Imaging and Adjuvant Therapies

**89**

**Chapter 5**

**Abstract**

**1. Introduction**

and emerging settings.

Oncological, Vascular, and Spinal

Contrast-enhanced ultrasound (CEUS) is a real-time, feasible technique. Both intraoperatively and bedside, it satisfies the need for serial assessment and easy performability. Initially employed in neuro-oncology, it has recently overcome this first application. The chapter aims to give a comprehensive view of its use in oncological, vascular, and spinal neurosurgery. CEUS versatility across the aforementioned areas is analyzed, underlining its complementarity to other well-settled imaging techniques. Its major oncological (both cerebral and spinal) and vascular (including aneurysms, AVMs, dAVFs, carotid plaques, and stroke) application and state of the art are discussed. The chapter is focused on reporting CEUS advantages and disadvantages, giving an insight to future perspectives and applications.

**Keywords:** contrast-enhanced ultrasound, CEUS, ultrasonography, brain tumors,

Neurosurgery is experiencing the rediscovery of intraoperative ultrasound (ioUS). In particular, growing enthusiasm was shown after the introduction of contrast-enhanced ultrasound (CEUS) in the field of neuro-oncology, following the leads of other surgeries such as thyroid and hepatic surgery. Besides this pioneering use in brain and spinal oncology, other applications including stroke, brain traumatology, vascular neurosurgery, and peripheral nerve surgery [1–9] were reported. Those experiences in literature proved the integration of ioUS and CEUS to be a valuable tool in different neurosurgical scenarios: it provides a truly real-time, feasible, and modern intraoperative imaging technique, allowing the assessment of unexposed, hidden, anatomical, and pathological structures [10] in both traditional

Standard B-mode ultrasound has been presented since several years in many neurosurgical operating rooms: it represented de facto one of the first tools to study anatomy through unexposed, hidden, parenchymal tissues. For this reason, it is incorrect to classify ioUS/CEUS use as an innovation, being it more a rediscovery:

spinal tumors, intraoperative imaging, neuro-oncology

**2. CEUS in neurosurgery: where do we stand?**

Uses of Contrast-Enhanced

Ultrasound in Neurosurgery

*Giuseppe Maria Della Pepa*

#### **Chapter 5**

## Oncological, Vascular, and Spinal Uses of Contrast-Enhanced Ultrasound in Neurosurgery

*Giuseppe Maria Della Pepa*

#### **Abstract**

Contrast-enhanced ultrasound (CEUS) is a real-time, feasible technique. Both intraoperatively and bedside, it satisfies the need for serial assessment and easy performability. Initially employed in neuro-oncology, it has recently overcome this first application. The chapter aims to give a comprehensive view of its use in oncological, vascular, and spinal neurosurgery. CEUS versatility across the aforementioned areas is analyzed, underlining its complementarity to other well-settled imaging techniques. Its major oncological (both cerebral and spinal) and vascular (including aneurysms, AVMs, dAVFs, carotid plaques, and stroke) application and state of the art are discussed. The chapter is focused on reporting CEUS advantages and disadvantages, giving an insight to future perspectives and applications.

**Keywords:** contrast-enhanced ultrasound, CEUS, ultrasonography, brain tumors, spinal tumors, intraoperative imaging, neuro-oncology

#### **1. Introduction**

Neurosurgery is experiencing the rediscovery of intraoperative ultrasound (ioUS). In particular, growing enthusiasm was shown after the introduction of contrast-enhanced ultrasound (CEUS) in the field of neuro-oncology, following the leads of other surgeries such as thyroid and hepatic surgery. Besides this pioneering use in brain and spinal oncology, other applications including stroke, brain traumatology, vascular neurosurgery, and peripheral nerve surgery [1–9] were reported.

Those experiences in literature proved the integration of ioUS and CEUS to be a valuable tool in different neurosurgical scenarios: it provides a truly real-time, feasible, and modern intraoperative imaging technique, allowing the assessment of unexposed, hidden, anatomical, and pathological structures [10] in both traditional and emerging settings.

#### **2. CEUS in neurosurgery: where do we stand?**

Standard B-mode ultrasound has been presented since several years in many neurosurgical operating rooms: it represented de facto one of the first tools to study anatomy through unexposed, hidden, parenchymal tissues. For this reason, it is incorrect to classify ioUS/CEUS use as an innovation, being it more a rediscovery:

ioUS has been employed in neurosurgery since the 1960s [11], and it granted intraoperative imaging and navigation well before more evolved technologies, such as intraoperative CT (iCT), intraoperative MRI (iMRI), indocyanine green video angiography (ICG-VA), and navigation, were broadly available [12–15]

Nonetheless, significant limitations of ioUS as a reliable and feasible application in neurosurgery were represented by both imaging interpretation, unfamiliar to neurosurgeons, and artifacts related to manipulation. A good evidence of this is that as surgical resection advances, the ioUS image quality decreases: due to surgically induced artifacts and edema, imaging interpretation becomes challenging [1]. Moreover, all information provided by ultrasound (US) relies on echogenicity of insonated structures: no dynamic information, such as overall vascularization, is given through standard B-mode ultrasonography.

Even though the aforementioned limitations could have prevented further research, major technological advancements in the US field, such as image fusion for navigation, CEUS, and elastosonography, have been developed; new applications in their usage in neurosurgery, although on a small scale, have constantly been achieved and reported in recent years [16–20].

Being capable of highlighting tumor tissue not relying on its echogenicity but on its vascularization, CEUS has been specifically found to be a versatile innovation. Introduced in other medical branches, such as hepatic oncological surgery, the technique is feasible in both diagnostic and intraoperative settings: it allows practitioners to differentiate between benign and malignant lesions, helps in localizing the target, and controls treatment efficacies [10, 19].

On the heel of these observations, CEUS intraoperative experiences have been borrowed to neurosurgery to overcome the strains of standard B-mode US imaging.

CEUS is a harmonic imaging modality that depicts the distribution of microbubble contrast agent in tissues. Thanks to their structure, sulfur hexafluoride-filled lipidic microbubbles cannot diffuse to the interstitial space, giving a representation of the vascular district only. The degree of contrast enhancement (CE) is a consequence of the density of the capillaries, which in turn is proportional to tissue activity [19, 21].

Microbubbles are visible through a contrast-specific algorithm that permits a real-time assessment of contrast enhancement, measurement of vascularity of focal lesions during different dynamic phases, and analysis of tissue perfusion; CEUS algorithm suppresses the linear US echo, thus producing a specific representation only of the microbubbles. In other words, images are a direct representation of vascularization and become independent from tissue echogenicity. Furthermore, microbubbles, being micron-sized, are not able to extravasate from vessels and behave as a purely intravascular contrast agent, allowing to study all vascular tree districts: arterial, venous, and capillary [19, 22]. On these bases, CEUS has been introduced in neurosurgery for the intraoperative visualization of brain tumors: it is a dynamic modality which permits to visualize them according to their degree of vascularization [1, 23].

This first application has led to the following use in a variety of neurosurgical fields. As shown in the herein presented review, a consistent literature has been published describing CEUS use in settings other than cerebral neuro-oncology, including spinal oncology, vascular neurosurgery (cerebral and spinal), TBI, and pediatric and peripheral nerve surgery.

Besides their undisputed value, traditional intraoperative imaging techniques (CT scan and MRI) have several limitations, including costs, temporary stop of surgical procedure, and time wasting. These important strains make iCT and iMRI hardly repeatable during surgery [12, 24].

**91**

[4, 8–10, 20].

**Figure 1.**

**3. Cerebral neuro-oncology**

in neurosurgery [28](**Figure 2**).

gliomas (HGGs).

*Oncological, Vascular, and Spinal Uses of Contrast-Enhanced Ultrasound in Neurosurgery*

Conversely, as demonstrated by several experiences, CEUS/ioUS is a feasible intraoperative imaging technique, as it is readily repeatable, dynamic, and inexpensive and provides a truly real-time dynamic visualization of anatomical characteristics and vascular patterns in several neurosurgical settings. Assessment is rapid, can be performed any time during surgery, and is independent of brain shift

*Diagrammatic representation of the fields of application of CEUS in neurosurgery.*

Besides, microbubbles do not only allow the visualization of high-definition intraoperative images after craniotomy but, as reported later, can enhance the resolution of intracranial arteries also in transcranial studies at bedside [25–27]. **Figure 1** summarizes the major fields of application of CEUS in neurosurgery.

The use of CEUS during neuro-oncological procedures has been recently included in the guidelines from the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB), representing a paradigm shift for the use of US

In comparison with other imaging modes, CEUS showed itself as a rapid, practical, and cost-effective technique, suggesting additional and alternative information about brain tumor vasculature and perfusion, being B-mode limited in providing only morphological information regarding the lesion. In their seminal study, Prada et al. [29] demonstrated how, once enhanced, the tumor is highlighted and reveals other specific characteristics of both low-grade gliomas (LGGs) and high-grade

LGGs show a mild, dotted CE with diffuse appearance and blurred margins. Arterial feeders are usually not identifiable, microbubble transit is regular and organized, and venous drainage is diffuse through numerous capillaries and consequently not discernible. Relying not on its echogenicity but upon vascularization, CEUS proved to be particularly valuable in differentiating oncological tissue from surrounding edema, thus helping in depicting the true limits of infiltration [30, 31]. HGGs have a high CE with a more nodular, nonhomogeneous appearance and fast perfusion patterns, with a rapid CE, marked by rapid arterial phase, very fast CE peak, and chaotic transit of microbubbles within the lesion. The arterial supply

*DOI: http://dx.doi.org/10.5772/intechopen.91320*

*Oncological, Vascular, and Spinal Uses of Contrast-Enhanced Ultrasound in Neurosurgery DOI: http://dx.doi.org/10.5772/intechopen.91320*

#### **Figure 1.**

*Neurosurgical Procedures - Innovative Approaches*

given through standard B-mode ultrasonography.

achieved and reported in recent years [16–20].

the target, and controls treatment efficacies [10, 19].

ioUS has been employed in neurosurgery since the 1960s [11], and it granted intraoperative imaging and navigation well before more evolved technologies, such as intraoperative CT (iCT), intraoperative MRI (iMRI), indocyanine green video

Nonetheless, significant limitations of ioUS as a reliable and feasible application in neurosurgery were represented by both imaging interpretation, unfamiliar to neurosurgeons, and artifacts related to manipulation. A good evidence of this is that as surgical resection advances, the ioUS image quality decreases: due to surgically induced artifacts and edema, imaging interpretation becomes challenging [1]. Moreover, all information provided by ultrasound (US) relies on echogenicity of insonated structures: no dynamic information, such as overall vascularization, is

Even though the aforementioned limitations could have prevented further research, major technological advancements in the US field, such as image fusion for navigation, CEUS, and elastosonography, have been developed; new applications in their usage in neurosurgery, although on a small scale, have constantly been

Being capable of highlighting tumor tissue not relying on its echogenicity but on its vascularization, CEUS has been specifically found to be a versatile innovation. Introduced in other medical branches, such as hepatic oncological surgery, the technique is feasible in both diagnostic and intraoperative settings: it allows practitioners to differentiate between benign and malignant lesions, helps in localizing

On the heel of these observations, CEUS intraoperative experiences have been borrowed to neurosurgery to overcome the strains of standard B-mode US

CEUS is a harmonic imaging modality that depicts the distribution of microbubble contrast agent in tissues. Thanks to their structure, sulfur hexafluoride-filled lipidic microbubbles cannot diffuse to the interstitial space, giving a representation of the vascular district only. The degree of contrast enhancement (CE) is a consequence of the density of the capillaries, which in turn is proportional to tissue

Microbubbles are visible through a contrast-specific algorithm that permits a real-time assessment of contrast enhancement, measurement of vascularity of focal lesions during different dynamic phases, and analysis of tissue perfusion; CEUS algorithm suppresses the linear US echo, thus producing a specific representation only of the microbubbles. In other words, images are a direct representation of vascularization and become independent from tissue echogenicity. Furthermore, microbubbles, being micron-sized, are not able to extravasate from vessels and behave as a purely intravascular contrast agent, allowing to study all vascular tree districts: arterial, venous, and capillary [19, 22]. On these bases, CEUS has been introduced in neurosurgery for the intraoperative visualization of brain tumors: it is a dynamic modality which permits to visualize them according to their degree of

This first application has led to the following use in a variety of neurosurgical fields. As shown in the herein presented review, a consistent literature has been published describing CEUS use in settings other than cerebral neuro-oncology, including spinal oncology, vascular neurosurgery (cerebral and spinal), TBI, and

Besides their undisputed value, traditional intraoperative imaging techniques (CT scan and MRI) have several limitations, including costs, temporary stop of surgical procedure, and time wasting. These important strains make iCT and iMRI

angiography (ICG-VA), and navigation, were broadly available [12–15]

**90**

imaging.

activity [19, 21].

vascularization [1, 23].

pediatric and peripheral nerve surgery.

hardly repeatable during surgery [12, 24].

*Diagrammatic representation of the fields of application of CEUS in neurosurgery.*

Conversely, as demonstrated by several experiences, CEUS/ioUS is a feasible intraoperative imaging technique, as it is readily repeatable, dynamic, and inexpensive and provides a truly real-time dynamic visualization of anatomical characteristics and vascular patterns in several neurosurgical settings. Assessment is rapid, can be performed any time during surgery, and is independent of brain shift [4, 8–10, 20].

Besides, microbubbles do not only allow the visualization of high-definition intraoperative images after craniotomy but, as reported later, can enhance the resolution of intracranial arteries also in transcranial studies at bedside [25–27].

**Figure 1** summarizes the major fields of application of CEUS in neurosurgery.

#### **3. Cerebral neuro-oncology**

The use of CEUS during neuro-oncological procedures has been recently included in the guidelines from the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB), representing a paradigm shift for the use of US in neurosurgery [28](**Figure 2**).

In comparison with other imaging modes, CEUS showed itself as a rapid, practical, and cost-effective technique, suggesting additional and alternative information about brain tumor vasculature and perfusion, being B-mode limited in providing only morphological information regarding the lesion. In their seminal study, Prada et al. [29] demonstrated how, once enhanced, the tumor is highlighted and reveals other specific characteristics of both low-grade gliomas (LGGs) and high-grade gliomas (HGGs).

LGGs show a mild, dotted CE with diffuse appearance and blurred margins. Arterial feeders are usually not identifiable, microbubble transit is regular and organized, and venous drainage is diffuse through numerous capillaries and consequently not discernible. Relying not on its echogenicity but upon vascularization, CEUS proved to be particularly valuable in differentiating oncological tissue from surrounding edema, thus helping in depicting the true limits of infiltration [30, 31].

HGGs have a high CE with a more nodular, nonhomogeneous appearance and fast perfusion patterns, with a rapid CE, marked by rapid arterial phase, very fast CE peak, and chaotic transit of microbubbles within the lesion. The arterial supply

#### **Figure 2.**

*B-mode CEUS evaluation of a high-grade glioma. The microbubble contrast medium allows to visualize the tumor parenchyma with its necrotic non-enhancing component. In advanced phases of resection, CEUS can be repeated to identify inadvertent residuals.*

was clearly visible, showing many macrovessels within the lesion and a typical peripheral enhancement that moved toward the inner areas of the lesion. The venous phase was rapid (5–10 seconds), and the venous drainage system was diffuse, with multiple medullary veins aiming toward the periventricular zone. CEUS in HGGs is useful in differentiating solid from cystic components. In the specific case of glioblastomas (GBMs), CEUS CE is consistent in proliferating areas, and, on the contrary, no CE at all is seen in necrotic zones and surrounding brain parenchyma. Two CE patterns are identifiable in GBM: (1) heterogeneous with nodular high CE spots interspersed by low CE areas of necrosis and (2) peripheral rim CE surrounding a central core of necrosis without CE. In all cases, GBM shows a clearly demarcated border after UCA administration due to the different vascularization of the tumor and healthy brain parenchyma [29](**Figure 3**).

Highlighting the residual tumor tissue with great accuracy and overcoming the difficulties of ultrasound interpretation caused by artifacts, edema, and surgical manipulation [10, 23, 32], CEUS has been demonstrated valuable in guiding tumor resection. In conclusion, the introduction of CEUS embodies one of the most recent innovations in HGG surgery.

Furthermore, in a series of publications, CEUS showed its capability in identifying tumor remnants after HGG surgery [10, 23, 30]. These are generally defined as nodular tissue at the edges of the surgical cavity, depicting an early and persistent enhancement, compared to the surrounding brain parenchyma. Because of artifacts due to surgical manipulation, B-mode evaluation alone can show unclear results if performed after neurosurgical resection. In the advanced phase of surgery, CEUS can fill the gap left by ioUS, guiding the surgeon also in the final survey at the end of the procedure [33]. Moreover, US is independent of brain shift, and this grants useful information to surgeons throughout the procedure also in advanced phases of resection, such as final survey at the end of the procedure.

CEUS potential in detecting inadvertent residuals proved particularly effective in a 5-ALA-guided setting [10], where the resection is built with the 5-ALA assistance, and CEUS supplementary supports the surgeon by providing information before and after resection. Incomplete resections also in a 5-ALA setting can indeed result from residual tumor covered by blood, cottonoid, or overlapping normal brain: in these scenarios it does not light up under blue light conditions and can be missed [34–37]. Moreover, in deep fields or conditions of non-orthogonal working corridors, microscope light might fail to thoroughly illuminate the surgical field, resulting in blind corners facilitating a partial removal. Thus, CEUS final survey

**93**

**Figure 3.**

erative imaging techniques.

*Oncological, Vascular, and Spinal Uses of Contrast-Enhanced Ultrasound in Neurosurgery*

has a role of refinement of the 5-ALA procedure by identifying sub-centimetric remnants. The two techniques approach the surgical field from a different point of view: 5-ALA fluorescence is a result of direct microscope illumination, whereas ultrasounds investigate through brain tissue, depicting also distant, unexposed, hidden cerebral or neoplastic anatomy. Indeed, they observe two different phenomena: 5-ALA is an expression of glial cell metabolism, whereas CEUS is a consequence of pathological tumor vascularization. When integrated, these complementary

*CEUS visualization of lesion's vascular characteristics of a hemangiopericytoma of the cauda equina after CEUS—The exams depict the main feeders afferent to the lesion (red arrowheads) and the main venous drainage outgoing the lesion (blue arrows). The tumor is highly and rapidly enhancing after intraoperative contrast administration confirming its highly vascularized characteristics. Vessels not directly related to the* 

CEUS-assisted intraoperative imaging does not modify the overall surgical procedure, as it does not interrupt the central phase of surgery and the overall surgical strategy, is not time demanding, and does not require expensive equipment; these considerations are surely important, especially when compared with other intraop-

Also, CEUS provides other valuable information to identify vascular supply, giving further insight into the surgical strategy, facilitating vascular deafferentation and removal, and thus maximizing resection voiding neurological sequelae result-

Serious weaknesses of CEUS in vascularization assessment are angle of insonation susceptibility, low-flow veins not always visible, and small vessel overestimation due to blooming artifacts that scatter color signals nearby the vessel margins [17]. Possible limitations in the assessment of resection margin are

techniques increase the chance of identifying neoplastic residual tissue.

ing from damaged healthy brain tissues or vessels [38].

*tumor and belonging to conus medullaris can be identified (green asterisk).*

*DOI: http://dx.doi.org/10.5772/intechopen.91320*

*Oncological, Vascular, and Spinal Uses of Contrast-Enhanced Ultrasound in Neurosurgery DOI: http://dx.doi.org/10.5772/intechopen.91320*

#### **Figure 3.**

*Neurosurgical Procedures - Innovative Approaches*

was clearly visible, showing many macrovessels within the lesion and a typical peripheral enhancement that moved toward the inner areas of the lesion. The venous phase was rapid (5–10 seconds), and the venous drainage system was diffuse, with multiple medullary veins aiming toward the periventricular zone. CEUS in HGGs is useful in differentiating solid from cystic components. In the specific case of glioblastomas (GBMs), CEUS CE is consistent in proliferating areas, and, on the contrary, no CE at all is seen in necrotic zones and surrounding brain parenchyma. Two CE patterns are identifiable in GBM: (1) heterogeneous with nodular high CE spots interspersed by low CE areas of necrosis and (2) peripheral rim CE surrounding a central core of necrosis without CE. In all cases, GBM shows a clearly demarcated border after UCA administration due to the different vascularization of

*B-mode CEUS evaluation of a high-grade glioma. The microbubble contrast medium allows to visualize the tumor parenchyma with its necrotic non-enhancing component. In advanced phases of resection, CEUS can be* 

Highlighting the residual tumor tissue with great accuracy and overcoming the difficulties of ultrasound interpretation caused by artifacts, edema, and surgical manipulation [10, 23, 32], CEUS has been demonstrated valuable in guiding tumor resection. In conclusion, the introduction of CEUS embodies one of the most recent

Furthermore, in a series of publications, CEUS showed its capability in identifying tumor remnants after HGG surgery [10, 23, 30]. These are generally defined as nodular tissue at the edges of the surgical cavity, depicting an early and persistent enhancement, compared to the surrounding brain parenchyma. Because of artifacts due to surgical manipulation, B-mode evaluation alone can show unclear results if performed after neurosurgical resection. In the advanced phase of surgery, CEUS can fill the gap left by ioUS, guiding the surgeon also in the final survey at the end of the procedure [33]. Moreover, US is independent of brain shift, and this grants useful information to surgeons throughout the procedure also in advanced phases of

CEUS potential in detecting inadvertent residuals proved particularly effective in a 5-ALA-guided setting [10], where the resection is built with the 5-ALA assistance, and CEUS supplementary supports the surgeon by providing information before and after resection. Incomplete resections also in a 5-ALA setting can indeed result from residual tumor covered by blood, cottonoid, or overlapping normal brain: in these scenarios it does not light up under blue light conditions and can be missed [34–37]. Moreover, in deep fields or conditions of non-orthogonal working corridors, microscope light might fail to thoroughly illuminate the surgical field, resulting in blind corners facilitating a partial removal. Thus, CEUS final survey

the tumor and healthy brain parenchyma [29](**Figure 3**).

resection, such as final survey at the end of the procedure.

innovations in HGG surgery.

*repeated to identify inadvertent residuals.*

**Figure 2.**

**92**

*CEUS visualization of lesion's vascular characteristics of a hemangiopericytoma of the cauda equina after CEUS—The exams depict the main feeders afferent to the lesion (red arrowheads) and the main venous drainage outgoing the lesion (blue arrows). The tumor is highly and rapidly enhancing after intraoperative contrast administration confirming its highly vascularized characteristics. Vessels not directly related to the tumor and belonging to conus medullaris can be identified (green asterisk).*

has a role of refinement of the 5-ALA procedure by identifying sub-centimetric remnants. The two techniques approach the surgical field from a different point of view: 5-ALA fluorescence is a result of direct microscope illumination, whereas ultrasounds investigate through brain tissue, depicting also distant, unexposed, hidden cerebral or neoplastic anatomy. Indeed, they observe two different phenomena: 5-ALA is an expression of glial cell metabolism, whereas CEUS is a consequence of pathological tumor vascularization. When integrated, these complementary techniques increase the chance of identifying neoplastic residual tissue.

