**4. Where we are going**

Treatments and better outcomes for primary brain tumors have long lagged behind those of other tumors. Rapid advances in neurooncology, cancer and CNS immunology, and progress in genomics have created more therapeutic opportunities than ever before [2, 3]. There is no doubt that significant changes have occurred in management of glioma patients. In the past three decades, we have led to the discovery of hundreds of molecular alterations in grades II, III, and IV gliomas. Among these molecular alterations, three are particularly noteworthy, because they occur early during glioma formation, are prevalent in glioma, or are strongly associated with overall survival. Codeletion of chromosome arms 1p and 19q (1p/19q codeletion), which is associated with the oligodendroglial histologic type and with sensitivity to chemotherapy with alkylating agents. The second was mutation in either IDH1 or IDH2 gene associated with a distinctive tumor cell metabolism. The third was mutation in the promoter of TERT, which is seen in both the most aggressive human glioma (grade IV astrocytoma) and the least aggressive diffuse human glioma (grade II oligodendroglioma) [11, 18].

Pamir and his group (2017) stated that molecular subsets in hemispheric diffuse gliomas result in different tumor biology and clinical behaviors [20]. Eckel-Passow et al. [21] published significant study on a sample of 1081 gliomas, which they divided into five molecular

previously considered inoperable are today more accessible and safer for resection; the surgeon has greater self-confidence and better preoperative knowledge about the tumor and can expect better result of the glioma resection itself; and patients can expect a better outcome. This is particularly important for those lesions for which neurosurgical resection and the extent of resection (EOR) is still the most important part of treatment and standard

To achieve as good result as possible, somatosensory evoked potentials (SSEPs), motor evoked potentials (MEPs), visual evoked potentials (VEPs), brainstem auditory evoked potentials (BAEPs), and electrocorticography (ECoG) are used nowadays routinely during glioma surgery. For brainstem gliomas, specific mapping with direct electrical stimulation (DES), corticobulbar tract MEP monitoring, and free-running electromyography (EMG) of the various muscles innervated by the cranial nerves are also required. Awake craniotomy and intraoperative mapping of language and sensorimotor functions with DES have become standard techniques for removal of cerebral neoplasms affecting eloquent cortical areas and

The present data provide prognostic information for patients with pilocytic astrocytoma and confirm that age and tumor size had a significant effect on OS [18]. For patients with anaplastic astrocytic gliomas, Nayak et al. [18] have found the median overall survival 2.9 years, and 1-year OS rate was 87%. Novel therapeutics is needed in patients with tumors not amenable to resection or radiosurgery [19]. The joint efforts of neuroscientists, researchers, and clinicians have provided an unprecedented ability to localize lesions and to assess the human brain function at

Treatments and better outcomes for primary brain tumors have long lagged behind those of other tumors. Rapid advances in neurooncology, cancer and CNS immunology, and progress in genomics have created more therapeutic opportunities than ever before [2, 3]. There is no doubt that significant changes have occurred in management of glioma patients. In the past three decades, we have led to the discovery of hundreds of molecular alterations in grades II, III, and IV gliomas. Among these molecular alterations, three are particularly noteworthy, because they occur early during glioma formation, are prevalent in glioma, or are strongly associated with overall survival. Codeletion of chromosome arms 1p and 19q (1p/19q codeletion), which is associated with the oligodendroglial histologic type and with sensitivity to chemotherapy with alkylating agents. The second was mutation in either IDH1 or IDH2 gene associated with a distinctive tumor cell metabolism. The third was mutation in the promoter of TERT, which is seen in both the most aggressive human glioma (grade IV astrocytoma) and

the least aggressive diffuse human glioma (grade II oligodendroglioma) [11, 18].

Pamir and his group (2017) stated that molecular subsets in hemispheric diffuse gliomas result in different tumor biology and clinical behaviors [20]. Eckel-Passow et al. [21] published significant study on a sample of 1081 gliomas, which they divided into five molecular

of care [14–16].

subcortical pathways [17].

**4. Where we are going**

the microscopic, mesoscopic, and macroscopic scales [14].

4 Glioma - Contemporary Diagnostic and Therapeutic Approaches

**Figure 1.** Overall survival in the glioma molecular groups based on 1p/19q, IDH, and TERT promoter mutations in tumors (taken from Eckel-Passow et al. [21]).

groups according to three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (**Figure 1**). They concluded that "the groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis" [21]. In favor of this, in the future, we should also incorporate alterations in ATRX, TP53, EGFR, or PTEN or other alterations that might be useful to consider in the diagnosis of glioma [11].

