As a brain tumor are tumors of neuroectodermal tissue of the central nervous system , respectively. Other intracranial tumors, such as meningiomas , do not count as brain tumors in the strict sense. However, from a certain size onwards they also influence brain structures due to the mass, they are counted as brain tumors in the broader sense.
Most brain tumors occur sporadically, that is, without a recognizable family connection. Brain tumors occur more frequently as part of some neurocutaneous syndromes ( phacomatoses ). These include neurofibromatosis , tuberous sclerosis and von Hippel-Lindau syndrome . Li Fraumeni syndrome , Turcot syndrome, and rhabdoid predisposition syndrome are very rare .
The diagnosis is made using imaging tests and a brain biopsy . The treatment depends on the localization of the tumor, the size, the tissue of origin and the general condition of the patient. Typically, the surgical removal of the tumor ( resection , possibly awake craniotomy ) comes first , in the case of malignant tumors this may be followed by radiation and / or chemotherapy .
Brain tumor or also brain tumor
The brain tumor or also brain tumor comprises an abundance of different tumor diseases in the brain. The original meaning of the word tumor comes from Latin and means "swelling". A brain tumor is a proliferation of cells in the brain or, in a broader sense, the surrounding structures such as the meninges or cranial nerves. In the process, degenerate cells ( cancer cells ) grow unchecked in the brain tissue and form tumors. While benign brain tumors usually grow slowly and clearly distinguish themselves from healthy tissue, malignant brain tumors grow faster and at the same time aggressively penetrate the surrounding brain tissue. The surrounding, healthy brain cells are partially or completely destroyed. Occasionally, benign brain tumors can turn into malignant tumors as the disease progresses. In contrast to many other tumor diseases, benign brain tumors can also become life-threatening because the skull limits the possibilities of escape for healthy brain tissue. The tumor exerts pressure on the sensitive brain cells and limits their function or damages them. Benign and malignant brain tumors are rare forms of tumors. They make up about two percent of all cancers. They appear comparatively more frequently in children than in adults. The doctor basically differentiates between a primary and a secondary brain tumor. While the primary brain tumor develops from the brain cells or the cells of the meninges, secondary brain tumors always develop as a result of secondary tumors (metastases) of other cancers. These settle from the original cancer (e.g. lung cancer, skin cancer) and migrate into the brain tissue via the blood or lymph vessels and the nerve water (cerebrospinal fluid, liquor). Secondary brain tumors are therefore tumors that develop, for example, from degenerate skin or lung cells in the brain.
In addition to the classification into the categories benign or malignant as well as primary or secondary, doctors classify the brain tumor based on the tissue type causing it. In addition to the actual nerve cells, the brain consists of various other cell types:
- Neuromas: tumors from nerve cells
- Meningiomas : tumors from cells in the meninges
- Gliomas: Develop from so-called glial cells, which form the support and supply structure for the nerve cells
- Lymphomas: Forms from certain cells of the immune system called lymphocytes.
- Medulloblastoma: It develops from embryonic, immature cells in the brain, especially in childhood.
- Ependymomas : arise from cells that form the covering tissue of the nervous system
- Mixed tumors: Form from different types of cells in the brain
Neuro-oncology and causes
Risk factors and causes for the development of brain tumors are largely unknown, neuro-oncology deals with the causes and clinical characteristics, with the detection and treatment of brain tumors. According to the current state of knowledge, neither environmental factors, eating habits, emotional stress, stress nor electromagnetic fields in the frequency range of mobile radio lead to a higher risk of brain tumors. There is also no connection between brain injuries and the occurrence of brain tumors.
Only direct, radioactive irradiation of the head in childhood, as it is sometimes necessary for the treatment of other serious diseases, increases the risk of developing a brain tumor as an adult. In very rare cases the disease is hereditary and is associated with hereditary diseases, such as neurofibromatosis type 1 and 2, Turcot syndrome, Hippel-Lindau syndrome and Li-Fraumeni syndrome.
In neurofibromatosis of type 1 (Recklinghausen's disease), in addition to other tumors, there are also gliomas, especially pilocytic astrocytomas , brain tumors which are often located (on both sides) on the optic nerve. Characteristic of neurofibromatosis type 2 are acoustic neuromas located on both sides, tumors of the spinal cord or multiple meningiomas. Turcot syndrome can lead to medulloblastoma in children and glioblastoma in adults . The Hippel-Lindau syndrome is mainly associated with hemangiomas in the area of the cerebellum and spinal cord, with the Li-Fraumeni syndrome not only very different tumors but also astrocytomas and plexus carcinomas.
The symptoms or signs that a brain tumor can trigger are very diverse and depend on the location of the tumor. They occur individually or in combination and are divided into four main groups:
Intracranial pressure sign
- Headache (which comes on again, especially at night and morning)
- Nausea and vomiting
- Impaired consciousness (drowsiness or coma)
- Congestive papilla (edema of the retina of the eye)
- slowed pulse
- Numbness (in one half of the body, on individual limbs)
- Muscle weakness and paralysis
- Hearing loss
- Speech disorder
- Speech disorder
- Swallowing disorder
- Sensitivity disorder (e.g. to heat, cold, pressure or touch)
- Visual disturbance (e.g. blurred vision, visual field defects)
- Personality changes (e.g., mild irritability, increased distractibility)
- Changes in mental health (depression, apathy , anxiety)
- Impaired memory (difficulty concentrating, forgetfulness)
In the case of a brain tumor, the course cannot be predicted in principle. The chances of a cure are good for some types of tumors, for others a cure is considered unlikely. The chances of success in treating a brain tumor depend on factors including:
- Location of the brain tumor
- Type of tumor cells and associated growth behavior
- Sensitivity of tumor cells to radiation and chemotherapy
A number of diagnostic procedures are available if a brain tumor is suspected. After anamnesis and clinical examination, imaging and tissue analysis methods can be used to make a targeted diagnosis. The preoperative diagnostic procedures include:
Computed tomography (CT)
In a computed tomography (CT) is a computerized evaluation of several, from different directions captured X-ray images to a three-dimensional image of the object in question to obtain. In contrast to conventional X-ray recordings, this enables statements to be made about the volume structure of an X-rayed body.
