain Sci. 2018, 8, 202 8 of 16 Table 1. Cont. Author and Study Design N Pts Tumor Grade GTR Sen % Sp% Primary Endpoint Results Year The reliability of IOUS depends on tumor type. It is beneficial to use IOUS for the resection of To evaluate intra-operative ultrasound Renner et al., HGG 22 metastases and a few high-grade Prospective Study 36 76.2% / / (IOUS) as a tool of resection control 2005 [44] Others 14 gliomas. Concerning the after brain tumor surgery. volumetric accuracy, the value of IOUS is worse than its value of navigation and resection control. Low-grade Low-grade astrocytoma: astrocytoma: 72% 100% To investigate whether the images Reformatted images from 3D US Anaplastic Anaplastic from the 3D US imaging system HGG 15 volumes give a good delineation of Unsgaard et al., Clinical Article astrocytoma: astrocytoma: provide the surgeon with sufficient 28 LGG 7 76.6% metastases and the solid part of 2005 [27] (Prospective Study) 86% 75% information to do a safe delineation of Others 6 gliomas before starting the Glioblastoma: Glioblastoma: the margins of gliomas and metastases resection. 88% 56% during the operation. Metastasis: Metastasis: 100% 100% During surgery performed on To investigate whether (IOUS) helped relapsed, irradiated, high-grade the surgeon navigate towards the gliomas, IOUS provided a reliable tumor as seen in preoperative method of navigating towards the Mursc et al., Original Article 25 HGG 25 / / / magnetic resonance imaging and core of the tumor. At the borders, 2017 [45] (Prospective Study) whether IOUS was able to distinguish it did not reliably distinguish between tumor margins and the between remnants or tumor-free surrounding tissue. tissue, but hypoechoic areas seldom contained tumor tissue. The use of IOUS might help achieve a more successful GTR in To expand on results from the both adult and pediatric previous study in order to provide neurosurgical patients and might Clinical Article Glioma 50.8% Glioma 100% Sweeney et al., HGG 110 more evidence on the usage of IOUS in improve surgical outcomes. (Retrospective 260 81% Metastatic Metastatic 2018 [30] Others 150 the determination of gross-total It might be useful to study the review) tumors 47.4% tumors 100% resection (GTR) in both adult and combined efficacy of IOUS and pediatric patients with brain tumors. intraoperative fluorescence imaging in achieving a higher GTR rate in invasive CNS tumor cases. IOUS was a valuable tool in localizing lesions, selecting the proper approach, con- trolling the Original Article Sun et al, 2007 Gliomas 68 To evaluate the value of IOUS extent of resection and displaying (Retrospective 110 / / / [46] Others 42 in neurological operations. the distribution of vasculature. Study) IOUS can provide more reliable safe guard for minimally invasive neurosurgery. Brain Sci. 2018, 8, 202 9 of 16 Table 1. Cont. Author and Study Design N Pts Tumor Grade GTR Sen % Sp% Primary Endpoint Results Year The use of IOUS may play an important role in achieving a Clinical Article HGG 5 To evaluate the correlation of extent of greater extent of resection by Smith et al., 61.1% (Retrospective 62 LGG 34 71% resection between IOUS and providing real-time information on 2016 [47] Review) Others 23 postoperative MRI. tumor volume and location in the setting of brain shift throughout the course of an operation. To evaluate the ideal application and Although iMRI remains the typical interactions of intraoperative imaging method of choice, lioUS MRI (iMRI), conventional has shown to be beneficial in a Lothes et al., Original Article low-frequency intraoperative 11 LGG 11 / / / combined setup. Evaluation of 2016 [25] (Prospective Study) ultrasound (cioUS), and lioUS was significantly superior to high-frequency linear array cioUS in most indications except intraoperative ultrasound (lioUS) to for subcortical lesions. optimize surgical workflow. Combining awake surgery with 3DUS is feasible and beneficial. It To emphasize the convenience and does not entail any additional Original Article Moiyadi et al., HGG 17 feasibility of the use of navigable surgical workflow modification or (Retrospective 22 78% / / 2017 [48] LGG 5 three-dimensional US with awake patient discomfort. This combined Study) surgery for gliomas. modality intraoperative monitoring can be beneficial for eloquent region tumors. Integration of probabilistic fiber tracking and navigated ultrasonography into To assess whether the combined use of intraoperative neuro-navigation navigated ultrasonography with the facilitated anatomic orientation Original Article integration of FMRIB Software Library Rueckriegel et al., during glioma resection. (Retrospective 11 / 27.27% / / based probabilistic fiber tracking into 2016 [49] Combination with navigated Study) neuronavigations technically feasible ultrasonography provided a and achievable in the preoperative three-dimensional estimation of and intraoperative workflow. intra-operative brain shift and, therefore, improved the reliability of neuronavigation. CEUS is extremely specific in the identification of residual tumor. To assess the capability of The ability of CEUS to distinguish contrast-enhanced ultrasound (CEUS) between tumor and artifacts or Prada et al., to identify residual tumor mass during