WHO grade I tumors and WHO grade II tumors should not be grouped together as low grade, because the two disease processes are markedly different. For patients with grade II glioma who had undergone subtotal tumor resection, Buckner and colleagues suggest combination of chemotherapy in addition to radiation therapy [22]. Opposite to the real low-grade lesions are, for example, dysembryoplastic neuroepithelial tumors are associated with continuous growth and inevitable malignant transformation. This fact supports the concept that grade II gliomas are premalignant and that the use of early aggressive surgical treatment is a very important part of their treatment pathway [18]. Al-Tamimi and Duffau's group [23] suggest that after radical resection, the presence of foci of transformation within a background of grade II tumor does not necessarily require immediate adjuvant therapy. They suggest that a tailored approach should be used, taking into account the extent of resection, the full histopathologic and molecular profile of the tumor, and careful evaluation of the resection margins [15, 17, 23].

Speaking of high-grade glioma, despite the efforts made in research on new therapeutics, the last WHO classification of CNS tumors from year 2016 brought about some changes (**Table 1**) [7].

Demarcation of glioma borders is a subject of comprehensive research, considering that it is difficult to clearly define the line between tumor and healthy brain tissue macroscopically or with today available imaging techniques like functional MRI (fMRI), positron emission tomography (PET), spectroscopy, and diffusion tensor imaging (DTI) [6, 17, 24]. Contemporary neurophysiology plays a very important role in guidance of brain tumor surgery [17]. For tumors located in proximity to critical functional areas, the use of intraoperative electrostimulation


chance for a comprehensive interdisciplinary assessment of the glioma pathophysiology, with direct implications in terms of the medical and surgical treatment strategies available for patients [26]. The concept of individualized surgery in brain tumor neurosurgery, that is, specifically in neurooncology of glial tumors is actually based on the goal to provide as radical tumor resection as possible, without causing (additional) neurological deficit (**Figure 2**) [27]. Unfortunately, the prognosis of patients with grade IV malignant glioma particularly recurrent is dismal, and there is currently no effective therapy, but there are some promising agents as vaccine immunotherapy or recombinant nonpathogenic poliorhinovirus chimera (PVSRIPO) [28, 29]. Desjardins et al. have recently reported that overall survival among the patients who received PVSRIPO immunotherapy was higher at 24 and 36 months than the rate among controls [29]. Extension of surgical excision is still an important predictor of outcome. Achieving a gross total resection of the tumor without significant complication requires a thorough understanding of available surgical approaches [15, 17, 30–32]. For majority of those patients, short-course radiotherapy with concurrent and adjuvant TMZ will bring a benefit, while gain from bevacizumab is limited [13]. There have been some ideas that certain antiepileptics also have a favorable effect on the outcome with glioma patients, but these studies have not given affirmative results [33]. To provide a highly personalized medicine, we will

Introductory Chapter: Glioma - Merciless Medical Diagnosis

http://dx.doi.org/10.5772/intechopen.82863

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also have to make additional effort toward molecular neuropathology [30].

What do we want to see in the future? A patient from the supposed risk group will be scanned with MRI spectroscopy, 7T MRI, or similar MRI prototype. At the level of a robot medical center, needle biopsy of tumor will be performed, which will be followed by oncogenomic characterization of lesion, with gene map reading and defining. Research in the field of stem cells also has an important place and implications in the future. By way of stem cells, a specific

**Figure 2.** Contrast-enhanced axial T1 MRI scan of 54-year-old female patient with IDH-mutant glioblastoma. (A) Preoperative MRI and (B) 4 years after extensive surgical resection, followed with TMZ and radiotherapy treatment. Small part of recurrent tumor is visible 50 months after initial resection. Patient is still without any neurological deficit.

IDH, isocitrate dehydrogenase; NOS, not otherwise specified; RELA, reticuloendotheliosis viral oncogene homolog A [7]. † The last WHO classification of CNS tumors brought about some changes based on molecular findings.

**Table 1.** Simplified and modified from WHO 2016 classification of neuroepithelial tissue tumors.

mapping (IEM) during awake craniotomy helps to maximize the extent of resection and to minimize the risk of permanent neurological morbidity, allowing a substantial increase in the survival and quality of life of patients [14, 17, 25].
