Glioblastoma , also known as glioblastoma multiforme ( GBM ), is the most aggressive cancer that begins in the brain. Initially, the signs and symptoms of glioblastoma are not specific. They may include headaches, personality changes, nausea, and symptoms similar to stroke. The worsening of symptoms is often rapid. This can lead to unconsciousness.
The cause of most cases is unclear. Unusual risk factors include genetic disorders such as neurofibromatosis and Li-Fraumeni syndrome, and previous radiation therapy. Glioblastomas represent 15% of brain tumors. They can start from normal brain cells or progress from low level astrocytoma. Diagnosis is usually made by a combination of CT scans, MRI scans, and tissue biopsies.
There is no clear way to prevent illness. Usually, treatment involves surgery, after which chemotherapy and radiation therapy are used. Temozolomide drugs are often used as part of chemotherapy. High doses of steroids can be used to help reduce swelling and reduce symptoms. It is unclear whether trying to remove all or only most of the cancer is better.
Despite the maximum treatment, the cancer usually recurs. The most common survival length after diagnosis is 12 to 15 months, with less than 3% to 5% of people who survive longer than five years. Without treatment, survival is usually three months. It is the most common cancer that begins in the brain and the second most common brain tumor, after meningioma. About 3 per 100,000 people develop this disease a year. It most often begins about 64 years and occurs more often in men than in women. Immunotherapy is being studied in glioblastoma with promising results.
Video Glioblastoma
Signs and symptoms
Common symptoms include seizures, headache, nausea and vomiting, memory loss, personality changes, mood or concentration; and local neurological problems.
The type of resulting symptoms is more dependent on the location of the tumor than on its pathological properties. The tumor can start producing symptoms quickly, but sometimes it is an asymptomatic condition until it reaches a very large size.
Maps Glioblastoma
Risk factors
The cause of most cases is unclear. About 5% develop from another type of brain tumor known as low-grade astrocytoma.
Genetics
Unusual risk factors include genetic disorders such as neurofibromatosis, Li-Fraumeni syndrome, tuberous sclerosis, or Turcot syndrome. Previous radiation therapy is also a risk. For unknown reasons, GBM is more common in men.
Environment
Other associations include exposure to smoking, pesticides, and work in petroleum refining or rubber manufacturing.
Glioblastoma has been associated with SV40, HHV-6, and cytomegalovirus viruses.
Pathogenesis
The origin of glioblastoma cellular is unknown. Because of the similarities in immunostaining glial cells and glioblastoma, it has long been assumed that gliomas such as glioblastoma are derived from glial type cells. But more recent studies show that astrocytes, oligodendrocyte progenitor cells and neural stem cells can also function as home cells.
Glioblastoma multiforme tumor is characterized by a small area of ​​necrotic tissue surrounded by anaplastic cells. This characteristic, as well as the presence of hyperplastic blood vessels, distinguishes tumors from Grade 3 astrocytomas, which do not have this feature.
GBM usually forms in cerebral white matter, grows rapidly, and can become very large before producing symptoms. Less than 10% is formed more slowly after degeneration of low-grade astrocytoma or anaplastic astrocytoma. This is called secondary GBM and is more common in younger patients (mean age 45 versus 62 years). The tumor may extend into the meninges or ventricular wall, leading to a high protein content in cerebrospinal fluid (CSF) (& gt; 100 mg/dL), as well as occasional pleocytosis of 10 to 100 cells, mostly lymphocytes. Malignant cells carried in CSF can spread (rarely) to the spinal cord or cause meningeal gliomatosis. However, GBM metastasis outside the central nervous system is highly unusual. About 50% of GBM occupy more than one lobe of the hemisphere or bilateral. These types of tumors usually arise from the cerebrum and may show classical infiltration throughout the corpus callosum, producing bilateral butterfly gliomas.
The tumor can have various appearances, depending on the amount of bleeding, necrosis, or age. CT scans will usually show an inhomogeneous mass with a center of hypodens and a raised ring of variables surrounded by edema. Mass effects of tumors and edema may suppress the ventricle and cause hydrocephalus.