CEUS-assisted intraoperative imaging does not modify the overall surgical procedure, as it does not interrupt the central phase of surgery and the overall surgical strategy, is not time demanding, and does not require expensive equipment; these considerations are surely important, especially when compared with other intraoperative imaging techniques.

Also, CEUS provides other valuable information to identify vascular supply, giving further insight into the surgical strategy, facilitating vascular deafferentation and removal, and thus maximizing resection voiding neurological sequelae resulting from damaged healthy brain tissues or vessels [38].

Serious weaknesses of CEUS in vascularization assessment are angle of insonation susceptibility, low-flow veins not always visible, and small vessel overestimation due to blooming artifacts that scatter color signals nearby the vessel margins [17]. Possible limitations in the assessment of resection margin are evaluating the tumor removal degree of patients with recurrent gliomas or patients with gliomas after radiotherapy [39].

CEUS can also be compared with perfusion MRI in both preoperative and postoperative settings: US offers a morphologic representation of GBM similar to the one provided by preoperative gadolinium-enhanced T1-weighted MRI [40]. Several experiences in literature compared, instead, CEUS with pMRI in a postoperative setting [41, 42] and suggested it as a cost-effective method in evaluating changes in tumor vascularity during the follow-up period in patients with brain tumors who are undergoing radiotherapy, chemotherapy, or antiangiogenic therapy.

When combined with fusion imaging including US with MRI, CEUS has several advantages over B-mode alone [43, 44]:


Recent reports highlighted other potential applications of CEUS in cranial oncological surgery, although these experiences are still anecdotal with few cases reported. Apart from the evaluation of intraoperative resection control, CEUS has been used as biopsy guidance to correctly localize the needle and target the most representative samples for pathology [5, 45] or to guide and assess hemodynamic effects after intraoperative embolization of highly vascularized tumors such as hemangioblastomas [20, 38]. In addition, CEUS use can space from a bedside technique adding helpful information not only in noninvasive staging of tumors but also in differentiating tumor recurrence from radionecrosis as postulated by Vicenzini et al. [46] and Mattei et al. [47]; relying on microbubble diffusion through vascularization radionecrosis shows a completely different, poorer, enhancement pattern compared to HGGs.

CEUS has thus proven its utility in:


**95**

*Oncological, Vascular, and Spinal Uses of Contrast-Enhanced Ultrasound in Neurosurgery*

Primary spinal tumors are relatively rare lesions, for which MRI represents the gold standard for diagnosis. Nevertheless, MRI may not always differentiate accurately between different types of intramedullary tumors: even if not well defined nor standardized, the role of CEUS in this surgical field appears as a problem solver. Even though a small number of cases were reported, it has proven to be a simple and relatively inexpensive technique representing a realtime dynamic procedure that can be performed during a spinal tumor surgery. Its

1.Better characterization of the location of the intramedullary lesions [49, 50].

2.Easier identification of vascular structures, giving further insight in vascular

3.Possible combination with color Doppler to better identify the main arterial

2.Reduced visibility of low-flow veins and possible overestimation of small

3.Less defined imaging due to a reduced depth of the explored surgical field

Providing an angiogram-like display of the parent and downstream vessel segments in high spatial resolution, CEUS might be a feasible tool for both aneurysm and arteriovenous malformation (AVM) treatment. Indeed, it could implement their intraoperative management by providing real-time imaging: this is true both in the visualization of the vascular supply before the intervention and in flow assessment at the end of the procedure [51]. Furthermore, since it allows the identification of target vessels even when covered by brain parenchyma, it could be synergistically used with ICG-VA, which relies on direct vessel visualization, in

Focusing on aneurysms, CEUS was found particularly useful in occlusion followup after endovascular treatment. As opposed to a neuro-oncological setting, in which CEUS examination can be performed only after craniotomy, in the vascular setting, it can amplify vessel resolution also during transcranial examination. CEUS can selectively monitor intracranial aneurysms and detect refilling rate in aneurysms with a minor neck remnant. In the end, they suggested to perform transcranial color-coded duplex sonography (TCCS) examination with contrast enhancement at the time of initial surveillance with digital subtraction angiography (DSA) and, if findings were similar, to undertake an additional follow-up by TCCS alone until changes in

deafferentation and then surgical removal [8, 9, 49, 50].

1.Possibility to analyze one portion of the lesion at the time.

situations in which a complex approach is required [13, 52].

4.As for HGG surgery, CEUS helps in the identification of inadvertent

feeders and draining vessels [8, 9].

vessels due to blooming artifacts.

compared to brain surgery [4, 8, 9]

The important drawbacks in this setting are:

*DOI: http://dx.doi.org/10.5772/intechopen.91320*

**4. Spinal tumors**

benefits include:

remnants [8].

**5. Vascular applications**

8.Guiding to intraoperative biopsy and tissue sampling [5, 45]

*Oncological, Vascular, and Spinal Uses of Contrast-Enhanced Ultrasound in Neurosurgery DOI: http://dx.doi.org/10.5772/intechopen.91320*

#### **4. Spinal tumors**

*Neurosurgical Procedures - Innovative Approaches*

with gliomas after radiotherapy [39].

advantages over B-mode alone [43, 44]:

CEUS has thus proven its utility in:

anatomy [5, 7, 41, 42].

2.Characterizing glioma grade [29, 30, 48].

its lack of contrast enhancement [46, 47].

8.Guiding to intraoperative biopsy and tissue sampling [5, 45]

different angles.

1.Detection of poor sonographic visibility tumor.

easier way to discern the structure of the brain.

4.Improved orientation and compensation for the brain shift.

evaluating the tumor removal degree of patients with recurrent gliomas or patients

are undergoing radiotherapy, chemotherapy, or antiangiogenic therapy.

CEUS can also be compared with perfusion MRI in both preoperative and postoperative settings: US offers a morphologic representation of GBM similar to the one provided by preoperative gadolinium-enhanced T1-weighted MRI [40]. Several experiences in literature compared, instead, CEUS with pMRI in a postoperative setting [41, 42] and suggested it as a cost-effective method in evaluating changes in tumor vascularity during the follow-up period in patients with brain tumors who

When combined with fusion imaging including US with MRI, CEUS has several

2.Better recognition of the tumor and edema tissue compared with reconstructive preoperative coplanar-enhanced MRI in real time and multiplane from

3.Application by neurosurgeons who lack the expertise in US technology as an

Recent reports highlighted other potential applications of CEUS in cranial oncological surgery, although these experiences are still anecdotal with few cases reported. Apart from the evaluation of intraoperative resection control, CEUS has been used as biopsy guidance to correctly localize the needle and target the most representative samples for pathology [5, 45] or to guide and assess hemodynamic effects after intraoperative embolization of highly vascularized tumors such as hemangioblastomas [20, 38]. In addition, CEUS use can space from a bedside technique adding helpful information not only in noninvasive staging of tumors but also in differentiating tumor recurrence from radionecrosis as postulated by Vicenzini et al. [46] and Mattei et al. [47]; relying on microbubble diffusion through vascularization radionecrosis shows a completely different, poorer, enhancement pattern compared to HGGs.

1.Highlighting tumors and their phases compared to brain parenchyma [42].

4.Showing vascular rearrangement that takes place with tumor removal [17].

5.Highlighting residual tumor (especially feasible in a 5-ALA setting) [10, 30, 39].

6.Aiding surgical decision-making through serial imaging assessment of surgical

7.Helping in differential diagnosis of radionecrosis with neoplastic tissue due to

3.Assessing vascularization and degree of overall perfusion [29, 30].

**94**

Primary spinal tumors are relatively rare lesions, for which MRI represents the gold standard for diagnosis. Nevertheless, MRI may not always differentiate accurately between different types of intramedullary tumors: even if not well defined nor standardized, the role of CEUS in this surgical field appears as a problem solver. Even though a small number of cases were reported, it has proven to be a simple and relatively inexpensive technique representing a realtime dynamic procedure that can be performed during a spinal tumor surgery. Its benefits include:


The important drawbacks in this setting are:


#### **5. Vascular applications**

Providing an angiogram-like display of the parent and downstream vessel segments in high spatial resolution, CEUS might be a feasible tool for both aneurysm and arteriovenous malformation (AVM) treatment. Indeed, it could implement their intraoperative management by providing real-time imaging: this is true both in the visualization of the vascular supply before the intervention and in flow assessment at the end of the procedure [51]. Furthermore, since it allows the identification of target vessels even when covered by brain parenchyma, it could be synergistically used with ICG-VA, which relies on direct vessel visualization, in situations in which a complex approach is required [13, 52].

Focusing on aneurysms, CEUS was found particularly useful in occlusion followup after endovascular treatment. As opposed to a neuro-oncological setting, in which CEUS examination can be performed only after craniotomy, in the vascular setting, it can amplify vessel resolution also during transcranial examination. CEUS can selectively monitor intracranial aneurysms and detect refilling rate in aneurysms with a minor neck remnant. In the end, they suggested to perform transcranial color-coded duplex sonography (TCCS) examination with contrast enhancement at the time of initial surveillance with digital subtraction angiography (DSA) and, if findings were similar, to undertake an additional follow-up by TCCS alone until changes in

aneurysm status. Transcranial examination is cost-effective, rapid, easily repeatable, and feasible compared to standard digital subtraction angiogram or angio-MRI monitoring.

To summarize, CEUS in the setting of intracranial aneurysms has the following advantages:


The main drawback underlined in both papers was the limited acoustic window in aneurysms located outside the circle of Willis, despite the introduction of contrast agent [25, 26].

In dural arteriovenous fistula (dAVF) surgery, both cranial and spinal, one of the most important steps is the correct identification of the fistulous site [53–55]. In the two reported cases [4, 56], CEUS allowed both pre- and post-ligation real-time visualization of site of the fistula and blood flow changes occurring in the spinal cord and perimedullary plexus. Not only it does encompass the limitations of Doppler imaging, which can be used simultaneously to confirm the type of flow and flow dynamics, but, as already in the case of aneurysms, it might be integrated with other imaging modalities such as fluorescence [11, 51]. However, larger series are needed to determine the significance of this tool in the obliteration of intradural spinal dAVFs [51] (**Figure 4**).

Pioneer experiences have recently been reported also in AVM surgery. Providing an angiogram-like display of the parent and downstream vessel segments in high spatial resolution, CEUS is a feasible tool for both aneurysms and AVM treatments. Indeed, it could implement their intraoperative management by providing real-time imaging: this is true both in visualization of the vascular supply before the intervention and in flow assessment at the end of the procedure. Furthermore, since it allows the identification of target vessels even when covered by the brain parenchyma, it has been proposed as a complement to standard ICG-VA.

The integration of color Doppler sonography and CEUS allows to:


Knowledge of the vascular characteristics of the AVM and the relationships of the nidus with the brain parenchyma is mandatory during these complex surgical

**97**

**Figure 4.**

AVM-related arterial vessels (**Figure 5**).

*Oncological, Vascular, and Spinal Uses of Contrast-Enhanced Ultrasound in Neurosurgery*

procedures; hence, the real-time identification of the feeding arteries and draining veins is surely valuable during surgery. Basically, the operative strategy is guided throughout the procedure by several CEUS assessments with temporary clipping of the feeding vessel, and real-time confirmation of the hemodynamic modification inside the nidus is semiquantitatively evaluated both by means of color Doppler US and CEUS. This reduces the risk of inadvertently sacrificing parenchymal non-

*vessels not directly related to the dAVF are not visualized at this early arterial stage (arterial stage).*

*B-mode and color Doppler visualization of a spinal dAVF characteristic. Epidural standard B-mode imaging showing the spinal cord anatomical proportional plan features: Green arrow, dura mater; blue arrow, peridural venous plexus; yellow arrow, spinal cord gray matter; white arrow, spinal cord white matter; red arrows, vertebral arteries. Color Doppler sonography displaying radicular artery (red arrow) and engorged peridural veins (blue arrows) with a turbulent flow. Doppler US confirms the arterialized nature of peridural plexus veins. After CEUS administration the main feeders afferent to the lesion can be observed and the main venous arterialized drainage outgoing the lesion (red arrows), thus identifying fistulous point. Peridural venous* 

*DOI: http://dx.doi.org/10.5772/intechopen.91320*

*Oncological, Vascular, and Spinal Uses of Contrast-Enhanced Ultrasound in Neurosurgery DOI: http://dx.doi.org/10.5772/intechopen.91320*

#### **Figure 4.**

*Neurosurgical Procedures - Innovative Approaches*

presented in coiled aneurysms.

the intensive care unit (ICU).

contrast agent [25, 26].

surrounding vessels

occlusion of feeders

1.Accurate display of flow direction and velocity.

monitoring.

advantages:

aneurysm status. Transcranial examination is cost-effective, rapid, easily repeatable, and feasible compared to standard digital subtraction angiogram or angio-MRI

To summarize, CEUS in the setting of intracranial aneurysms has the following

2.Increased focus and resolution, allowing detection of very low flow as often

3.Gives the possibility to be performed immediately as a control examination in

4.Produces less severe metal artifacts compared to other imaging modalities.

The main drawback underlined in both papers was the limited acoustic window in aneurysms located outside the circle of Willis, despite the introduction of

In dural arteriovenous fistula (dAVF) surgery, both cranial and spinal, one of the most important steps is the correct identification of the fistulous site [53–55]. In the two reported cases [4, 56], CEUS allowed both pre- and post-ligation real-time visualization of site of the fistula and blood flow changes occurring in the spinal cord and perimedullary plexus. Not only it does encompass the limitations of Doppler imaging, which can be used simultaneously to confirm the type of flow and flow dynamics, but, as already in the case of aneurysms, it might be integrated with other imaging modalities such as fluorescence [11, 51]. However, larger series are needed to determine the significance of this tool in the obliteration of intradural spinal dAVFs [51] (**Figure 4**). Pioneer experiences have recently been reported also in AVM surgery. Providing an angiogram-like display of the parent and downstream vessel segments in high spatial resolution, CEUS is a feasible tool for both aneurysms and AVM treatments. Indeed, it could implement their intraoperative management by providing real-time imaging: this is true both in visualization of the vascular supply before the intervention and in flow assessment at the end of the procedure. Furthermore, since it allows the identification of target vessels even when covered by the brain

parenchyma, it has been proposed as a complement to standard ICG-VA. The integration of color Doppler sonography and CEUS allows to:

2.Identify AVM feeders from non-AVM-related vessels

1.Accurately display flow direction and velocity within the nidus and in

3.Evaluate the flow modifications produced into the nidus after temporary

5.Assess restored venous flow into surrounding veins before dissection and

Knowledge of the vascular characteristics of the AVM and the relationships of the nidus with the brain parenchyma is mandatory during these complex surgical

isolation of the venous compartments of the malformation

4.Assess completeness of devascularization and eventual residual flow to the AVM

**96**

*B-mode and color Doppler visualization of a spinal dAVF characteristic. Epidural standard B-mode imaging showing the spinal cord anatomical proportional plan features: Green arrow, dura mater; blue arrow, peridural venous plexus; yellow arrow, spinal cord gray matter; white arrow, spinal cord white matter; red arrows, vertebral arteries. Color Doppler sonography displaying radicular artery (red arrow) and engorged peridural veins (blue arrows) with a turbulent flow. Doppler US confirms the arterialized nature of peridural plexus veins. After CEUS administration the main feeders afferent to the lesion can be observed and the main venous arterialized drainage outgoing the lesion (red arrows), thus identifying fistulous point. Peridural venous vessels not directly related to the dAVF are not visualized at this early arterial stage (arterial stage).*

procedures; hence, the real-time identification of the feeding arteries and draining veins is surely valuable during surgery. Basically, the operative strategy is guided throughout the procedure by several CEUS assessments with temporary clipping of the feeding vessel, and real-time confirmation of the hemodynamic modification inside the nidus is semiquantitatively evaluated both by means of color Doppler US and CEUS. This reduces the risk of inadvertently sacrificing parenchymal non-AVM-related arterial vessels (**Figure 5**).

#### **Figure 5.**

*CEUS and color Doppler US evaluation of an AVM, in which main arterial feeders (red arrows) can be identified, as well as the nidus (green arrow) and venous drains (green arrow). Color Doppler shows the flow direction, arterial vs. venous flow, and confirms turbulent flow within the malformation.*

In advanced phases of dissection, CEUS allows the surgeon to:

a.Spatially identify in which area of the nidus residual flow is present.

b.Establish a gross estimation of the overall residual flow within the malformation (as CEUS enhancement is directly proportional to flow).

Furthermore, the restored venous flow into AVM draining veins can be reliably identified providing a final confirmation of completeness of nidal deafferentation, before the procedure is completed.

#### **6. Stroke**

An adequate supply of blood containing oxygen and nutrients is crucial for the recovery and survival of brain tissue. Monitoring of cerebral perfusion is essential in the prevention of secondary brain damage in patients with acute brain injury. CEUS has been suggested as a new method to measure cerebral perfusion in patients both with acute brain injury at the ICU and in the acute state of cerebral ischemia. The technique has a high temporal resolution which can be used at the bedside; moreover, the contrast enhancement can be used for visualization of the cerebral vasculature to overcome the restricted level of acoustic intensity. However, in this context the accuracy of CEUS for the detection of hyperperfusion has not yet been assessed.

This aligns with the idea that for patients after ischemic stroke, CEUS may serve as an additional clinical tool for the bedside evaluation of brain tissue perfusion and response to recanalization therapy, with more efforts to be made to improve its reliability [57–59]. However, when it comes to this clinical application, two key problems arise:

**99**

**8. Conclusions**

*Oncological, Vascular, and Spinal Uses of Contrast-Enhanced Ultrasound in Neurosurgery*

conventional transcranial color-coded sonography.

1.Analyze plaque morphology and characteristics [61]

however important limitations associated with this finding.

2.Identify vulnerable plaques and detect neovascularization [62–65]

Moreover, a comparison and a proof of the relationship between CEUS and 3DT1-WI MRI plaque imaging were recently published [69]. However, on board with the purpose of this review, we decided to focus only on those works in which a prospective relationship between CEUS on carotid intraplaque neovascularization and ischemic stroke was analyzed. The grade of contrast enhancement was an independent risk factor for ischemic stroke or recurrent transitory ischemic attack. Therefore, the grade of CEUS contrast enhancement could become a predictive index of ischemic stroke, identifying those patients in need of an effective treatment. A potential source of bias coming from the exclusive selection of large plaques, a semiquantitative grading system, and a relatively small sample size are

CEUS has reached in recent years a wide utilization in various neurosurgical fields, mainly in neuro-oncological surgery. Despite its main limitations in being

3.Perioperatively assess the procedure to be performed [66–68]

1.Different protocols were used by the involved research groups, and, more crucial, patients presenting with acute stroke were examined at different time

2.Patients with insufficient insonation conditions were excluded in advance, and the percentage of stroke patients for which the technique could represent a consistent improvement remains questionable. Indeed, in cited studies [57–59], one of the inclusion criteria was a sufficient temporal acoustic window for

As a last note, CEUS can be used as a follow-up strategy in stroke patients: it is a fast and repeatable bedside technique [3]. However, these potential advantages are undermined by (1) a small sample of studies; (2) non-validated comparison with the other imaging technique already in use in this particular area; and (3) the need

Carotid atherosclerotic disease represents a major current health problem accounting for approximately 20% of all cases of cerebral ischemia. Risk stratification and patient management are traditionally based on the presence or absence of symptoms and the degree of stenosis, both of which have been found to correlate with the occurrence of stroke. US is the cornerstone of both screening and diagnostic approach of carotid disease, and introduction of CE has been providing promising results, leading to the publication of recommendation of use [28, 60]. An impressive number of works demonstrated CEUS is a feasible and effective

*DOI: http://dx.doi.org/10.5772/intechopen.91320*

for specific ecographic equipment.

**7. Carotid plaques**

tool to:

windows.

*Oncological, Vascular, and Spinal Uses of Contrast-Enhanced Ultrasound in Neurosurgery DOI: http://dx.doi.org/10.5772/intechopen.91320*


As a last note, CEUS can be used as a follow-up strategy in stroke patients: it is a fast and repeatable bedside technique [3]. However, these potential advantages are undermined by (1) a small sample of studies; (2) non-validated comparison with the other imaging technique already in use in this particular area; and (3) the need for specific ecographic equipment.

#### **7. Carotid plaques**

*Neurosurgical Procedures - Innovative Approaches*

In advanced phases of dissection, CEUS allows the surgeon to:

*direction, arterial vs. venous flow, and confirms turbulent flow within the malformation.*

tion (as CEUS enhancement is directly proportional to flow).

before the procedure is completed.

**6. Stroke**

**Figure 5.**

assessed.

problems arise:

a.Spatially identify in which area of the nidus residual flow is present.

*CEUS and color Doppler US evaluation of an AVM, in which main arterial feeders (red arrows) can be identified, as well as the nidus (green arrow) and venous drains (green arrow). Color Doppler shows the flow* 

b.Establish a gross estimation of the overall residual flow within the malforma-

Furthermore, the restored venous flow into AVM draining veins can be reliably identified providing a final confirmation of completeness of nidal deafferentation,

An adequate supply of blood containing oxygen and nutrients is crucial for the recovery and survival of brain tissue. Monitoring of cerebral perfusion is essential in the prevention of secondary brain damage in patients with acute brain injury. CEUS has been suggested as a new method to measure cerebral perfusion in patients both with acute brain injury at the ICU and in the acute state of cerebral ischemia. The technique has a high temporal resolution which can be used at the bedside; moreover, the contrast enhancement can be used for visualization of the cerebral vasculature to overcome the restricted level of acoustic intensity. However, in this context the accuracy of CEUS for the detection of hyperperfusion has not yet been

This aligns with the idea that for patients after ischemic stroke, CEUS may serve as an additional clinical tool for the bedside evaluation of brain tissue perfusion and response to recanalization therapy, with more efforts to be made to improve its reliability [57–59]. However, when it comes to this clinical application, two key

**98**

Carotid atherosclerotic disease represents a major current health problem accounting for approximately 20% of all cases of cerebral ischemia. Risk stratification and patient management are traditionally based on the presence or absence of symptoms and the degree of stenosis, both of which have been found to correlate with the occurrence of stroke. US is the cornerstone of both screening and diagnostic approach of carotid disease, and introduction of CE has been providing promising results, leading to the publication of recommendation of use [28, 60]. An impressive number of works demonstrated CEUS is a feasible and effective tool to:


Moreover, a comparison and a proof of the relationship between CEUS and 3DT1-WI MRI plaque imaging were recently published [69]. However, on board with the purpose of this review, we decided to focus only on those works in which a prospective relationship between CEUS on carotid intraplaque neovascularization and ischemic stroke was analyzed. The grade of contrast enhancement was an independent risk factor for ischemic stroke or recurrent transitory ischemic attack. Therefore, the grade of CEUS contrast enhancement could become a predictive index of ischemic stroke, identifying those patients in need of an effective treatment. A potential source of bias coming from the exclusive selection of large plaques, a semiquantitative grading system, and a relatively small sample size are however important limitations associated with this finding.

