*2.1.1.4. The present, challenges, and future of biopsy*

One of the disadvantages of the established stereotaxy is deviation during the procedure and its execution at the present time in the MRI or CT preoperative images. Currently, efforts are being made to overcome the problem by real-time MRI-induced biopsy with promising results [10, 11]. In certain cases, when we have an extremely small tumor, the precision of biopsy is questionable with disappointing pathohistological results. Today, microelectrodes are used to do the microrecording of the brain electrical potential on the biopsy path and in the target tumor zone with the absence of electrical potentials, performing biopsy by the "real time" method and increasing safety and precision [10].

Since fluorescence 5 ALA has already found its use in tumor surgery and increased radicalism of resection, it is also applied in biopsy; a decrease in negativity of results was observed [11].

Because of the existence of brain blood barriers and inadequate chemotherapeutic penetration of brain tumor, convection-enhanced delivery is developed, which represents a modality of combined surgical and colon tumor treatment. Locally, the medicine (chemotherapeutic) is placed into the brains of rats by using a frameless catheter; it is used in the treatment of diffuse brain stem gliomas [12].

### *2.1.2. Subtotal resection*

Glioma resection in which a portion of tumor can still be seen in postoperative images is called subtotal resection (STR). STR should be performed only when it is not possible to perform gross total resection (GTR). To have better results of STR, tumor mass must be removed as much as possible to preserve functionality of the patient and quality of life. All technical supports should be used to optimize STR. Intraoperative MRI should be used in every STR to optimize glioma safe removal [8].

techniques, the incidence of gross total resection has increased [8]. On the other hand, without technical development, microsurgical GTR of glioma cannot be always achieved because of the deep location of tumor, located in the eloquent regions, and/or both hemispheres spanned [14]. Aggressive GTR can lead to increased morbidity and complications without improving survival [15, 16]. GTR is shown to be an independent factor of overall survival (OS), but, in respect of STR, evidence is not clear for its benefit [6–8, 15]. Like for STR, in GTR also, intraoperative MRI and all technical supports should be used to have a better resection and to

**Figure 2.** A 19-year-old male patient admitted to our department comatose, with Glasgow Coma Scale score—GCS 4, with respiratory dysfunction (August 2015). Urgent surgery was performed with GTR, pathohistology confirmed LGG. Three weeks later, the patient was discharged from the department in good condition—awake, walking alone with Karnofsky score 80. Preoperative axial, sagittal, and coronal postcontrast T1-weighted MRI (A-C) show a huge tumor in the cerebellum, predominantly on the left side with adherence to the brain stem and propagation down to C2 (Siemens MRI Avanto 1.5 T). Two and a half years postoperative contrast T1-weighted MRI, in March 2018 (D–F), shows complete

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Surgical resection of pathological tumor mass, almost nonfunctional brain region, is common, standard, and the oldest neurosurgical approach to contemporary neuro-oncology. Historically, glioma surgery was a controversial topic, but many recent studies have demonstrated the crucial

preserve the eloquent brain areas.

tumor resection with no signs of tumor rest or recurrence.

*2.1.4. Supratotal resection*

### *2.1.3. Gross total resection*

Some mathematical modeling studies estimated that at least 78% of preoperative tumor volume must be resected to increase survival and resection brings an incremental benefit of up to 98% [13]. The surgical resection technique that brings this benefit with clear margins is called gross total resection, **Figures 2** and **3**. Since the beginning of wide use of modern operative

**Figure 2.** A 19-year-old male patient admitted to our department comatose, with Glasgow Coma Scale score—GCS 4, with respiratory dysfunction (August 2015). Urgent surgery was performed with GTR, pathohistology confirmed LGG. Three weeks later, the patient was discharged from the department in good condition—awake, walking alone with Karnofsky score 80. Preoperative axial, sagittal, and coronal postcontrast T1-weighted MRI (A-C) show a huge tumor in the cerebellum, predominantly on the left side with adherence to the brain stem and propagation down to C2 (Siemens MRI Avanto 1.5 T). Two and a half years postoperative contrast T1-weighted MRI, in March 2018 (D–F), shows complete tumor resection with no signs of tumor rest or recurrence.

techniques, the incidence of gross total resection has increased [8]. On the other hand, without technical development, microsurgical GTR of glioma cannot be always achieved because of the deep location of tumor, located in the eloquent regions, and/or both hemispheres spanned [14]. Aggressive GTR can lead to increased morbidity and complications without improving survival [15, 16]. GTR is shown to be an independent factor of overall survival (OS), but, in respect of STR, evidence is not clear for its benefit [6–8, 15]. Like for STR, in GTR also, intraoperative MRI and all technical supports should be used to have a better resection and to preserve the eloquent brain areas.