The comparison of transmitted and received radiation intensity provides information about the attenuation (absorption) by the tissue to be examined, the degree of absorption being given in gray values and with the help of the Hounsfield index.
Magnetic resonance imaging (MRI)
The magnetic resonance imaging (MRI), also called magnetic resonance imaging is a diagnostic imaging procedure for the preparation of organs and tissues with the help of magnetic fields. A strong magnetic field is applied in the tomograph, whereby the atomic nuclei (usually hydrogen nuclei / protons) in the human body align themselves using the magnetic field. This is followed by a specific change in this arrangement by means of a frequency pulse, which steers the atomic nuclei out of the magnetic field lines and synchronizes their tumbling movement.
Functional magnetic resonance imaging (fMRI)
The functional magnetic resonance imaging (fMRI) in the strict sense refers to methods that activated brain regions (usually based on the blood oxygenation) with high spatial resolution can represent. The use of the method can be useful when planning a neurosurgical operation, for example, to delimit a tumor from the brain region that is important for movement. With the help of fMRI, the most suitable access route to the tumor can be found or it can be checked whether an intervention is sensible and possible at all.
Magnetic resonance spectroscopy (MRS)
The magnetic resonance spectroscopy (MRS) is a diagnostic procedure for the preparation of biochemical processes or metabolic processes. Mainly the techniques of magnetic resonance tomography are used. While the signals of the hydrogen atom are analyzed in the MRI, in the MRS it is also the signals of sugar, neurotransmitters or their metabolic products.
Positron Emission Tomography (PET)
The positron emission tomography (PET) has application in metabolically related issues neurooncology. Compared to healthy body cells, tumor cells have an increased metabolic rate, which is reflected in an increased need for glucose and amino acids. This property of tumors is used in PET. The patient is administered weakly radioactively labeled substances (tracers) which correspond to the body's own metabolites and which are absorbed by the cells as such, but not metabolized. This enables the visualization of cells and tissues (especially rapidly spreading tumors) with increased metabolic activity.
Knowledge of the histology is of crucial importance in the therapeutic concept of any tumor disease. Even with the methods of CT, MRT and PET with the highest imaging quality available today, the diagnosis cannot be fully assured. In most cases, the further treatment planning of patients is closely linked to the histological tumor diagnosis. The stereotactic tumor biopsy, supported by cross-sectional imaging, is a standard neurosurgical procedure for confirming the diagnosis because of its great accuracy and low complication rate. For this purpose, a stereotaxic ring with four locators is attached to the patient's head. These locators describe a rectangular space in which each point can be described by an exact, computer-determined indication of the height, width and depth.
For the treatment of primary brain tumors and brain metastases , surgical removal, radiation and chemotherapy are mainly available. In addition to these classic three options, there are additional therapy concepts and modern approaches that are tested in clinical studies or can also be used as an individual healing attempt.
The neurosurgery includes the diagnosis and surgical treatment of diseases, deformities and injuries of the central nervous system (CNS). Depending on the location and size of the brain tumor as well as the condition and symptoms of the patient, a brain tumor can be removed as far as possible (also by means of awake craniotomy for certain brain tumors) or only partially removed. Sometimes neurosurgical treatment is not possible at all, so the tumor is inoperable. This is particularly the case when the tumor lies directly in functional areas that would be severely impaired or even destroyed by an operation.
5-aminolevulinic acid / fluorescence-assisted surgery
Resection with the administration of 5-aminolevulinic acid (5-ALA) can be useful in order to be able to remove diffusely growing malignant gliomas that are difficult to distinguish from the surrounding healthy brain tissue . The patient has to drink a solution of 5-ALA before the neurosurgical procedure. Due to an enzyme defect in the tumor cell, the substance selectively accumulates mainly there. During the operation, the neurosurgeon can switch on a blue light that causes the tumor cells to fluoresce in a red-violet color. The clinical value of the 5-ALA procedure was investigated in an international, randomized, controlled study. This was able to show that twice as many brain tumors were completely removed radiologically with the administration of 5-ALA and accordingly fewer cases with a postoperative residual tumor occurred (35% under 5-ALA vs. 50 to 70% without 5-ALA).
In the case of tumors in the area of the language centers, the operation can also be carried out while the patient is awake and pain-free in order to monitor the language function during tumor removal. The aim here is not to damage the neighboring functional brain regions and to preserve all brain functions.
Dextroscope Virtual Reality
The three-dimensional operation planning in the virtual simulator for the preoperative simulation of the most suitable minimally invasive access and for planning the suitable surgical strategy.
The "Navigated Brain Stimulation" (abbreviation NBS) is a method for assessing the exact location of the primary motor cortex. With this method, an individual map of the movement center can be created before the operation. In order to operate on a brain tumor, it has so far been common practice to irritate the surrounding brain regions during the procedure. If the patient reacts to this, the surgeon knows where regions for speech and movement are. The location of these areas can differ from person to person. This means that the attending physician only finds out during the operation where the critical areas are located. In comparison, the neurosurgeon can use the navigated brain stimulation to collect information about important areas before the operation and optimize the operation strategy. The NBS system displays the standard MRT images of the patient's brain using a camera and fixed points attached to the patient in 3D. The center of movement is localized with millimeter precision through stimulation with a magnetic coil. Since the data from the NBS system can be imported into the neuronavigation device and the surgical microscope, they are also available during the neurosurgical procedure. Compared to direct stimulation of the cortex during the operation, it saves operating time and the treatment result can possibly be optimized. Studies are currently underway on the use of the NBS for operations in the language center and other functionally important areas.
Neuroendoscopic surgery - intracranial
By using a narrow neuroendoscope, the expanded ventricular system can be inspected.