#### **8. Conclusions**

CEUS has reached in recent years a wide utilization in various neurosurgical fields, mainly in neuro-oncological surgery. Despite its main limitations in being an operator-dependent technique and its shared drawbacks with US technology, it revealed itself as a promising tool: CEUS is comparable and complementary to traditional imaging techniques, allows for a serial assessment, is easily performable in different settings, and has a wide range of future applications yet to be explored.

### **Author details**

Giuseppe Maria Della Pepa Institute of Neurosurgery, Policlinico Universitario Agostino Gemelli IRCSS, Catholic University of Rome, Italy

\*Address all correspondence to: giuseppemaria.dellapepa@policlinicogemelli.it

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

**101**

*Oncological, Vascular, and Spinal Uses of Contrast-Enhanced Ultrasound in Neurosurgery*

spinal tumors: A technical note. Acta Neurochirurgica. 2018;**160**(9):1873-1874

[10] Della Pepa GM, Sabatino G, la Rocca G. "Enhancing vision" in high grade glioma surgery: A feasible integrated 5-ALA + CEUS protocol to improve radicality. World Neurosurgery.

[11] Altieri R et al. Intra-operative ultrasound: Tips and tricks for making the most in neurosurgery. Surgical Technology International.

[12] Barbagallo G et al. Intraoperative computed tomography, navigated ultrasound, 5-amino-levulinic acid fluorescence and neuromonitoring in brain tumor surgery: Overtreatment or useful tool combination? Journal of Neurosurgical Sciences. 2019. [Epub

[13] Marchese E et al. Application of Indocyanine green video

angiography in vascular neurosurgery. Journal of Neurosurgical Sciences.

[14] Panciani PP et al. 5-aminolevulinic acid and neuronavigation in high-grade glioma surgery: Results of a combined approach. Neurocirugía (Asturias,

neuronavigation system for superficial vein identification: Safe and quick method to avoid intraoperative bleeding and vein closure: Technical

[16] Perin A et al. USim: A new device and app for case-specific, intraoperative ultrasound simulation and rehearsal in neurosurgery. A Preliminary Study. Operative Neurosurgery.

2019;**129**:401-403

2018;**33**:353-360

ahead of print]

2019;**63**(6):656-660

Spain). 2012;**23**(1):23-28

[15] Ricciardi L et al. Use of

note. World Neurosurgery.

2018;**117**:92-96

2018;**14**(5):572-578

*DOI: http://dx.doi.org/10.5772/intechopen.91320*

ultrasound imaging in glioma surgery: Beyond gray-scale B-mode. Frontiers in

[2] Becker A et al. Contrast-enhanced ultrasound ventriculography. Operative Neurosurgery. 2012;**71**:ons296-ons301

[3] Bilotta F et al. Contrast-enhanced ultrasound imaging in detection of changes in cerebral perfusion. Ultrasound in Medicine and Biology.

[4] Della Pepa GM et al. Integration of real-time intraoperative contrastenhanced ultrasound and color Doppler ultrasound in the surgical treatment of spinal cord Dural Arteriovenous fistulas. World Neurosurgery.

[5] Arlt F et al. Intraoperative 3D contrast-enhanced ultrasound (CEUS): A prospective study of 50 patients with brain tumours. Acta Neurochirurgica.

[6] Bailey C et al. Contrast-enhanced ultrasound and elastography imaging of the neonatal brain: A review— Ultrasound techniques for imaging of the neonatal brain. Journal of Neuroimaging. 2017;**27**(5):437-441

[7] Cheng L-G et al. Intraoperative contrast enhanced ultrasound evaluates the grade of glioma. BioMed Research

[8] Della Pepa GM et al. Real-time intraoperative contrast-enhanced ultrasound (CEUS) in vascularized spinal tumors: A technical note. Acta Neurochirurgica. 2018;**160**(6):1259-1263

[9] Della Pepa GM, Mattogno PP, Olivi A. Comment on the article—Realtime intraoperative contrast-enhanced ultrasound (CEUS) in vascularized

International. 2016;**2016**:1-9

[1] Del Bene M et al. Advanced

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#### **References**

*Neurosurgical Procedures - Innovative Approaches*

an operator-dependent technique and its shared drawbacks with US technology, it revealed itself as a promising tool: CEUS is comparable and complementary to traditional imaging techniques, allows for a serial assessment, is easily performable in different settings, and has a wide range of future applications yet to be explored.

**100**

**Author details**

Giuseppe Maria Della Pepa

Catholic University of Rome, Italy

provided the original work is properly cited.

Institute of Neurosurgery, Policlinico Universitario Agostino Gemelli IRCSS,

\*Address all correspondence to: giuseppemaria.dellapepa@policlinicogemelli.it

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

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*Neurosurgical Procedures - Innovative Approaches*

[25] Turner CL et al. Intracranial aneurysms treated with endovascular coils: Detection of recurrences using unenhanced and contrastenhanced transcranial colorcoded duplex sonography. Stroke.

2005;**36**(12):2654-2659

discussion 871-2

[26] Turner CL, Higgins JN, Kirkpatrick PJ. Assessment of transcranial color-coded duplex sonography for the surveillance of intracranial aneurysms treated with Guglielmi detachable coils. Neurosurgery. 2003;**53**(4):866-871;

[27] Wendl C et al. Evaluating postinterventional occlusion grades of cerebral aneurysms with transcranial contrast-enhanced ultrasound (CEUS) using a matrix probe. Ultraschall in der Medizin—European Journal of Ultrasound. 2015;**36**(02):168-173

[28] Sidhu P et al. The EFSUMB

2018;**39**(02):e2-e44

2014;**74**(5):542-552

International. 2014;**2014**:1-9

[30] Prada F et al. Intraoperative contrast-enhanced ultrasound for brain tumor surgery. Neurosurgery.

[31] Mattei L et al. Neurosurgical tools to extend tumor resection in hemispheric low-grade gliomas: Conventional and contrast enhanced ultrasonography. Child's Nervous System. 2016;**32**(10):1907-1914

[32] Trevisi G et al. Reliability of intraoperative ultrasound in detecting

guidelines and recommendations for the clinical practice of contrast-enhanced ultrasound (CEUS) in non-hepatic applications: Update 2017 (long version). Ultraschall in der Medizin— European Journal of Ultrasound.

[29] Prada F et al. Intraoperative cerebral glioma characterization with contrast enhanced ultrasound. BioMed Research

[17] Prada F et al. Intraoperative navigated angiosonography for skull base tumor surgery. World Neurosurgery. 2015;**84**(6):1699-1707

[18] Prada F et al. Preoperative

[19] Prada F et al. From grey scale B-mode to elastosonography: Multimodal ultrasound imaging in meningioma surgery—Pictorial essay and literature review. BioMed Research

International. 2015;**2015**:1-13

and color Doppler: Guided intraoperative embolization of intracranial highly vascularized Tumors'. World Neurosurgery.

2019;**131**:18

2018;**45**(1):E6

[20] Della Pepa GM et al. Erratum to 'contrast-enhanced ultrasonography

2019;**128**:547-555. World Neurosurgery.

[21] Prada F et al. Dynamic assessment of venous anatomy and function in neurosurgery with real-time

intraoperative multimodal ultrasound: Technical note. Neurosurgical Focus.

[22] Prada F et al. Intraoperative cerebral angiosonography with ultrasound contrast agents: How I do it. Acta Neurochirurgica. 2015;**157**(6):1025-1029

[23] Prada F et al. Identification of residual tumor with intraoperative contrast-enhanced ultrasound during glioblastoma resection. Neurosurgical

[24] Certo F et al. Supramarginal resection of glioblastoma: 5-ALA fluorescence, combined intraoperative strategies and correlation with survival. Journal of Neurosurgical Sciences.

Focus. 2016;**40**(3):E7

2019;**63**(6):625-632

2014;**36**(02):174-186

magnetic resonance and intraoperative ultrasound fusion imaging for realtime neuronavigation in brain tumor surgery. Ultraschall in der Medizin— European Journal of Ultrasound.

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[33] Dallabona M et al. Impact of mass effect, tumor location, age, and surgery on the cognitive outcome of patients with high-grade gliomas: A longitudinal study. Neuro-Oncology Practice. 2017;**4**(4):229-240

[34] Bongetta D et al. Low-cost fluorescein detection system for high-grade glioma surgery. World Neurosurgery. 2016;**88**:54-58

[35] Raffa G et al. Multimodal surgical treatment of high-grade gliomas in the motor area: The impact of the combination of navigated transcranial magnetic stimulation and fluoresceinguided resection. World Neurosurgery. 2019. [Epub ahead of print]

[36] Raffa G et al. Surgery of malignant motor-eloquent gliomas guided by sodium-fluorescein and navigated transcranial magnetic stimulation: A novel technique to increase the maximal safe resection. Journal of Neurosurgical Sciences. 2019. [Epub ahead of print]

[37] Panciani PP et al. Fluorescence and image guided resection in high grade glioma. Clinical Neurology and Neurosurgery. 2012;**114**(1):37-41

[38] Della Pepa GM et al. CEUS and color doppler-guided intraoperative embolization of intracranial highly vascularized tumors. World Neurosurgery. 2019;**128**:547-555

[39] Yu S-Q et al. Diagnostic significance of intraoperative ultrasound contrast in evaluating the resection degree of brain glioma by transmission electron microscopic examination. Chinese Medical Journal. 2015;**128**(2):186-190

[40] Prada F et al. Contrast-enhanced MR imaging versus contrast-enhanced US: A comparison in glioblastoma surgery by using intraoperative fusion imaging. Radiology. 2017;**285**(1):242-249

[41] Harrer J et al. Comparison of perfusion harmonic imaging and perfusion MR imaging for the assessment of microvascular characteristics in brain tumors. Ultraschall in der Medizin— European Journal of Ultrasound. 2007;**29**(01):45-52

[42] Harrer JU. Second harmonic imaging: A new ultrasound technique to assess human brain tumour perfusion. Journal of Neurology, Neurosurgery and Psychiatry. 2003;**74**(3):333-342

[43] Wu DF et al. Using real-time fusion imaging constructed from contrast-enhanced ultrasonography and magnetic resonance imaging for highgrade glioma in neurosurgery. World Neurosurgery. 2019;**125**:e98-e109

[44] Wu D-F et al. The real-time ultrasonography for fusion image in glioma neurosurgery. Clinical Neurology and Neurosurgery. 2018;**175**:84-90

[45] Lekht I et al. Versatile utilization of real-time intraoperative contrastenhanced ultrasound in cranial neurosurgery: Technical note and retrospective case series. Neurosurgical Focus. 2016;**40**(3):E6

[46] Vicenzini E et al. Semiquantitative human cerebral perfusion assessment with ultrasound in brain spaceoccupying lesions: Preliminary data. Journal of Ultrasound in Medicine. 2008;**27**(5):685-692

[47] Mattei L et al. Differentiating brain radionecrosis from tumour recurrence: A role for contrast-enhanced ultrasound? Acta Neurochirurgica. 2017;**159**(12):2405-2408

[48] Engelhardt M et al. Feasibility of contrast-enhanced Sonography during resection of cerebral tumours: Initial results of a prospective study. Ultrasound in Medicine and Biology. 2007;**33**(4):571-575

[49] Vetrano I et al. Intraoperative ultrasound and contrast-enhanced ultrasound (CEUS) features in a case of intradural extramedullary dorsal schwannoma mimicking an intramedullary lesion. Ultraschall in der Medizin—European Journal of Ultrasound. 2015: p. s-0034-1399669

[50] Vetrano IG et al. Discrete or diffuse intramedullary tumor? Contrast-enhanced intraoperative ultrasound in a case of intramedullary cervicothoracic hemangioblastomas mimicking a diffuse infiltrative glioma: Technical note and case report. Neurosurgical Focus. 2015;**39**(2):E17

[51] Acerbi F et al. Indocyanine green and contrast-enhanced ultrasound videoangiography: A synergistic approach for real-time verification of distal revascularization and aneurysm occlusion in a complex distal middle cerebral artery aneurysm. World Neurosurgery. 2019;**125**:277-284

[52] Scerrati A et al. Indocyanine green video-angiography in neurosurgery: A glance beyond vascular applications. Clinical Neurology and Neurosurgery. 2014;**124**:106-113

[53] Bertuccio A et al. Intracranial and spinal dural arterio-venous fistula (DAVF): A surgical series of 107 patients. Acta Neurochirurgica. Supplement. 2016;**123**:177-183

[54] Della Pepa GM et al. Angioarchitectural features of high-grade intracranial dural arteriovenous fistulas: Correlation with aggressive clinical presentation and hemorrhagic risk. Neurosurgery. 2017;**81**(2):315-330

[55] Signorelli F et al. Diagnosis and management of dural arteriovenous fistulas: A 10 years single-center experience. Clinical Neurology and Neurosurgery. 2015;**128**:123-129

[56] Prada F et al. Spinal dural arteriovenous fistula: Is there a role for intraoperative contrast-enhanced ultrasound? World Neurosurgery. 2017;**100**:712.e15-712.e18

[57] Federlein J et al. Ultrasonic evaluation of pathological brain perfusion in acute stroke using second harmonic imaging. Journal of Neurology, Neurosurgery, and Psychiatry. 2000;**69**(5):616-622

[58] Seidel G et al. Perfusion harmonic imaging in acute middle cerebral artery infarction. Ultrasound in Medicine and Biology. 2003;**29**(9):1245-1251

[59] Wiesmann M et al. Parametric perfusion imaging with contrast-enhanced ultrasound in acute ischemic stroke. Stroke. 2004;**35**(2):508-513

[60] Rafailidis V et al. Contrastenhanced ultrasound of the carotid system: A review of the current literature. Journal of Ultrasound. 2017;**20**(2):97-109

[61] Ballotta E et al. Carotid endarterectomy for symptomatic low-grade carotid stenosis. Journal of Vascular Surgery. 2014;**59**(1):25-31

[62] Hamada O et al. Contrastenhanced ultrasonography for detecting histological carotid plaque rupture: Quantitative analysis of ulcer. International Journal of Stroke. 2016;**11**(7):791-798

[63] Amamoto T et al. Intra-plaque vessels on contrast-enhanced ultrasound sonography predict carotid plaque histology. Cerebrovascular Diseases. 2018;**46**(5-6):265-269

**105**

*Oncological, Vascular, and Spinal Uses of Contrast-Enhanced Ultrasound in Neurosurgery*

*DOI: http://dx.doi.org/10.5772/intechopen.91320*

histopathology of carotid plaques and serum high sensitive C-reactive protein levels in patients undergoing carotid endarterectomy. Journal of Huazhong University of Science and Technology. Medical Sciences. 2017;**37**(3):425-428

[65] Schmidt C et al. Identification of neovascularization by contrast– enhanced ultrasound to detect unstable carotid stenosis. PLoS One.

[66] Shao A et al. Comparison of carotid artery endarterectomy and carotid artery stenting in patients with atherosclerotic carotid stenosis. The Journal of Craniofacial Surgery.

[67] Oikawa K et al. Preoperative cervical carotid artery contrastenhanced ultrasound findings are associated with development of microembolic signals on transcranial Doppler during carotid exposure in endarterectomy. Atherosclerosis.

[68] Motoyama R et al. Utility of complementary magnetic resonance plaque imaging and contrast-enhanced ultrasound to detect carotid vulnerable plaques. Journal of the American Heart Association. 2019;**8**(8). [Epub ahead of

[69] Shimada H et al. Evaluation of the time-dependent changes and the vulnerability of carotid plaques using contrast-enhanced carotid ultrasonography. Journal of Stroke and Cerebrovascular Diseases.

2017;**12**(4):e0175331

2014;**25**(4):1441-1447

2017;**260**:87-93

2018;**27**(2):321-325

print]

[64] Xiong L et al. Correlation of enhancement degree on contrastenhanced ultrasound with

*Oncological, Vascular, and Spinal Uses of Contrast-Enhanced Ultrasound in Neurosurgery DOI: http://dx.doi.org/10.5772/intechopen.91320*

[64] Xiong L et al. Correlation of enhancement degree on contrastenhanced ultrasound with histopathology of carotid plaques and serum high sensitive C-reactive protein levels in patients undergoing carotid endarterectomy. Journal of Huazhong University of Science and Technology. Medical Sciences. 2017;**37**(3):425-428

*Neurosurgical Procedures - Innovative Approaches*

[55] Signorelli F et al. Diagnosis and management of dural arteriovenous fistulas: A 10 years single-center experience. Clinical Neurology and Neurosurgery. 2015;**128**:123-129

[56] Prada F et al. Spinal dural arteriovenous fistula: Is there a role for intraoperative contrast-enhanced ultrasound? World Neurosurgery.

[57] Federlein J et al. Ultrasonic evaluation of pathological brain perfusion in acute stroke using second harmonic imaging. Journal of Neurology, Neurosurgery, and Psychiatry. 2000;**69**(5):616-622

[58] Seidel G et al. Perfusion harmonic imaging in acute middle cerebral artery infarction. Ultrasound in Medicine and

Biology. 2003;**29**(9):1245-1251

[60] Rafailidis V et al. Contrastenhanced ultrasound of the carotid system: A review of the current literature. Journal of Ultrasound.

[61] Ballotta E et al. Carotid endarterectomy for symptomatic low-grade carotid stenosis. Journal of Vascular Surgery. 2014;**59**(1):25-31

[62] Hamada O et al. Contrastenhanced ultrasonography for detecting histological carotid plaque rupture: Quantitative analysis of ulcer. International Journal of Stroke.

[63] Amamoto T et al. Intra-plaque vessels on contrast-enhanced

ultrasound sonography predict carotid plaque histology. Cerebrovascular Diseases. 2018;**46**(5-6):265-269

perfusion imaging with contrast-enhanced ultrasound in acute ischemic stroke. Stroke.

2004;**35**(2):508-513

2017;**20**(2):97-109

2016;**11**(7):791-798

[59] Wiesmann M et al. Parametric

2017;**100**:712.e15-712.e18

[48] Engelhardt M et al. Feasibility of contrast-enhanced Sonography during resection of cerebral tumours: Initial results of a prospective study. Ultrasound in Medicine and Biology.

[49] Vetrano I et al. Intraoperative ultrasound and contrast-enhanced ultrasound (CEUS) features in a case of intradural extramedullary dorsal schwannoma mimicking an intramedullary lesion. Ultraschall in der Medizin—European Journal of Ultrasound. 2015: p. s-0034-1399669

[50] Vetrano IG et al. Discrete or diffuse intramedullary tumor? Contrast-enhanced intraoperative ultrasound in a case of intramedullary cervicothoracic hemangioblastomas mimicking a diffuse infiltrative

glioma: Technical note and case report. Neurosurgical Focus. 2015;**39**(2):E17

[51] Acerbi F et al. Indocyanine green and contrast-enhanced ultrasound videoangiography: A synergistic approach for real-time verification of distal revascularization and aneurysm occlusion in a complex distal middle cerebral artery aneurysm. World Neurosurgery. 2019;**125**:277-284

[52] Scerrati A et al. Indocyanine green video-angiography in neurosurgery: A glance beyond vascular applications. Clinical Neurology and Neurosurgery.

[53] Bertuccio A et al. Intracranial and spinal dural arterio-venous fistula (DAVF): A surgical series of 107 patients. Acta Neurochirurgica. Supplement. 2016;**123**:177-183

[54] Della Pepa GM et al. Angioarchitectural features of high-grade intracranial dural arteriovenous fistulas: Correlation with

aggressive clinical presentation and hemorrhagic risk. Neurosurgery.

2014;**124**:106-113

2017;**81**(2):315-330

2007;**33**(4):571-575

**104**

[65] Schmidt C et al. Identification of neovascularization by contrast– enhanced ultrasound to detect unstable carotid stenosis. PLoS One. 2017;**12**(4):e0175331

[66] Shao A et al. Comparison of carotid artery endarterectomy and carotid artery stenting in patients with atherosclerotic carotid stenosis. The Journal of Craniofacial Surgery. 2014;**25**(4):1441-1447

[67] Oikawa K et al. Preoperative cervical carotid artery contrastenhanced ultrasound findings are associated with development of microembolic signals on transcranial Doppler during carotid exposure in endarterectomy. Atherosclerosis. 2017;**260**:87-93

[68] Motoyama R et al. Utility of complementary magnetic resonance plaque imaging and contrast-enhanced ultrasound to detect carotid vulnerable plaques. Journal of the American Heart Association. 2019;**8**(8). [Epub ahead of print]

[69] Shimada H et al. Evaluation of the time-dependent changes and the vulnerability of carotid plaques using contrast-enhanced carotid ultrasonography. Journal of Stroke and Cerebrovascular Diseases. 2018;**27**(2):321-325

**107**

**Chapter 6**

**Abstract**

Brain Tumors

gliomas, and radiation necrosis.

System (Monteris, Inc.; approved in 2007).

**1. Introduction**

MR-Guided Laser Interstitial

Thermal Therapy for Treatment of

*Alexa Semonche, Evan Luther, Katherine Berry, Ashish Shah,* 

*Daniel Eichberg, Long Di, Michael Kader and Michael E. Ivan*

Minimally invasive technologies for intracranial lesions are a rapidly growing area of surgical neuro-oncology. Magnetic resonance (MR)-guided laser interstitial thermal therapy (LITT) is novel adjunctive therapy for patients who are poor candidates for open surgical resection. Recent developments in modern stereotaxy, fiber optics, and MR thermography imaging have improved the safety profile of LITT, enabling its emergence as an attractive alternative adjunct therapy for intracranial lesions which are deep-seated, refractory to standard therapies, or in patients with multiple comorbidities. In this chapter, we review the technological principles underlying LITT and provide a comprehensive, up-to-date summary of the evidence regarding the indications, outcomes, and limitations of LITT for a diverse array of intracranial tumors, including dural-based lesions, metastases,

**Keywords:** LITT, laser, glioma, glioblastoma, astrocytoma, ablation

**1.1 LITT surgical procedure and current commercial platforms**

LITT is a minimally invasive neurosurgical technique that delivers focused thermal energy from a laser light source via a fiber optic ensheathed in a catheter targeted to an intracranial lesion under stereotactic neuronavigation [1–6]. Currently, there are two Food and Drug Administration (FDA)-approved LITT platforms available for use in the United States: the Visualase Thermal Therapy System (Medtronic, Inc.; approved in 2009) and the Neuroblate Laser Ablation

The Visualase and Neuroblate LITT platforms share similar components and a standardized general workflow. The patient is first induced under general anesthesia or monitored anesthesia care (MAC). The trajectory for stereotactic placement of the laser catheter is planned using standard neuronavigation technology with preoperative T1-weighted gadolinium enhanced magnetic resonance imaging (MRI) studies. The trajectory should be planned so that the catheter traverses the longest axis of the lesion without risking injury to any critical

#### **Chapter 6**

## MR-Guided Laser Interstitial Thermal Therapy for Treatment of Brain Tumors

*Alexa Semonche, Evan Luther, Katherine Berry, Ashish Shah, Daniel Eichberg, Long Di, Michael Kader and Michael E. Ivan*

#### **Abstract**

Minimally invasive technologies for intracranial lesions are a rapidly growing area of surgical neuro-oncology. Magnetic resonance (MR)-guided laser interstitial thermal therapy (LITT) is novel adjunctive therapy for patients who are poor candidates for open surgical resection. Recent developments in modern stereotaxy, fiber optics, and MR thermography imaging have improved the safety profile of LITT, enabling its emergence as an attractive alternative adjunct therapy for intracranial lesions which are deep-seated, refractory to standard therapies, or in patients with multiple comorbidities. In this chapter, we review the technological principles underlying LITT and provide a comprehensive, up-to-date summary of the evidence regarding the indications, outcomes, and limitations of LITT for a diverse array of intracranial tumors, including dural-based lesions, metastases, gliomas, and radiation necrosis.