### *2.1.4. Supratotal resection*

**c.** Setting the catheter into tumor cavity

154 Glioma - Contemporary Diagnostic and Therapeutic Approaches

*2.1.1.4. The present, challenges, and future of biopsy*

time" method and increasing safety and precision [10].

Unrelated to the use of neuronavigation in oncology or the treatment of gliomas, neuronavigation can be used in ventriculostomy, electrode placement for deep brain stimulation, endo-

One of the disadvantages of the established stereotaxy is deviation during the procedure and its execution at the present time in the MRI or CT preoperative images. Currently, efforts are being made to overcome the problem by real-time MRI-induced biopsy with promising results [10, 11]. In certain cases, when we have an extremely small tumor, the precision of biopsy is questionable with disappointing pathohistological results. Today, microelectrodes are used to do the microrecording of the brain electrical potential on the biopsy path and in the target tumor zone with the absence of electrical potentials, performing biopsy by the "real

Since fluorescence 5 ALA has already found its use in tumor surgery and increased radicalism of resection, it is also applied in biopsy; a decrease in negativity of results was observed [11]. Because of the existence of brain blood barriers and inadequate chemotherapeutic penetration of brain tumor, convection-enhanced delivery is developed, which represents a modality of combined surgical and colon tumor treatment. Locally, the medicine (chemotherapeutic) is placed into the brains of rats by using a frameless catheter; it is used in the treatment of diffuse

Glioma resection in which a portion of tumor can still be seen in postoperative images is called subtotal resection (STR). STR should be performed only when it is not possible to perform gross total resection (GTR). To have better results of STR, tumor mass must be removed as much as possible to preserve functionality of the patient and quality of life. All technical supports should be used to optimize STR. Intraoperative MRI should be used in every STR to

Some mathematical modeling studies estimated that at least 78% of preoperative tumor volume must be resected to increase survival and resection brings an incremental benefit of up to 98% [13]. The surgical resection technique that brings this benefit with clear margins is called gross total resection, **Figures 2** and **3**. Since the beginning of wide use of modern operative

• intratumoral chemotherapy • intratumoral radiotherapy

• cyst drainage

scopic neurosurgery, etc.

brain stem gliomas [12].

*2.1.2. Subtotal resection*

optimize glioma safe removal [8].

*2.1.3. Gross total resection*

Surgical resection of pathological tumor mass, almost nonfunctional brain region, is common, standard, and the oldest neurosurgical approach to contemporary neuro-oncology. Historically, glioma surgery was a controversial topic, but many recent studies have demonstrated the crucial

**Figure 3.** An 11-year old girl with glial tumor in the posterior fossa producing hydrocephalus, admitted to the neurosurgical department with impairment of consciousness, walk and gait disturbance, fully dependent on parents (June 2015). Preoperative T1W axial, coronal, and sagittal contrast brain MRI (A–C) revealed a huge glial tumor, predominantly solid, mostly located in the left cerebellar hemisphere with partial involvement of the fourth ventricular floor and compression to the brain stem (low grade glioma). Two and half years of postoperative contrast T1W MRI shows no recurrence of tumor (D–F, March 2018). The child is in full condition without any neurological deficit.

place of glioma resection in the management of low and high grade gliomas [5]. Over time, the approach to glioma changed from minimally invasive biopsy to maximally possible resection (STR or GTR). Today, total resection changed from temporal lobectomy to very aggressive frontal lesion—paralesional resection of high grade glioma. In the past decade, supratotal resection became a popular approach technique for glioma resection. Supratotal resection includes, like GTR, a total tumor resection with radical resection of perilesional brain tissue, nonglioma region, **Figure 4**. Even after GTR, because of the infiltrative behavior of glioma, probably there are some cells left, which is the biggest challenge to a successful resection and increase in recurrence, OS, and progression-free survival (PFS) [5, 17]. With conventional MRI, it is almost impossible to estimate spatial extent of infiltrative glioma [5]. In low grade glioma, tumor cells are found up to 20 mm beyond MRI seen abnormalities, while in GBM, cells are found diffusely in the hemisphere on the GBM site, even contralaterally [17]. These cells lead to diffuse spread of tumor and its recurrence [5]. Visualization of these cells is beyond any known technique. With supratotal resection of the margins around tumor visible on FLAIRweighted MRI, there is a limited possibility of leaving residual cells. This resection impacts also on the history of malignant transformation of glioma, which occurs after diagnosis in 4-year