For this purpose, the endoscope is inserted into the ventricular system through a small drill hole in the skull . Every area of the brain chambers can be viewed by the endoscope through various angled optics. The introduction of instruments into the working channel of the endoscope (small grasping forceps, ultrasound probes, coagulation and balloon catheters) allows various interventions to be carried out. Membranes, septa or cysts blocking the flow of cerebrospinal fluid can be opened and fenestrated (septostomies, cyst wall resections and evacuations). Tumors that grow in the area of the cerebral chambers can be inspected and tumor samples taken for tissue and molecular type diagnosis (endoscopic biopsy). In the case of an occlusive hydrocephalus (hydrocephalus occlusus), the internal liquor spaces at the bottom of the III. Ventricle with the outer liquor spaces, the subarachnoid space (ventriculostomy). In this way, a free CSF passage between the inner and outer spaces can be restored and an implantation of drainage systems (shunt implantation) can be avoided.
Endosonography and Neuronavigation
To combine neuroendoscopy and modern ultrasound technology, ultrasound probes have been developed that can be inserted into the ventricles of the brain through the working channel of the endoscope. The ultrasound probes allow examination of the brain tissue adjacent to the cerebral chambers beyond the examination of the walls of the brain chambers (endosonography). Furthermore, they enable safe control of the endoscope in the ventricular system through continuous image generation. Neuronavigation enables the transfer of structural and functional image data (MRT, CT, MR angiography, PET) to the operating theater area, which enables precise orientation and precise control of target structures. The integration of the endoscope into the neuronavigation ensures the exact positioning of the endoscope and safe control in the brain.
Endoscopically assisted microneurosurgery
The use of minimally invasive approaches can reduce the stress on the patient from the surgical procedure. On the other hand, smaller access points reduce the surgeon's field of vision. The restricted field of vision can be expanded through the assisted use of neuroendoscopy in open neurosurgery (surgery by opening the roof of the skull). The endoscope, which can be equipped with various angled optics, is introduced into the surgical area through the skull opening (trepanation). The surgeon can see around important structures, ie “around the corner”, as it were. The endoscopically assisted surgical technique may come. a. in the supply of vascular wall sacs (aneurysms), after cerebral haemorrhage or in the removal of tumors at the base of the skull.
Robot-assisted with computer-assisted surgery
For years, stereotactic biopsies have been performed internationally with this handling technique, for example.
Neurophysiological intraoperative monitoring
Electrophysiological methods are used to protect functionally important brain areas and sensory nerves during neurosurgical operations. Processes in the language region can be carried out in local anesthesia on the awake patient while stimulating the language center. By utilizing the phase reversal when stimulating sensitive pathways, the center of movement can be better localized and paralysis of the extremities can be prevented. When removing tumors on the auditory and equilibrium nerves, the acoustic pathway and the motor facial nerve in the immediate vicinity are functionally monitored. This means that hearing can be maintained depending on the size of the tumor, and the dreaded facial paralysis does not occur or only occurs briefly. In patients, the recordings of cerebral waveforms and the registration of sensory stimuli (evoked potentials) provide important information on the condition and prognosis, but it can also influence surgical decisions.
As multimodal monitoring, comprehensive intraoperative electrophysiological monitoring of various body functions, such as B. movement or language. In the case of certain diseases, this is also used in so-called awake operations, in which the patient has to fulfill various parameters while removing part of the anesthesia.
Brain mapping or brain mapping
The concepts of an interindividually constant anatomical localization of linguistic areas developed in the last century have not been able to hold up, in contrast to the sensorimotor cortex, which shows almost no interindividual variability and can often be clearly localized using magnetic resonance imaging.
For this reason, in the case of tumor locations in or near speech-active centers, surgery has so far either been refrained from in order to avoid a significant reduction in the patient's quality of life due to severe language disorders (aphasia), or the tumor has only been partially resected in areas that are suspected to be speech-active centers.
Surgical techniques with intraoperative electrophysiological localization (“ brain mapping ” or “electrical stimulation mapping”) of speech-active areas were first used by Penfield et al. presented during epilepsy surgery. In some neurosurgical centers today, a modified technique is used in patients with low-grade gliomas or other lesions in the vicinity of suspected function-critical, "speech-coquent" areas, in order to use intermittent function monitoring (electrical stimulation of cortical function-sensitive areas and mapping) to localize the individual in a more voice-active manner To locate areas exactly and thus to avoid neurological and neuropsychological deficits caused by surgery as far as possible. "Brain mapping" is currently probably the safest method for verifying functional areas of the brain.
However, such a test on the awake patient is associated with severe psychological stress, despite being pain-free, and from our point of view is only considered for individual patients . Since human language is a very complex phenomenon, only certain partial aspects or functions can always be localized both by means of apparatus-based imaging examinations and by intraoperative stimulation using different paradigms. The definition of “adequate” paradigms for pre- and intraoperative language testing is currently the subject of very controversial discussion in the field of neuropsychological research.
Navigated transcranial magnetic stimulation (nTMS) maps brain tumors before surgery to test whether areas of the brain are affected for movement or speech.
High-field magnetic resonance tomography / open magnetic resonance tomography
Routine interventions such as biopsies, periradicular therapies or the catheter system for brachytherapy are carried out on the open magnetic resonance tomograph .
Pediatric brain tumor surgery
In addition to diseases of the blood-forming system, brain tumors of the central nervous system are the most common neoplasms in childhood. The most common localization is in the posterior fossa. However, children are also admitted whose tumors are located in the chambers of the cerebrum or in the area of the anterior skull base. Pediatric neurosurgery makes special demands on the neurosurgeon and forms a specialty in neurosurgery. Whenever possible, complete tumor extirpation is sought in children. Postoperatively, MRI controls are performed routinely to document the extent of tumor extirpation. This is an important prerequisite for objectively determining the initial postoperative situation for u. U. to show necessary further therapy modalities. If the diagnosis of the tumor requires it, radiation and / or chemotherapy are carried out according to nationally recognized study protocols. The treatment of hydrocephalus is another area of focus in pediatric neurosurgery. In addition to an individual valve-controlled shunt operation, endoscopic ventriculocisternostomy means that shunt implantation can be dispensed with in many cases. Multi-chamber malformation hydrocephali can also be treated successfully in this way.