normal brain on B-mode is based Prospective study 10 HGG 10 / / / 2016 [50] glioblastoma multiforme (GBM) on its capacity to show the surgery, to increase the extent of vascularization degree. Therefore, resection. CEUS can play a decisive role in the process of maximizing GBM resection. Brain Sci. 2018, 8, 202 10 of 16 Table 1. Cont. Author and Study Design N Pts Tumor Grade GTR Sen % Sp% Primary Endpoint Results Year Intraoperative US should be considered as a really valuable tool To evaluate the role of intraoperative in guiding the surgeon’s LGG 14 US imaging Prada et al., hands in brain lesion removal, Prospective Study 58 HGG 27 / / / Associated whit conventional 2015 [38] providing real-time feedback and Others 17 neuronavigation in brain tumor allowing the operator to modify surgery. the surgical strategy based on the real intraoperative situation. iCEUS adds valuable anatomic and biological information such as To evaluate and describe different vascularization, microcirculation, brain pathologies by means of and tissue perfusion dynamic, intraoperative contrast-enhanced which will possibly provide ultrasound further insights into the pathology Prospective Study LGG 16 (iCEUS) compared with preliminary of brain tumors. It might help the Prada et al., (in an off -label 71 HGG 37 / / / baseline US and preoperative MRI. surgeon to tailor the approach to 2014 [39] setting) Others 18 This technique, being dynamic and the lesion, highlighting the lesion, continuous, allows a real-time direct clarifying between tumor and view of the vascularization and flow edematous brain tissue, and distribution patterns of different types showing afferent and efferent of neurosurgical lesions. vessels and hyperperfused areas, thus possibly modifying the intraoperative surgical strategy. CEUS is a fast, safe, dynamic, To perform the first characterization of real-time, and economic tool that Prospective Study Prada et al., LGG 22 cerebral glioma using CEUS and to might be helpful during surgery in (in an off -label 69 / / / 2014 [51] HGG 47 possibly achieve an intraoperative differentiating malignant and setting) differentiation of different gliomas. benign gliomas and refining surgical strategy. Intraoperative US imaging combined with neuro-navigator To demonstrate the usefulness of US represents a major innovation in Prada et al., intraoperative use in conjunction with Prospective study 67 / / / / neurosurgery; it is reliable, 2014 [37] the navigation system as a guiding accurate, easy to use, permitting a tool in brain tumor surgery. continuous real-time feedback without interrupting surgery. US was highly sensitive in detecting all types of pathology, was safe and precise in planning trajectories to intraparenchymal Original Artile HGG 62 HGG 46.77% To assess the utility of routine use of lesions and was accurate in Policicchio et al., (Retrospective 162 LGG 9 LGG 55.56% / / iUS during various types of checking extent of resection in 2018 [52] Review) Others 91 Metastases 86.67% intracranial surgery. more than 80% of cases. iUS is a versatile and feasible tool; it could improve safety and its use may be considered in routine intracranial surgery. Brain Sci. 2018, 8, 202 11 of 16 Table 1. Cont. Author and Study Design N Pts Tumor Grade GTR Sen % Sp% Primary Endpoint Results Year Intraoperative ultrasound is an 34 (15 pts excellent tool in localizing low To evaluate the importance of Petridis et al., ultrasound was grade gliomas intraoperatively. It Retrospective Study LGG 34 17.6% / / intraoperative diagnostic ultrasound 2015 [53] used and in 19 is an inexpensive, real time for localization of low-grade gliomas. not). neuronavigational tool, which overcomes brain shift. To analyze the impact of OS and PFS were longer in patients intraoperative resection control Original article that had a GTR using ioUS (either Neidert et al., modalities on over- all survival (OS) (Retrospective 76 HGG 76 / / / ioUS alone or ioUS in combination 2016 [54] and progression-free survival (PFS) Study) with ioMRI) compared to those following gross total resection (GTR) patients without ioUS. of glioblastoma. The results of this study demonstrate that 3D ultrasound To evaluate the effectiveness of can be effectively used as a 111 HGG 75 Navigated 3D ultrasound as a novel stand-alone navigation modality Moiyadi et al., Retrospective Study (81 with US, LGG 12 53% / / intraoperative imaging adjunct during the resection of brain 2016 [55] 30without US) Others 24 permitting quick real-time updates to tumors. The ability to provide facilitate tumor resection repeated, high-quality intraoperative updates is useful for guiding resection. iCEUS has potential for safe, real-time, dynamic contrast-based imaging for routine use in neurooncological surgery and image-guided biopsy. ICEUS To provide further clinical data on the eliminates the effect of anatomical HGG 1 versatile application of Intraoperative Lekht et al., distortions associated with Retrospective Study 5 LGG 1 / / / contrast-enhanced ultrasound 2016 [56] standard neuronavigation and Others 3 (iCEUS) through a technical note and provides quantitative perfusion illustrative case series. data in real time, which may hold major implications for intraoperative diagnosis, tissue