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The most common supratentorial tumors are those of glial origin, hence it is not surprising that the clinical study and surgical treatment of gliomas is virtually coextensive with the historical development of neurosurgery as a specialty. In 1884, Bennett and Godlee performed the first successful resection of a brain tumor that had been localized by neurological examination; the lesion was a low-grade tumor, but the patient succumbed to infection less than 2 weeks after the procedure. Although Sir Victor Horsley was greatly fascinated by this case, he was soon discouraged by his inability to save his own patients with malignant gliomas. During the early years of neurosurgery, periods of enthusiasm and neglect waxed and waned in regard to the surgery of the gliomas, and this fact was reflected in the conflicting recommendations put forward by Cushing, Dandy, and McKenzie. Indeed, the development of Cushing's own surgical technique often mirrored the evolution of prevailing views concerning the relative merits of active therapy and benign neglect. Initially, Cushing advocated external decompression, with removal of the bone flap and creation of subgaleal and muscular pockets into which the tumor might herniate. Toward the end of his career, he came to accept the concept of radical internal decompression (i.e., tumor resection) with preservation of contiguous brain; his own technical contributions, especially the development of silver clips and electrocautery, were largely responsible for making such procedures possible. From 1901 to 1912, Harvey Cushing's operative mortality for glial tumors was 30.9 percent, but by the end of his career he had reduced this to 11 percent. The technical difficulties of dealing with these tumors remained relatively unchanged until the introduction of corticosteroids and other perioperative aids in the 1960s. Because glial tumors are so common in clinical practice and because successful application of new therapeutic modalities may well depend on the continued development of surgical technique, the early diagnosis and operative treatment of glial tumors remain a major challenge for every neurosurgeon.

Clinical Features

The symptoms and signs produced by intracranial tumors fall into two general categories, nonspecific findings secondary to elevations in the intracranial pressure (ICP) and site-specific findings secondary to the actual location of the neoplasm. Although the tempo with which symptoms and signs develop may give a clue to the underlying nature of the tumor, their specific character depends on the location of the tumor and not on its histology. The nonspecific symptoms and signs of elevated ICP include headache, drowsiness, visual obscuration; nausea, vomiting, nuchal rigidity, papilledema, and sixth nerve palsy. The headache of brain tumor is usually nonlocalizing but may lateralize to the side of the lesion. The headache is typically worse in the morning and may be relieved after an episode of vomiting or the onset of physical activity. It is thought that morning headaches are secondary to mild CO2 retention during sleep and concomitant cerebral vasodilatation. Eventually the headache becomes nearly constant, but its intensity is rarely as severe as that of migraine or subarachnoid hemorrhage. Headache is the initial symptom in almost 40 percent of patients with glioblastoma multiforme and in more than 35 percent of all patients with cerebral gliomas. It is the most frequent chief complaint and the most prevalent symptom at the time of diagnosis. Headache is the universal complaint of patients with brain tumors and must be carefully investigated in all likely suspects.

The drowsiness observed in brain tumor patients is caused by mechanical and vascular compromise of the diencephalon, and the neck stiffness is produced by herniation of the cerebellar tonsils through the foramen magnum. Of course, papilledema or choked disc is a direct reflection of an elevated ICP. It is important to remember that the presence of venous pulsations is almost always indicative of an ICP of less than 180 mmH20. Falsely localizing signs in brain tumor suspects, such as a sixth nerve palsy, are usually caused by compression of the involved cranial nerve against an adjacent structure (e.g., the petrous pyramid) and are usually reflective of brain swelling or hydrocephalus. Nonspecific symptoms and signs secondary to elevated ICP are more commonly observed in high-grade tumors than in relatively more benign low-grade astrocytomas and oligodendrogliomas. Nevertheless, a quarter to a third of all glioma patients complain of drowsiness or lethargy; at diagnosis, more than one-half of all patients have papilledema, and almost 40 percent of the patients with glioblastoma have a depressed level of consciousness.