Stereotaxic and the "functional stereotaxic"
In stereotactic interventions, point brain operations are performed with the help of various probes or cannulas. The basis for this is a three-dimensional coordinate system which, as a result of imaging diagnostics (e.g. through computed tomography or magnetic resonance tomography), enables the brain to be “measured” down to the millimeter. Since the operation is associated with minimal tissue trauma, it can usually be performed under local anesthesia. In order to achieve the greatest possible accuracy, special requirements are placed on the equipment.
In deep brain stimulation, with the help of a fully implantable pulse generator via stereotactically inserted electrodes, an electrical stimulation of precisely defined brain structures stereotaxic is carried out. The stimulation parameters can be changed telemetrically after the implantation in order to increase the effectiveness of the therapy or to reduce side effects as the underlying disease progresses.
In radiation therapy , high-energy radiation (e.g. from photons or electrons) is used to disrupt the cell division process and prevent tumor cells from growing. Accelerated, energy-charged particles hit the tumor area and can damage the genetic material of the cells. Tumor tissue is more sensitive to radiation than normal tissue. This property is used in radiation therapy, where tumor tissue is damaged more than healthy tissue. Radiation therapy is carried out according to a radiation plan and is carried out either as the sole therapy or in combination with surgical and chemotherapeutic treatment methods.
The name brachytherapy is derived from the Greek word "brachys", which means "short". In this procedure, the distance between the tumor and the radiation source is short, because the latter is inserted directly into the brain. This mostly temporary implantation of radioactive grains (seeds, a few mm long) is carried out using thin needles that are integrated into a stereotactic 3D frame system. For this purpose, a small drill hole is required in the area of the skull. Brachytherapy enables the administration of a high local dose with less impact on the healthy surrounding tissue due to the direct proximity to the tumor with a short range and thus a steep dose drop.
To plan the irradiation, a CT is made of the patient's head and transferred to the Cyberknife's positioning system. This calculates the exact position of the tumor with the help of two axes and forwards the coordinates to the robot, which continuously compares the position of the patient during the treatment. With this treatment method, there is no need to attach a frame to the patient's head and a high level of accuracy can be achieved despite smaller movements during the irradiation .
Intensity-modulated radiation therapy
The intensity-modulated radiotherapy (IMRT) is a further development of the computer-assisted three-dimensional radiation. The irradiation planning is based on the cross-sectional imaging of computed tomography, which allows a three-dimensional volume reconstruction of the target volumes to be irradiated and the risk structures. In contrast to conventional 3D planning, in which the intensity of the individual irradiation fields is constant over the entire field area, with IMRT these are broken down into several small segments. By superimposing these irregular partial fields, so-called intensity-modulated radiation fields are generated, which lead to the desired dose distribution. Technically, this modulation is u. a. made possible by lamellar screens that drive through the field independently of each other. This means that some areas of the entire irradiation field are open for a shorter time, some longer. This results in a "dose range". The IMRT treatment planning uses special algorithms to calculate the dose distribution.
The intensity-modulated radiation therapy is used when the target volume has a very complex shape or important, critical and radiation-sensitive structures are located close to the tumor. In such cases, IMRT enables the dose to be precisely adjusted to the target volume in which the tumor cells are located. Thus, the surrounding tissue is spared as much as possible, which reduces the side effects of the treatment. Most of the time, IMRT is only used when it is not possible to protect the healthy surrounding tissue in another, simpler way.
The gamma knife consists of a hemispherical helmet on which around 200 individual cobalt-60 radiation sources are arranged. These emit gamma radiation , i.e. energy-charged particles that penetrate tissue. Before the treatment, the exact position of the tumor is determined with the help of a frame that is attached to the patient's head. A combination with other imaging methods such as MRI or PET may also be useful. The individual radiation sources are then aimed at the tumor with great precision. The rays formed by each individual source are superimposed in a punctiform manner and together result in the required total dose. This is measured in such a way that the tumor can be irradiated in high doses, while the surrounding tissue reaches a low, less harmful dose. During the treatment, the patient is driven into the irradiation device several times, each time a different point is irradiated. All treated points together result in the complete tumor after a treatment time of 30–120 minutes.
Treatment with the gamma knife is suitable for metastases, acoustic neurinomas and neurinomas of other cranial nerves, meningiomas, pituitary adenomas as well as chordomas and chondrosarcomas.
In tomotherapy , CT imaging and radiation equipment are combined. A rotating accelerator can be used to generate CT images and to irradiate tumors. Immediate imaging prior to irradiation checks the patient's position and, if necessary, corrects the target volume. The rotation of the radiation device is combined with a continuous table feed, which leads to a spiral delivery of the radiation therapeutic dose. In this way, small as well as large tumors can be irradiated precisely and with modulation of intensity, while the surrounding organs sensitive to radiation are relatively spared.
Proton Therapy / Heavy Ion and Proton Gantry
The proton therapy using proton beams , for example, in a synchrotron or cyclotron produced are accelerated and shot targeted to the tumor. The method is used in particular in patients for whom conventional X-ray irradiation cannot be used adequately because the tumor is either too deep in the body or is surrounded by sensitive organs. Proton therapy enables an optimized dose distribution within the region to be irradiated.
Antiprotonic stereography (ASTER) is a hypothetical imaging and therapeutic procedure. In the ASTER, antiprotons are first shot in a beam into the body and annihilate there after they have been captured by atomic nuclei.