**Keywords:** LITT, laser, glioma, glioblastoma, astrocytoma, ablation

#### **1. Introduction**

#### **1.1 LITT surgical procedure and current commercial platforms**

LITT is a minimally invasive neurosurgical technique that delivers focused thermal energy from a laser light source via a fiber optic ensheathed in a catheter targeted to an intracranial lesion under stereotactic neuronavigation [1–6]. Currently, there are two Food and Drug Administration (FDA)-approved LITT platforms available for use in the United States: the Visualase Thermal Therapy System (Medtronic, Inc.; approved in 2009) and the Neuroblate Laser Ablation System (Monteris, Inc.; approved in 2007).

The Visualase and Neuroblate LITT platforms share similar components and a standardized general workflow. The patient is first induced under general anesthesia or monitored anesthesia care (MAC). The trajectory for stereotactic placement of the laser catheter is planned using standard neuronavigation technology with preoperative T1-weighted gadolinium enhanced magnetic resonance imaging (MRI) studies. The trajectory should be planned so that the catheter traverses the longest axis of the lesion without risking injury to any critical structures. Stereotactic registration of the laser catheter and trajectory planning can be performed using either a traditional headframe or frameless setup. Frameless stereotaxy requires an additional computed-tomography (CT) with fiducial markers, which is then merged with the pre-operative MRI for registration with neuronavigation.

Following stereotactic registration, a Precision Aiming Device (PAD) is aligned over the planned skull entry site using neuronavigation. A single 4 mm skin incision and burr hole is made over the entry point. The surgeon may elect to perform a concurrent needle biopsy for histopathological diagnosis. After this, a reducing cannula followed by the laser catheter is inserted through this burr hole using the PAD to ensure proper entry angle to follow the planned trajectory. Once the laser applicator probe's position is fixed using a plastic anchor bolt embedded in the skull, the patient is transferred, under anesthesia, to a MRI suite. Care is taken to prevent contamination in the operating room until T2 weighted MRI confirms the correct placement of the laser fiber. Then, near-infrared laser light (980 nm in the Visualase, system, 1064 nm in the Neuroblate system) is delivered through the fiber optic cable within the applicator probe to the target lesion. Following LITT treatment, the catheter is removed and the stab incision is closed with absorbable sutures. An example of the Visualase LITT catheter after stereotactic placement is shown in **Figure 1**.

The delivery of thermal energy to the intracranial target is controlled by several mechanisms. The fiber optic laser catheter is encased in a cooling sheath, through which cooled saline (in the Visualase system) or a C02 gas (in the Neuroblate system) is circulated. This mechanism prevents the heating of brain parenchyma along the catheter path so that thermal damage is restricted to the region surrounding the distal tip [7]. At the distal tip, the distribution of laser light to surrounding target tissue is controlled via a diffusing tip to produce a spherical zone of ablation centered at the tip. Available only in the NeuroBlate system, laser light can be delivered through a small aperture along the lateral surface of the distal catheter to provide a cone-shaped region of directional ablation.

Finally, real-time MR thermography is performed concurrently with laser ablation to generate a thermal damage estimate (TDE) heat map, i.e., a color-coded visual representation of cumulative thermal damage to structures on a T2-weighted MRI (**Figure 2**).

#### **Figure 1.**

*(A) Intraoperative setup showing precision aiming device (PAD) (white arrow) and stealth neuronavigation wand (Medtronic, Inc.) to set laser catheter trajectory. (B) MRI-compatible laser catheter and plastic bone anchor after stereotactic PAD-assisted intracranial placement.*

**109**

immediately post-LITT.

previously [14].

*MR-Guided Laser Interstitial Thermal Therapy for Treatment of Brain Tumors*

A computer workstation has software that allows the user to adjust laser output parameters and deliver laser energy in a series of doses until the TDE map covers the total area of the target. This is typically achieved with 10–15 W doses of laser light delivered in 30s–3 minutes intervals for a total of 10–30 minutes. The user also sets minimum and maximum temperature threshold markers on MR images defining the boundaries of the lesion. Minimum temperature markers ensure that temperatures sufficient for ablation are achieved within the target lesion volume (50–90°C), while maximum temperature thresholds ensure that off-target regions do not reach damaging temperatures [8]. Surpassing the maximum temperature threshold triggers automatic system shutoff [9]. The majority of patients have a

*(A) Real-time MR thermography provides a continuously updated heat map with concentric temperature zones. (B) Thermal damage estimate (TDE) mapping for LITT. Orange pixels estimate a zone of ablation* 

Post-operative T1-weighted gadolinium enhanced MRI is typically obtained on day one following LITT, 1–3 months post-operatively, and then at longer follow-up intervals depending on clinical status. There is a typical radiographic increase in size of the ablated lesion in the acute period following LITT, peaking around 3–4 days and reaching a 45% increase in cross-sectional area corresponding to a 75% increase in volume [12, 13]. The initial increase in size seen within the first 24 hours post-op likely represents the tendency to "over-ablate" lesions and is secondary to perilesional edema that is difficult to differentiate radiographically. A significant amount of size variability is also seen in these newly ablated lesions and is attributed to multiple factors including heterogeneous gadolinium dispersion during the ablation process, heterogeneous disruption of vascular integrity, and the "extreme" variability in the amount of edema surrounding the lesion. These findings clearly lead to imaging heterogeneity and suggest that an accurate measurement of the lesion would be difficult to obtain in the first 24 hours post-LITT. Therefore, it has been suggested that MRI is more accurate at determining LITT ablation size and shape at 24 hours post-ablation rather than

On T1-weighted gadolinium enhanced MRI, the thermal ablation zone has a thin enhancing rim with potential surrounding edema and enhancing residual blood products/protein coagulation [8]. Residual tumor remaining after subtotal ablation can be detected on this first post-operative scan. The extent of ablation can be determined by comparing volumetric analysis of the ablation zone postoperatively to the volume of the lesion on the pre-operative MRI, as described

hospital stay less than 48 hours following LITT [8–11].

*based on a user-set threshold for sufficient ablation temperature (typically 50°C).*

*DOI: http://dx.doi.org/10.5772/intechopen.88347*

**Figure 2.**

*MR-Guided Laser Interstitial Thermal Therapy for Treatment of Brain Tumors DOI: http://dx.doi.org/10.5772/intechopen.88347*

#### **Figure 2.**

*Neurosurgical Procedures - Innovative Approaches*

stereotactic placement is shown in **Figure 1**.

neuronavigation.

MRI (**Figure 2**).

structures. Stereotactic registration of the laser catheter and trajectory planning can be performed using either a traditional headframe or frameless setup. Frameless stereotaxy requires an additional computed-tomography (CT) with fiducial markers, which is then merged with the pre-operative MRI for registration with

Following stereotactic registration, a Precision Aiming Device (PAD) is aligned over the planned skull entry site using neuronavigation. A single 4 mm skin incision and burr hole is made over the entry point. The surgeon may elect to perform a concurrent needle biopsy for histopathological diagnosis. After this, a reducing cannula followed by the laser catheter is inserted through this burr hole using the PAD to ensure proper entry angle to follow the planned trajectory. Once the laser applicator probe's position is fixed using a plastic anchor bolt embedded in the skull, the patient is transferred, under anesthesia, to a MRI suite. Care is taken to prevent contamination in the operating room until T2 weighted MRI confirms the correct placement of the laser fiber. Then, near-infrared laser light (980 nm in the Visualase, system, 1064 nm in the Neuroblate system) is delivered through the fiber optic cable within the applicator probe to the target lesion. Following LITT treatment, the catheter is removed and the stab incision is closed with absorbable sutures. An example of the Visualase LITT catheter after

The delivery of thermal energy to the intracranial target is controlled by several mechanisms. The fiber optic laser catheter is encased in a cooling sheath, through which cooled saline (in the Visualase system) or a C02 gas (in the Neuroblate system) is circulated. This mechanism prevents the heating of brain parenchyma along the catheter path so that thermal damage is restricted to the region surrounding the distal tip [7]. At the distal tip, the distribution of laser light to surrounding target tissue is controlled via a diffusing tip to produce a spherical zone of ablation centered at the tip. Available only in the NeuroBlate system, laser light can be delivered through a small aperture along the lateral surface of the distal

Finally, real-time MR thermography is performed concurrently with laser ablation to generate a thermal damage estimate (TDE) heat map, i.e., a color-coded visual representation of cumulative thermal damage to structures on a T2-weighted

*(A) Intraoperative setup showing precision aiming device (PAD) (white arrow) and stealth neuronavigation wand (Medtronic, Inc.) to set laser catheter trajectory. (B) MRI-compatible laser catheter and plastic bone* 

*anchor after stereotactic PAD-assisted intracranial placement.*

catheter to provide a cone-shaped region of directional ablation.

**108**

**Figure 1.**

*(A) Real-time MR thermography provides a continuously updated heat map with concentric temperature zones. (B) Thermal damage estimate (TDE) mapping for LITT. Orange pixels estimate a zone of ablation based on a user-set threshold for sufficient ablation temperature (typically 50°C).*

A computer workstation has software that allows the user to adjust laser output parameters and deliver laser energy in a series of doses until the TDE map covers the total area of the target. This is typically achieved with 10–15 W doses of laser light delivered in 30s–3 minutes intervals for a total of 10–30 minutes. The user also sets minimum and maximum temperature threshold markers on MR images defining the boundaries of the lesion. Minimum temperature markers ensure that temperatures sufficient for ablation are achieved within the target lesion volume (50–90°C), while maximum temperature thresholds ensure that off-target regions do not reach damaging temperatures [8]. Surpassing the maximum temperature threshold triggers automatic system shutoff [9]. The majority of patients have a hospital stay less than 48 hours following LITT [8–11].

Post-operative T1-weighted gadolinium enhanced MRI is typically obtained on day one following LITT, 1–3 months post-operatively, and then at longer follow-up intervals depending on clinical status. There is a typical radiographic increase in size of the ablated lesion in the acute period following LITT, peaking around 3–4 days and reaching a 45% increase in cross-sectional area corresponding to a 75% increase in volume [12, 13]. The initial increase in size seen within the first 24 hours post-op likely represents the tendency to "over-ablate" lesions and is secondary to perilesional edema that is difficult to differentiate radiographically. A significant amount of size variability is also seen in these newly ablated lesions and is attributed to multiple factors including heterogeneous gadolinium dispersion during the ablation process, heterogeneous disruption of vascular integrity, and the "extreme" variability in the amount of edema surrounding the lesion. These findings clearly lead to imaging heterogeneity and suggest that an accurate measurement of the lesion would be difficult to obtain in the first 24 hours post-LITT. Therefore, it has been suggested that MRI is more accurate at determining LITT ablation size and shape at 24 hours post-ablation rather than immediately post-LITT.

On T1-weighted gadolinium enhanced MRI, the thermal ablation zone has a thin enhancing rim with potential surrounding edema and enhancing residual blood products/protein coagulation [8]. Residual tumor remaining after subtotal ablation can be detected on this first post-operative scan. The extent of ablation can be determined by comparing volumetric analysis of the ablation zone postoperatively to the volume of the lesion on the pre-operative MRI, as described previously [14].

### **2. Current applications of LITT in neuro-oncology**

#### **2.1 Patient selection**

LITT offers a minimally-invasive cytoreductive therapy for patients with surgically-inaccessible or treatment-refractory tumors who would likely not benefit from open surgical resection. Selection of appropriate cases for LITT is of primary concern. Over the past two decades, the first institutional experiences with LITT using MR thermography and modern stereotactic targeting were published, demonstrating both representative successes and complications associated with the procedure, including post-operative symptomatic edema, neurological deficit, and hemorrhage [4, 8, 15]. These results signaled the need to refine patient selection criteria to maximize changes of treatment success while minimizing risk of complications. From these initial studies in addition to our own institutional experiences [14, 16–18], we can summarize the following indications for LITT:


Additionally, we can summarize the following restrictions to best avoid procedural complications:


**111**

*MR-Guided Laser Interstitial Thermal Therapy for Treatment of Brain Tumors*

In the following sections we review the current state of LITT for treatment for a

Recent studies have shown that greater extent of surgical resection improves progression-free and overall survival in high-grade gliomas (HGGs) [22, 23]. Although HGGs inevitably recur, some patients may not be able to undergo conventional open surgical resection due to medical comorbidities, inability to tolerate general anesthesia, or have surgically inaccessible tumor locations. In addition, risk of neurological morbidity increases with repeat craniotomy and previous radiation therapy increases risk of impaired wound healing and radiation necrosis or secondary tumor formation [24]. Up to 40% of GBM tumors are considered surgically "unresectable" based on either their location in deep or eloquent brain regions or their proximity to critical neurovascular structures [14, 25]. For these patients, laser interstitial thermal therapy (LITT) provides an alternative option for cytore-

The first case series reporting the use of LITT in gliomas was published in 1990 by Sugiyama et al., which described the successful total ablation of five deep-seated gliomas. This has been followed by several larger case series for both recurrent and newly-diagnosed glioblastoma multiforme (GBM) [8, 10, 11, 15, 26–30]. In these series, median recurrence-free survival ranged from 1.5 to 14.3 months and overall survival ranged from 6.9 to 16 months. These reports are consistent with estimated median survival of 14.8 and 6 months for newly-diagnosed and recurrent gliomas under standard therapy, respectively [31]. Our institutional data for deep-seated (at least 2 cm from dura) newly diagnosed gliomas further evidenced the procedural safety and efficacy in 7 patients, with a median progression-free survival of 14.3 months and 85% patients remaining alive at 14 months follow-up. As such, LITT is an emerging safe adjuvant therapy for gliomas that are considered surgically inaccessible. A recent meta-analysis reported an overall survival of nearly 14 months (range: 0.1–23 months) for patients treated with LITT and adjuvant chemoradiation, which was comparable to reported outcomes after standard treat-

ment (gross total resection and adjuvant chemoradiation) [16, 32–34].

Although evidence is more limited for dural-based lesions, the published studies

to date support the safety and efficacy of LITT for these lesions. An initial case series by Ivan et al. reported outcomes in 5 patients with 3 recurrent low-grade meningiomas, 1 grade III malignant meningioma, and 1 solitary fibrous tumor. Ivan et al. report an average extent of ablation of 80% and a local control rate of 60% at a mean follow-up of 59.3 weeks. The procedure was well-tolerated in these patients with no complications reported [18]. Only one other case series of three patients has been reported [35]. Two patients had grade III anaplastic meningiomas while the third had a low-grade lesion. The authors report an average extent of ablation of 75% with 2 of 3 lesions recurring by 9 weeks. One patient experienced transient

In comparison to other reports of LITT for intracranial lesions, these studies report lower extent of ablation rates, which may be attributable to tissue consistency. In these studies, the presence of a grade III malignant meningioma complicates the picture regarding the efficacy of LITT for dural-based lesions. Nonetheless, the procedure is generally well-tolerated, justifying further investiga-

*DOI: http://dx.doi.org/10.5772/intechopen.88347*

variety of intracranial tumors.

**2.2 Glioma**

ductive therapy.

**2.3 Dural-based lesions**

hemiparesis with dysarthria, which resolved.

tion into its utility for these lesions.

In the following sections we review the current state of LITT for treatment for a variety of intracranial tumors.

#### **2.2 Glioma**

*Neurosurgical Procedures - Innovative Approaches*

**2.1 Patient selection**

structures).

radiation).

dural complications:

and impaired wound healing.

Performance Score (KPS) of at least 70.

the shortest trajectory involves eloquent tissue.

**2. Current applications of LITT in neuro-oncology**

[14, 16–18], we can summarize the following indications for LITT:

order to confer a significant survival benefit [16, 19–21].

LITT offers a minimally-invasive cytoreductive therapy for patients with surgically-inaccessible or treatment-refractory tumors who would likely not benefit from open surgical resection. Selection of appropriate cases for LITT is of primary concern. Over the past two decades, the first institutional experiences with LITT using MR thermography and modern stereotactic targeting were published, demonstrating both representative successes and complications associated with the procedure, including post-operative symptomatic edema, neurological deficit, and hemorrhage [4, 8, 15]. These results signaled the need to refine patient selection criteria to maximize changes of treatment success while minimizing risk of complications. From these initial studies in addition to our own institutional experiences

1.Anatomic location permits a reasonable expectation of an 80% ablation in

2.Lesion location is inaccessible via conventional open surgery (e.g., lesions located adjacent to deep structures such as the basal ganglia, thalamus, splenium, etc., in eloquent motor or speech areas, or near critical neurovascular

3.Lesions have failed previous treatments (i.e., previous craniotomy or

4.Patients have medical comorbidities, low pre-operative functional status, or history of previous craniotomy/radiation therapy who are unable to tolerate prolonged anesthesia, blood loss, or who are at high risk of surgical morbidity

5.Pediatrics: although cases must be carefully selected, there are currently no

Additionally, we can summarize the following restrictions to best avoid proce-

1.Functional status: patients should still have a pre-operative functional status appropriate for a minimally-invasive surgical procedure under anesthesia; in our institutional experience, patients are eligible if they have a Karnofsky

2.Lesion size: LITT should be limited to lesions with <3 cm diameter in any

3.LITT trajectory: careful precautions must be made while choosing a trajectory to avoid critical neurovascular structures. In some cases, passing through virgin white matter should take priority over creating the shorter trajectory if

guideline also reduces risk of damage to critical brain regions.

dimension. This size restriction stems from Jethwa et al., who reported the case of patient with a large (>3 cm) lesion treated with LITT who later underwent hemicraniectomy for medically-refractory post-ablation edema [8]. The <3 cm

changes in protocol for the use of LITT in pediatric neurosurgery.

**110**

Recent studies have shown that greater extent of surgical resection improves progression-free and overall survival in high-grade gliomas (HGGs) [22, 23]. Although HGGs inevitably recur, some patients may not be able to undergo conventional open surgical resection due to medical comorbidities, inability to tolerate general anesthesia, or have surgically inaccessible tumor locations. In addition, risk of neurological morbidity increases with repeat craniotomy and previous radiation therapy increases risk of impaired wound healing and radiation necrosis or secondary tumor formation [24]. Up to 40% of GBM tumors are considered surgically "unresectable" based on either their location in deep or eloquent brain regions or their proximity to critical neurovascular structures [14, 25]. For these patients, laser interstitial thermal therapy (LITT) provides an alternative option for cytoreductive therapy.

The first case series reporting the use of LITT in gliomas was published in 1990 by Sugiyama et al., which described the successful total ablation of five deep-seated gliomas. This has been followed by several larger case series for both recurrent and newly-diagnosed glioblastoma multiforme (GBM) [8, 10, 11, 15, 26–30]. In these series, median recurrence-free survival ranged from 1.5 to 14.3 months and overall survival ranged from 6.9 to 16 months. These reports are consistent with estimated median survival of 14.8 and 6 months for newly-diagnosed and recurrent gliomas under standard therapy, respectively [31]. Our institutional data for deep-seated (at least 2 cm from dura) newly diagnosed gliomas further evidenced the procedural safety and efficacy in 7 patients, with a median progression-free survival of 14.3 months and 85% patients remaining alive at 14 months follow-up. As such, LITT is an emerging safe adjuvant therapy for gliomas that are considered surgically inaccessible. A recent meta-analysis reported an overall survival of nearly 14 months (range: 0.1–23 months) for patients treated with LITT and adjuvant chemoradiation, which was comparable to reported outcomes after standard treatment (gross total resection and adjuvant chemoradiation) [16, 32–34].

#### **2.3 Dural-based lesions**

Although evidence is more limited for dural-based lesions, the published studies to date support the safety and efficacy of LITT for these lesions. An initial case series by Ivan et al. reported outcomes in 5 patients with 3 recurrent low-grade meningiomas, 1 grade III malignant meningioma, and 1 solitary fibrous tumor. Ivan et al. report an average extent of ablation of 80% and a local control rate of 60% at a mean follow-up of 59.3 weeks. The procedure was well-tolerated in these patients with no complications reported [18]. Only one other case series of three patients has been reported [35]. Two patients had grade III anaplastic meningiomas while the third had a low-grade lesion. The authors report an average extent of ablation of 75% with 2 of 3 lesions recurring by 9 weeks. One patient experienced transient hemiparesis with dysarthria, which resolved.

In comparison to other reports of LITT for intracranial lesions, these studies report lower extent of ablation rates, which may be attributable to tissue consistency. In these studies, the presence of a grade III malignant meningioma complicates the picture regarding the efficacy of LITT for dural-based lesions. Nonetheless, the procedure is generally well-tolerated, justifying further investigation into its utility for these lesions.

#### **2.4 Brain metastases**

LITT is a promising adjuvant therapy for recurrent brain metastases refractory to stereotactic radiosurgery (SRS). The first case series of LITT for brain metastases was reported by Carpentier et al. [41]. A subsequent Phase I clinical trial by the same authors, published in 2011, reported 6-month local control rates of 60 and 85% for partially and fully-ablated metastatic tumors, respectively [36]. In 2016, Ali et al. identified an 80% extent of ablation threshold, below which all cases eventually recurred [37]. Similarly, Ahluwalia et al. reported a 0% recurrence rate in 100% ablated lesions [38]. A recent systematic review found that reports of median overall survival after LITT for metastases ranged from 5.8 to 19.8 months [39]. Across studies, the most commonly reported complications were temporary neurologic deficit due to unintentional thermal ablation of eloquent structures, followed by hemorrhage. Although a 1–3 day period of post-operative edema on T2 FLAIR MRI sequences frequently occurs post-ablation, this typically resolves. In four rare instances of malignant edema requiring hemicraniectomy, the lesion volumes were far greater than 3 cm in diameter [39]. These recent studies support that LITT is safe and effective in cases where 80–100% lesional ablation can be achieved.

#### **2.5 Radiation necrosis**

LITT was first described for radiation necrosis (RN) by Rahmathulla et al. [40]. In this report, a single patient presented with progressive dysphagia following radiosurgery for brain metastasis almost 2 years prior. Because the symptoms did not respond to medical management with steroids, he was treated with LITT. Following LITT, he achieved steroid independence [40]. This study was followed by larger single-center retrospective case series which reported use of LITT for radiation necrosis with initial diagnoses of glioma or metastases. In these studies <50% of patients achieved steroid freedom, and up to 20% of patients required open craniotomy for surgical resection in the months following LITT [38]. In a study of LITT for radiation necrosis or post-radiosurgery recurrent metastasis, Rao et al., reported a median progression-free survival of 37 weeks with only 2 recurrences in 15 patients [5]. The authors concluded that LITT is a safe, well-tolerated procedure for patients with radiation necrosis or metastatic recurrence.

Our institutional experience with 20 patients with biopsy-proven RN between 2015 and 2018 also supports these conclusions (unpublished data). At 1 year follow-up, 80% of patients remained recurrence free, with a median progressionfree survival of 12.3 and 24.4 months overall survival. No permanent complications occurred (unpublished data).

Overall evidence supports LITT as a safe procedure for radiation necrosis that is medically refractory or surgically inaccessible. In these patients, steroid freedom as well as progression-free and overall survival are important clinical outcomes.

#### **3. Illustrative case series**

Here we present four cases of patients treated by the department of surgical neuro-oncology at the University of Miami illustrating the use of LITT for gliomas, dural-based lesions, brain metastases, and radiation necrosis.

#### **3.1 Case 1: recurrent glioma**

A 37-year-old female with previous history of left frontoparietal craniotomy and chemoradiation for high-grade glioma 2 years prior presented with progressive

**113**

**Figure 4.**

**Figure 3.**

*MR-Guided Laser Interstitial Thermal Therapy for Treatment of Brain Tumors*

lesion was ablated according to the following parameters:

free for 24.3 weeks with an overall survival of 1 year.

enhancement on surveillance MRI suggesting recurrence (**Figure 3A**). The patient was recommended LITT due to the lesion's proximity to the left motor strip. The

1.Test dose at 3 W for 30 seconds to confirm location of catheter tip on MR

3.Increase in laser power at 20% maximum intervals for 30 seconds—1.5 min-

The patient recovered without complications. Although some residual tumor was present on postoperative imaging (**Figure 3C**), the patient remained recurrence

A 65-year-old female with previous history of craniotomy for resection of a right parafalcine meningioma and subsequent craniectomy for a wound infection

*(A) A 37-year-old female with periventricular ring-enhancing mass abutting the left motor strip on axial T1-weighted MRI with contrast. (B) Intraoperative sagittal MRI showing laser catheter trajectory. (C) Immediate post-operative axial T1-weighted MRI with contrast demonstrating near-total lesional ablation.*

*(A) Pre-operative T1-weighted MRI with contrast showing recurrence of right parafalcine meningioma.* 

*(B) Post-operative T1-weighted MRI with contrast showing near-total lesional ablation.*

2.Increase in laser power to 50% maximum power for up to 3 minutes.

utes in series until maximal ablation zone is achieved (**Figure 3B**).

*DOI: http://dx.doi.org/10.5772/intechopen.88347*

thermography.

**3.2 Case 2: meningioma**

*MR-Guided Laser Interstitial Thermal Therapy for Treatment of Brain Tumors DOI: http://dx.doi.org/10.5772/intechopen.88347*

enhancement on surveillance MRI suggesting recurrence (**Figure 3A**). The patient was recommended LITT due to the lesion's proximity to the left motor strip. The lesion was ablated according to the following parameters:


The patient recovered without complications. Although some residual tumor was present on postoperative imaging (**Figure 3C**), the patient remained recurrence free for 24.3 weeks with an overall survival of 1 year.

#### **3.2 Case 2: meningioma**

*Neurosurgical Procedures - Innovative Approaches*

LITT is a promising adjuvant therapy for recurrent brain metastases refractory to stereotactic radiosurgery (SRS). The first case series of LITT for brain metastases was reported by Carpentier et al. [41]. A subsequent Phase I clinical trial by the same authors, published in 2011, reported 6-month local control rates of 60 and 85% for partially and fully-ablated metastatic tumors, respectively [36]. In 2016, Ali et al. identified an 80% extent of ablation threshold, below which all cases eventually recurred [37]. Similarly, Ahluwalia et al. reported a 0% recurrence rate in 100% ablated lesions [38]. A recent systematic review found that reports of median overall survival after LITT for metastases ranged from 5.8 to 19.8 months [39]. Across studies, the most commonly reported complications were temporary neurologic deficit due to unintentional thermal ablation of eloquent structures, followed by hemorrhage. Although a 1–3 day period of post-operative edema on T2 FLAIR MRI sequences frequently occurs post-ablation, this typically resolves. In four rare instances of malignant edema requiring hemicraniectomy, the lesion volumes were far greater than 3 cm in diameter [39]. These recent studies support that LITT is safe

and effective in cases where 80–100% lesional ablation can be achieved.

procedure for patients with radiation necrosis or metastatic recurrence.

2015 and 2018 also supports these conclusions (unpublished data). At 1 year follow-up, 80% of patients remained recurrence free, with a median progressionfree survival of 12.3 and 24.4 months overall survival. No permanent complications

Our institutional experience with 20 patients with biopsy-proven RN between

Overall evidence supports LITT as a safe procedure for radiation necrosis that is medically refractory or surgically inaccessible. In these patients, steroid freedom as well as progression-free and overall survival are important clinical outcomes.

Here we present four cases of patients treated by the department of surgical neuro-oncology at the University of Miami illustrating the use of LITT for gliomas,

A 37-year-old female with previous history of left frontoparietal craniotomy and chemoradiation for high-grade glioma 2 years prior presented with progressive

dural-based lesions, brain metastases, and radiation necrosis.

LITT was first described for radiation necrosis (RN) by Rahmathulla et al. [40]. In this report, a single patient presented with progressive dysphagia following radiosurgery for brain metastasis almost 2 years prior. Because the symptoms did not respond to medical management with steroids, he was treated with LITT. Following LITT, he achieved steroid independence [40]. This study was followed by larger single-center retrospective case series which reported use of LITT for radiation necrosis with initial diagnoses of glioma or metastases. In these studies <50% of patients achieved steroid freedom, and up to 20% of patients required open craniotomy for surgical resection in the months following LITT [38]. In a study of LITT for radiation necrosis or post-radiosurgery recurrent metastasis, Rao et al., reported a median progression-free survival of 37 weeks with only 2 recurrences in 15 patients [5]. The authors concluded that LITT is a safe, well-tolerated

**2.4 Brain metastases**

**2.5 Radiation necrosis**

occurred (unpublished data).

**3. Illustrative case series**

**3.1 Case 1: recurrent glioma**

**112**

A 65-year-old female with previous history of craniotomy for resection of a right parafalcine meningioma and subsequent craniectomy for a wound infection

#### **Figure 3.**

*(A) A 37-year-old female with periventricular ring-enhancing mass abutting the left motor strip on axial T1-weighted MRI with contrast. (B) Intraoperative sagittal MRI showing laser catheter trajectory. (C) Immediate post-operative axial T1-weighted MRI with contrast demonstrating near-total lesional ablation.*

#### **Figure 4.**

*(A) Pre-operative T1-weighted MRI with contrast showing recurrence of right parafalcine meningioma. (B) Post-operative T1-weighted MRI with contrast showing near-total lesional ablation.*

at an outside institution presented with progressive lesion regrowth over several MRI studies (**Figure 4A**). Because of her complicated surgical history, she was recommended LITT. Postoperative MRI imaging showed 97% extent of ablation (**Figure 4B**) and the patient recovered without complications. Patient remained recurrence free until non-neurologic death 4 years later.

#### **3.3 Case 3: metastasis**

A 31-year-old female with past medial history of metastatic breast cancer previously treated with whole brain radiation and stereotactic radiation for five intracranial metastatic lesions. She presented with headaches photophobia, dizziness, and fatigue. T1-weighted gadolinium enhanced MRI showed interval growth of one lesion in the right parietal lobe. Due to her extensive previous radiation history and the proximity of the lesion to the receptive speech area of the posterior left temporal lobe, the patient was treated with LITT, achieving near-total

#### **Figure 5.**

*(A) A 31-year-old female patient with recurrent metastatic breast cancer adjacent to the receptive speech area of the posterior temporal lobe. (B) Post-LITT procedure T1-weighted MRI shows lesional ablation.*

#### **Figure 6.**

*(A) A 69-year-old female patient with progressive enhancement after treatment of metastatic lung adenocarcinoma. (B) Post-LITT procedure T1-weighted MRI with contrast shows successful lesion ablation.*

**115**

**4.2 Limitations of LITT**

*MR-Guided Laser Interstitial Thermal Therapy for Treatment of Brain Tumors*

laser catheter placement confirmed diagnosis of radiation necrosis.

metastases, radiation necrosis, dural-based lesions, and gliomas. The advantage of LITT in treating intracranial lesions include:

therapy or other adjuvant therapy [10, 17].

ablation (**Figure 5B**). Patient remained recurrence free until last follow-up at

A 69-year-old woman with history of metastatic lung adenocarcinoma previously treated with open surgical resection and stereotactic radiosurgery presented with asymptomatic progressive enhancement on surveillance MRI (**Figure 6A**). Because of her treatment history, the patient elected to undergo LITT. Patient recovered without complications and remained recurrence free at last follow-up, over 1 year after LITT (**Figure 6B**). Intraoperative needle biopsy performed prior to

Technological advances in MR thermography and stereotactic surgery over the past two decades have facilitated the development of commercial LITT platforms. Evidence from both prospective and retrospective studies show that LITT is a safe alternative for cytoreduction in a wide variety of intracranial lesions, including

1.Cytoreductive therapy in poor open-surgical candidates: a minimally invasive approach through a single burr hole reduces the risk of morbidity associated with craniotomy for surgical resection. This is especially relevant for patients who previously underwent open craniotomy or maximal radiotherapy, who are at higher risk of neurological sequelae and wound infection with repeat craniotomy [21, 24] or in patients with tumors in deep or eloquent regions of

brain that would otherwise be considered surgically inaccessible.

2.Short procedure time: LITT has a shorter procedure time compared to open craniotomy. With shorter recovery times, LITT does not interrupt chemo-

3.Potential for repeated use: unlike stereotactic radiosurgery, LITT can be repeatedly applied and can thus be used as a salvage therapy in treatmentrefractory tumors while avoiding the increased risk of secondary malignancy

Patient selection is of critical importance to ensure safe and effective use of LITT. To summarize, lesions should be <3 cm in diameter, in a region that can be accessed via a linear laser catheter trajectory without injury to critical structures and in patients who are able to tolerate a minimally-invasive surgical procedure under anesthesia. In addition, the lesion should have identifiable margins such that at least 80% of the target area can be feasibly ablated with a roughly-spherical ablation zone.

Limitations of LITT include complications; the most common adverse events include intracranial hemorrhage and transient neurological deficit [10, 39, 41].

or radiation necrosis associated with ionizing radiation [7, 16].

*DOI: http://dx.doi.org/10.5772/intechopen.88347*

**4.1 Current role of LITT in neurosurgery**

16 months post-procedure.

**4. Discussion**

**3.4 Case 4: radiation necrosis**

ablation (**Figure 5B**). Patient remained recurrence free until last follow-up at 16 months post-procedure.

#### **3.4 Case 4: radiation necrosis**

A 69-year-old woman with history of metastatic lung adenocarcinoma previously treated with open surgical resection and stereotactic radiosurgery presented with asymptomatic progressive enhancement on surveillance MRI (**Figure 6A**). Because of her treatment history, the patient elected to undergo LITT. Patient recovered without complications and remained recurrence free at last follow-up, over 1 year after LITT (**Figure 6B**). Intraoperative needle biopsy performed prior to laser catheter placement confirmed diagnosis of radiation necrosis.

### **4. Discussion**

*Neurosurgical Procedures - Innovative Approaches*

**3.3 Case 3: metastasis**

recurrence free until non-neurologic death 4 years later.

at an outside institution presented with progressive lesion regrowth over several MRI studies (**Figure 4A**). Because of her complicated surgical history, she was recommended LITT. Postoperative MRI imaging showed 97% extent of ablation (**Figure 4B**) and the patient recovered without complications. Patient remained

A 31-year-old female with past medial history of metastatic breast cancer previously treated with whole brain radiation and stereotactic radiation for five intracranial metastatic lesions. She presented with headaches photophobia, dizziness, and fatigue. T1-weighted gadolinium enhanced MRI showed interval growth of one lesion in the right parietal lobe. Due to her extensive previous radiation history and the proximity of the lesion to the receptive speech area of the posterior left temporal lobe, the patient was treated with LITT, achieving near-total

*(A) A 31-year-old female patient with recurrent metastatic breast cancer adjacent to the receptive speech area* 

*of the posterior temporal lobe. (B) Post-LITT procedure T1-weighted MRI shows lesional ablation.*

*(A) A 69-year-old female patient with progressive enhancement after treatment of metastatic lung adenocarcinoma. (B) Post-LITT procedure T1-weighted MRI with contrast shows successful lesion ablation.*

**114**

**Figure 6.**

**Figure 5.**

#### **4.1 Current role of LITT in neurosurgery**

Technological advances in MR thermography and stereotactic surgery over the past two decades have facilitated the development of commercial LITT platforms. Evidence from both prospective and retrospective studies show that LITT is a safe alternative for cytoreduction in a wide variety of intracranial lesions, including metastases, radiation necrosis, dural-based lesions, and gliomas.

The advantage of LITT in treating intracranial lesions include:


Patient selection is of critical importance to ensure safe and effective use of LITT. To summarize, lesions should be <3 cm in diameter, in a region that can be accessed via a linear laser catheter trajectory without injury to critical structures and in patients who are able to tolerate a minimally-invasive surgical procedure under anesthesia. In addition, the lesion should have identifiable margins such that at least 80% of the target area can be feasibly ablated with a roughly-spherical ablation zone.

#### **4.2 Limitations of LITT**

Limitations of LITT include complications; the most common adverse events include intracranial hemorrhage and transient neurological deficit [10, 39, 41].

Intracranial hemorrhage may be secondary to laser catheter misplacement, offtarget thermal ablation, or (in the case of brain metastases) an underlying patient coagulopathy [8, 39, 42]. This risk can be reduced with preoperative neuroimaging (e.g., computed tomography angiogram (CTA)) to better inform laser trajectory planning. Estimates of hemorrhage range from 0.98 to 14.2% of cases [39, 42].

Permanent neurological deficits are rare [42], but transient neurological deficits have been reported to occur in up to 35% of patients [39, 42]. Examples of commonly reported neurological deficits include weakness, hemianopsia, seizures, and dysphagia are often attributed to direct thermal injury to functional brain areas or cerebral edema. Cerebral edema is frequently observed in the immediate post-operative period following LITT, but is unlikely to cause permanent neurological deficits and may be controlled with a short course of steroids. Treatment of large (>3 cm) or use of multiple laser probes or laser trajectories is associated with a higher risk of significant cerebral edema [43].

Rare (<5% of all cases) complications include permanent neurological deficit, malignant cerebral edema requiring hemicraniectomy, infection (e.g., ventriculitis, meningitis, or brain abscess), diabetes insipidus, hyponatremia, and intracranial hypertension. There are only two recorded deaths attributed to LITT in the literature, from postoperative meningitis and intracranial hemorrhage, respectively [44].

Another limitation of LITT is that it is only appropriate for certain patients. As discussed previously, previous treatment history, baseline neurological functional status, and anticipated extent of ablation are also factors that limit use of LITT to selected patients.

#### **4.3 Future directions**

Recent studies have focused on expanding the selection criteria for LITT, for example by staging the treatment of larger (>3 cm) lesions and application to other tumors, such as pediatric tuberous sclerosis and hypothalamic hamartomas [45]. In addition, the application of computer algorithms to better predict laser ablation dynamics may further improve the procedural safety profile [46].

Another body of research is investigating the secondary effects of LITT, including blood–brain barrier (BBB) disruption, which may offer a window of opportunity for enhanced delivery of chemotherapy [47, 48]. Other studies are investigating the potential immunostimulatory effects of LITT [49, 50]. In this sense, LITT could both ablate and facilitate a future antitumor immune response [51].

Finally, future investigations will require prospective, randomized-controlled trials to evaluate the clinical outcomes of LITT compared to other salvage therapies, such as repeat craniotomy or radiosurgery.

#### **5. Conclusion**

In this chapter we reviewed the current evidence regarding safety and efficacy of LITT for four types of intracranial lesions: gliomas, metastases, dural-based lesions, and radiation necrosis. Although future randomized controlled trials are necessary to compare clinical outcomes, the evidence so far supports LITT as a safe and viable minimally-invasive approach to cytoreduction in patients with gliomas that are poor open surgical candidates.

**117**

**Author details**

Long Di, Michael Kader and Michael E. Ivan\*

provided the original work is properly cited.

\*Address all correspondence to: mivan@med.miami.edu

*MR-Guided Laser Interstitial Thermal Therapy for Treatment of Brain Tumors*

Michael Ivan is a consultant for Medtronic. The other authors have no financial, personal, or institutional interests in any of the materials, devices, or drugs described in this article. Laser Ablation is only an Food and Drug Administration

Alexa Semonche, Evan Luther, Katherine Berry, Ashish Shah, Daniel Eichberg,

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

Department of Neurological Surgery, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, United States

*DOI: http://dx.doi.org/10.5772/intechopen.88347*

approved procedure for the ablation of soft tissue.

**Conflict of interest**

#### **Acknowledgements**

The authors have no source of financial support to report.

*MR-Guided Laser Interstitial Thermal Therapy for Treatment of Brain Tumors DOI: http://dx.doi.org/10.5772/intechopen.88347*

### **Conflict of interest**

*Neurosurgical Procedures - Innovative Approaches*

significant cerebral edema [43].

selected patients.

**5. Conclusion**

open surgical candidates.

**Acknowledgements**

**4.3 Future directions**

Intracranial hemorrhage may be secondary to laser catheter misplacement, offtarget thermal ablation, or (in the case of brain metastases) an underlying patient coagulopathy [8, 39, 42]. This risk can be reduced with preoperative neuroimaging (e.g., computed tomography angiogram (CTA)) to better inform laser trajectory planning. Estimates of hemorrhage range from 0.98 to 14.2% of cases [39, 42].

have been reported to occur in up to 35% of patients [39, 42]. Examples of commonly reported neurological deficits include weakness, hemianopsia, seizures, and dysphagia are often attributed to direct thermal injury to functional brain areas or cerebral edema. Cerebral edema is frequently observed in the immediate post-operative period following LITT, but is unlikely to cause permanent neurological deficits and may be controlled with a short course of steroids. Treatment of large (>3 cm) or use of multiple laser probes or laser trajectories is associated with a higher risk of

Permanent neurological deficits are rare [42], but transient neurological deficits

Rare (<5% of all cases) complications include permanent neurological deficit, malignant cerebral edema requiring hemicraniectomy, infection (e.g., ventriculitis, meningitis, or brain abscess), diabetes insipidus, hyponatremia, and intracranial hypertension. There are only two recorded deaths attributed to LITT in the literature, from postoperative meningitis and intracranial hemorrhage, respectively [44]. Another limitation of LITT is that it is only appropriate for certain patients. As discussed previously, previous treatment history, baseline neurological functional status, and anticipated extent of ablation are also factors that limit use of LITT to

Recent studies have focused on expanding the selection criteria for LITT, for example by staging the treatment of larger (>3 cm) lesions and application to other tumors, such as pediatric tuberous sclerosis and hypothalamic hamartomas [45]. In addition, the application of computer algorithms to better predict laser ablation

Another body of research is investigating the secondary effects of LITT, including blood–brain barrier (BBB) disruption, which may offer a window of opportunity for enhanced delivery of chemotherapy [47, 48]. Other studies are investigating the potential immunostimulatory effects of LITT [49, 50]. In this sense, LITT could

Finally, future investigations will require prospective, randomized-controlled trials to evaluate the clinical outcomes of LITT compared to other salvage therapies,

In this chapter we reviewed the current evidence regarding safety and efficacy of LITT for four types of intracranial lesions: gliomas, metastases, dural-based lesions, and radiation necrosis. Although future randomized controlled trials are necessary to compare clinical outcomes, the evidence so far supports LITT as a safe and viable minimally-invasive approach to cytoreduction in patients with gliomas that are poor

dynamics may further improve the procedural safety profile [46].

both ablate and facilitate a future antitumor immune response [51].

The authors have no source of financial support to report.

such as repeat craniotomy or radiosurgery.

**116**

Michael Ivan is a consultant for Medtronic. The other authors have no financial, personal, or institutional interests in any of the materials, devices, or drugs described in this article. Laser Ablation is only an Food and Drug Administration approved procedure for the ablation of soft tissue.

### **Author details**

Alexa Semonche, Evan Luther, Katherine Berry, Ashish Shah, Daniel Eichberg, Long Di, Michael Kader and Michael E. Ivan\* Department of Neurological Surgery, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Miami, United States

\*Address all correspondence to: mivan@med.miami.edu

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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2011;**115**(1):3-8

2003;**98**(6):1175-1181

2006;**59**(2):208-215

2013;**73**(6):1007-1017

[25] Fazeny-Dorner B, Wenzel C, Veitl M, Piribauer M, Rossler K, Dieckmann K, et al. Survival and prognostic factors of patients with unresectable glioblastoma multiforme. Anti-Cancer Drugs. 2003;**14**(4):305-312

[26] Schwarzmaier HJ, Eickmeyer F, von Tempelhoff W, Fiedler VU, Niehoff H, Ulrich SD, et al. MR-guided laserinduced interstitial thermotherapy of recurrent glioblastoma multiforme: Preliminary results in 16 patients. European Journal of Radiology.

[27] Hawasli AH, Bagade S, Shimony JS, Miller-Thomas M, Leuthardt EC. Magnetic resonance imaging-guided focused laser interstitial thermal therapy for intracranial lesions: Singleinstitution series. Neurosurgery.

[28] Mohammadi AM, Schroeder JL. Laser interstitial thermal therapy

*DOI: http://dx.doi.org/10.5772/intechopen.88347*

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[15] Schwarzmaier HJ, Eickmeyer F, von Tempelhoff W, Fiedler VU,

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[17] Diaz R, Ivan ME, Hanft S,

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[35] Rammo R, Scarpace L,

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[36] Carpentier A, McNichols RJ, Stafford RJ, Guichard JP, Reizine D, Delaloge S, et al. Laser thermal therapy: Real-time MRI-guided and computercontrolled procedures for metastatic brain tumors. Lasers in Surgery and Medicine. 2011;**43**(10):943-950

[37] Ali MA, Carroll KT, Rennert RC, Hamelin T, Chang L, Lemkuil BP, et al. Stereotactic laser ablation as treatment for brain metastases that recur after stereotactic radiosurgery: A multiinstitutional experience. Neurosurgical Focus. 2016;**41**(4):E11

[38] Ahluwalia M, Barnett GH, Deng D, Tatter SB, Laxton AW, Mohammadi AM, et al. Laser ablation after stereotactic radiosurgery: A multicenter prospective study in patients with metastatic brain tumors and radiation necrosis. Journal of Neurosurgery. 2018;**130**(3):804-811

[39] Alattar AA, Bartek J Jr, Chiang VL,

Sloan A, et al. Stereotactic laser ablation as treatment for brain metastases recurring after stereotactic

radiosurgery: A systematic literature

Mohammadi AM, Barnett GH,

review. World Neurosurgery. 2019;S1878-8750(19)31195-7

[40] Rahmathulla G, Recinos PF, Valerio JE, Chao S, Barnett GH. Laser interstitial thermal therapy for focal cerebral radiation necrosis: A case report and literature review. Stereotactic

and Functional Neurosurgery.