**Figure 4.** A 38-year old female patient admitted to our neurosurgical department after a large glioma was found in the right temporal region. The patient was with mild left-sided hemiparesis and dizziness (January 2016). Supratotal resection was done and tumor completely resected with 1 cm perilesional tissue. She was discharged from hospital 5 days after the surgery without any neurological deficit. Chemotherapy (temozolomide) and the whole brain irradiation were done immediately. Brain MRI (A–C) was performed prehospitally, T2W axial sequence and T1W axial and coronal postcontrast sequence show extensive, solid cystic tumor located right temporoparietally, surrounded by peripheral edema with compression signs on the right side of the cerebral chamber and signs of mediosagital structure shift to the left. Twelve months after the surgery (March 2017), there was no recurrence on control MRI (middle row, pictures D-F). The same patient 16 months after the surgery (G–I). It was IDH negative glioblastoma multiforme, Grade IV, wild type. Although a complete neurosurgical resection was performed, recurrence was revealed on 16 months follow-up MRI (July 2017), not even on the site of the previous surgery but on the contralateral side as multicentric lesion in the brain stem. MRI T1W axial postcontrast sequence showed multicentric lesions in the left cerebellar pedunculate area, left parietal paraventricular, and left parietal supraventricular areas. The postoperative area on the right did not show any recurrence of the primary tumor. Despite all given therapy, the patient died 17 months after the surgery. This example confirms the thesis that glioblastomas are a diffuse disease, and probably, even after extremely vast surgery, tumor

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reoccurrence will occur relatively soon. IDH, Isocitrate dehydrogenase.

**Figure 4.** A 38-year old female patient admitted to our neurosurgical department after a large glioma was found in the right temporal region. The patient was with mild left-sided hemiparesis and dizziness (January 2016). Supratotal resection was done and tumor completely resected with 1 cm perilesional tissue. She was discharged from hospital 5 days after the surgery without any neurological deficit. Chemotherapy (temozolomide) and the whole brain irradiation were done immediately. Brain MRI (A–C) was performed prehospitally, T2W axial sequence and T1W axial and coronal postcontrast sequence show extensive, solid cystic tumor located right temporoparietally, surrounded by peripheral edema with compression signs on the right side of the cerebral chamber and signs of mediosagital structure shift to the left. Twelve months after the surgery (March 2017), there was no recurrence on control MRI (middle row, pictures D-F). The same patient 16 months after the surgery (G–I). It was IDH negative glioblastoma multiforme, Grade IV, wild type. Although a complete neurosurgical resection was performed, recurrence was revealed on 16 months follow-up MRI (July 2017), not even on the site of the previous surgery but on the contralateral side as multicentric lesion in the brain stem. MRI T1W axial postcontrast sequence showed multicentric lesions in the left cerebellar pedunculate area, left parietal paraventricular, and left parietal supraventricular areas. The postoperative area on the right did not show any recurrence of the primary tumor. Despite all given therapy, the patient died 17 months after the surgery. This example confirms the thesis that glioblastomas are a diffuse disease, and probably, even after extremely vast surgery, tumor reoccurrence will occur relatively soon. IDH, Isocitrate dehydrogenase.

place of glioma resection in the management of low and high grade gliomas [5]. Over time, the approach to glioma changed from minimally invasive biopsy to maximally possible resection (STR or GTR). Today, total resection changed from temporal lobectomy to very aggressive frontal lesion—paralesional resection of high grade glioma. In the past decade, supratotal resection became a popular approach technique for glioma resection. Supratotal resection includes, like GTR, a total tumor resection with radical resection of perilesional brain tissue, nonglioma region, **Figure 4**. Even after GTR, because of the infiltrative behavior of glioma, probably there are some cells left, which is the biggest challenge to a successful resection and increase in recurrence, OS, and progression-free survival (PFS) [5, 17]. With conventional MRI, it is almost impossible to estimate spatial extent of infiltrative glioma [5]. In low grade glioma, tumor cells are found up to 20 mm beyond MRI seen abnormalities, while in GBM, cells are found diffusely in the hemisphere on the GBM site, even contralaterally [17]. These cells lead to diffuse spread of tumor and its recurrence [5]. Visualization of these cells is beyond any known technique. With supratotal resection of the margins around tumor visible on FLAIRweighted MRI, there is a limited possibility of leaving residual cells. This resection impacts also on the history of malignant transformation of glioma, which occurs after diagnosis in 4-year