Modern magnetic resonance tomographic methods allow not only a high-resolution representation of the structure of the brain but also an analysis of the connectivity, i.e. the connections between the individual areas and centers. Fiber tracking describes the visualization of railway systems or fiber bundles that connect functional centers in the brain (e.g. motor language production and language understanding). The representation of these path systems is called fiber tracking. These can be included in the preoperative access planning or can be displayed directly in the surgeon's surgical microscope during the operation. The method takes advantage of an effect that flowing water has on magnetic resonance imaging. In a water glass, for example, water can flow evenly in all directions. There is no preference for any direction. In this way, one could measure a so-called “isotropy” at every point in a magnetic resonance tomography of the water glass. In the brain, on the one hand, water is found in blood vessels; on the other hand, it is also found in the tissue within the nerve cells and the connective tissue cells surrounding them. In larger fiber bundles, water can flow preferentially in the direction of the fibers. One speaks of a «focal anisotropy». This can be determined by special magnetic resonance tomographic measurements for each point in the brain and is described by an "eigenvector". A further development was the color coding shown for the first time by Pajevic and Pierpaoli in 1999, in which fibers in the head-toe direction are shown in blue, fibers in the left-right direction are shown in red and fibers in the front-back direction are shown in green. This made it possible, for example, to show the pyramid track as a strong, deep blue structure. For tumors that are close to functional pathways, fiber tracking is a standardized part of surgical planning. This mainly affects tumors near the speech, vision and movement center. In the run-up to the operation, the presentation of the path systems for the patient is planned individually and included in the access planning.
Tumor therapy fields (TTFields) or Alternating Electric Field Therapy are alternating electrical fields that disrupt cell division and thus cause the tumor cells to die. Since brain cells no longer divide in adults, this effect remains limited to the tumor when applied to the head.
The treatment takes place in a magnetic field applicator ('nano-activator'), which generates an alternating magnetic field that is harmless to normal tissue. This field causes the nanoparticles introduced to vibrate, which creates heat directly in the tumor tissue. Depending on the temperature reached and the duration of treatment, the tumor is destroyed or sensitized for accompanying radiation or chemotherapy. This therapy enables longer relapse-free survival times for patients with recurrent glioblastomas.
The nanoparticles are very small particles of iron oxide dissolved in water with a shell of aminosilanes and a diameter of approx. 15 nanometers . The particles are set into oscillation by a magnetic field that changes polarity up to 100,000 times per second.
Depending on the temperatures reached in the tumor and the duration of treatment, the tumor cells are either irreparably damaged or they become more sensitive to accompanying radio or chemotherapy.
In radiation therapy, the term is used both for repeated radiation and for a local increase in radiation dose with few side effects to improve the response rate of radiation therapy.
Cancer cells have the property of increasingly dividing and thereby forming growths or tumors. This is exactly where chemotherapy or cytostatics come into play. They disrupt cell division, for example by integrating into the genetic make-up of cancer cells. They can also block metabolic processes that are important for cell division. However, since healthy cells also divide, there are side effects from cytostatics, especially in areas where healthy cells are also increasingly dividing, e.g. B. in skin, mucous membranes, hair and blood-forming cells in the bone marrow. Most of these side effects go away when you stop chemotherapy. In recent years, so-called targeted drugs have been combined more and more frequently for cancer. These include in particular antibodies and kinase inhibitors. Depending on the type of tumor, these drugs are used individually or in combination with cytostatics. Often a combination of the drugs contributes to an even more effective tumor treatment. The choice of drug combination depends largely on the type of cancer and the stage of the disease in which the patient is. Chemotherapy can be useful in different stages of cancer. Sometimes it is used before or after the surgical removal of a tumor (so-called neoadjuvant or adjuvant treatment), sometimes in combination with radiation therapy and in other cases independently of surgery or radiation therapy.
Dosage form of a drug therapy
Most cytotoxic drugs are given by infusion into a vein. Only a few cytostatics can also be taken as tablets. Patients are often recommended to have a so-called port implanted for the administration of cytostatics . A port is a small reservoir that is placed under the skin near the collarbone in an outpatient surgical procedure and connects to large veins. This reservoir can be punctured by the doctor in order to connect to the infusion with cytostatics.
Clinical studies are offered as part of brain tumor therapy in many centers. Those affected have the chance to benefit from new therapeutic approaches that are otherwise not yet available. The hope for a higher quality of life or a cure is countered by the fear of possible risks, since one cannot yet know everything about a new procedure.
Clinical trials, however, are not daring experiments on humans. The safety of the participants must be guaranteed at all times. The preclinical tests (laboratory and animal tests), which form the basis of the study protocol, are followed by three phases of clinical testing:
In phase I (toxicity test), the toxicity and tolerance of a new substance are examined with very few participants.
In phase II (effectiveness test), the mode of action, the type of application and the dose are tested on a larger group of patients.
In phase III (comparison with proven methods), a large number of patients are tested to determine whether the new therapy is superior.
If the results of all three phases prove the safety and effectiveness of a therapy, an application for approval is submitted.
Permanent information about clinical studies is a basic requirement for optimal therapy and education of brain tumor patients.
Experimental therapy methods
The so-called biological therapies combat brain tumor cells by selectively influencing their physiological properties or by modulating the physiological environment of the tumor cells. These include gene therapy, immunotherapy, antiangiogenic therapy, and immunotoxin therapy, to name just the most advanced experimental methods to date. The tumor-selective effect of these methods in combination with the excellent biological safety profile appear to be promising, but there is still no evidence of their effectiveness that is necessary for standardized clinical application and can only be obtained in large studies. An uncritical or unfounded optimistic view of the actual efficiency of these methods should therefore definitely be avoided at this point in time.
Cancer immunotherapy or tumor vaccinations can support the body in the fight against cancer. The aim of immunotherapy is to sensitize the patient's immune system to one's own tumor and to initiate the destruction of the tumor by the body's own immune cells (lymphocytes). A distinction is generally made between active and passive immunotherapy methods. The passive methods include the systemic or local intratumoral application of so-called biological response modifiers (BRM), mostly natural substances that occur in very small amounts in the human body and that can influence the immune system, e.g. B. Interferons and Interleukins. These substances stimulate tumor-killing immune cells and are therefore able in some cases to bring about an immunologically mediated tumor control. To the active immunotherapy methods tumor vaccines, which represent a vaccine produced on the basis of the patient's own tumor cells kept in culture and most of which are injected several times under the patient's skin. Practical successes in the anti-tumor vaccination of brain tumor patients could be compared to patients with other tumor types such. B. Not yet documented skin cancer (melanoma).
Mice with human presentation molecules
In the future, doctors want to improve treatment results by means of tumor vaccination. To do this, they have to find protein structures that differ in cancer cells and healthy cells. As a rule, it is gene mutations in the genome of the tumor cells that cause such differences. They produce altered proteins that can be recognized by the immune cells. Researchers were successful in their search : They discovered a mutation that enabled them to develop a vaccine. It is based on a “spelling mistake” in the genome: in an enzyme called isocitrate dehydrogenase 1 (IDH1), an amino acid is swapped at a certain position . There, the cancer cells mostly incorporate a histidine instead of the amino acid arginine provided in the original blueprint. This change shows up in over 70 percent of gliomas. Such a common and highly specific mutation made immunologists sit up and take notice. "The amino acid exchange gives the protein in the cancer cells novel immunological properties that can be recognized by the immune cells," says Prof. Michael Platten. “The same mutation does not occur in any other tumor type with such frequency.” The modified protein can be detected with an antibody developed by Platten's colleague Andreas von Deimling. It has been shown to be present on all cells of a glioma in which the mutation arose. “This means that with a vaccination that sharpens the patient's immune system against the altered IDH1, we could fight the tumor without harming healthy cells,” concludes Platten. As a vaccine, a research group from the DKFZ and several universities recreated the IDH1 segment with the exchanged amino acids, in the form of a peptide. This is what small molecules are called that are made up of amino acids. They designed its structure so that it fits exactly into one of the molecules on the surface of the tumor cells that carry the target structures for the immune cells. Without such a "presentation plate" there is no defense reaction. To find out whether the vaccine also works in humans, the researchers resorted to a trick: they equipped mice with presentation molecules that were derived from humans. Then they inoculated the animals with the peptide, which they simply injected under the skin. As a result, immune cells and antibodies could be detected that recognized the changed IDH1 of the tumor cells, but not the normal enzyme of healthy body cells. This immune reaction stopped the growth of cancer cells with the IDH1 mutation in the test animals. The function of the normal enzyme, on the other hand, which plays a role in the energy metabolism in healthy body cells, was not affected by the vaccination. “This is a good sign that vaccination with the peptide can support the body's immune system in the fight against cancer cells,” says Platten. When it comes to cancer, Helmut Salih , Senior Consultant in Charge at the University Hospital Tübingen, wants to shoot faster. "The drugs should work like magic balls," quoted Salih Paul Ehrlich, one of the early "medicine popes" in Germany, who among other things developed a drug treatment for syphilis. These bullets always hit, whereas today's cancer therapies are more like shotgun shots that destroy many other structures in addition to the target. Salih's magic balls are antibodies that he and colleagues develop for the treatment of leukemia.
Gene therapy in the narrower sense means the artificial modification of the gene set of diseased body cells, which also includes tumor cells. Specially modified virus particles or physically defined particles (liposomes, gold particles), also called vectors, serve as gene transfer tools. The gene therapy vectors most widely used to date have been derived from retroviruses. Based on other types of viruses, e.g. B. Adenovirus, further gene therapy vectors of the new generation are currently being constructed, which can smuggle larger amounts of genetic information into non-dividing cells (e.g. resting tumor cells) and are much more stable in the patient's body and at the same time have fewer side effects. Since particularly high-grade gliomas grow rapidly and rapidly infiltrate the surrounding normal brain tissue, local intratumoral gene therapy using single vector injections does not seem to be very suitable as the sole treatment option. In contrast, this type of gene therapy makes sense as an additional option to standard neurosurgery-radiotherapeutic treatment and could possibly also improve the effectiveness of chemotherapy.
This is a new method for the selective killing of brain tumor cells on the basis of differences in the structure of their cell membrane compared to normal brain cells. An immunotoxin is produced by the artificial bacterial compound a toxic substance or vegetable origin with a specific for the tumor protein ( protein ). The inactive form of an immunotoxin is absorbed into the tumor cell after binding and activated there by further metabolic processes, whereby the affected cells are quickly killed. Immunotoxin therapy is carried out in patients with malignant gliomas using catheters stereotactically implanted in the tumor over several days. The longer effect of the immunotoxin should make it possible to kill not only the main tumor mass but also remaining glioma cells at some distance from the visible tumor margin and to achieve long-lasting tumor control.
This method is based on the fact that malignant brain tumor cells often express the protein tenascin on their surface. An antibody against Tenascin could be produced to which a radioactive element (131-iodine or 188-rhenium) is coupled. If this “radiating” antibody is administered into the cavity created by surgical tumor removal, it migrates into the surrounding tissue and binds to remaining brain tumor cells. The radioactive isotopes have a radiation energy that is sufficient to destroy cells over short distances. The radioactivity is brought specifically to the tumor cell by the antibody and can kill it while protecting healthy brain tissue. The prerequisite for the treatment is the presence of a so-called reservoir (Ommaya reservoir), which lies under the scalp and is connected to a thin catheter, the tip of which extends into the operating cavity. The radioactively labeled antibody can be injected into the operating cavity through the reservoir. Depending on the response to radioimmunotherapy, this can be repeated up to three times. Since the antibody is also absorbed to a small extent via the bloodstream, it can at least theoretically lead to an impairment of the bone marrow function and thus blood formation.
Oncolytic virus treatment for glioblastoma could be improved by blocking certain immune cells.