[41] Carpentier A, McNichols RJ, Stafford RJ, Itzcovitz J, Guichard JP, Reizine D, et al. Real-time magnetic resonance-guided laser thermal therapy for focal metastatic brain

2012;**90**(3):192-200

Akbari SHA, Kim AH, Tao Y, Luo J, et al. Glioblastoma treated with magnetic resonance imaging-guided laser interstitial thermal therapy: Safety, efficacy, and outcomes. Neurosurgery.

[30] Shah AH, Burks JD, Buttrick SS, Debs L, Ivan ME, Komotar RJ. Laser interstitial thermal therapy as a primary treatment for deep inaccessible gliomas. Neurosurgery. 2019;**84**(3):768-777

[31] Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, et al. Radiotherapy plus

concomitant and adjuvant

2005;**352**(10):987-996

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[32] Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant

temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. The Lancet Oncology. 2009;**10**(5):459-466

[33] Allahdini F, Amirjamshidi A, Reza-Zarei M, Abdollahi M. Evaluating the prognostic factors effective on the outcome of patients with glioblastoma multiformis: Does maximal resection of the tumor lengthen the median survival? World Neurosurgery. 2010;**73**(2):128-134. Discussion e16

[34] Lacroix M, Abi-Said D, Fourney DR, Gokaslan ZL, Shi W, DeMonte F, et al. A multivariate analysis of 416 patients with glioblastoma multiforme: Prognosis, extent of resection, and survival. Journal of Neurosurgery. 2001;**95**(2):190-198

in treatment of brain tumors—The neuroblate system. Expert Review of Medical Devices. 2014;**11**(2):109-119

[29] Kamath AA, Friedman DD,

2019;**84**(4):836-843

**120**

[42] Pruitt R, Gamble A, Black K, Schulder M, Mehta AD. Complication avoidance in laser interstitial thermal therapy: Lessons learned. Journal of Neurosurgery. 2017;**126**(4):1238-1245

[43] Ashraf O, Patel NV, Hanft S, Danish SF. Laser-induced thermal therapy in neuro-oncology: A review. World Neurosurgery. 2018;**112**:166-177

[44] Mohammadi AM, Hawasli AH, Rodriguez A, Schroeder JL, Laxton AW, Elson P, et al. The role of laser interstitial thermal therapy in enhancing progression-free survival of difficult-to-access high-grade gliomas: A multicenter study. Cancer Medicine. 2014;**3**(4):971-979

[45] Xu DS, Chen T, Hlubek RJ, Bristol RE, Smith KA, Ponce FA, et al. Magnetic resonance imaging-guided laser interstitial thermal therapy for the treatment of hypothalamic hamartomas: A retrospective review. Neurosurgery. 2018;**83**(6):1183-1192

[46] Jermakowicz WJ, Mahavadi AK, Cajigas I, Dan L, Guerra S, Farooq G, et al. Predictive modeling of brain tumor laser ablation dynamics. Journal of Neuro-Oncology. 2019;**144**(1):193-203

[47] Sabel M, Rommel F, Kondakci M, Gorol M, Willers R, Bilzer T. Locoregional opening of the rodent blood-brain barrier for paclitaxel using Nd:YAG laser-induced thermo therapy: A new concept of adjuvant glioma therapy? Lasers in Surgery and Medicine. 2003;**33**(2):75-80

[48] Leuthardt EC, Duan C, Kim MJ, Campian JL, Kim AH, Miller-Thomas MM, et al. Hyperthermic laser ablation of recurrent glioblastoma leads to temporary disruption of the peritumoral blood brain barrier. PLoS One. 2016;**11**(2):e0148613

[49] Vogl TJ, Straub R, Eichler K, Woitaschek D, Mack MG. Malignant liver tumors treated with MR imagingguided laser-induced thermotherapy: Experience with complications in 899 patients (2,520 lesions). Radiology. 2002;**225**(2):367-377

[50] Ivarsson K, Myllymaki L, Jansner K, Stenram U, Tranberg KG. Resistance to tumour challenge after tumour laser thermotherapy is associated with a cellular immune response. British Journal of Cancer. 2005;**93**(4):435-440

[51] Axelsson A, Pantaleone C, Astrom S. Initial findings of immunostimulating interstitial laser thermotherapy of solid tumors. Journal for Clinical Studies. 2017;**9**:28-31

**123**

further to its poor immunogenicity [1].

**Chapter 7**

**Abstract**

immune checkpoint molecules

**1. Introduction**

Immunotherapy for Glioblastomas

Glioblastoma (GBM), a WHO grade IV brain tumor, is an aggressive tumor with

poor prognosis; even with current standard care of triple therapy, consisting of surgical resection, chemo and radiation therapy, the patients' median survival time is only approximately 15 months. Recent practice shows that immunotherapy made some progress in some other solid tumors, like melanoma or non-small cell lung cancer. This chapter is going to review some advances in immunotherapy for GBM.

**Keywords:** glioblastoma (GBM), Blood-brain barrier (BBB), immunotherapy, epidermal growth factor receptor variant III (EGFRvIII), AMG 595 monoclonal antibody, vaccine, rindopepimut, T cells, PD-1 and PDL-1, overall survival (OS),

Glioblastoma (GBM), a World Health Organization (WHO) designed grade IV tumor, is an aggressive and most lethal form of brain tumor with extremely poor prognosis. Although there exists a standard triple therapy (surgical, chemo and radiation), the average survival time for patients with GBM is less than 2 years. Due to the presence of blood-brain barrier (BBB), a naturally made special structure of the vascular wall inside brain parenchyma, it allows only smaller molecules get through the BBB into brain parenchyma, which makes it even more difficult for the chemotherapeutic agent to reach the target tumor cells. In addition, due to the infiltration nature of this tumor, surgical resection with GTR (gross total resection) without damage the brain function is almost impossible to archive. Radiation therapy may produce some partial control of the tumor; at the same time, it not only induces radiation necrosis but also causes additional mutation of the tumor. On the other hand, in contrast to mutations of many other solid tumors from other organ systems, most glioma-associated mutations offer slightly better prognosis for the patients, making the target therapy to those mutations less significant and less important. As mentioned above, it is vitally important and necessary to develop a minimally invasive and greatly effective method for treating the glioblastoma. In this regard, novel GBM treatments including immunotherapy are being investigated [1]. Key challenges in glioma-specific immunotherapy as with many other cancers are the limited immunogenicity of the cancer cells and the immunosuppressive environment of the tumor. Although specific antigens have been identified in several cancers, brain tumors, such as GBM, are considered poorly immunogenic [1]. In addition, the tumor's heterogeneity and its consistent mutations may contribute

*Wan-Ming Hu, Frank Y. Shan, Sanjib Mukherjee,* 

*Danijela Levacic and Jason H. Huang*

#### **Chapter 7**

## Immunotherapy for Glioblastomas

*Wan-Ming Hu, Frank Y. Shan, Sanjib Mukherjee, Danijela Levacic and Jason H. Huang*

#### **Abstract**

Glioblastoma (GBM), a WHO grade IV brain tumor, is an aggressive tumor with poor prognosis; even with current standard care of triple therapy, consisting of surgical resection, chemo and radiation therapy, the patients' median survival time is only approximately 15 months. Recent practice shows that immunotherapy made some progress in some other solid tumors, like melanoma or non-small cell lung cancer. This chapter is going to review some advances in immunotherapy for GBM.

**Keywords:** glioblastoma (GBM), Blood-brain barrier (BBB), immunotherapy, epidermal growth factor receptor variant III (EGFRvIII), AMG 595 monoclonal antibody, vaccine, rindopepimut, T cells, PD-1 and PDL-1, overall survival (OS), immune checkpoint molecules

#### **1. Introduction**

Glioblastoma (GBM), a World Health Organization (WHO) designed grade IV tumor, is an aggressive and most lethal form of brain tumor with extremely poor prognosis. Although there exists a standard triple therapy (surgical, chemo and radiation), the average survival time for patients with GBM is less than 2 years. Due to the presence of blood-brain barrier (BBB), a naturally made special structure of the vascular wall inside brain parenchyma, it allows only smaller molecules get through the BBB into brain parenchyma, which makes it even more difficult for the chemotherapeutic agent to reach the target tumor cells. In addition, due to the infiltration nature of this tumor, surgical resection with GTR (gross total resection) without damage the brain function is almost impossible to archive. Radiation therapy may produce some partial control of the tumor; at the same time, it not only induces radiation necrosis but also causes additional mutation of the tumor. On the other hand, in contrast to mutations of many other solid tumors from other organ systems, most glioma-associated mutations offer slightly better prognosis for the patients, making the target therapy to those mutations less significant and less important. As mentioned above, it is vitally important and necessary to develop a minimally invasive and greatly effective method for treating the glioblastoma. In this regard, novel GBM treatments including immunotherapy are being investigated [1]. Key challenges in glioma-specific immunotherapy as with many other cancers are the limited immunogenicity of the cancer cells and the immunosuppressive environment of the tumor. Although specific antigens have been identified in several cancers, brain tumors, such as GBM, are considered poorly immunogenic [1]. In addition, the tumor's heterogeneity and its consistent mutations may contribute further to its poor immunogenicity [1].

Immunotherapy has garnered increasing support in recent years as a treatment for brain tumors. The immune system has a tremendous capacity for targeting and eliminating tumor cells while sparing normal tissues. Following decades of preclinical development and success in other solid and blood-borne neoplasms, many immunotherapies are now being investigated in patients with GBM. Immunotherapeutic classes currently under investigation in patients with GBM include various vaccination strategies, adoptive T-cell immunotherapy, immune checkpoint blockage, monoclonal antibodies, and cytokine therapy. Trails include patients with either primary or recurrent GBM.

#### **2. Vaccine therapy**

#### **2.1 Adoptive T-cell immunotherapy (ALT)**

Over the past decade, the FDA has approved emerging immunotherapies for a variety of cancers [2]. At present, many studies have proven that the brain is no longer an immune-exempt organ, and there are many interactions between tumors and the brain immune system [3, 4]. The fully functional T-cell bank plays an important part in maintaining immune surveillance and initiating antitumor immune responses. However, glioblastoma (GBM) is particularly good at destroying antitumor immunity and causing severe T-cell dysfunction. In GBM patients, both local and systemic immunosuppressive disorders impair any possible antitumor response. Woroniecka et al. [5] have analyzed and summarized the categories and molecular mechanisms of T-cell dysfunction in GBMs, including senescence, tolerance, anergy, exhaustion, and ignorance.

Adoptive T-cell therapy for brain tumors has received increasing attention as a breakthrough emerging therapy. Adoptive T-cell therapy refers to engineering specific T cells to target the tumor cells and recognize tumor-specific antigens, and eventually cause tumor cells to die through the immune response. Because T-cell immune response is strong and specific, it can distinguish tumor tissue from healthy tissue, and can target malignant cells to prevent distant metastasis, and T cells can proliferate to maintain therapeutic effect. Currently, T-cell immunotherapy includes three types of tumor infiltrating lymphocytes (TIL), T-cell receptor (TCR), and chimeric antigen receptor (CAR). Among them, CAR T-cell therapy is the only therapy that has made significant progress in clinical application. Chimeric antigen receptor T (CAR T) cell therapy refers to using the patient's own T lymphocytes, which have been re-engineered, loaded with receptors and co-stimulatory molecules that recognize tumor antigens, and expanded into the patient's body after in vitro expansion to identify and attack their own tumor cell. GBM cells can express a variety of antigens, such as human epidermal growth factor receptor 2 (HER2), interleukin 13 receptor subunit α-2 (IL13Rα2), ephrin-A2 (EphA2), and epidermal growth factor receptor variant III (EGFRvIII), which have been successfully targeted using chimeric antigen receptors T cells (CARs-T) in preclinical models [6].

Studies have shown that CAR T cells targeting EGFRvIII play a role in the treatment of GBM, and multiple trials are ongoing or under preparation. A Phase I study involving 10 patients with relapsed GBM demonstrates the safety and feasibility of EGFRvIII CAR T-cell therapy [7]. IL13Rα2-CARsT cells can produce cytokines, including interferon γ (IFNγ) and tumor necrosis factor-α (TNF-α), and display cytolytic activity by generating a pro-inflammatory microenvironment in mice bearing gliomas. Phase I trials (NCT00730613) for recurrent GBM have been completed and promising results have been shown [8]. Another IL13Ra2-targeted CAR

**125**

**2.2 Peptide vaccine**

immunogenicity of peptide [1].

*Immunotherapy for Glioblastomas*

challenges.

*DOI: http://dx.doi.org/10.5772/intechopen.91759*

T-cell therapy for patients with recurrent GBM has also shown significant effects [1–7]. Ahmed and colleagues reported a Phase I study involving 17 HER2 + GBM patients treated with HER2-specific CAR-modified virus-specific T cells, which

Although CAR T cells have high therapeutic potential, complex GBM biological characteristics and tumor microenvironment make CAR T-cell therapy also face

In the future, with the continuous deepening of research, adoptive T-cell strategies

ALT therapy has now evolved to leverage advances in gene engineering and retroviral delivery. Patient-derived T cells can be engineered with antigen-specific T-cell receptors (TCRs) or tumor-specific chimeric antigen receptors (CARs) to confer target recognition independent of and in addition to naturally occurring TCRs. The best studied of these T-cell modifications are CARs. CARs are synthetic receptors that couple the single-chain Fv fragment of a monoclonal antibody with various T-cell signaling molecules, thus endowing T cells with the antigen-specific recognition of the humoral compartment, the intracellular signaling required for cytotoxicity, and the co-stimulation necessary for sustained activity. As such, CAR T cells recognize target antigens without a need for MHC peptide presentation, circumventing one major mechanism of tumor immune escape-MHC downregulation. CAR T-cell therapy has demonstrated promising results and FDA approval for

Clinically, adoptive T-cell therapy has demonstrated its effectiveness with CAR-based treatment for CD19C B-cell malignancies. A clinical trial for 11 recurrent GBM patients has demonstrated infusions of autologous adoptively transferred human cytomegalovirus (CMV)-specific T cells increased OS to > 57 weeks, with four patients maintaining no progression throughout the study period [12].

Peptide vaccination concerns generation of vaccine based on peptide sequences representing a tumor antigen-specific target. Peptide vaccinations offer the advantage of high specificity and ease of antigen generation. Limitations include poor

Rindopepimut (CDX-110) is a 14mer amino acid peptide that spans the EGFRvIII mutation site conjugated with keyhole limpet hemocyanin (KLH). In a small singlearm Phase II multicenter trail, 18 patients with newly diagnosed GBM completing standard of care therapy were vaccinated with rindopepimut combined with

granulocyte-macrophage colony-stimulating factor (GM-CSF) resulting in a median OS of 26 months [4]. Overall, this vaccine was well tolerated with minimal toxicity.

CAR T cells cannot target intracellular proteins, and tumors may shed their targets and escape treatment. There may also be insufficient proliferation of T cells, resulting in treatment that is not durable. Some researchers are engineering and modifying T cells to improve their antitumor efficacy. Interleukin 12 is an effective pro-inflammatory cytokine. Yeku designed a CAR T cell that carries and expresses IL-12, and proved that the CAR T cell has enhanced proliferation ability, decreased apoptosis, and increased cells toxicity, thereby enhancing antitumor efficacy in ovarian peritoneal cancer [10]. Kevin Bielamowicz et al. created trivalent T cells with three specific CAR molecules (trivalent CAR T cells) to overcome the patient's antigenic variability in glioblastoma. Compared with monovalent and bivalent CAR T cells, trivalent CAR T cells mediate powerful immune synapses by forming more microtubule tissue centers between CAR T cells and tumor targets, and show

achieved safety, feasibility, and anti-GBM activity endpoint [9].

stronger cytotoxicity according to each patient [6].

hematological malignancy is expected shortly [11].

will definitely open up a bright path for GBM immunotherapy.

#### *Immunotherapy for Glioblastomas DOI: http://dx.doi.org/10.5772/intechopen.91759*

*Neurosurgical Procedures - Innovative Approaches*

**2. Vaccine therapy**

include patients with either primary or recurrent GBM.

**2.1 Adoptive T-cell immunotherapy (ALT)**

ance, anergy, exhaustion, and ignorance.

Immunotherapy has garnered increasing support in recent years as a treatment for brain tumors. The immune system has a tremendous capacity for targeting and eliminating tumor cells while sparing normal tissues. Following decades of preclinical development and success in other solid and blood-borne neoplasms, many immunotherapies are now being investigated in patients with GBM. Immunotherapeutic classes currently under investigation in patients with GBM include various vaccination strategies, adoptive T-cell immunotherapy, immune checkpoint blockage, monoclonal antibodies, and cytokine therapy. Trails

Over the past decade, the FDA has approved emerging immunotherapies for a variety of cancers [2]. At present, many studies have proven that the brain is no longer an immune-exempt organ, and there are many interactions between tumors and the brain immune system [3, 4]. The fully functional T-cell bank plays an important part in maintaining immune surveillance and initiating antitumor immune responses. However, glioblastoma (GBM) is particularly good at destroying antitumor immunity and causing severe T-cell dysfunction. In GBM patients, both local and systemic immunosuppressive disorders impair any possible antitumor response. Woroniecka et al. [5] have analyzed and summarized the categories and molecular mechanisms of T-cell dysfunction in GBMs, including senescence, toler-

Adoptive T-cell therapy for brain tumors has received increasing attention as a breakthrough emerging therapy. Adoptive T-cell therapy refers to engineering specific T cells to target the tumor cells and recognize tumor-specific antigens, and eventually cause tumor cells to die through the immune response. Because T-cell immune response is strong and specific, it can distinguish tumor tissue from healthy tissue, and can target malignant cells to prevent distant metastasis, and T cells can proliferate to maintain therapeutic effect. Currently, T-cell immunotherapy includes three types of tumor infiltrating lymphocytes (TIL), T-cell receptor (TCR), and chimeric antigen receptor (CAR). Among them, CAR T-cell therapy is the only therapy that has made significant progress in clinical application. Chimeric antigen receptor T (CAR T) cell therapy refers to using the patient's own T lymphocytes, which have been re-engineered, loaded with receptors and co-stimulatory molecules that recognize tumor antigens, and expanded into the patient's body after in vitro expansion to identify and attack their own tumor cell. GBM cells can express a variety of antigens, such as human epidermal growth factor receptor 2 (HER2), interleukin 13 receptor subunit α-2 (IL13Rα2), ephrin-A2 (EphA2), and epidermal growth factor receptor variant III (EGFRvIII), which have been successfully targeted using chimeric antigen receptors T cells (CARs-T) in preclinical

Studies have shown that CAR T cells targeting EGFRvIII play a role in the treatment of GBM, and multiple trials are ongoing or under preparation. A Phase I study involving 10 patients with relapsed GBM demonstrates the safety and feasibility of EGFRvIII CAR T-cell therapy [7]. IL13Rα2-CARsT cells can produce cytokines, including interferon γ (IFNγ) and tumor necrosis factor-α (TNF-α), and display cytolytic activity by generating a pro-inflammatory microenvironment in mice bearing gliomas. Phase I trials (NCT00730613) for recurrent GBM have been completed and promising results have been shown [8]. Another IL13Ra2-targeted CAR

**124**

models [6].

T-cell therapy for patients with recurrent GBM has also shown significant effects [1–7]. Ahmed and colleagues reported a Phase I study involving 17 HER2 + GBM patients treated with HER2-specific CAR-modified virus-specific T cells, which achieved safety, feasibility, and anti-GBM activity endpoint [9].

Although CAR T cells have high therapeutic potential, complex GBM biological characteristics and tumor microenvironment make CAR T-cell therapy also face challenges.

CAR T cells cannot target intracellular proteins, and tumors may shed their targets and escape treatment. There may also be insufficient proliferation of T cells, resulting in treatment that is not durable. Some researchers are engineering and modifying T cells to improve their antitumor efficacy. Interleukin 12 is an effective pro-inflammatory cytokine. Yeku designed a CAR T cell that carries and expresses IL-12, and proved that the CAR T cell has enhanced proliferation ability, decreased apoptosis, and increased cells toxicity, thereby enhancing antitumor efficacy in ovarian peritoneal cancer [10]. Kevin Bielamowicz et al. created trivalent T cells with three specific CAR molecules (trivalent CAR T cells) to overcome the patient's antigenic variability in glioblastoma. Compared with monovalent and bivalent CAR T cells, trivalent CAR T cells mediate powerful immune synapses by forming more microtubule tissue centers between CAR T cells and tumor targets, and show stronger cytotoxicity according to each patient [6].

In the future, with the continuous deepening of research, adoptive T-cell strategies will definitely open up a bright path for GBM immunotherapy.

ALT therapy has now evolved to leverage advances in gene engineering and retroviral delivery. Patient-derived T cells can be engineered with antigen-specific T-cell receptors (TCRs) or tumor-specific chimeric antigen receptors (CARs) to confer target recognition independent of and in addition to naturally occurring TCRs. The best studied of these T-cell modifications are CARs. CARs are synthetic receptors that couple the single-chain Fv fragment of a monoclonal antibody with various T-cell signaling molecules, thus endowing T cells with the antigen-specific recognition of the humoral compartment, the intracellular signaling required for cytotoxicity, and the co-stimulation necessary for sustained activity. As such, CAR T cells recognize target antigens without a need for MHC peptide presentation, circumventing one major mechanism of tumor immune escape-MHC downregulation. CAR T-cell therapy has demonstrated promising results and FDA approval for hematological malignancy is expected shortly [11].

Clinically, adoptive T-cell therapy has demonstrated its effectiveness with CAR-based treatment for CD19C B-cell malignancies. A clinical trial for 11 recurrent GBM patients has demonstrated infusions of autologous adoptively transferred human cytomegalovirus (CMV)-specific T cells increased OS to > 57 weeks, with four patients maintaining no progression throughout the study period [12].

#### **2.2 Peptide vaccine**

Peptide vaccination concerns generation of vaccine based on peptide sequences representing a tumor antigen-specific target. Peptide vaccinations offer the advantage of high specificity and ease of antigen generation. Limitations include poor immunogenicity of peptide [1].

Rindopepimut (CDX-110) is a 14mer amino acid peptide that spans the EGFRvIII mutation site conjugated with keyhole limpet hemocyanin (KLH). In a small singlearm Phase II multicenter trail, 18 patients with newly diagnosed GBM completing standard of care therapy were vaccinated with rindopepimut combined with granulocyte-macrophage colony-stimulating factor (GM-CSF) resulting in a median OS of 26 months [4]. Overall, this vaccine was well tolerated with minimal toxicity.