Molecular changes
Four subtypes of glioblastoma have been identified:
- Classic: Ninety-seven percent of tumors in the 'classical' subtype carry an extra copy of the epidermal growth factor receptor gene (EGFR), and most have higher epidermal growth factor receptor expression (EGFR) than normal expression, while the TP53 gene (p53), which often mutates in glioblastoma, rarely mutates in this subtype. The loss of heterozygosity (LOH) in chromosome 10 is also frequently seen in classical subtypes along with chromosome amplification 7. Proneural subtypes often have a high rate of change in TP53 (p53), and in PDGFRA, the gene encoding the derived platelet growth factor receptor, and at IDH1, encoding the isocitrate dehydrogenase-1 gene.
- Mesenchymal subtypes are characterized by high mutation rates or other changes in NF1, genes that encode Neurofibromin 1 and slight changes in the EGFR gene and less EGFR expression than other types.
- Neural subtypes are characterized by expression of neuronal markers such as NEFL, GABRA1, SYT1 and SLC12A5, while often present themselves as normal cells on pathological assessment.
Many other genetic changes have been described in glioblastoma, and most of them are grouped in two pathways, RB and PI3K/AKT. Glioblastoma has changes in 68-78% and 88% of these pathways, respectively.
Another important change is the MGMT methylation, a DNA enzyme "suicide". Methylation is intended to damage DNA transcription and, therefore, the expression of MGMT enzymes. Because the MGMT enzyme can only repair one DNA alkylation because of a suicidal repair mechanism, its low recoil capacity and MGMT gene promoter methylation greatly affect the DNA repair capacity. Indeed, MGMT methylation is associated with an improved response to treatment with chemo-damaging chemotherapy, such as temozolomide.
Glioblastoma cell-like cells
Cancer cells with properties similar to stem cells have been found in glioblastoma (this may be the cause of their resistance to conventional treatments, and high recurrence rates). Cells called glioblastoma like this cell are located in a niche around the arterioles, protecting these cells against therapy by maintaining a relatively hypoxic environment. Biomarkers for cells in glioblastoma that exhibit cancer stem cell properties, the Hes3 transcription factor, have been shown to regulate their numbers when placed in culture.
Metabolism
The IDH1 gene encodes for isocitrate dehydrogenase 1 enzymes and is often mutated in glioblastoma (primary GBM: 5%, secondary GBM & 80%). By generating very high concentrations of "oncometabolite" D-2-hydroxyglutarate and propagating the function of the wild-type IDH1 enzyme induced major changes in metabolism IDH1 -mutated glioblastoma, compared with IDH1 wild-type glioblastoma or healthy astrocytes. Among other things, it increases the dependence of glioblastoma cells on glutamine or glutamate as an energy source. It has been hypothesized that IDH1 -the mutated glioblastoma has a very high glutamate demand and uses these amino acids and neurotransmitters as a chemotactic signal. Because healthy astrocytes excrete glutamate, the represented glioblastoma cells do not support tumor structures that are dense but migrate, attacking and spreading to healthy areas of the brain where glutamate concentrations are higher. This may explain the invasive behavior of glioblastoma represented by IDH1 .
ion channel
In addition, glioblastoma multiforme showed many changes in the gene encoding ion channels, including upregulation of potassium gBK channels and ClC-3 chloride channels. It has been hypothesized that by increasing the regulation of these ion channels, glioblastoma tumor cells can facilitate increased ionic motion above the cell membrane, thereby increasing the movement of H 2 O through osmosis, which helps glioblastoma cells in altering cell volume very quickly.. This is particularly helpful in their highly aggressive invasive behavior, because rapid adaptation in cell volume can facilitate movement through the intricate matrix of the extracellular brain.
