WHAT IS A GLIOMA?

WHAT ARE THE SIGNS AND SYMPTOMS OF A GLIOMA?

HOW IS A GLIOMA DIAGNOSED?

WHAT TREATMENT OPTIONS ARE AVAILABLE FOR MALIGNANT GLIOMA?

WHAT IS A GLIOMA?

Gliomas are a class of tumor that develops from glial (neuroepithelial or support) cells. Astrocytes, ependymal, and oligodendroglial cells are all examples of glial cells that compose the supportive tissue of the brain. Gliomas comprise nearly one-half of primary brain tumors and one-fifth of all primary spinal cord tumors.

Contemporary classification of gliomas is based on the World Health Organization (WHO) system, which classifies the tumors according to the cell of origin and histologic features identified by the pathologist or neuropathologist.

• Low grade gliomas are slow growing, and are assigned either a I or II grade. From a practical standpoint, grade I tumors (such as the pilocytic astrocytoma) are usually excluded from conversation dealing with gliomas, as they constitute a distinctive pathologic and clinical entity.

Pilocytic astrocytoma. This tumor is composed of a loose network of neoplastic cells and parallel bundles of their cytoplasmic processes	Pilocytic astrocytoma. This smear preparation shows the cytologic features of a low grade astrocytic neoplasm, including high cellularity, prominent fibrillary processes, and low grade nuclei

• High grade (malignant) gliomas grow much more quickly, and are assigned either a III (anaplastic) or IV (glioblastoma multiforme) grade. Combined, grade III and IV gliomas represent about 40% of all primary brain tumors in patients aged 40-49 years, and 60% in patients older than 60 years. In most clinical series, grade III tumors comprise approximately 10% and grade IV 90% of the total number of high grade, malignant primary brain tumors.

Malignant gliomas are one of the most devastating tumors that can affect any given individual. Grade IV gliomas, often referred to as Glioblastoma Multiforme or “GBM”, possess multiple genetic and chromosomal abnormalities which cause these tumors to grow rapidly. However, it is very rare for such tumors to metastasize (spread) outside the central nervous system. As a GBM progresses, portions of the tumor often outgrow the immediate blood supply and die or “undergo necrosis”. In contrast, peripheral regions of the tumor readily recruit the growth of new blood vessels (angiogenesis), enabling continued rapid growth of the GBM.

WHAT ARE THE SIGNS AND SYMPTOMS OF A GLIOMA?

The presenting symptom(s) of a glioma depend on the location of the tumor within the brain and its rate of growth. Common symptoms include:

• Headaches
• Seizures
• difficulty speaking
• weakness/paralysis in one part of the body or face
• difficulty with vision
• impairment of sensation
• impairment of balance
• nausea/vomiting
• behavioral changes
• impairment of memory or thinking

The clinical course of an untreated malignant glioma is characterized by relentless invasive growth and, even with treatment, near universal recurrence.

HOW IS A GLIOMA DIAGNOSED?

The majority of patients harboring a malignant glioma have had one or more of the aforementioned clinical symptoms of varying duration (usually weeks to months). Occasionally, a patient may present with no prior neurological symptoms.

• MRI and CT: In evaluating most brain tumors, magnetic resonance imaging (MRI) of the brain is usually preferred over a CT scan. MRI is better at establishing a presumptive diagnosis and delineating the suspected brain tumor in three planes, thereby allowing more exact localization of the tumor in relation to critical areas of the brain.

• Multi-voxel magnetic resonance spectroscopy (MRS) is now readily available at most medical centers. MRS is capable of characterizing the “chemical fingerprint” of a brain lesion non-invasively.
• Positron emission tomography (PET) scanning can provide information about the metabolic potential of a brain lesion; a more intense signal suggests a greater reproductive potential, and in the case of a glioma, a more aggressive and faster-growing tumor.

• Biopsy: The gold standard for accurate diagnosis of a glioma is a pathologic examination of tissue samples obtained from biopsy. The field of neuropathology is quickly being redefined by the use of highly specific immunologic and molecular markers. Such tests use special (histologic) stains that are linked to an antibody that specifically binds to a particular receptor on the surface of either normal cells or tumor cells.