The site-specific findings of supratentorial tumors are either irritative or destructive in nature, but their precise expression always depends on the location of the tumor in respect to the functional organization of the brain. Lesions within the substance of the temporal lobe or in the vicinity of the motor cortex are far more likely to produce seizures than are similar neoplasms of the occipital pole. Similarly, mental apathy, memory loss, and personality disturbance are more frequently seen with frontotemporal tumors, and hemiparesis and sensory loss with frontoparietal lesions. Seizures are the second most common complaint at the time of diagnosis and are more frequently seen with oligodendrogliomas and astrocytomas (75 and 65 percent of cases, respectively) than with glioblastoma multiforme. More than a third of all glioma patients suffer from seizures as the initial manifestation of their disease, and the average duration of this symptom prior to diagnosis is about 12 months in patients with glioblastoma and about 3 years in patients with low-grade gliomas. Focal neurological findings are much more common in malignant astrocytomas than in other glial tumors, and this is especially true for motor weakness. Nevertheless, it must be emphasized that although more than 60 percent of patients with glioblastoma suffer from hemiparesis at the time of diagnosis, only 3 percent complain of weakness as the initial symptom. At the outset of their disease, patients with gliomas have relatively low rates of hemiparesis, dysphasia, hemianesthesia, and hemianopsia, but by the time of diagnosis, some or all of these findings are present in the majority of patients. Tumors in relatively silent areas produce symptoms and signs by virtue of edema that extends into adjacent functional zones, and the symptoms can often be ameliorated through the administration of corticosteroids. Complete loss of function is indicative of direct invasion and is rarely reversed by any form of therapy.

The frequency with which different site-specific findings are encountered in clinical practice depends heavily on the diagnostic acumen of the physicians in charge of the patient. For example, retrospective studies of patients with malignant astrocytoma have indicated that subtle personality change is often missed on the initial history and physical examination. In patients with glioblastoma, personality change occurs an average of more than 8 months prior to diagnosis and is the second earliest warning signal, next to seizures. At the time of diagnosis, up to 60 percent of patients with gliomas demonstrate some disturbance of orientation, memory, emotion, or judgement; this seems to be especially true for patients with oligodendroglioma. Late in the clinical course, it is much more difficult to evaluate personality and mental change in the presence of a depressed sensorium.

Because the benefits of therapy to a certain extent depend on the functional status of the patient, it is vitally important that the correct diagnosis be made and proper treatment instituted prior to the onset of hemiplegia or stupor. The majority of patients with glioblastoma multiforme, malignant astrocytoma, and oligodendroglioma have tumors in the frontal and temporal lobes or at the frontoparietal junction. Hence it is not surprising that the frequency of site-specific findings in these diseases is roughly similar, although there is some tendency for seizures to be associated with oligodendrogliomas and for personality disturbances to be more common in patients with glioblastoma. Of far greater importance is the tempo with which the site-specific findings appear. A rapid evolution of symptoms and signs is associated with malignancy, while a history of many years' duration is more consistent with a low-grade astrocytoma or oligodendroglioma. Finally, the proper interpretation of symptoms and signs can be made only within the context of the whole patient, especially as certain demographic factors (e.g., age and sex) bear heavily upon the correct diagnosis.