Diagnosis
When viewed with MRI, glioblastoma often appears as ring-enhancing lesions. Its appearance is not specific, however, as other lesions such as abscess, metastasis, multiple multiple sclerosis tumefactive, and other entities may have similar appearances. The exact diagnosis of GBM suspected in CT or MRI requires stereotactic or craniotomy biopsy with tumor resection and pathologic confirmation. Because tumor levels are based on the most malignant part of the tumor, biopsy or subtotal tumor resection can lead to lesion enlargement. Imaging tumor blood flow using MRI perfusion and measuring tumor metabolite concentrations by MR spectroscopy can add standard MRI values ​​in certain cases by showing an increase in relative cerebral blood volume and an increase in peak choline respectively, but pathology remains the gold standard for molecular diagnosis and characterization.
It is important to distinguish primary glioblastoma from secondary glioblastoma. These tumors occur spontaneously ( de novo ) or have progressed from a low-grade glioma, respectively. Primary glioblastoma has a poorer prognosis, different tumor biology and may have different responses to therapy, which makes this a critical evaluation to determine the patient's prognosis and therapy. More than 80% of secondary glioblastomas carry mutations in IDH1 , while these mutations are rare in primary glioblastoma (5-10%). Thus, the IDH1 mutation is a useful tool for distinguishing primary and secondary glioblastomas because they are histopathologically very similar and differences without molecular biomarkers are unreliable.
Treatment
It is very difficult to treat glioblastoma because of several complicated factors:
- The tumor cells are very resistant to conventional therapy.
- The brain is susceptible to damage due to conventional therapy.
- The brain has a very limited capacity to repair itself.
- Many drugs can not cross the blood-brain barrier to act on the tumor.
The treatment of primary brain tumors and brain metastases consists of symptomatic and palliative therapy.
Symptomatic therapy
Supportive care focuses on relieving symptoms and improving the patient's neurological function. The main support agents are anticonvulsants and corticosteroids.
- Historically, about 90% of patients with glioblastoma have anticonvulsant treatment, although it is estimated that only about 40% of patients require this treatment. Recently, it has been recommended that neurosurgeons do not administer prophylactic anticonvulsants, and must wait until seizures occur before prescribing the drug. Those who receive phenytoin along with radiation may have serious skin reactions such as erythema multiforme and Stevens-Johnson syndrome.
- Corticosteroids, usually dexamethasone given 4 to 8 mg every 4 to 6 hours, may reduce peritumoral edema (by rearranging the blood brain barrier), reducing the effect of mass and decreasing intracranial pressure, with decreased headache or drowsiness./li>
palliative therapy
Palliative care is usually done to improve the quality of life and to achieve longer survival time. This includes surgery, radiation therapy, and chemotherapy. Adequate maximum resection with maximum tumor-free margin is usually performed along with external beam radiation and chemotherapy. Overall tumor resection is associated with a better prognosis.
Surgery
Surgery is the first stage of treatment of glioblastoma. The average GBM tumor contains 10 cells 11 , which is reduced to 10 9 cells after surgery (99% reduction). The benefits of surgery include resection for pathological diagnosis, alleviation of symptoms associated with mass effects, and potentially eliminating the disease before secondary resistance to radiotherapy and chemotherapy occurs.
The greater the rate of removal of the tumor, the better. The removal of 98% or more of the tumors has been associated with a significantly longer healthy time than if less than 98% of the tumors were removed in retrospective analysis. The likelihood of early completion of the tumor can be increased if surgery is guided by a fluorescent dye known as 5-aminolevulinic acid. GBM cells are broadly infiltrative through the brain at diagnosis, and although there is a "total resection" of all clear tumors, most people with GBM then develop recurrent tumors either near the original site or at a further location in the brain. Other modalities, usually radiation and chemotherapy, are used after surgery in an effort to suppress and slow the recurrent disease.