Another randomized Phase II trial including 65 newly diagnosed EGFRvIIIpositive patients with GBM was undertaken. Patients again received rindopepimut combined with GM-CSF following tumor resection and TMZ chemoradiation. The median OS was 24.6 months. Randomized Phase III clinical trial currently underway and initial Phase III data showed increased progression-free survival (PFS) and OS from point of diagnosis [1].

#### **3. Monoclonal antibodies to EGFRvIII**

The epidermal growth factor receptor (EGFR) gene expression is associated with a malignant phenotype in multiple cancers, like colon cancer, non-small cell lung cancer, head and neck squamous cell carcinoma, and GBM [13].

The EGFR gene amplification has been reported to be the most common genetic alteration in primary GBMs (40–70%) [13]. In approximately about 50–60% of GBMs with EGFR overexpressed, there is a specific type of EGFR gene variant generally called as EGFR variant III (EGFRvIII) [14]. EGFRvIII is the most common result of gene rearrangement after EGFR gene amplification [15–17]. Histone modification of gene enhancer on chromosome 7p12 leads to EGFRvIII formation [18]. Juxtaposition of EGFR exon 1 and 8 forms a novel glycine residue between these two exons. Deletion of EGFR exon 2–7 yields a truncated transmembrane protein receptor that lacks the extracellular ligand-binding domain but retains the constitutional tyrosine kinase activity that stimulates malignant growth [19, 20]. At present, there is no evidence of EGFRvIII expression in wild type human tissues [17, 21–25]. Thus, EGFRvIII serves as a unique tumor-specific antigen and is a candidate for targeted therapy [26]. EGFRvIII can show ligand-independent activity and continuously activate downstream signaling pathway [27, 28], which promotes proliferation, reduces apoptosis, enhances tumor cell xenograft ability, and increases angiogenesis and invasion [22, 27, 29–31].

According to current research, antibodies that target EGFRvIII for the treatment of gliomas include ABT-414 and AMG-595.

Depatuxizumab mafodotin (depatux-m, ABT-414) is a tumor-specific selection antibody drug conjugate (ADC) composed of an anti-EGFR antibody ABT-806 and a potent microtubule inhibitor (MMAF). Studies by Philips et al. have shown that ABT-414 can selectively kill the tumor cells with EGFRwt or EGFRvIII overexpressed tumor in vivo xenograft models and in vitro. ABT-414 combined with radiotherapy and chemotherapy can significantly inhibit tumor growth in vivo [32]. At present, the clinical trials for the treatment of glioma with ABT-414 mainly include NCT02343406, NCT02573324, NCT02590263, and NCT01800695.

AMG 595 is an antibody-drug conjugate comprising a fully humanized, anti-EGFRvIII monoclonal antibody linked to the maytansinoid DM1, a semisynthetic derivative of maytansine. AMG595 binds to EGFRvIII but not native EGFR; after binding, the AMG595-EGFRvIII complex is internalized via the lysosomal pathway, leading to the release of DM1 and mitotic arrest and potent growth inhibition [13]. AMG 595 exhibited favorable pharmacokinetics and is a unique therapy with possible benefit for some patients with EGFRvIII-mutated GBM with limited therapeutic options [26].

#### **4. Immune checkpoint blockade**

As early as 1863, Rudolf Virchow reported the inflammatory infiltration in tumor tissues and proposed an important connection between cancer and the

**127**

effects in GBM.

*Immunotherapy for Glioblastomas*

glioma models [34].

popular markers.

**4.1 PD-1 and PD-L1**

distribution of PD-L1 in GBM tissues.

*DOI: http://dx.doi.org/10.5772/intechopen.91759*

immune system [33]. In the following researches, the concept of "immune checkpoint molecules" was proposed. One of the important physiological functions of the immune checkpoint molecule is to keep the activation of the immune system within the normal range. Dysfunction of immunological checkpoint molecules can lead to immune evasion in many human tumors. Nowadays, immune checkpoint therapies are attracting a lot of attention from scientists who are devoted to cancer treatment. It has been recognized that coinhibitory receptors on T cells play an essential role in attenuating the strength and duration of T cell-mediated immune responses. These inhibitory receptors are referred to as immune checkpoint molecules, which are responsible for maintaining self-tolerance and preventing autoimmune reactions [34]. To date, the two most intensely investigated coinhibitory molecules are CTLA-4 (that acts early in T-cell activation) and PD1 (that blocks T cell at late stages of the immune response). It has been demonstrated that blockade of CTL4 and PD1 could induce tumor regression and promote long-term survival in mouse

Among a lot of immune checkpoint molecules, the membrane-bound molecules programmed death 1 (PD-1) and its ligand PD-L1 (PD-1/PD-L1) are the two most

The programmed cell death ligand 1 (PD-L1) protein belongs to the B7 family, and is widely expressed in almost all tumor cells as well as many normal cells. The combination of PD-L1 and PD-1 provides a strong inhibitory signal that inhibits the proliferation, activation, and infiltration of cytotoxic T lymphocytes (CTLs) [35, 36], thereby mediating the immunosuppressive effects of tumors. This is considered to be the major negative regulatory mechanism of CTLs in the cancer microenvironment. More importantly, in addition to binding to PD-1, PD-L1 can also bind to other co-stimulatory molecules such as CD28, CD80, and CTLA-4 in cancer cells [37], which indicates that PD-L1 can mediate a broader and more complex immune regulation mechanism. Therefore, it is important to analyze the expression and cell

Glioblastoma (GBM) creates immune evasion and suppression, thereby evading the body's immune system and promoting tumor growth. Despite standard management composed of the maximal surgical resection with the combination of radiation therapy and chemotherapy, the median survival time of GBM patients is only 12–15 months after diagnosis [38]. At present, it is found that immunological checkpoint proteins can be blocked by related checkpoint inhibitors, thus becoming a viable target for tumor therapy. Therefore, it is very meaningful to explore new immunotherapy to counteract the immunosuppressive effects in GBM, and necessary to explore new immunotherapy to counteract the immunosuppressive

**4.2 Expression and cell distribution of PD-L1 in human glioma tissues**

The PD-1 ligand, PD-L1 (also known has B7-H1), has been observed to be expressed in GBMs and GBM-associated macrophages, but the positivity rate in GBMs is controversial and highly variable, probably due to the selections of different antibodies by those researches [34, 39, 40]. Berghoff et al. [41] used a non-commercial anti-PD-L1 antibody, 5H1, showed membranous PD-L1 expression in 37.6% of newly diagnosed and 16.7% of recurrent GBMs, and diffuse/fibrillary PD-L1 expression in 84.4% of newly diagnosed and 72.2% of recurrent GBMs. However, in a study with 1035 GBM specimens using SP142 antibody, the positive rate of PD-L1 was only

#### *Immunotherapy for Glioblastomas DOI: http://dx.doi.org/10.5772/intechopen.91759*

*Neurosurgical Procedures - Innovative Approaches*

**3. Monoclonal antibodies to EGFRvIII**

OS from point of diagnosis [1].

and invasion [22, 27, 29–31].

of gliomas include ABT-414 and AMG-595.

Another randomized Phase II trial including 65 newly diagnosed EGFRvIIIpositive patients with GBM was undertaken. Patients again received rindopepimut combined with GM-CSF following tumor resection and TMZ chemoradiation. The median OS was 24.6 months. Randomized Phase III clinical trial currently underway and initial Phase III data showed increased progression-free survival (PFS) and

The epidermal growth factor receptor (EGFR) gene expression is associated with a malignant phenotype in multiple cancers, like colon cancer, non-small cell

The EGFR gene amplification has been reported to be the most common genetic alteration in primary GBMs (40–70%) [13]. In approximately about 50–60% of GBMs with EGFR overexpressed, there is a specific type of EGFR gene variant generally called as EGFR variant III (EGFRvIII) [14]. EGFRvIII is the most common result of gene rearrangement after EGFR gene amplification [15–17]. Histone modification of gene enhancer on chromosome 7p12 leads to EGFRvIII formation [18]. Juxtaposition of EGFR exon 1 and 8 forms a novel glycine residue between these two exons. Deletion of EGFR exon 2–7 yields a truncated transmembrane protein receptor that lacks the extracellular ligand-binding domain but retains the constitutional tyrosine kinase activity that stimulates malignant growth [19, 20]. At present, there is no evidence of EGFRvIII expression in wild type human tissues [17, 21–25]. Thus, EGFRvIII serves as a unique tumor-specific antigen and is a candidate for targeted therapy [26]. EGFRvIII can show ligand-independent activity and continuously activate downstream signaling pathway [27, 28], which promotes proliferation, reduces apoptosis, enhances tumor cell xenograft ability, and increases angiogenesis

According to current research, antibodies that target EGFRvIII for the treatment

Depatuxizumab mafodotin (depatux-m, ABT-414) is a tumor-specific selection antibody drug conjugate (ADC) composed of an anti-EGFR antibody ABT-806 and a potent microtubule inhibitor (MMAF). Studies by Philips et al. have shown that ABT-414 can selectively kill the tumor cells with EGFRwt or EGFRvIII overexpressed tumor in vivo xenograft models and in vitro. ABT-414 combined with radiotherapy and chemotherapy can significantly inhibit tumor growth in vivo [32]. At present, the clinical trials for the treatment of glioma with ABT-414 mainly

include NCT02343406, NCT02573324, NCT02590263, and NCT01800695.

AMG 595 is an antibody-drug conjugate comprising a fully humanized, anti-EGFRvIII monoclonal antibody linked to the maytansinoid DM1, a semisynthetic derivative of maytansine. AMG595 binds to EGFRvIII but not native EGFR; after binding, the AMG595-EGFRvIII complex is internalized via the lysosomal pathway, leading to the release of DM1 and mitotic arrest and potent growth inhibition [13]. AMG 595 exhibited favorable pharmacokinetics and is a unique therapy with possible benefit for some patients with EGFRvIII-mutated GBM with limited therapeu-

As early as 1863, Rudolf Virchow reported the inflammatory infiltration in tumor tissues and proposed an important connection between cancer and the

lung cancer, head and neck squamous cell carcinoma, and GBM [13].

**126**

tic options [26].

**4. Immune checkpoint blockade**

immune system [33]. In the following researches, the concept of "immune checkpoint molecules" was proposed. One of the important physiological functions of the immune checkpoint molecule is to keep the activation of the immune system within the normal range. Dysfunction of immunological checkpoint molecules can lead to immune evasion in many human tumors. Nowadays, immune checkpoint therapies are attracting a lot of attention from scientists who are devoted to cancer treatment.

It has been recognized that coinhibitory receptors on T cells play an essential role in attenuating the strength and duration of T cell-mediated immune responses. These inhibitory receptors are referred to as immune checkpoint molecules, which are responsible for maintaining self-tolerance and preventing autoimmune reactions [34]. To date, the two most intensely investigated coinhibitory molecules are CTLA-4 (that acts early in T-cell activation) and PD1 (that blocks T cell at late stages of the immune response). It has been demonstrated that blockade of CTL4 and PD1 could induce tumor regression and promote long-term survival in mouse glioma models [34].

Among a lot of immune checkpoint molecules, the membrane-bound molecules programmed death 1 (PD-1) and its ligand PD-L1 (PD-1/PD-L1) are the two most popular markers.

#### **4.1 PD-1 and PD-L1**

The programmed cell death ligand 1 (PD-L1) protein belongs to the B7 family, and is widely expressed in almost all tumor cells as well as many normal cells. The combination of PD-L1 and PD-1 provides a strong inhibitory signal that inhibits the proliferation, activation, and infiltration of cytotoxic T lymphocytes (CTLs) [35, 36], thereby mediating the immunosuppressive effects of tumors. This is considered to be the major negative regulatory mechanism of CTLs in the cancer microenvironment. More importantly, in addition to binding to PD-1, PD-L1 can also bind to other co-stimulatory molecules such as CD28, CD80, and CTLA-4 in cancer cells [37], which indicates that PD-L1 can mediate a broader and more complex immune regulation mechanism. Therefore, it is important to analyze the expression and cell distribution of PD-L1 in GBM tissues.

Glioblastoma (GBM) creates immune evasion and suppression, thereby evading the body's immune system and promoting tumor growth. Despite standard management composed of the maximal surgical resection with the combination of radiation therapy and chemotherapy, the median survival time of GBM patients is only 12–15 months after diagnosis [38]. At present, it is found that immunological checkpoint proteins can be blocked by related checkpoint inhibitors, thus becoming a viable target for tumor therapy. Therefore, it is very meaningful to explore new immunotherapy to counteract the immunosuppressive effects in GBM, and necessary to explore new immunotherapy to counteract the immunosuppressive effects in GBM.

#### **4.2 Expression and cell distribution of PD-L1 in human glioma tissues**

The PD-1 ligand, PD-L1 (also known has B7-H1), has been observed to be expressed in GBMs and GBM-associated macrophages, but the positivity rate in GBMs is controversial and highly variable, probably due to the selections of different antibodies by those researches [34, 39, 40]. Berghoff et al. [41] used a non-commercial anti-PD-L1 antibody, 5H1, showed membranous PD-L1 expression in 37.6% of newly diagnosed and 16.7% of recurrent GBMs, and diffuse/fibrillary PD-L1 expression in 84.4% of newly diagnosed and 72.2% of recurrent GBMs. However, in a study with 1035 GBM specimens using SP142 antibody, the positive rate of PD-L1 was only

19% [42]. Our own data, using the same standard in NSCLC (cutoff value was ≥1% of tumor cells expression), showed PD-L1 (clone number 28-8) expressed in 52% (69/133) of GBMs (see **Figure 1**).

#### **4.3 Prognostic value of PD-L1 in GBM patients**

Many studies have investigated the association between PD-L1 expression levels and the prognosis of GBM patients. But the results from different studies are non-conclusive. Nduom et al. [43] discovered that positive PD-L1 expression was associated with a poor prognosis, though this result has limited significance. Two recent studies have suggested that positive PD-L1 immunostaining in human GBM tissue means a poor prognosis [44, 45]. However, Berghoff et al. proposed the PD-L1 was not a negative predictor of survival [41], and Lee et al. [46] found the PD-L1 expression did not appear to be an independent factor for unfavorable prognosis according to multivariate analysis.

Efforts aimed at inhibiting the PD-1/PDL1 pathway have shown more promising results. In a preclinical study using the GL261 glioma mouse model, combination of anti-PD-1 antibodies and radiotherapy doubled median survival and elicited long-term survival in 15–40% of mice compared with either treatment alone [34]. Clinically, pembrolizumab, a PD-L1 antibody has been approved by the FDA, to apply in the treatment of metastatic melanoma and NSCLC. In GBM, nivolumab, another PD-1 antibody, developed for GBM patients is being tested with two clinical trials [34].

A randomized Phase III study aimed at testing nivolumab versus bevacizumab in recurrent GBM patients will also test combination therapy of nivolumab and ipilimumab. Another two Phase I/II trials will analyze the effectiveness of combinatorial pembrolizumab and bevacizumab, and combinatorial pembrolizumab with MRI-guided laser ablation in recurrent GBM patients. In addition, MED14736, a humanized PD-L1 mAb, is currently being tested in clinical trials for GBM patients combined with radiotherapy and bevacizumab [34].

Currently, immunological checkpoint inhibitor drugs associated with PD-L1 for the treatment of glioblastoma are undergoing relevant clinical trials. Nivolumab is a fully humanized IgG4 subtype programmed death-1 (PD-1) immune checkpoint inhibitor antibody that binds with high affinity to PD-1 receptors on T cells and blocks their interaction with PD-L1 and restores T-cell antitumor function. There are several clinical trials of nivolumab for GBMs. The first large-scale randomized clinical trial of Checkmate 143(NCT 02017717) evaluated the safety and efficacy

#### **Figure 1.**

*The positive staining of PD-L1 in tumor cells by immunohistochemical stain. The brown color of the glioma cell membrane indicates the positive staining.*

**129**

**5. Conclusion**

therapeutic treatment [12].

patients with GBM.

*Immunotherapy for Glioblastomas*

*DOI: http://dx.doi.org/10.5772/intechopen.91759*

patients compared with bevacizumab [48].

therapy was not effective for most GBM patients [50, 51].

ongoing clinical trial evaluating pidilizumab for GBM [52].

of nivolumab in GBM patients. In addition, the trial included a study comparing nivolumab monotherapy with bevacizumab in patients with recurrent GBM [47]. However, in the third phase of the clinical trial, 369 patients with first recurrence of GBM were recruited and it was found that nivolumab failed to prolong OS in

Pembrolizumab is another humanized monoclonal IgG4 anti-PD-1 antibody. Pembrolizumab was evaluated in 29 patients with high-grade malignant gliomas, including overall response rate (ORR) on contrast MRI, characterizing toxicities, progression-free survival (PFS), and overall survival (OS) [49]. Another trial about pembrolizumab showed that this drug is well tolerated, but the anti-PD-1 mono-

In addition, other PD-L1 immune checkpoint inhibitor drugs for GBM that are being studied include durvalumab, atezolizumab, pidilizumab, and so on. Durvalumab is a fully humanized immunoglobulin G1k monoclonal antibody that blocks the binding of PD-L1 to PD-1 and CD80, thereby enhancing the identification and killing of tumor cells by T cells. Atezolizumab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody directly targeting PD-L1. It prevents the interaction of PD-L1 with the receptors PD-1 and B7.1 by binding to L1. Currently, three open clinical trials (NCT 01375842, NCT02458638, and NCT03174197) are investigating atezolizumab in GBM patients. Pidilizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody directed against human PD-1 to block the combination between PD-1 and its ligands, PD-L1 and PD-L2. NCT01952769 is an

In future, besides PD-L1, more immune checkpoint inhibitors will be put into clinical trials to target this highly malignant brain tumor in future. Overall, the combination of various immune checkpoint modulators has shown promising effectiveness in the treatment of some solid tumors. The application of combinatorial checkpoint modulators in GBM and other tumors therefore requires further investigation into the interplay of co-stimulatory and coinhibitory molecules [34].

Although still in its infancy, immunotherapy for cancers has already shown significant effect against some types of malignancy, such as melanoma and lung cancer. Current open clinical trials of immunotherapy for GBM predominantly focus on dendritic cell (DC) vaccines and antibodies targeting immunosuppressive checkpoints have achieved promising immune activity and clinical responses. However, durable and sustained response remains rare, highlighting the need for novel promising approaches including gene therapy and combinatorial immuno-

Current obstacles for immune therapy for GBM lie in: (1) finding drugs to penetrate the BBB; (2) identifying specific, suitable, and immunogenic tumor antigens; and (3) identifying appropriate pre- and post-therapeutic biomarkers to reliably evaluate the treatment effect [34]. Additional research is necessary in the future to overcome those difficulties and identify a good treatment option or options for

#### *Immunotherapy for Glioblastomas DOI: http://dx.doi.org/10.5772/intechopen.91759*

*Neurosurgical Procedures - Innovative Approaches*

**4.3 Prognostic value of PD-L1 in GBM patients**

prognosis according to multivariate analysis.

combined with radiotherapy and bevacizumab [34].

cal trials [34].

(69/133) of GBMs (see **Figure 1**).

19% [42]. Our own data, using the same standard in NSCLC (cutoff value was ≥1% of tumor cells expression), showed PD-L1 (clone number 28-8) expressed in 52%

Many studies have investigated the association between PD-L1 expression levels and the prognosis of GBM patients. But the results from different studies are non-conclusive. Nduom et al. [43] discovered that positive PD-L1 expression was associated with a poor prognosis, though this result has limited significance. Two recent studies have suggested that positive PD-L1 immunostaining in human GBM tissue means a poor prognosis [44, 45]. However, Berghoff et al. proposed the PD-L1 was not a negative predictor of survival [41], and Lee et al. [46] found the PD-L1 expression did not appear to be an independent factor for unfavorable

Efforts aimed at inhibiting the PD-1/PDL1 pathway have shown more promising results. In a preclinical study using the GL261 glioma mouse model, combination of anti-PD-1 antibodies and radiotherapy doubled median survival and elicited long-term survival in 15–40% of mice compared with either treatment alone [34]. Clinically, pembrolizumab, a PD-L1 antibody has been approved by the FDA, to apply in the treatment of metastatic melanoma and NSCLC. In GBM, nivolumab, another PD-1 antibody, developed for GBM patients is being tested with two clini-

A randomized Phase III study aimed at testing nivolumab versus bevacizumab in recurrent GBM patients will also test combination therapy of nivolumab and ipilimumab. Another two Phase I/II trials will analyze the effectiveness of combinatorial pembrolizumab and bevacizumab, and combinatorial pembrolizumab with MRI-guided laser ablation in recurrent GBM patients. In addition, MED14736, a humanized PD-L1 mAb, is currently being tested in clinical trials for GBM patients

Currently, immunological checkpoint inhibitor drugs associated with PD-L1 for the treatment of glioblastoma are undergoing relevant clinical trials. Nivolumab is a fully humanized IgG4 subtype programmed death-1 (PD-1) immune checkpoint inhibitor antibody that binds with high affinity to PD-1 receptors on T cells and blocks their interaction with PD-L1 and restores T-cell antitumor function. There are several clinical trials of nivolumab for GBMs. The first large-scale randomized clinical trial of Checkmate 143(NCT 02017717) evaluated the safety and efficacy

*The positive staining of PD-L1 in tumor cells by immunohistochemical stain. The brown color of the glioma cell* 

**128**

**Figure 1.**

*membrane indicates the positive staining.*

of nivolumab in GBM patients. In addition, the trial included a study comparing nivolumab monotherapy with bevacizumab in patients with recurrent GBM [47]. However, in the third phase of the clinical trial, 369 patients with first recurrence of GBM were recruited and it was found that nivolumab failed to prolong OS in patients compared with bevacizumab [48].

Pembrolizumab is another humanized monoclonal IgG4 anti-PD-1 antibody. Pembrolizumab was evaluated in 29 patients with high-grade malignant gliomas, including overall response rate (ORR) on contrast MRI, characterizing toxicities, progression-free survival (PFS), and overall survival (OS) [49]. Another trial about pembrolizumab showed that this drug is well tolerated, but the anti-PD-1 monotherapy was not effective for most GBM patients [50, 51].

In addition, other PD-L1 immune checkpoint inhibitor drugs for GBM that are being studied include durvalumab, atezolizumab, pidilizumab, and so on. Durvalumab is a fully humanized immunoglobulin G1k monoclonal antibody that blocks the binding of PD-L1 to PD-1 and CD80, thereby enhancing the identification and killing of tumor cells by T cells. Atezolizumab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody directly targeting PD-L1. It prevents the interaction of PD-L1 with the receptors PD-1 and B7.1 by binding to L1. Currently, three open clinical trials (NCT 01375842, NCT02458638, and NCT03174197) are investigating atezolizumab in GBM patients. Pidilizumab is a humanized immunoglobulin (Ig) G1 monoclonal antibody directed against human PD-1 to block the combination between PD-1 and its ligands, PD-L1 and PD-L2. NCT01952769 is an ongoing clinical trial evaluating pidilizumab for GBM [52].

In future, besides PD-L1, more immune checkpoint inhibitors will be put into clinical trials to target this highly malignant brain tumor in future. Overall, the combination of various immune checkpoint modulators has shown promising effectiveness in the treatment of some solid tumors. The application of combinatorial checkpoint modulators in GBM and other tumors therefore requires further investigation into the interplay of co-stimulatory and coinhibitory molecules [34].

#### **5. Conclusion**

Although still in its infancy, immunotherapy for cancers has already shown significant effect against some types of malignancy, such as melanoma and lung cancer. Current open clinical trials of immunotherapy for GBM predominantly focus on dendritic cell (DC) vaccines and antibodies targeting immunosuppressive checkpoints have achieved promising immune activity and clinical responses. However, durable and sustained response remains rare, highlighting the need for novel promising approaches including gene therapy and combinatorial immunotherapeutic treatment [12].

Current obstacles for immune therapy for GBM lie in: (1) finding drugs to penetrate the BBB; (2) identifying specific, suitable, and immunogenic tumor antigens; and (3) identifying appropriate pre- and post-therapeutic biomarkers to reliably evaluate the treatment effect [34]. Additional research is necessary in the future to overcome those difficulties and identify a good treatment option or options for patients with GBM.

#### **Author details**

Wan-Ming Hu1 , Frank Y. Shan2 \*, Sanjib Mukherjee2 , Danijela Levacic2 and Jason H. Huang2

1 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou, P.R. China

2 Department of Neurosurgery and Cancer Center, Baylor Scott and White Health, College of Medicine, Texas A&M University, Texas, USA

\*Address all correspondence to: yshan918@gmail.com

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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**130**

**Author details**

Wan-Ming Hu1

P.R. China

and Jason H. Huang2

, Frank Y. Shan2

College of Medicine, Texas A&M University, Texas, USA

\*Address all correspondence to: yshan918@gmail.com

provided the original work is properly cited.

\*, Sanjib Mukherjee2

1 Department of Pathology, Sun Yat-sen University Cancer Center, Guangzhou,

2 Department of Neurosurgery and Cancer Center, Baylor Scott and White Health,

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

, Danijela Levacic2

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[2] Choi BD, Maus MV, June CH, Sampson JH. Immunotherapy for glioblastoma: Adoptive T-cell strategies. Clinical Cancer Research. 2019;**25**(7):2042-2048

[3] Palma L, Di Lorenzo N, Guidetti B. Lymphocytic infiltrates in primary glioblastomas and recidivous gliomas. Incidence, fate, and relevance to prognosis in 228 operated cases. Journal of Neurosurgery. 1978;**49**(6):854-861

[4] Brooks WH, Markesbery WR, Gupta GD, Roszman TL. Relationship of lymphocyte invasion and survival of brain tumor patients. Annals of Neurology. 1978;**4**(3):219-224

[5] Woroniecka KI, Rhodin KE, Chongsathidkiet P, Keith KA, Fecci PE. T-cell dysfunction in glioblastoma: Applying a new framework. Clinical Cancer Research. 2018;**24**(16):3792-3802

[6] Bielamowicz K, Fousek K, Byrd TT, Samaha H, Mukherjee M, Aware N, et al. Trivalent CAR T cells overcome interpatient antigenic variability in glioblastoma. Neuro-Oncology. 2018;**20**(4):506-518

[7] O'Rourke DM, Nasrallah MP, Desai A, Melenhorst JJ, Mansfield K, Morrissette J, et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Science Translational Medicine. 2017;**9**(399)

[8] Brown CE, Badie B, Barish ME, Weng L, Ostberg JR, Chang WC, et al. Bioactivity and safety of

IL13Ralpha2-redirected chimeric antigen receptor CD8+ T cells in patients with recurrent glioblastoma. Clinical Cancer Research. 2015;**21**(18):4062-4072

[9] Ahmed N, Brawley V, Hegde M, Bielamowicz K, Kalra M, Landi D, et al. HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: A phase 1 dose-escalation trial. JAMA Oncology. 2017;**3**(8):1094-1101

[10] Yeku OO, Purdon TJ, Koneru M, Spriggs D, Brentjens RJ. Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment. Scientific Reports. 2017;**7**(1):10541

[11] Farber SH, Elsamadicy AA, Atik AF, Suryadevara CM, Chongsathidkiet P, Fecci PE, et al. The Safety of available immunotherapy for the treatment of glioblastoma. Expert Opinion on Drug Safety. 2017;**16**(3):277-287

[12] Huang B, Zhang H, Gu L, Ye B, Jian Z, Stary C, et al. Advances in immunotherapy for glioblastoma multiforme. Journal of Immunology Research. 2017;**2017**:3597613

[13] Hamblett KJ, Kozlosky CJ, Siu S, Chang WS, Liu H, Foltz IN, et al. AMG 595, an anti-EGFRvIII antibody-drug conjugate, induces potent antitumor activity against EGFRvIII-expressing glioblastoma. Molecular Cancer Therapeutics. 2015;**14**(7):1614-1624

[14] Keller S, Schmidt M. EGFR and EGFRvIII promote angiogenesis and cell invasion in glioblastoma: Combination therapies for an effective treatment. International Journal of Molecular Sciences. 2017;**18**(6):1295

[15] Ekstrand AJ, Sugawa N, James CD, Collins VP. Amplified and rearranged epidermal growth factor receptor genes in human glioblastomas reveal deletions of sequences encoding portions of the N- and/or C-terminal tails. Proceedings of the National Academy of Sciences of the United States of America. 1992;**89**(10):4309-4313

[16] Malden LT, Novak U, Kaye AH, Burgess AW. Selective amplification of the cytoplasmic domain of the epidermal growth factor receptor gene in glioblastoma multiforme. Cancer Research. 1988;**48**(10):2711-2714

[17] Sugawa N, Ekstrand AJ, James CD, Collins VP. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. Proceedings of the National Academy of Sciences of the United States of America. 1990;**87**(21):8602-8606

[18] Shinojima N, Tada K, Shiraishi S, Kamiryo T, Kochi M, Nakamura H, et al. Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Research. 2003;**63**(20):6962-6970

[19] Donson AM, Addo-Yobo SO, Handler MH, Gore L, Foreman NK. MGMT promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric glioblastoma. Pediatric Blood & Cancer. 2007;**48**(4):403-407

[20] Kreth S, Limbeck E, Hinske LC, Schutz SV, Thon N, Hoefig K, et al. In human glioblastomas transcript elongation by alternative polyadenylation and miRNA targeting is a potent mechanism of MGMT silencing. Acta Neuropathologica. 2013;**125**(5):671-681

[21] Wikstrand CJ, Hale LP, Batra SK, Hill ML, Humphrey PA, Kurpad SN, et al. Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and

malignant gliomas. Cancer Research. 1995;**55**(14):3140-3148

[22] Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proceedings of the National Academy of Sciences of the United States of America. 1994;**91**(16):7727-7731

[23] Moscatello DK, Holgado-Madruga M, Godwin AK, Ramirez G, Gunn G, Zoltick PW, et al. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Research. 1995;**55**(23):5536-5539

[24] Olapade-Olaopa EO, Moscatello DK, MacKay EH, Horsburgh T, Sandhu DP, Terry TR, et al. Evidence for the differential expression of a variant EGF receptor protein in human prostate cancer. British Journal of Cancer. 2000;**82**(1):186-194

[25] Viana-Pereira M, Lopes JM, Little S, Milanezi F, Basto D, Pardal F, et al. Analysis of EGFR overexpression, EGFR gene amplification and the EGFRvIII mutation in Portuguese highgrade gliomas. Anticancer Research. 2008;**28**(2A):913-920

[26] Rosenthal M, Curry R, Reardon DA, Rasmussen E, Upreti VV, Damore MA, et al. Safety, tolerability, and pharmacokinetics of anti-EGFRvIII antibody-drug conjugate AMG 595 in patients with recurrent malignant glioma expressing EGFRvIII. Cancer Chemotherapy and Pharmacology. 2019;**84**(2):327-336

[27] Gan HK, Cvrljevic AN, Johns TG. The epidermal growth factor receptor variant III (EGFRvIII): Where wild things are altered. The FEBS Journal. 2013;**280**(21):5350-5370

**133**

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[28] Batra SK, Castelino-Prabhu S, Wikstrand CJ, Zhu X, Humphrey PA, Friedman HS, et al. Epidermal growth factor ligand-independent, unregulated,

cell-transforming potential of a naturally occurring human mutant EGFRvIII gene. Cell Growth & Differentiation. 1995;**6**(10):1251-1259

[29] Nagane M, Coufal F, Lin H, Bogler O, Cavenee WK, Huang HJ. A common mutant epidermal growth factor receptor confers enhanced tumorigenicity on human glioblastoma cells by increasing proliferation and reducing apoptosis. Cancer Research.

[30] Narita Y, Nagane M, Mishima K, Huang HJ, Furnari FB, Cavenee WK. Mutant epidermal growth factor receptor signaling down-regulates p27 through activation of the phosphatidylinositol 3-kinase/Akt pathway in glioblastomas. Cancer Research. 2002;**62**(22):6764-6769

[31] Lal A, Glazer CA, Martinson HM, Friedman HS, Archer GE, Sampson JH, et al. Mutant epidermal growth factor receptor up-regulates molecular effectors of tumor invasion. Cancer Research. 2002;**62**(12):3335-3339

[32] Phillips AC, Boghaert ER, Vaidya KS, Mitten MJ, Norvell S, Falls HD, et al. ABT-414, an antibody-

drug conjugate targeting a tumor-selective EGFR epitope. Molecular Cancer Therapeutics.

[33] Balkwill F, Mantovani A. Inflammation and cancer: Back to Virchow? Lancet. 2001;**357**(9255):539-545

[34] Bloch O, Crane CA, Kaur R, Safaee M, Rutkowski MJ, Parsa AT. Gliomas promote immunosuppression

macrophages. Clinical Cancer Research.

through induction of B7-H1 expression in tumor-associated

2013;**19**(12):3165-3175

2016;**15**(4):661-669

1996;**56**(21):5079-5086

*DOI: http://dx.doi.org/10.5772/intechopen.91759*

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[36] Intlekofer AM, Thompson CB. At the bench: Preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. Journal of Leukocyte

2002;**8**(8):793-800

Biology. 2013;**94**(1):25-39

[37] Dong H, Zhu G, Tamada K,

Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nature Medicine. 1999;**5**(12):1365-1369

[38] Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant

temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. The Lancet Oncology. 2009;**10**(5):459-466

[39] Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, et al. Loss of tumor suppressor PTEN

[40] Liu Y, Carlsson R, Ambjorn M, Hasan M, Badn W, Darabi A, et al. PD-L1 expression by neurons nearby tumors indicates better prognosis in glioblastoma patients. The Journal of Neuroscience. 2013;**33**(35):14231-14245

[41] Berghoff AS, Kiesel B, Widhalm G, Rajky O, Ricken G, Wohrer A, et al. Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro-Oncology.

Medicine. 2007;**13**(1):84-88

2015;**17**(8):1064-1075

[42] Xiu J, Piccioni D, Juarez T, Pingle SC, Hu J, Rudnick J, et al.

function increases B7-H1 expression and immunoresistance in glioma. Nature

#### *Immunotherapy for Glioblastomas DOI: http://dx.doi.org/10.5772/intechopen.91759*

*Neurosurgical Procedures - Innovative Approaches*

in human glioblastomas reveal deletions of sequences encoding portions of the N- and/or C-terminal tails. Proceedings of the National Academy of Sciences of the United States of America.

malignant gliomas. Cancer Research.

[22] Nishikawa R, Ji XD, Harmon RC, Lazar CS, Gill GN, Cavenee WK, et al. A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. Proceedings of the National Academy of Sciences of the United States of America. 1994;**91**(16):7727-7731

[23] Moscatello DK, Holgado-

1995;**55**(23):5536-5539

2000;**82**(1):186-194

2008;**28**(2A):913-920

2019;**84**(2):327-336

2013;**280**(21):5350-5370

et al. Safety, tolerability, and pharmacokinetics of anti-EGFRvIII antibody-drug conjugate AMG 595 in patients with recurrent malignant glioma expressing EGFRvIII. Cancer Chemotherapy and Pharmacology.

Madruga M, Godwin AK, Ramirez G, Gunn G, Zoltick PW, et al. Frequent expression of a mutant epidermal growth factor receptor in multiple human tumors. Cancer Research.

[24] Olapade-Olaopa EO, Moscatello DK, MacKay EH, Horsburgh T, Sandhu DP, Terry TR, et al. Evidence for the

differential expression of a variant EGF receptor protein in human prostate cancer. British Journal of Cancer.

[25] Viana-Pereira M, Lopes JM, Little S, Milanezi F, Basto D, Pardal F, et al. Analysis of EGFR overexpression, EGFR gene amplification and the EGFRvIII mutation in Portuguese highgrade gliomas. Anticancer Research.

[26] Rosenthal M, Curry R, Reardon DA, Rasmussen E, Upreti VV, Damore MA,

[27] Gan HK, Cvrljevic AN, Johns TG. The epidermal growth factor receptor variant III (EGFRvIII): Where wild things are altered. The FEBS Journal.

1995;**55**(14):3140-3148

[16] Malden LT, Novak U, Kaye AH, Burgess AW. Selective amplification of the cytoplasmic domain of the epidermal growth factor receptor gene in glioblastoma multiforme. Cancer Research. 1988;**48**(10):2711-2714

[17] Sugawa N, Ekstrand AJ, James CD, Collins VP. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged

[18] Shinojima N, Tada K, Shiraishi S, Kamiryo T, Kochi M, Nakamura H, et al. Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Research. 2003;**63**(20):6962-6970

[19] Donson AM, Addo-Yobo SO, Handler MH, Gore L, Foreman NK. MGMT promoter methylation correlates with survival benefit and sensitivity to temozolomide in pediatric

2007;**48**(4):403-407

elongation by alternative

2013;**125**(5):671-681

glioblastoma. Pediatric Blood & Cancer.

[20] Kreth S, Limbeck E, Hinske LC, Schutz SV, Thon N, Hoefig K, et al. In human glioblastomas transcript

polyadenylation and miRNA targeting is a potent mechanism of MGMT silencing. Acta Neuropathologica.

[21] Wikstrand CJ, Hale LP, Batra SK, Hill ML, Humphrey PA, Kurpad SN, et al. Monoclonal antibodies against EGFRvIII are tumor specific and react with breast and lung carcinomas and

genes in human glioblastomas. Proceedings of the National Academy of Sciences of the United States of America. 1990;**87**(21):8602-8606

1992;**89**(10):4309-4313

**132**

[28] Batra SK, Castelino-Prabhu S, Wikstrand CJ, Zhu X, Humphrey PA, Friedman HS, et al. Epidermal growth factor ligand-independent, unregulated, cell-transforming potential of a naturally occurring human mutant EGFRvIII gene. Cell Growth & Differentiation. 1995;**6**(10):1251-1259

[29] Nagane M, Coufal F, Lin H, Bogler O, Cavenee WK, Huang HJ. A common mutant epidermal growth factor receptor confers enhanced tumorigenicity on human glioblastoma cells by increasing proliferation and reducing apoptosis. Cancer Research. 1996;**56**(21):5079-5086

[30] Narita Y, Nagane M, Mishima K, Huang HJ, Furnari FB, Cavenee WK. Mutant epidermal growth factor receptor signaling down-regulates p27 through activation of the phosphatidylinositol 3-kinase/Akt pathway in glioblastomas. Cancer Research. 2002;**62**(22):6764-6769

[31] Lal A, Glazer CA, Martinson HM, Friedman HS, Archer GE, Sampson JH, et al. Mutant epidermal growth factor receptor up-regulates molecular effectors of tumor invasion. Cancer Research. 2002;**62**(12):3335-3339

[32] Phillips AC, Boghaert ER, Vaidya KS, Mitten MJ, Norvell S, Falls HD, et al. ABT-414, an antibodydrug conjugate targeting a tumor-selective EGFR epitope. Molecular Cancer Therapeutics. 2016;**15**(4):661-669

[33] Balkwill F, Mantovani A. Inflammation and cancer: Back to Virchow? Lancet. 2001;**357**(9255):539-545

[34] Bloch O, Crane CA, Kaur R, Safaee M, Rutkowski MJ, Parsa AT. Gliomas promote immunosuppression through induction of B7-H1 expression in tumor-associated macrophages. Clinical Cancer Research. 2013;**19**(12):3165-3175

[35] Dong H, Strome SE, Salomao DR, Tamura H, Hirano F, Flies DB, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion. Nature Medicine. 2002;**8**(8):793-800

[36] Intlekofer AM, Thompson CB. At the bench: Preclinical rationale for CTLA-4 and PD-1 blockade as cancer immunotherapy. Journal of Leukocyte Biology. 2013;**94**(1):25-39

[37] Dong H, Zhu G, Tamada K, Chen L. B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nature Medicine. 1999;**5**(12):1365-1369

[38] Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, et al. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. The Lancet Oncology. 2009;**10**(5):459-466

[39] Parsa AT, Waldron JS, Panner A, Crane CA, Parney IF, Barry JJ, et al. Loss of tumor suppressor PTEN function increases B7-H1 expression and immunoresistance in glioma. Nature Medicine. 2007;**13**(1):84-88

[40] Liu Y, Carlsson R, Ambjorn M, Hasan M, Badn W, Darabi A, et al. PD-L1 expression by neurons nearby tumors indicates better prognosis in glioblastoma patients. The Journal of Neuroscience. 2013;**33**(35):14231-14245

[41] Berghoff AS, Kiesel B, Widhalm G, Rajky O, Ricken G, Wohrer A, et al. Programmed death ligand 1 expression and tumor-infiltrating lymphocytes in glioblastoma. Neuro-Oncology. 2015;**17**(8):1064-1075

[42] Xiu J, Piccioni D, Juarez T, Pingle SC, Hu J, Rudnick J, et al. Multi-platform molecular profiling of a large cohort of glioblastomas reveals potential therapeutic strategies. Oncotarget. 2016;**7**(16):21556-21569

[43] Nduom EK, Wei J, Yaghi NK, Huang N, Kong LY, Gabrusiewicz K, et al. PD-L1 expression and prognostic impact in glioblastoma. Neuro-Oncology. 2016;**18**(2):195-205

[44] Han J, Hong Y, Lee YS. PD-L1 expression and combined status of PD-L1/PD-1-positive tumor infiltrating mononuclear cell density predict prognosis in glioblastoma patients. Journal of Pathology and Translational Medicine. 2017;**51**(1):40-48

[45] Zeng J, Zhang XK, Chen HD, Zhong ZH, Wu QL, Lin SX. Expression of programmed cell death-ligand 1 and its correlation with clinical outcomes in gliomas. Oncotarget. 2016;**7**(8):8944-8955

[46] Lee KS, Lee K, Yun S, Moon S, Park Y, Han JH, et al. Prognostic relevance of programmed cell death ligand 1 expression in glioblastoma. Journal of Neuro-Oncology. 2018;**136**(3):453-461

Abedalthagafi M, Barakeh D, Foshay KM. Immunogenetics of glioblastoma: The future of personalized patient management. NPJ Precision Oncology. 2018;**2**:27

[47] Omuro A, Vlahovic G, Lim M, Sahebjam S, Baehring J, Cloughesy T, et al. Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. Neuro-Oncology. 2018;**20**(5):674-686

[48] Reiss SN, Yerram P, Modelevsky L, Grommes C. Retrospective review of safety and efficacy of programmed cell death-1 inhibitors in refractory high grade gliomas. Journal for Immunotherapy of Cancer. 2017;**5**(1):99 [49] Majd N, de Groot J. Challenges and strategies for successful clinical development of immune checkpoint inhibitors in glioblastoma. Expert Opinion on Pharmacotherapy. 2019;**20**(13):1609-1624

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[50] Harrison RA, Anderson MD, Cachia D, Kamiya-Matsuoka C, Weathers SS, O'Brien BJ, et al. Clinical trial participation of patients with glioblastoma at The University of Texas MD Anderson Cancer Center. European Journal of Cancer. 2019;**112**:83-93

[51] Caccese M, Indraccolo S,

2019;**135**:128-134

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2019;**20**(13):1609-1624

Multi-platform molecular profiling of a large cohort of glioblastomas reveals potential therapeutic strategies. Oncotarget. 2016;**7**(16):21556-21569

[43] Nduom EK, Wei J, Yaghi NK, Huang N, Kong LY, Gabrusiewicz K, et al. PD-L1 expression and prognostic

impact in glioblastoma. Neuro-Oncology. 2016;**18**(2):195-205

[44] Han J, Hong Y, Lee YS. PD-L1 expression and combined status of PD-L1/PD-1-positive tumor infiltrating mononuclear cell density predict prognosis in glioblastoma patients. Journal of Pathology and Translational

Medicine. 2017;**51**(1):40-48

2016;**7**(8):8944-8955

2018;**136**(3):453-461

Oncology. 2018;**2**:27

[45] Zeng J, Zhang XK, Chen HD, Zhong ZH, Wu QL, Lin SX. Expression of programmed cell death-ligand 1 and its correlation with clinical outcomes in gliomas. Oncotarget.

[46] Lee KS, Lee K, Yun S, Moon S, Park Y, Han JH, et al. Prognostic relevance of programmed cell death ligand 1 expression in glioblastoma.

Journal of Neuro-Oncology.

Abedalthagafi M, Barakeh D, Foshay KM. Immunogenetics of

glioblastoma: The future of personalized patient management. NPJ Precision

[47] Omuro A, Vlahovic G, Lim M, Sahebjam S, Baehring J, Cloughesy T, et al. Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: Results from exploratory phase I cohorts of CheckMate 143. Neuro-Oncology. 2018;**20**(5):674-686

[48] Reiss SN, Yerram P, Modelevsky L, Grommes C. Retrospective review of safety and efficacy of programmed cell death-1 inhibitors in refractory high grade gliomas. Journal for

Immunotherapy of Cancer. 2017;**5**(1):99

**134**

### *Edited by Alba Scerrati and Pasquale De Bonis*

In the last few years, the development of new technologies in the medical field has allowed procedures and improved surgical techniques to be performed, which until recently would have been unthinkable.Modern neurosurgery is forever tied to technological progress: the development of robotics and robotic-assisted surgery; enhanced visualization, perfusion, and function monitoring in vascular surgery; new techniques of bone reconstruction; new cerebral imaging tools; and alternative treatments such as laser interstitial thermal therapy or immunotherapy for tumors. This book is designed to be a comprehensive introduction to these new developments and to their application in clinical practice. We have tried to provide a unique background and insights to coherently present these new technologies.

Published in London, UK © 2020 IntechOpen © wenht / iStock

Neurosurgical Procedures - Innovative Approaches

Neurosurgical Procedures

Innovative Approaches

*Edited by Alba Scerrati and Pasquale De Bonis*