**Foreword 2**

Gliomas are the most common primary brain tumors in neurosurgical practice. The defining characteristics of primary brain tumors have evolved through three periods: classical, histological, and molecular. The classical period began with Rudolf Virchow, who defined tumor cells of glial origin both macroscopically and microscopically in 1863. Dr. Percival Bailey and Dr. Harvey Cushing (1926) noticed that not all glial tumors behave in the same manner. They reviewed more than 400 verified gliomas and concluded that there was more than one tumor type, and prognosis varied according to the pathological findings: the histological period. They made the first classification of glial tumors. Then this classification changed and evolved into four grades defined by the World Health Organization depending on their histopathological features: cellularity, nuclear atypia, mitotic activity, necrosis, and vascular endothelial proliferation, which became accepted worldwide. These histopathological features had been assumed to be intimately related with prognosis. However, longevity had been noticed in patients more than was expected even with higher grade gliomas, so new queries have begun to clarify this black hole. The third period started with advancements in molecular biology and genetics that have yielded a better understanding of gliomas' etiology and prognosis with more delicate knowledge and targeted molecular therapies. Molecular genetic as well as epigenetic regulation was found to be deregulated in gliomas. Some of these changes were proven to be indicators of specific disease processes and have significantly improved our ability to predict clinical behavior by supporting morphological diagnosis. There are many ongoing clinical and laboratory studies whose objective is to develop target therapies for gliomas, aimed at inhibition of tumor proliferation, function, angiogenesis, invasion, apoptosis as well as understanding the tumor microenvironment, all of which increase tumor heterogeneity. All of these advances were made possible by a better scientific understanding of gliomas.

In this book, these research questions have been answered using current knowledge: the receptor tyrosine kinase pathway and its relation with tumor microenvironment, diagnosis and management of diffuse astrocytoma/oligodendroglioma, up-to-date treatment modalities of gliomas, and antioxidant supplementation during treatment.

I believe that this book is a wonderful contribution to neurological sciences and will enhance understanding of tumor pathogenesis and cellular and molecular pathways of gliomas with a glimpse into future treatment modalities that would improve life expectancy and health-related quality of life in glioma patients.

> *M. Necmettin Pamir, MD* Chair and Professor of Neurosurgery Department of Neurosugery Acıbadem University, School of Medicine Istanbul, Turkey

Preface

gliomas.

Contemporary treatment of gliomas is perhaps one of the best examples of teamwork and collaboration in neurosurgical subspecialties. Along with the neurosurgeon, the neuroradi‐ ologist, neuropathologist, neuro-oncologist, radiation oncologist, physiatrist, clinical nurse practitioner coordinator, and others are irreplaceable team members. Furthermore, surgical neuro-oncology has proven to be one of the most resilient neurosurgical subspecialties.

Despite the lack of significant progress in the treatment of high-grade gliomas and the sur‐ vival of high-grade glioma patients over many years, slow and steady persistence coupled with discoveries in various areas have yielded noticeable improvement in patient survival and quality of life. For example, postoperative survival of more than 2 years for glioblasto‐ ma multiforme (GBM) patients has become increasingly frequent. In addition, long-term survivors of the same disease are not necessarily found in rare case reports. Nonetheless, we

In the past decade, there has been significant surgical improvement in this field. Improve‐ ment of surgical anatomical understanding of the white matter tracts is because of practice by the surgeon and research of brain anatomy acquired during surgical anatomy labs for white matter fiber dissection techniques, as well as the development of more advanced magnetic resonance imaging tractography software. Furthermore, intraoperative frameless navigation systems have become more sophisticated, and intraoperative ultrasound guidance of tumor resection has become more advanced. There have also been further technological improve‐ ments of ultrasound tumor aspirators. Every year, surgical microscope manufacturers add more technological features that improve their effectiveness. In addition, 5-aminolevulinic acid fluorescence-guided resection of malignant glioma has recently been gaining popularity. Molecular diagnostics in gliomas has complemented histopathological analysis, and we are now able to distinguish less aggressive subtypes of GBMs from the more aggressive ones. Treatment protocols matching different molecular characteristics have been established, in‐ cluding protocols for tumor recurrence. Finally, the introduction of portable devices deliver‐ ing low intensity, intermediate frequency, and alternating electric fields using non-invasive disposable transducer arrays has become the standard of care in the treatment of malignant

remain far from meaningful, long-term success in the treatment of those patients.