Oligodendroglioma. This microscopic field shows a densely cellular tumor composed of nests of epithelioid cells divided by delicate fibrovascular stroma. Note the scattered foci of calcification	Oligodendroglioma. This image demonstrates that the tumor consists of epithelioid cells with round nuclei and perinuclear halos

Glioblastoma multiforme. Features of these highly malignant glial tumors include neovascularization and endothelial proliferation with “glomeruloid” vessels and perivascular concentration of the neoplastic cells	Glioblastoma multiforme. Features of these highly malignant glial tumors include neovascularization and endothelial proliferation with “glomeruloid” vessels and perivascular concentration of the neoplastic cells

WHAT TREATMENT OPTIONS ARE AVAILABLE FOR MALIGNANT GLIOMA?

Traditional treatment options

Traditional treatment options for malignant gliomas include: surgery, radiation therapy, and chemotherapy.

Surgery

Open surgery, through a window cut into the skull (craniotomy), is the primary form of treatment for malignant gliomas. The goal of surgery is to remove as much of the visible tumor as possible without damaging normal neurological functions. The invasive and infiltrating nature of malignant gliomas make this a very challenging task, despite recent advances in operative neurosurgery. Although an array of new technologies, such as operating microscopes, microdissection techniques, intraoperative computerized image-guidance, intraoperative ultrasound, intraoperative brain mapping, and most recently, real time MR imaging have been used, complete surgical resection of gliomas remains no easy.

Radiation therapy and chemotherapy


Radiation therapy and chemotherapy are widely used as secondary or adjuvant treatments following surgery. Both therapies have a growth-suppressant effect on the tumor. Among patients who are not surgical candidates, either radiation or chemotherapy can be used as an initial treatment. Patients who are poor operative candidates generally include those who:

1. are medically unstable

2. have multiple active cancers simultaneously

3. have tumor spread to both brain hemispheres

4. have a glioma in an inoperable location (e.g. brain stem)

5. are opposed to surgery

A therapeutic role for postoperative radiation therapy was clearly established 25 years ago. The typical total dose of conventional radiation therapy used to treat malignant gliomas is approximately 60 Gray (Gy). Such treatment is delivered to the tumor, plus a 2-3 cm margin surrounding the tumor. The purpose of the additional margin of radiation is to compensate for less than perfect beam alignment and to treat the area of surrounding normal brain that is in the process of being infiltrated with tumor cells that are not visible by either MR or CT imaging.

With conventional radiation therapy, the daily dose is intentionally kept low and the technique of delivery is designed to maintain a uniform intensity of radiation, i.e. dose homogeneity.

Typical modern radiation therapy uses a linear accelerator to fire beams of radiation at a tumor from several directions. Most contemporary methods of radiation therapy use computer-controlled beam shaping devices to better conform the target volume to the shape of the tumor being treated. The best of these techniques, termed Intensity Modulated Radiation Therapy (IMRT), uses a computer to vary the intensity and shape of each radiation beam. The net benefit of IMRT is to better conform the dose of radiation to the tumor, even when the lesion has a very complex shape.

Complications of Radiation Therapy

are following:

• With conventional daily-fractionated radiation therapy, the common short-term side-effects (which occur in days to weeks) are fatigue, loss of appetite and nausea.
• Skin rashes and hair loss often also occur over substantial regions of scalp.
• Delayed side-effects (occurring within months to years) can include varying degrees of memory loss and impairment of reasoning or thinking.
• More rarely, patients can experience impairment of pituitary function or radiation necrosis (a collection of dead tumor cells and scar tissue). Radiation necrosis can produce symptoms that are often very similar to the initial tumor presentation and includes severe headache, motor weakness, visual problems, or seizures.

Noval treatment options

THERAPY OF LOCAL IMMUNOTHERAPY OF THE TUMOR BED FOR GLIOMA (WU NIANCENG’S THERAPY)

This therapy, that has been invented by professor Wu Nianceng in our hospital, is special for treatment of malignant glioma.

 BACKGROUND and PRINCIPLE

The survival rate for malignant glioma remains dismal. Extensive surgical resections, radiotherapy with or without radiosensitizers, and various chemotherapy regimens have shown little impact on survival, which ranged from 14 to 60 weeks with 18-survivorship from 0% to 37 percent. This has stimulated work to identify additional therapeutic modalities that might improve prognosis.