Inhibition of tumor blood vessel formation (neoangiogenesis inhibition)
The inhibition of the formation of new blood vessels in the tumor (neoangiogenesis) has already found its way into the therapy of malignant brain tumors: The greatly increased metabolism and oxygen demand in a rapidly growing tumor can only be met if the tumor itself stimulates blood vessels to grow and new branches to train. To do this, it sends messenger substances into the surrounding tissue, which dock onto special antenna molecules (receptors) on blood vessel cells and thereby cause them to grow. Both the messenger substances themselves and their receptors can be therapeutically inhibited. Several clinical studies that have tested this therapeutic concept for malignant gliomas, however, had negative results.
The results of large studies examining the effectiveness of the monoclonal antibody bevacizumab against the vascular messenger substance VEGF in glioblastomas are currently being assessed differently. An approval for bevacizumab for brain tumors in Germany is still pending. Nevertheless, the substance is often used for glioblastomas in Germany on the basis of an individual application for reimbursement of costs by the insurer.
Influence of cell signaling pathways
Tumor cells are characterized by a disruption of biological signal pathways within the cell and in communication with other cells. This concerns programs for the control of cell division, for cell specialization (differentiation) and for the initiation of a planned (programmed) cell death (apoptosis). Some substances that, according to scientific knowledge, are capable of correcting these signal pathways are currently in clinical trials. These include 13-cis-retinoic acid, inhibitors of the formation of tumor necrosis factor beta and signaling molecules that trigger programmed cell death.
CUSP9 a drug cocktail - Scientists, including the Ulm neurosurgeon Professor Marc-Eric Halatsch, have developed a “drug cocktail” that may improve the survival time of patients with a relapse. Almost all components of the so-called CUSP9 protocol have already been approved for the treatment of other diseases.
Experimental neurosurgical procedures
Intraoperative Optical Imaging (IOI)
A new examination technique that uses light rays to convert brain activity into images could make tumor operations on the brain even safer in the future. The aim of cancer surgery on the brain is to completely eliminate the tumor - ideally, a small part of the neighboring healthy tissue is also removed in order to detect cell nests that have established themselves there. On the other hand, the surgeons want to protect healthy tissue if it is responsible for important functions such as feeling, language, movement or vision.
Brain tumor tissue is now easily identifiable, for example with dyes, magnetic resonance imaging, computed tomography or ultrasound. "To this day, unfortunately, we cannot see in healthy tissue which functions it is responsible for," explained Gabriele Schackert, Director of the Clinic and Polyclinic for Neurosurgery at the Dresden University Hospital. But this would be important in order to be able to operate even more specifically.
Brain activity is usually associated with increased blood flow. This in turn changes the light absorption when the surface of the brain is irradiated with a lamp - increased brain activity increases the absorption. The IOI takes advantage of this phenomenon. “In our study, we delivered light electrical impulses to the median nerve that runs on the inside of the forearm and gives it the feeling in the hand,” says Schackert. The median nerve reflexively passed the impulses on to its higher-level center in the brain, which is responsible for the feeling. It was now also activated and thus supplied with more blood. A camera integrated in the surgical microscope films the light-irradiated brain surface during this process.
There is a filter in front of the camera, which preferentially lets through wavelengths in which the blood shows a strong absorption. A computer converts the information into images. A two-dimensional map is created within ten to 15 minutes, in which the activated brain region can be recognized. "The pictures are accurate and reliable".
Previously, the Dresden researchers had succeeded in localizing the visual center by stimulating the optic nerve - they shone into the patient's eye. "This means that we can for the first time recognize important brain functions almost in real time," says Schackert. If the IOI proves itself in everyday clinical practice, this would be an important step forward for patient safety.
During brain operations with the snake robot, there is no longer a need to drill a hole in the patient's head. Therefore, the procedure is much gentler and the healing process is shorter. Flexible robotic arms will soon enable minimally invasive operations that are less stressful for the patient, even for abdominal surgery.
The snake-shaped robot is made up of several thin tubes that are plugged into one another, similar to a car antenna. It is made of a nickel-titanium alloy that is super elastic. The robot can thus be stretched and deformed, but can still return to its original shape at any time. The individual tubes are bent before they are used. A special computer program calculates for each patient individually which curvatures fit the anatomy of the planned location.
Removal by new laser, "SRS microscopy"
A laser is fired at the tissue. The properties of the light beam change due to the tissue it hits. The different chemical composition of cancer cells and normal tissue means that the exact outline of a tumor can be identified. Clinical tests with patients have already been carried out very successfully.
Researchers at the University of Michigan Medical School and Harvard University have found that making all the outlines of tumors clearly visible is crucial. Surgeons have always been particularly careful when performing operations on brain tumors, since removing the surrounding tissue could lead to impairments. The procedure presented in Science Translational Medicine uses a laser to analyze the chemistry of the tissue and make the tumor visible in a different color. Removing a brain tumor is considered a balancing act. If too little is removed, the cancer can recur. Removing too much can significantly affect the quality of life of the patient. So it is crucial to know the boundaries of the tumor. Surgeons remove sections of the tumor and surrounding tissue and examine them under a microscope to understand the outline.
So-called Raman spectroscopy is used to analyze the light reflection , with which the material properties of works of art, for example, are examined.
Onkoknife, iKnife, or intelligent scalpel
Tumors are removed with the help of electric knives - they allow the tissue to evaporate, producing smoke. The new scalpel, which iKnife has christened, can identify the composition by analyzing the smoke - this is how cancer cells can be identified. With the new technology, much more healthy tissue can be preserved.
Prof. Zoltan Takats officially expects the iKnife to start in 2016.
Intraoperative PET-CT or PET-MR intraoperatively
It is foreseeable that new future technologies in the operating theater such as PET-CT or PET-MR will be based on an intraoperative platform consisting of imaging and navigation.
Experimental blasting methods
The aim is to find boron compounds that are non-toxic and that accumulate in tumor tissue in order to be able to selectively destroy it by means of neutron radiation. The idea for the BNCT was developed by Gordon L. Locher in 1936 and is currently still in development. Promising results in the treatment of certain brain tumors have been achieved.
This type of therapy is not aimed directly at tumor growth, but treats complaints and symptoms that arise either from the tumor disease or from the treatment.
Typical indications for supportive therapy are tumor-specific symptoms (intracranial pressure, headache, seizures), complications related to tumor treatment (vomiting, pain, infections, thromboses, changes in the blood count) or psychological problems.
In the advanced stage of the disease, supportive and palliative therapy measures are by definition identical. However, the maintenance of quality of life should always be in the foreground of therapeutic considerations in diseases with a rapid course.
The supportive measures for brain tumor patients include:
- Therapy of epileptic seizures
- psycho-oncological support
- Therapy of chronic brain edema
- Avoid nausea and vomiting
- Thrombosis prophylaxis
- Pain management
- Therapy of psychosyndrome
- Aids for bedridden
Patients place hope in natural remedies , herbal medicines, homeopathy, and other gentle methods. This can be traced back to the desire to do something against the disease yourself and to leave no stone unturned, also as an expression of “not wanting to admit it”. In Germany, the popularity of traditional healing methods from Asia and America has increased enormously in recent years. Ayurveda , Chinese medicine and shamanic remedies are representative here . Many of these methods are used alongside or in addition to standard therapy, but in many cases there is no scientific evidence of their effectiveness and safety, especially for use in brain tumors.
One possibility of systematising brain tumors is to differentiate them with regard to cellular origin, cell composition and growth behavior. These aspects form the basis of the WHO classification of the World Health Organization, the current version of which is from 2007. It differentiates between four basic tumor grades:
- WHO grade I: benign tumors, e.g. B. pilocytic astrocytoma; Characteristics: highly differentiated, extremely slow growth, good prognosis
- WHO grade II: semi-benign (semi-benign) tumors, e.g. B. astrocytoma, oligodendroglioma; Characteristics: highly differentiated, slow growth, good prognosis
- WHO grade III: semi-malignant (semimalignant) tumors, e.g. B. anaplastic astrocytoma; Characteristics: little differentiated, rapid growth, unfavorable prognosis
- WHO grade IV: malignant tumors, e.g. B. Glioblastoma multiforme; Characteristics: undifferentiated, very rapid growth, very poor prognosis
Types of brain tumors
According to the WHO classification of tumors of the central nervous system , the following entities are distinguished according to the following grades:
- Astrocytic tumors
- Pilocytic astrocytoma , (WHO grade I)
- Subependymal giant cell astrocytoma , (WHO grade I)
- Pilomyxoid astrocytoma , (WHO grade II)
- Astrocytoma (variants: fibrillar, protoplasmic, gemistocytic), (WHO grade II)
- Pleomorphic xanthoastrocytoma , (WHO grade II)
- Anaplastic astrocytoma (WHO grade III)
- Glioblastoma (variants: gliosarcoma , giant cell glioblastoma), (WHO grade IV)
- Oligodendroglial tumors
- Oligoastrocytoma , (WHO grade II)
- Anaplastic oligoastrocytoma, (WHO grade III)
- Ependymal tumors
- Myxopapillary ependymoma
- Ependymoma (variants: cellular, papillary, tanycytic, clear cell)
- Anaplastic ependymoma
- Choroid plexus tumors
- Gliomas of unexplained ancestry
- Gliomatosis cerebri
- Chordoid glioma of the third ventricle
- Neural and mixed neural – glial tumors
- Dysplastic gangliocytoma of the cerebellum ( Lhermitte-Duclos syndrome )
- Desmoplastic infantile ganglioglioma
- Dysembryoplastic neuroepithelial tumor
- Anaplastic ganglioglioma
- Central neurocytoma
- Extraventricular neurocytoma
- Cerebellar liponeurocytoma
- Angiocentric Glioma
- Papillary glioneuronal tumor
- Rosette-forming glioneuronal tumor of the fourth ventricle
- Neuroblastic tumors
- Olfactory neuroblastoma
- Olfactory neuroepithelioma
- Pineal parenchyma tumors ( pinealomas )
- Embryonic tumors
- Meningeothelial tumors
- Meningioma (variants: meningeothelial, fibroblastic, transitionell, psammomatös, agniomatös, mikozystisch, secretory)
- Atypical meningioma (variants: clear cell, chordoid), (WHO grade II)
- Anaplastic meningioma (variants: papillary, rhabdoid), (WHO grade III)
- Mesenchymal, non-meningothelial tumors
- Primary melanocytic tumors
- Tumors of uncertain histogenesis
- Hemangioblastoma (Von Hippel Lindau Disease)
Lymphomas and hematopoietic tumors
Germ cell tumors
- Embryonic carcinoma
- Yolk sac tumor
- Chorionic carcinoma
- Teratoma (variants: mature, immature, with malignant transformation)
- Mixed germ cell tumors
Sella region tumors
- Craniopharyngioma (variants: adamantinous, papillary)
- Granular cell tumor
- Spindle cell cytoma of the adenohypophysis
An exact prognostic statement regarding its course cannot be made for any brain tumor. Even benign tumors can have a poor prognosis, namely if they impair vital brain functions in an unfavorable place and are inoperable. Conversely, a small, malignant tumor that is easy to operate and can be removed as a whole may have a better prognosis.
However, since many brain tumors can grow quickly, the brain takes on many vital functions as a sensitive control center and many tumors cannot or only partially be removed despite today's technology, there are many disease courses in which death occurs after just a few months. However, the prognosis of the individual depends on so many factors that even average values should always be treated with caution.
WHO Classification of Tumors of the Central Nervous System. (Eds. Cavenee, Louis, Ohgaki & Wiestler) Lyon, IARC Press, 2007 ISBN 92-832-2430-2
- General information on diagnosis and therapy of brain tumors from the German Brain Tumor Aid
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