Recent status in the treatment of gliomas:
Patients will typically start with a craniotomy and surgical resection and these days the technology has improved quite a bit so a lot of these patients will have pre-op and intra-operative imaging, awake craniotomies or real-time monitoring of neurological condition, and some neuro techniques using fluorescence imaging where pre-operatively, a patient is given a fluorescent compound that actually tags tumor cells because at surgery, especially with lower grade gliomas, it is very difficult to distinguish abnormal cancer tissue from the normal brain and this technique can really help. Then the tissue sample goes to a pathologist and a name and histology [is given] for the tumor and a grade.
The most important thing these days are the biomarkers that not only help classify tumors, but also are predictive of response to certain therapies. Treatment is tailored, as much as it can be, to the particular type of glioma but most patients will go on to receive external beam radiation therapy. Patients with many of the tumor types will receive the radiation combined with the oral, alkylating agent temozolomide.
Historically, the field of neuro-oncology, from the perspective of chemotherapy, started with drugs such as carmustine and  thereafter, PCV (procarbazine, lomustine and vincristine). PCV was a very commonly adopted strategy until what we call the temozolamide era emerged. Temozolamide was developed in the 1980s and 1990s and the clinical trials started in the late 1990s. It is an oral alkylating agent that is much better tolerated than PCV chemotherapies or the nitrosoureas used historically like carmustine.
A real change in the field happened in 2005 with the publication of the so-called Stupp protocol based on our colleague Roger Stupp who led an international trial testing the role of temozolamide chemotherapy given concurrent with radiation and followed by adjuvant or maintenance oral temozolomide. The field shifted at that point because we had not really had a positive clinical trial for decades prior to that, so there was finally a standard drug therapy. From that success in glioblastoma multiple groups around the world have tested temozolomide in a variety of other glioma subtypes, including anaplastic astrocytoma and oligodendrogliomas.
All of these tend to be quite sensitive to temozolomides, and oligodendrogliomas in particular are one of the most chemo-sensitive human, solid malignancies. One of the downsides of temozolomide is that its activity is very dependent on a DNA repair enzyme, MGMT [O6-methylguanine DNA methyltransferase], so patients that have high expression of MGMT donít do well  because the alkylating damage induced by temozolomide is quickly repaired.
About 40% of patients with glioblastoma have random hyper-methylation of the MGMT gene promoter region, effectively shutting off the gene, and diminishing MGMT expression in the tumor cells. Those folks, the 40% or so with this MGMT promoter methylation, have much better prognosis and response. So a sort of hole in our field that remains are the 60% of patients with GBM that donít harbor the MGMT promoter methylation which is a very easily determined biomarker in the lab and is routinely done these days.
Essentially 60% of patients receive no benefit from the drug and there really is not an effective chemotherapy agent in standard practice at this point for this unmethylated MGMT promoter situation.
Concerning novel therapies in development or novel combinations for either of these tumor types, the first caveat is that, unfortunately, lagging behind other cancers in that regard. We all went through the era of targeted therapies and the promise of targeted therapies and weíve seen those evolve. For example, EGFR inhibitors for lung cancer.
The issue is the presence of the blood brain barrier and the way our clinical trials were designed were insufficient at detecting that the vast majority of these compounds were not brain-penetrant. A huge number of negative phase II and phase III clinical trials testing these approaches. They never had a chance because they were not getting into the brain in sufficient concentrations.

I mention that because we are in the midst of the newest revolution with immunotherapies including oncolytic viruses and vaccine approaches and we are facing the same kinds of challenges compared to other cancer types. What seems to be promising now is the combination of immunotherapy strategies with anti-angiogenic strategies. So, bevacizumab is fully FDA approved and is routinely used for recurrent gliomas, especially glioblastoma, and it has excellent symptomatic effects although has never really been shown to enhance survival. The immunotherapies have been a challenge on their own.

All of the published vaccine trials have not shown much promise and the checkpoint inhibitors, when used as single agents essentially have no activity. When combined, they have some activity but a lot of toxicity. Newer trials that have shown promise have combined those approaches, whether it's vaccine-based, or checkpoint inhibitor based combined with bevacizumab or other experimental anti-VEGF [Vascular endothelial growth factor] treatments. That is one of the major areas of focus for those of us involved in cooperative group and other trials, trying to find the optimal combination approaches and there have been some exciting early results as there always are when you are trying new things and it remains to be seen how things evolve over the next couple of years.1 (29-December-2018) 

In summary, headache, seizures, mental change, and hemiparesis are the cardinal clinical features of supratentorial gliomas. A first seizure in a patient over 40 years of age should be considered indicative of a brain tumor until proved otherwise. Together with papilledema, mental change and hemiparesis are the most frequent findings on the initial physical examination; they provide important clues as to the location and extent of the tumor. Prior to the advent of computed tomography (CT), underdiagnosis of bilateral spread in cases of glioblastoma was common, but careful neurological assessment often yields insights complementary to those provided by modem imaging techniques. Irrespective of the precise combination of clinical findings, it is the relentless progression of the disease that stamps it as an intracranial tumor. Because apoplectic onset occurs in only 3 to 4 percent of brain tumor patients and radiographic progression usually accompanies clinical deterioration, there should be little difficulty in separating patients suspected of having a brain tumor from those with such other intracranial processes as cerebrovascular diseases.



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Introduction |Imaging | Astrocytomas | Glioblastoma Multiforme | Oligodendrogliomas | Ependymomas | Pilocytic Astrocytomas | Gangliogliomas | Mixed Gliomas | Other Astrocytomas | Surgical treatment | Stereotactic Biopsy | Gliadel Wafers |Results and complications | When to Reoperate? | Colloid cyst

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