Immunotherapy addresses anarea of demonstrated deficiency in patients with primary brain tumors, in whom numerous defects of cellular immunity have been discovered, including impaired delayed hypersensitivity for common recall and autologous tumor antigens, a decrease in circulating T-lymphocytes, shifts in lymphocyte subpopulation in peripheral blood, incomplete responseof peripheral blood lymphocytes to intrleukin-2, decreased mitogen-induced blastogenesis, which may affect the host’s ability to halt neoplastic growth. Surgery, radiotherapy, and chemotherapy also debilitate the immune system of patients with brain tumor. The tumors themselves have direct immunosuppressive effects via expression of suppressor factors, such as transforming growth factor-beta.

Based on above data, professor Wu has studied the effects of local administration of a special immunomodulator—S311 on glioma and invented a therapy called local immunotherapy in tumor bed for treatment and prevention of glioma.

PROCEDURE

Patients received routine surgical removal of tumor tissue visible as much as possible and then were given implantation of Ommiya capsule in tumor bed. The open end of the capsule was implanted in cavity of tumor and the closed end was put under the cranial skin. Postoperatively, from the fifth-seventh day, S311 was percutaneously infused into Ommiya capsule, 2mg per session, once every 2 days, for 5 session as a course. Afterward, a course of treatment was given every one month for 3 courses and then a course every 3 months for 3 courses, and again, a course every 12 months for longer duration as long as possible.S311, a sterile suspension of 2 mg RNA per vial in a tris-megnesium buffer stored frozen at –20°C, was obtained from Immunology Research Section of Navy Institute of Medicine (Shanghai).

CLINICAL APPLICATION AND RESULTS

• 45 patients who received this therapy from 1996 to 1997, had survival time of from 9 to 81 months with median of 38.5 months, and had overall survival rates of 96.2%, 86.7%, 79.0%, 74.28%, 61.5%, 55.5% and 50.0%, respectively, at 1, 2, 3, 4, 5, 6 and 7 years. Of 31 patients who are alive, 28 cases have disease-free survival, and 3 cases have presence of tumor on CT or MRI but tumor’s volume remains stable. Of 14 patients died, 9 died of tumor recurrence, and 5 died of non-tumor causes. Of 4 patients died after fourth year following the therapy, 3 died of non-tumor causes. Apart of transient fever, no serious adverse reaction was noted.

• These results were better than results of studies reported using the multimodality therapy (surgery, radiotherapy, chemotherapy), in which median survival time ranged from 10 to 14 months.

• From Jun 2002 to now, there are more 100 patients with glioma who have received this therapy with better results.

COMMENT

WHY his therapy can get a superior efficacy for glioma? May be because following considerations:

• S311 is a biologic response modifier consisting of sized membrane vesicles and ribosomes derived from preparation ofSerratia marcescens, has been shown to augment the activity of human natural-killer (NK) cellagainst tumor cells in vitro and to stimulate cytotoxity in the peripheral-blood mononuclear cells of patients, in whom this activity has been downregulated. NK-cell cytotoxicity was increased three to 10-fold within 24 hours of S311 injection. Also, it was proved that S311’s action appears to be via triggering of interferon-gamma production through binding of the low affinity immunoglobulin G Fc fragment receptor (type Ⅲ, CD 16), by acting in combination with interleukin-2 to produce synergistically enhanced cytotoxity, and by direct contrasuppressor activity in the face of down-regulated cytotoxity in patients with impaired immunity.

• Wu has used a special route of administration of the drug, and S311 was given infusion into tumor bed through implanted Ommiyo capsule. The modification was based on the following reasons:

• Local administration may eliminate the effect of blood-brain-barrier (BBB) and blood-tumor-barrier (BTB), which reduce delivery of lipid-soluble drugs into brain tumor;

A schematic of the Blood Brain Barrier (BBB) with associated astrocytes.

Trojan horse designs. Two different delivery architectures used for brain drug targeting. (A) Brain-derived neurotrophic factor (BDNF) is linked to a monoclonal antibody (MAb), which binds to the transferrin receptor (TFR) on the BBB, via streptavidin (SA)–biotin chemistry. The BDNF is surrounded by strands of polyethylene glycol (PEGylated), which inhibit the uptake of the drug by peripheral organs, particularly the liver. (B) Double-stranded plasmid DNA is encased in a liposome that is attached to PEGs that bind the MAb transport vector for nonviral brain gene delivery