differentiation, and quantification of extent of resection. To evaluate the usefulness of the use US monitoring with SMI images in of the latest innovative imaging the gray scale mode is a pioneering Case Report HGG 5 Ishikawa et al., technique for detecting very low-flow monitoring technique to recognize (Retrospective 15 LGG 2 / / / 2017 [57] components, Superb Microvascular tumor vessels and tumor margins Study) Others 8 Imaging (SMI), with US during brain and to differentiate tumor from tumor surgery surrounding healthy tissue. To assess histopathological basis of All of the assessed established imaging results of intraoperative imaging techniques detect Coburger et al., magnetic resonance imaging (iMRI), infiltrating tumor only to a certain Prospective Study 33 HGG 33 / 80% 100% 2017 [58] 5-aminolevulinic acid (5-ALA), and extent. Only 5-ALA showed a linear array intraoperative significant correlation with ultrasound (lioUS). histopathological findings. Brain Sci. 2018, 8, 202 12 of 16 Table 1. Cont. Author and Study Design N Pts Tumor Grade GTR Sen % Sp% Primary Endpoint Results Year Intraoperative resection control in To evaluate LGGs using the accuracy of linear array ultrasound lioUS reaches a degree of accuracy Coburger et al., Clinical Article in comparison to close to iMRI. Test results of lioUS 13 LGG 13 / 79% 67% 2015 [23] (Prospective Study) conventional intraoperative are superior to cioUS. cioUS often ultrasound (cioUS) and intraoperative fails to discriminate solid tumors high-field MRI (iMRI). from “normal” brain tissue during resection control. Tumor detection using a lioUS is significantly superior to cioUS. Overall test Original Article To evaluate sensitivity and specificity performance in lioUS is Coburger et al., (prospective 20 HGG 20 / 76% 58% of lioUS to detect residual tumor comparable with results of iMRI, 2015 [59] non-randomized in patients harboring a glioblastoma. while, the latter has a higher study) specificity and a significantly lower sensitivity in comparison with lioUS. To investigate the value of Intraoperative CEUS could intraoperative contrast enhanced help in determining boundary of ultrasound (CEUS) for evaluating the peritumoral brain edema of Cheng et al., Clinical Study HGG 50 88 / / / grade of glioma and the correlation glioma. Intraoperative CEUS 2016 [60] (Prospective Study) LGG 38 between microvessel density (MVD) parameters in cerebral gliomas and vascular endothelial growth factor could indirectly reflect the (VEGF). information of MVD and VEGF. Three-dimensional CEUS is a reliable intraoperative imaging modality and could improve imaging quality. Ninety percent of To examine contrast-enhanced and the high-grade gliomas (HGG, three-dimensional reconstructed ultra- glioblastoma and astrocytoma sound (3D CEUS) in brain tumor grade III) showed high contrast HGG 23 surgery regarding the up-take of uptake with an improved imaging Arlt et al., Clinical Article 50 LGG 6 GBM: 62% / / contrast agent pre- and post-tumor quality in more than 50%. Gross 2016 [40] (Prospective Study) Others 21 resection, imaging quality and in total resection and incomplete comparison, with postoperative resection of glioblastoma were magnetic resonance imaging in adequately highlighted by 3D different tumor entities. CEUS intraoperatively. The application of US contrast agent could be a helpful imaging tool, especially for resection control in glioblastoma surgery. Brain Sci. 2018, 8, 202 13 of 16 4. Conclusions The main objective in brain tumor surgery is to obtain a radical resection with minimal morbidity, as radical removal has been demonstrated to be a main factor affecting overall survival. The advent of neuronavigation has certainly brought significant advantages in brain tumor surgery, allowing identification of the lesion and its margins during the resection, but there is the great limitation of anatomic distortion after craniotomy. Intraoperative ultrasound has allowed us to overcome this limit. Furthermore, IOUS exerts a notable attraction due to the low cost, minimal interruption of the operative flow, and lack of radiation exposure. In experienced hands, sonographic features can help differentiate low-grade gliomas, which can exhibit calcifications and mild hyperechogenicity from high-grade gliomas, which can show necrotic degeneration [61]. Our literature review shows that the increasing use of ultrasound in brain tumors may allow more radical resections, thereby increasing overall survival. The studies analysed in our review show a great correlation between postoperative MRI and intraoperative ultrasound, especially for gliomas and metastases. Moreover, the lioUS appears to provide higher quality images compared to the cioUS, particularly concerning the visualization of the tumor residual. Contrast-enhanced ultrasound (CEUS) allows for the evaluation of the tumor vasculature, thus suggesting the histological diagnosis. In conclusion, the combined use of IOUS and neuronavigation may facilitate tumor removal, enhancing more radical resection, and thus improving patient overall survival and quality of life. 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Brain SciencesPubmed Central

Published: Nov 19, 2018

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