Radiotherapy
After surgery, radiotherapy becomes the mainstay of treatment for people with glioblastoma. Usually performed in conjunction with the administration of temozolomide (TMZ). Important clinical trials conducted in the early 1970s showed that among 303 GBM patients who were randomized to radiation or non-radiation therapy, those who received radiation had an average survival of more than twice that of those who did not. Subsequent clinical studies have sought to build the backbone of surgery followed by radiation. On average, radiotherapy after surgery can reduce tumor size to 10 cells 7 . All-brain radiotherapy does not improve when compared with more precise, targeted conformal radiotherapy. The total radiation dose of 60-65 Gy has been found to be optimal for treatment.
The GBM tumor is known to have a network zone showing hypoxia that is highly resistant to radiotherapy. Various approaches to chemotherapy radiosensitizers have been pursued with limited success in 2016. In 2010 new research approaches include preclinical and clinical investigations into the use of compounds increasing oxygen diffusion such as trans sodium crocetinate (TSC) as radiosensitizer, and by 2015 ongoing clinical trials.
Boron neutron retention therapy has been tested as an alternative treatment for glioblastoma multiforme but is not commonly used.
Chemotherapy
Most studies show no benefit from the addition of chemotherapy. However, a large clinical trial of 575 participants randomized to standard radiation versus radiation plus temozolomide chemotherapy showed that the group receiving temozolomide survived an average of 14.6 months compared with 12.1 months for the group receiving only radiation. This treatment regimen is now standard for most cases of glioblastoma in which the person is not enrolled in clinical trials. Temozolomide seems to work by making tumor cells radiation-sensitive.
High doses of temozolomide in high-grade gliomas produce low toxicity, but the results are proportional to the standard dose.
Antiangiogenic therapy with drugs such as bevacizumab control symptoms but does not affect overall survival.
Other modalities
Alternative electric field therapy is FDA-approved therapy for newly diagnosed and repeated glioblastoma. By 2015, preliminary results from phase three randomized clinical trials of alternating electric field therapy plus temozolomide in newly diagnosed glioblastoma reported a three-month increase in progression-free survival, and a five-month increase in overall survival compared with temozolomide therapy alone. , represents the first major trial in a decade to show improved survival in this setting. Despite these results, the efficacy of this approach is still controversial among medical experts.
Prognosis
The most common survival length after diagnosis is 12 to 15 months, with less than 3% to 5% of people who survive longer than five years. Without survival treatment is usually 3 months.
Increased age (& gt; 60 years) carries a worse prognostic risk. Death is usually due to widespread tumor infiltration with cerebral edema and increased intracranial pressure.
Good initial Karnofsky Performance Values ​​(PPP) and MGMT methylation were associated with longer survival. DNA testing can be performed on glioblastoma to determine whether the GGMT genotene promoter is methylated. Patients with methylated MGMT promoters had longer survival compared with non-methylated MGMT promoters, in part due to increased susceptibility to temozolomide. The characteristics of this DNA are intrinsic to the patient and currently can not be changed externally. Other positive prognostic markers for glioblastoma patients are gene mutations IDH1 , which can be tested by DNA-based methods or by immunohistochemistry using antibodies to the most common mutation, IDH1-R132H.
More prognostic strength can be obtained by combining the mutated status of IDH1 and the methylate status MGMT into a two-gene predictor. Patients with the IDH1 and MGMT methylation mutations had the longest survival, patients with mutations IDH1 or MGMT moderate survival methylation and patients without genetic events have the shortest survival.
Long-term benefits are also associated with patients receiving surgery, radiotherapy, and temozolomide chemotherapy. However, there is still much unknown why some patients last longer with glioblastoma. Age below 50 was associated with longer survival in glioblastoma multiforme, such as 98% resection and use of temozolomide chemotherapy and better Karnofsky performance scores. A new study confirms that younger age is associated with a much better prognosis, with a small percentage of patients under age 40 reaching a population-based cure. Population-based healing is estimated to occur when the risk of death of the population returns to a normal population, and in GBM, this is estimated to occur after 10 years.
UCLA Neuro-Oncology publishes real-time survival data for patients with this diagnosis. They are the only institution in the United States that shows how their patients perform. They also show a list of chemotherapy agents used to treat GBM tumors. Despite a poor prognosis, there are a small number of victims who have been GBM-free for more than 10-20 years.
According to a 2003 study, the prognosis of glioblastoma multiforme can be divided into three subgroups depending on PPP, patient age, and treatment.
Epidemiology
About 3 per 100,000 people develop this disease a year. It most often begins about 64 years and occurs more often in men than in women. This is the second most common central nervous system cancer after meningioma.
History
The term glioblastoma multiforme was introduced in 1926 by Percival Bailey and Harvey Cushing, based on the idea that the tumor originated from a primitive precursor of glial cells (glioblasts), and a highly variable appearance due to necrosis, bleeding and cyst (multiforme). ).
Research
The 2014 investigation made the screening of various drugs for anti-glioblastoma activity and identified 22 drugs with strong anti-glioblastoma activity, including a combination of irinotecan and statin.
MicroRNA
RNA interference, usually microRNA, is being studied in tissue culture, pathology specimens and in preclinical animal studies. The change of microRNA, though not a definitive biomarker, is also recognized as a prognostic and predictive tool of GBM development. These microRNA changes include regulated miR-10b and miR-21, while other microRNAs such as miR-15b, miR-137, and miR-181d appear to be inherited in GBM cases. MicroRNA-plasma screening is used to determine the prognosis of glioblastoma.
Immunotherapy
Glioblastoma relapse is associated with recurrence and persistence of tumor stem cells. In a small trial, the B tumor cell hibridoma vaccine against tumor stem cells induces a certain tumor immune reaction, which increases the immune response to the disease. Larger trials, including tests on different EGFR delivery patterns and their association with tumor stem cells are underway. The rindopepimut test fails in phase III trials by 2016. The immunotherapeutic approach and other types of vaccines are at different stages of development, but conclusive results are not yet available.
Gene therapy
Gene therapy has been explored as a method to treat glioblastoma and while animal models and early-stage clinical trials have been successful, by 2017, all gene therapy drugs that have been tested in phase III clinical trials for glioblastoma have failed.
Toca 511 & amp; Toca FC is a combination drug involving gene therapy and prodrug agents. In July 2017, the EMA has granted the status of a combination priority assessment, and the FDA has given it the Breakthrough Therapy Determination and FDA Rapid Path Determination for recurring high grade glioma (HGG), and the appointment of orphans for the treatment of glioblastoma.
Ofranergene obadenovec is an anti-angiogenic gene therapy. It is given the fastest pathway and orphan drug status by the FDA in 2013 for the treatment of glioblastoma multiforme and, by 2017, is in phase III clinical trials.
Intrana drug delivery
Direct nasal-to-brain delivery is being explored as a means to achieve higher drug concentrations, and hopefully more effectively in the brain. A clinical I/II phase study with glioblastoma patients in Brazil investigated natural perillyl alcohol compounds for intranasal delivery as aerosols. The results are encouraging and, by 2016, similar experiments have begun in the United States.
Chemotherapy
A molecule called VAL-083 (dianhydrogalactitol) is being studied to see if it helps in glioblastoma that is no longer responsive to temozolomide.
Risk factors
Studies have been conducted to see if consumption of preserved meat is a risk factor. No risk has been confirmed in 2013. Similarly, radiation exposure during medical imaging, formaldehyde, and residential electromagnetic fields, such as from cell phones and in-house electrical cables, has been studied as a risk factor. By 2015, they have not been proven to cause GBM. However, the meta-analysis published in 2007 found a correlation between the increase in the incidence of GBM and mobile phone use for more than 10 years, especially among those who always held the phone on one side of their head.
See also
- List of people with brain tumors
References
External links
- Information on Glioblastoma Multiforme (GBM) from the American Brain Tumor Association
- Course Syllabus AFIP - Astrocytoma Submitting Lecture Courses Lecture
- Image Database - MR & amp; CT of Glioblastoma
Source of the article : Wikipedia
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