**Figure 3.** An 11-year old girl with glial tumor in the posterior fossa producing hydrocephalus, admitted to the neurosurgical department with impairment of consciousness, walk and gait disturbance, fully dependent on parents (June 2015). Preoperative T1W axial, coronal, and sagittal contrast brain MRI (A–C) revealed a huge glial tumor, predominantly solid, mostly located in the left cerebellar hemisphere with partial involvement of the fourth ventricular floor and compression to the brain stem (low grade glioma). Two and half years of postoperative contrast T1W MRI shows no recurrence of tumor (D–F, March 2018). The child is in full condition without any neurological deficit.

156 Glioma - Contemporary Diagnostic and Therapeutic Approaches

periods on average [5]. Currently, a randomized controlled clinical trial of supratotal resection for all grade gliomas in noneloquent areas is being conducted with 120 participants; primary results are expected soon (2 years OS, PFS, and Karnofsky Performance Score (KPS)) [18]. The evolution of supratotal surgery from gross total to supratotal was possible due a number of technological advances (light microscope, microneurosurgical tools, magnetic resonance imaging, neuro-navigation, brain mapping, 5-ALA fluoroscency technique, tractography, etc.). Supratotal resection, concerning recently published findings of a few independent authors, resulted in better survival of glioma patients [13, 19].

are independent values for OS and GBM recurrence. They found that the residual volume of

As mentioned before, the overall technical development has made supratotal resection possible, with adequate balance between maximal resection of tumor with paralesional region and functional consideration for the eloquent region of the brain. To increase the extent of resection, before surgery, functional MRI, white-matter tractography is performed; during the surgery, intraoperative MRI or ultrasound and 5-ALA-guided resection are used [5]. All these techniques give a rich fund of information, but when the leak of functional information occurs, it signals to us that, while operating, we approached the eloquent brain areas resection [5, 28]. Electrostimulation mapping during supratotal resection is the most important technique used to identify cortical areas and subcortical pathways involved in eloquent functions (especially motor, sensory, language, and cognitive functions) [5, 28, 29]. The usage of electrostimulation in humans started in the 19th century, but the first one in neuro-oncology was used in the 90s of the 20th century by Mitchel Berger. He applied electrostimulation for the mapping of eloquent cortical areas. Hugues Duffau extended and summarized the indication of electrostimulation usage at cortical and subcortical levels intraoperatively [29].

Intraoperative bipolar electrostimulation mapping has become a mandatory tool in neuro-

**c.** perform resection according to individual corticosubcortical functional boundaries;

**d.** make a better neuro-oncological impact, with preservation of the quality of life [28, 30].

With intraoperative electrostimulation, resection is extended into the regions which were considered inoperable. By this extension, a great functional outcome has been documented with

**3. Surgical technique and oncofunctional balance**

**a.** study real time individual cortical functional organization;

**b.** study subcortical connectivity along resection;

 with 95% resection has the greatest reduction in death in GBM patients [14]. Because of this EOR feature, it is mandatory to perform GTR always when possible, depending on tumor location and quality of life after GTR. GTR has superiority over STR in elderly patients with high grade glioma. GTR resulted in better OS, PFS, and Karnofsky performance score [21]. In children with mean age of 11 years, GTR of high grade glioma resulted in better OS than STR, 3.4 years *vs.* 1.6 years, respectively. Female patients with GTR also had a better OS than male patients, 8.1 years *vs.* 2.4 years, respectively [26]. Concerning higher grade glioma, supratotal resection can have some benefits. In a study of Li et al. of 876 patients who had a GTR (100% EOR), 643 underwent resection of T2 FLAIR abnormality region. Approximately, 18% of them had negative EOR due to postoperative edema, and in positive patients—more than 53.21%— FLAIR resection was associated with improved OS compared with patients with less than 53.21% FLAIR resection (20.7 months *vs.* 15.5 months, p < 0.001) [27]. With supratotal resection, the usage of chemotherapy and radiotherapy was reduced after supratotal resection.

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<2 cm3

oncology allowing to:
