Center for Pediatric Neurooncology

Our motto: Only centralized care makes sense today

Center for Pediatric Neurooncology (CDNO) represents the nationally unique interdisciplinary project of the University Hospital in Motol and the 2nd Faculty of Medicine of Charles University. The cooperation of a number of clinics and institutes provides comprehensive diagnostic, therapeutic, nursing, rehabilitation and dispensary care for children and young patients with cancer of the central nervous system. Care does not end at the age of 18, but monitoring continues throughout life. The following workplaces in particular take part in the care:

• Department of Pediatric Hematology and Oncology, 2nd Medical Faculty, Charles University and Motol University Hospital
• Department of Neurosurgery for Children and Adults, 2nd Medical Faculty, Charles University and University Hospital Motol
• Department of Pediatric Neurology, 2nd Faculty of Medicine, Charles University and Motol University Hospital
• Department of Imaging Methods, 2nd Faculty of Medicine, Charles University and Motol University Hospital
• Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University and Motol University Hospital
• Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University and Motol University Hospital
• Department of Pediatrics, 2nd Medical Faculty, Charles University and University Hospital Motol
• Department of Anaesthesiology, Resuscitation and Intensive Care Medicine, 2nd Medical Faculty, Charles University and University Hospital Motol
• Department of Rehabilitation and Sports Medicine, 2nd Medical Faculty, Charles University and University Hospital Motol
• Motol Child Support and Palliative Care Team at Motol University Hospital

CDNO is designed to provide world-class professional care. Ensuring a high level of care depends mainly on the staffing of experienced experts, modern diagnostic background, instrumentation and continuity of other specializations. The physical proximity of all workplaces within one building and the constant availability of erudite experts and the most modern examination and treatment methods cannot be neglected.

The volume of patients treated and monitored with CDNO is crucial, and absolutely essential, for gaining experience. The center is the largest workplace of its kind in the Czech Republic and one of the largest in Europe. The activities of the center are under constant supervision, we have been monitoring clearly defined and objective indicators of the center's performance and quality for a long time. 

An integral part of CDNO's work is participation in basic and clinical research. The research group within the CDNO "Prague Brain Tumor Research Group" brings together participating clinics, the Laboratory of Solid Tumor Biology (LBSN) and the Laboratory of Molecular Pathology (LAMPA). Today, we cannot imagine research without extensive national and especially international cooperation; The CDNO is part of, for example, the European Reference Network on Pediatric Cancer (hemato-oncology), the International Society for Pediatric Oncology (SIOP) and the Innovative Therapies for Childhood Cancer (ITCC). This allows the participation of CDNOs in otherwise unavailable recent clinical trials. We can thus offer our patients a completely unique treatment in the Czech Republic and access to the most modern or only experimental treatment procedures.

All CDNO staff understand that the diagnosis of a central nervous system tumor in a child is a crucial event that will turn the life of the whole family upside down. Our proposed therapeutic procedure aims to minimize the unpleasant aspects of the treatment process and enable the whole family to return to normal life as soon as possible. In addition to the treatment itself, we also focus on the social aspects of the disease. Above all, we focus on continuing the patient's education through the school at the hospital, palliative and supportive care and, last but not least, on psychological counseling for the whole family. For families with patients with a particularly serious diagnosis, we have been offering a connection with the Motol Child Support Team from the beginning, which consists of experts who can significantly alleviate this situation for the family. Throughout the treatment process, we regularly and in detail inform the patient and his family about the nature of the disease, planned examinations, their results and subsequent treatment and its risks. We consider communication with the family and ongoing information to be a key part of our work. 

Our goals

• Complete healing of the patient where the biological nature of the tumor allows it
• Comprehensive interdisciplinary care in one place in real time
  Use of the latest methods to improve overall survival in incurable tumors
• Allowing to lead a normal life if possible with an incurable cancer
• Minimization of complications and side effects of treatment
• Introduction of new treatments in international academic studies
• Genetic counseling for families with children with cancer (siblings, other planned pregnancies)

CNS tumors are relatively rare in childhood (incidence about 4 / 100,000 children), yet they are the most common solid childhood cancer. Tumors can be benign or malignant. However, both types can endanger a child with a neurological deficit (eg limb mobility) or directly in life. However, compared to adults with the same diagnosis, children have a significantly better prognosis - most children with a CNS tumor live to adulthood. In the Czech Republic, the incidence of CNS tumors in children has been increasing slightly for a long time (approximately 1,4% per year), but fortunately their mortality has been declining for a long time. Every year, approximately 80-90 CNS tumors are newly diagnosed in the Czech Republic, more than half of which are either treated directly at our Center or are later referred to it for further care or long-term follow-up.

The cornerstone of the diagnostic process is taking a medical history, ie acquainting the doctor with the patient's problems; this is almost always done with the cooperation of parents. The doctor specifically asks about the symptoms that led the patient or parents to find him, specifying the duration, development (eg, which is followed by relief or vice versa), the intensity of the problem and more. This dialogue is followed by a physical examination, in which the doctor examines the patient and detects a possible neurological disorder (eg poorer limb mobility or absence of reflexes). This is followed by the imaging of the nervous system itself. The goal of imaging methods is not only to reveal the cause of the problem, but also to help plan a possible operational solution. Using advanced imaging techniques, we are therefore able to estimate the type of tumor relatively accurately, specify its location, vascular supply, and especially the relationship to the surrounding critical structures of the brain or spinal cord. Today we mainly use the following:

Computed tomography (CT) - The advantages of CT are easy availability in practically all hospitals in the Czech Republic, examination speed (basic brain examination takes less than a minute) and quality bone imaging. CT allows you to distinguish the root cause of the problem - for example, if it is a tumor, bleeding or stroke. Another disadvantage of CT is a certain radiation exposure, so it is used in childhood only in strictly necessary cases or if there is a risk of delay. It usually follows CT

Magnetic resonance imaging (MRI) - This advanced imaging technique is absolutely essential in the diagnosis of brain or spinal cord tumors. Most tumors have a typical MRI appearance. It will show very well the location of the tumor and the relationship to the surrounding structures (eg large blood vessels or cerebral nerves), the nature of the tumor (eg cysts or calcifications) and allow you to plan the best and safest approach to the disease using special sequences. The disadvantage of MRI is the time and necessity of the absolute calm of the child (ie the so-called "lie down" examination). For smaller children, this ensures that MRI is performed under general anesthesia; larger children can handle it without difficulty.

Special MRI screening methods include, for example:

• navigational MRI - a special, detailed examination, which is then used in the operating room for anatomical orientation

• functional MRI (fMRI) - allows to determine the relationship of the tumor to functionally important areas of the brain (eg area for limb motility or speech)

• brain imaging (DTI) - shows the relationship of the tumor to important nerve pathways (eg pathway for limb motility or visual pathway)

• MR spectroscopy (MRS) - shows the metabolic and chemical character of the tumor, can determine to some extent the degree of malignancy
• MR angiography (MRA) - basic information about the course of cerebral vessels, however, for more detailed imaging, cerebral angiography is added if necessary (see below)  

MRI is also a sovereign imaging technique for the detection of postoperative tumor residue and for long-term follow-up. In addition to postoperative imaging of the extent of resection, we also see possible surgical complications. In children, MRI of the brain is sometimes followed by an examination of the spinal canal, where we look for possible daughter foci. 

Brain Angiography (AG) - this is an invasive examination, in which the radiologist, after entering the arterial bed, gradually displays the vascular supply of the tumor directly through the inguinal artery. Sometimes the tumor can be so-called embolized from this approach, ie the blood flow to the tumor can be reduced or completely closed. This significantly facilitates the subsequent surgical solution in the case of very abundant tumors. 

Biopsy (direct collection of tumor tissue) - in some cases, we are not able to safely deal with the tumor due to its placement, so we perform a limited surgical procedure, where we only take a representative sample of the tumor with the most safe approach. Here we always try to use minimally invasive methods:

• Stereotactic (navigated) biopsy - after planning the safest trajectory (path), we make a short incision and take several samples from a small hole in the skull with a special probe inserted directly into the tumor

• Endoscopic biopsy - using an endoscope inserted into the ventricles, we take a sample of the tumor growing in the ventricular system. The advantage of this method is also the possibility to solve the cerebrospinal fluid circulation disorder during one operation. In some cases, minor expansion can be removed directly with an endoscope. We also have an endoscopic ultrasound tumor aspirator.
• Open biopsy - from the classic approach (craniotomy) we penetrate directly to the tumor and take several samples. In this case, after verification of local anatomical conditions, it can be established by partial removal of the tumor (if the anatomical situation allows).
• Perioperative biopsy - is performed at each operation; during tumor removal, part of it is sent for histological evaluation. The surgeon is then informed of the basic biological nature of the disease and can modify the operating tactics. Each sampling is followed by a thorough and definitive:

Histological and molecular-genetic examination of the removed tissue - absolutely essential and absolutely necessary to determine further treatment. Diagnosis is traditionally based on histopathological examination of the sample under a microscope by an experienced pathologist. However, its molecular-biological, genetic and epigenetic characterization is currently a necessary part of the examination of the sample. Only in this way can the most accurate diagnosis now be made and at the same time effective treatment targeted. This approach is implemented in the routine diagnostic procedure for all diagnosed brain tumors within the CDNO. In molecular biological diagnostics we use methods such as: Sanger sequencing, whole genome methylation array, NGS (next generation sequencing), MLPA (multiplex ligation assay), etc. It also works closely with the Heidelberg center to examine and analyze data on selected patient samples. For these tests, it is very important that the sample is processed correctly as soon as it is taken, which is guaranteed in the CDNO.

Multidisciplinary approach

Already during the diagnostic process, a wide interdisciplinary discussion of leading Czech experts in the fields of pediatric neurosurgery, hemato-oncology, neuroradiology and neurology takes place, or other experts are consulted according to the nature and location of the tumor (eg ENT or endocrinology). The result of this multidisciplinary seminar is a detailed treatment plan which aims to minimize the risks of treatment and maximize its success. Treatment options and risks are then clearly and thoroughly discussed with the patient and family. The family is also informed about the results of follow-up imaging examinations and further steps.

Tumor treatment depends mainly on its type, location and size; in addition, the age and general condition of the child should be taken into account. All patients in CDNO are comprehensively monitored during repeated visits to specialized clinics and by means of regular MRI checks. All MRIs are presented regularly at multidisciplinary seminars, where in the presence of a neuroradiologist, neurosurgeon, neurooncologist, pediatric neurologist and other specialists, it is decided on further treatment. It may consist of:

Observations

 There are certain types of tumors that are completely asymptomatic (usually detected at random during examination for unrelated problems) and at the same time their benign nature can be clearly judged by MRI. In these patients, regular MRI monitoring without the need for biopsy or resection is a completely legitimate procedure. If the tumor is symptomatic or shows signs of growth, we will change this approach to active. The knowledge that "I have a tumor in my head" sometimes leads the patient or his parents to seek active treatment. 

Operation

The aim of the operation is, if possible, radical (complete) removal of the tumor. If the tumor is well accessible, has a clear boundary compared to normal brain tissue, and can be easily demarcated, radical performance is relatively easy to perform. If the tumor does not exhibit these characteristics (ie, is located near or directly in an important center or does not have a clear boundary or disrupts important neurovascular structures), the neurosurgeon performs only partial removal of the tumor in an effort to preserve the functions of adjacent centers. Even a partial shrinkage of the tumor is often enough to relieve the problem and help in further treatment with other treatment modalities. We consider postoperative control MRI without signs of a tumor and a patient whose problems are improving or whose condition will not worsen to be the ideal result. "Pure" control MRI must not be taxed on a patient's deteriorating condition; here we prefer to leave the rest (so-called residues) of the tumor for further therapy or mere monitoring. To achieve the optimal result, we mainly use the following technologies: 

• navigational MRI - a special detailed examination, which is then used in the operating room for anatomical orientation
• functional MRI (fMRI) - allows to determine the relationship of the tumor to functionally important areas of the brain (eg area for limb motility or speech)
• brain imaging (DTI) - shows the relationship of the tumor to important nerve pathways (eg pathway for limb motility or visual pathway)
• tumor visualization using an operating microscope, endoscope or exoscope
• intraoperative ultrasound
• intraoperative fluorescence - after the previous application of the fluorescent substance, a special light in the microscope or exoscope allows us to show the remnants of the tumor at its edge, which cannot be detected by normal illumination
• intraoperative monitoring of nerve functions - methods that allow real-time localization and monitoring of the function of brain centers or cranial nerves (eg momentum or facial muscles). The aim is to prevent their possible damage, or to minimize this risk. 
• "Awake" craniotomy - conscious operation allows you to monitor speech functions during the operation
• perioperative analysis of tumor tissue by a specialized pathologist

Oncological treatment

• Chemotherapy
Chemotherapy uses medicinal substances (so-called chemotherapeutics) to destroy tumor cells or to stop or slow down their growth. It can be very effective on some types of CNS tumors. Which particular chemotherapeutic will be used depends on the histology and especially on the molecular genetic equipment of the tumor. Chemotherapy contributes to anticancer treatment through the following mechanisms:

• destroys tumor cells remaining after surgical or radiation treatment (adjuvant treatment)
• shrinks the tumor before surgery or radiotherapy (neoadjuvant treatment)
• cures the spread of tumor cells to other parts of the body
• supports the effect of radiotherapy
• by shrinking the tumor, it helps to improve the symptoms (problems) caused by the tumor pressure

• Biological treatment
Biological treatment is already standard in selected children's brain tumors. Its mechanism is usually the targeting of specific tumor mutations and signaling pathways, which are found by molecular biological examination and are very typical for some childhood tumors. Examples of drugs used:

• Bevacizumab
• Machinist
• Trametinib
• Nivolumab
• Larotrectinib
• dabrafenib

• Radiotherapy
Radiotherapy (also irradiation) treats cancer using high-energy rays. The effect of radiation is mainly local, so it mainly affects the tumor and its immediate surroundings. At CDNO, we have a number of modern methods of radiotherapy at our disposal. The type of tumor, its location, the age of the child and other factors determine which will be used. However, the principle is always to precisely target the target area and thus minimize the radiation dose to healthy tissues. After planning the total dose needed to destroy the tumor, it is divided into smaller parts (fractions) and then applied within a few weeks (Monday - Friday). For pediatric patients we use:

• fractionated stereotactic radiotherapy 
• Radiation Intensity Modulated Radiation Therapy (IMRT)
• image-guided radiotherapy (IGRT)

We also work closely with the Proton Center in Prague and the Leksell Gamma Knife in the Homolka Hospital.

Modern and experimental treatment procedures

Advances in childhood brain tumor research and CDNO's extensive international collaboration seek to provide the most advanced treatment available to our patients. One of these commonly used routes is clinical treatment studies, which allow the safety and efficacy of new drugs to be evaluated; at the same time, it offers the child participating in the study treatment that would not otherwise be available. Our neurooncology team is very experienced in selecting suitable patients for inclusion in such a study. CDNO is currently participating in the following studies:

• INFORM INdividualized Therapy FOr Relapsed Malignacies in Childhood
• LOGGIC Core BioClinical data Bank (LOGGIC - Low Grade Glioma In Children) - in cooperation with Hopp Children's Cancer Center Heidelberg, University Heidelberg, Germany (LOGGIC Core version 1.4)
• International Clinical Program for the Diagnosis and Treatment of Children, Adolescents and Young Adults with Ependymoma - in collaboration with the Center Léon Bérard, Lyon, France (ET-13-002)
• International prospective study in children with medulloblastoma (MB) older than 3 years and WNT biological profile (PNET 5 MB - LR and PNET 5 MB - WNT-HR), standard risk biological profile (SIOP PNET 5 MB - SR), or TP53 mutation, and the registry of the occurrence of MB in the context of genetic predisposition - in cooperation with Univ. Copper. Center Hamburg - Eppendorf, Germany (SIOP PNET 5 MB Version 12-2017, Jun 29)
• Phase 1/2 clinical trial of oral TRK inhibitor larotrectinib in pediatric patients with advanced solid tumors or primary central nervous system tumors - in collaboration with Bayer Consumer Care AG (BAY 2757556/20290)
• Selumetinib - a specific treatment program from Astra-Zeneca for patients with NF-1 and pleximore neurofibroma

In patients with diagnoses that are not suitable for inclusion in ongoing studies, for example because it is an atypical tumor, there are other ways to find and use the most modern drug available, mainly on the basis of a detailed molecular biological examination.

Glial tumors - benign (LGG) and malignant gliomas (HGG)

Glial tumors grow from the supporting tissue of neurons, called glia. They make up less than half of all childhood brain tumors. According to microscopic characteristics, they are traditionally divided into four grades according to severity or low- and high-grade. The most favorable (called pilocytic astrocytomas; grade 1) have an excellent prognosis and a high percentage of cured patients (over 90%). On the other side are the so-called glioblastomas (grade 4), the prognosis of which is serious despite all treatment. The treatment is based on the most radical resection, which in the case of the most favorable diagnoses is sufficient for permanent cure.

In the case of higher histological grades (especially 3 and 4), chemotherapy and radiotherapy usually follow. Based on the molecular equipment of the tumor, we are now able to offer other targeted treatment based on molecular alterations. A very specific glial tumor is the so-called diffuse pontine glioma, which is inoperable and whose prognosis is very serious. However, these patients may be candidates for the various experimental therapies available at our Center.

Ependymoma

Ependymoma arises from the lining of the ventricles (so-called ependyma). In children, they usually occur in the area of ​​the 4th ventricle, sometimes in the cerebral hemispheres, more rarely in the spinal cord. Treatment of ependymoma usually begins with maximally radical resection. The location and proximity of critical structures sometimes do not allow the tumor to be removed in its entirety and part of it must be left. The treatment procedure varies depending on the location of the ependymoma. In the area of ​​the posterior pit of the skull, radiotherapy to the area of ​​the tumor bed is necessary after complete resection. Epithymomas in the cerebral hemispheres also require radiotherapy, but patients who do not need radiotherapy can be selected based on histology and molecular profile. Spinal cord ependymomas are generally less aggressive and are based on complete removal, which in most cases does not require cancer treatment. 

Medulloblastoma

Medulloblastoma is the most common childhood CNS cancer (representing one-fifth of all CNS tumors). It is usually located in the cerebellum and fourth ventricle. The success of the treatment depends mainly on the possibility of removing the tumor radically, on its genetic equipment and on possible metastatic involvement. These factors determine the direction of further treatment and the prognosis. From oncological treatment, chemotherapy and radiotherapy are used, in strictly indicated cases also high-dose chemotherapy with autologous bone marrow transplantation. 

Germ cell tumors

These tumors most often occur in the suprasellar or pineal region; sometimes at the same time on both (so-called synchronous) and their typical feature is high sensitivity to radiotherapy. Except for teratomas, all germ cell tumors are malignant and can metastasize. In general, we divide them into germinal - tumors with a better prognosis - mixed and nongerminal, which include embryonic carcinoma, choriocarcinoma, carcinoma of the yolk sac and teratoma. These may be congenital tumors, but are most common during early puberty. These tumors are characterized by typical oncomarkers, which after cerebrospinal fluid collection can help us determine their histological nature and monitor the effectiveness of treatment. We are typically looking for B-hCG (beta-human chorionic gonadotropin), AFP (alpha-fetoprotein) and PLAP (placental alkaline phosphatase).

Craniopharyngeal

Craniopharyngeal tumors are benign tumors developing from Rathke's pituitary gland, accounting for 5 to 10% of pediatric CNS tumors. Macroscopically, they consist of solid and cystic components, they do not malignate, however, they may show infiltrative growth, which makes their operation difficult. They most often occur between 5 and 10 years. Prior to surgery, the patient must be endocrinologically examined for possible pituitary damage that affects postoperative recovery. The operation can be performed openly, endoscopically or transnasally transsphenoidally (through the nostrils). Postoperatively, we also monitor the levels of pituitary hormones and patients undergo steroid treatment, which serves to compensate for the hypoadrenergic state and to prevent postoperative complications. The success rate of therapy is 90 to 95%. In a small percentage of cases, the pathology returns, in which case the patient's prognosis worsens.        

meningioma

Meningeeomas are most often slow-growing, demarcated, benign lesions beginning in the meningothelial cells of the arachnoid (one of the cerebral sheaths). They are a much rarer entity in children than in adults, most often occurring between the ages of 10 and 20, and almost a quarter of them are found in patients with type 1 neurofibromatosis, where they can be multiple. Symptoms depend on the location of the meningioma, are often asymptomatic, and are either accidental or found in regular MRI scans in predisposed patients. The most reliable method for imaging meningiomas is MRI, if an abundant vascular supply is suspected, angiography is performed on the detailed imaging of all supply and drainage vessels before the operation itself. The main therapeutic method is surgery, these tumors may have higher surgical blood loss due to their significant vascularization, this risk may be reduced by embolization before the procedure, and during the procedure the losses are covered by transfusions. Upon successful removal, patients have a very good prognosis.

Schwannoma

Vestibular schwannoma is a benign tumor growing from Schwann cells enveloping the vestibular nerve. In children, it most often occurs in Neurofibromatosis type 2, more often we find it from the age of 15. The most common symptoms are hearing loss, ringing / whistling in the ear and loss of balance on the lesion side. Its location in the bridge of the bridge can also suppress the facial nerve, with signs of weakening of the muscles of the half face, or double vision. Before a possible operation, it is necessary to view the tumor on an MRI and perform a detailed hearing examination. However, surgery is not indicated for all lesions, as some may show no signs of growth for a long time.

Schwannomas are also found in the spine. They most often arise from the posterior (sensory) spinal roots. These are rare tumors, again often associated with neurofibromatosis. The most common symptoms are pain at the site of the lesion, impaired mobility or sensitivity of the limbs, impaired gait or impaired urination. The primary method of treatment is surgery, in which we try to preserve the affected spinal root, which is not always possible. The prognosis is excellent with total resection.

Search for hereditary predispositions to cancer

At present, the cause of cancer in children is not completely known. External influences (pollutants in the diet, air, etc.) do not play a role here as in adults. In about 10% of patients, we are able to use genetic testing to prove an inherited change (mutation) in one of the genes that increases the risk of cancer and thus reveal the cause of cancer. Therefore, we currently recommend a blood test for all newly diagnosed patients.

Genetic analysis of the DNA of the patient and his family will reveal a predisposition (higher susceptibility) to cancer. Genetic counseling provided by the Institute of Medical Biology and Genetics allows to determine the risks of transmission of these syndromes to other offspring. In the case of only a partial expression of the syndrome, purposefully look for the known complications associated with it.

• Management of the Center for Pediatric Neurooncology

  • Supervisor: MUDr. Michal Zapotocky, Ph.D. (Department of Pediatric Hematology and Oncology)

  • Deputy Head: Doc. MUDr. Vladimir Benes, Ph.D. (Department of Neurosurgery for Children and Adults)

• Doctors from individual clinics and institutes:

  • Department of Pediatric Hematology and Oncology

    • MUDr. Michal Zapotocky, Ph.D.

    • MD David Sumerauer, Ph.D.

    • MUDr. Ales Vicha, Ph.D.

    • MUDr. Jarmila Kruseova, Ph.D.

    • MUDr. Katerina Vanova, Ph.D.

    • MD Lucie Slámová, Ph.D.

    • MUDr. Adéla Mišov

  • Department of Neurosurgery for Children and Adults

    • Doc. MUDr. Vladimir Benes, Ph.D.

    • Doc. MD Michal Tichý, CSc

    • Doc. MD Petr Libý, Ph.D.

    • MD Jakub Táborský

    • MUDr. Jana Blazkova Jr.

  • Department of Pediatric Neurology

    • Prof. MD Pavel Kršek, Ph.D.

    • MD Martin Kudr, Ph.D.

    • MD Ivana Perníková

    • MD Alena Jahodová, Ph.D.

    • MD Bořivoj Petrák, CSc.

    • MUDr. Matthias Ebel

  • Department of Imaging Methods

    • MD Martin Kynčl, Ph.D.

    • MD Radek Pádr

  • Department of Pathology and Molecular Medicine

    • Prof. MD Josef Zámečník, Ph.D.

    • RNDr. Lenka Krsková, Ph.D.

    • MUDr. Miroslav Koblízek

  • Department of Biology and Medical Genetics

    • MD Markéta Havlovicová

    • MD Markéta Vlčková, Ph.D.

  • Pediatric clinic

    • Prof. MUDr. Zdenek Sumnik, Ph.D.

    • MUDr. Stanislava Kolouskova, CSc.

  • Department of Anaesthesiology, Resuscitation and Intensive Care

    • MD Jana Pavlíčková

    • MUDr. Jana Blazkova st.

    • MD Petr Pavlíček

  • Department of Rehabilitation and Sports Medicine

    • MD Olga Dyrhonová

    • MD Pavla Slivková

  • Motol Child Support and Palliative Care Team at Motol University Hospital
    

    • MUDr. Lucie Hrdličková

    • MUDr. Katalin Štěrbová

The facilities of the University Hospital in Motol and the 2nd Faculty of Medicine allow CDNO to benefit from the most modern instrumentation and laboratory equipment. For diagnostics, we mainly use top 3-body magnetic resonance imaging with the possibility of functional imaging and imaging of nerve pathways. Computed tomography, ultrasound, classical sciascopy (X-ray) and digital subtraction angiography are a matter of course. The laboratory relies on blood analysis, biochemical examination, examination of hormones and specific oncomarkers. Other specialized examination methods include, for example, EEG (electrical activity of the brain) with the possibility of video recording, evoked potentials, electromyography (conduction of excitations from the brain to the muscles), invasive measurement of intracranial pressure and more. 

To remove the tumor itself, we use a modern operating microscope with the possibility of fluorescent imaging of pathological tissue, exoscope (3D imaging), endoscope or ultrasonic tumor aspirator (aspirator). We have an endoscopic ultrasound tumor aspirator, with which we are able to remove smaller tumors in the area of ​​the ventricular system at least invasively. 

We monitor brain function and nerve integrity during surgery electrophysiologically. Orientation during performance in complex anatomical localizations, or minimizing access, is enabled by perioperative navigation showing in real time a place correlating with magnetic resonance. Anesthesiology has a ventilator for pediatric patients. 

Postoperative examination is not limited to classical histological analysis, but we use modern immunohistochemical methods that allow closer identification of the tumor and especially its molecular genetic equipment using DNA and RNA analysis. In this way, we discover known and new genetic subtypes of tumors, which is a necessary condition for starting modern or experimental treatment.

Few medical industries have experienced such a boom in pediatric neurooncology in the last decade. The clinics and institutes that make up the CDNO are among the European and world-renowned workplaces in their field, they regularly publish their treatment results and experimental work in renowned journals and scientific conferences, and participate in grant projects and international studies:

• INFORM INdividualized Therapy FOR Relapsed Malignancies in Childhood
• LOGGIC Core BioClinical data Bank (LOGGIC - Low Grade Glioma In Children) - in cooperation with Hopp Children's Cancer Center Heidelberg, University Heidelberg, Germany (LOGGIC Core version 1.4)
• International Clinical Program for the Diagnosis and Treatment of Children, Adolescents and Young Adults with Ependymoma - in collaboration with the Center Léon Bérard, Lyon, France (ET-13-002)
• International prospective study in children with medulloblastoma (MB) older than 3 years and WNT biological profile (PNET 5 MB - LR and PNET 5 MB - WNT-HR), standard risk biological profile (SIOP PNET 5 MB - SR), or TP53 mutation, and the registry of the occurrence of MB in the context of genetic predisposition - in cooperation with Univ. Copper. Center Hamburg - Eppendorf, Germany (SIOP PNET 5 MB Version 12-2017, Jun 29)
• Phase 1/2 clinical trial of oral TRK inhibitor larotrectinib in pediatric patients with advanced solid tumors or primary central nervous system tumors - in collaboration with Bayer Consumer Care AG (BAY 2757556/20290)
• Selumetinib - a specific treatment program from Astra-Zeneca for patients with NF-1 and pleximore neurofibroma

Within the Center for Pediatric Neurooncology, we bring patients from all over the Czech Republic and abroad to the Motol University Hospital. A sufficient number of cases guarantees the experience of neurosurgeons, enables the establishment of specialized seminars and participation in the latest medical studies. On average, our center operates 60-70 patients a year, and even more, thanks to centralization, is treated through the Department of Pediatric Hemato-Oncology. With this number of patients, the well-known equation applies even more than ever:

High patient volume = more experience = less complications = better results

Of course, there is a database (in compliance with all GPDR guidelines) of all treated and monitored patients and ongoing quality control of care. That is why we publish some generally accepted indicators of quality of care on these pages:

• Number of patients with newly diagnosed CNS cancer treated in CDNO

• Number of neurosurgical procedures for cancer
• Number of operations for disease recurrence
• 

• Interview of Martin Kovář on Radio Zet
  "Pediatric neurosurgery in Motol is at the world's top, says neurosurgeon Vladimír Beneš Jr.

https://www.radiozet.cz/podcast/detska-neurochirurgie-v-motole-je-na-svetove-spicce-tvrdi-neurochirurg-vladimir-benes-ml

STATUTE
CENTER FOR CHILDREN'S NEUROONCOLOGY
University Hospital in Motol

Preamble:

Based on the Charter of the University Hospital in Motol and in accordance with the Program for Improving the Quality and Safety of Health Services, the University Hospital in Motol is established Center for Pediatric Neurooncology (CDNO).

The mission of CDNO is to care for patients with cancer of the nervous system up to the age of 18 (hereinafter children) and their subsequent long-term follow-up. 

Article I
Introductory provisions

1. CDNO is a part of the University Hospital in Motol.

2. The full name is the Center for Pediatric Neurooncology.

3. The seat of the CDNO is the University Hospital in Motol, V Úvalu 84, 150 06, Prague 5.

4. The foreign language equivalents of the name Center for Pediatric Neurooncology are:

English: Center for Pediatric Neuro-oncology

French: Center de Neuro-oncologie Pédiatrique

German: Zentrum für pädiatrische Neuro-Onkologie

Russian: ентр детской нейроонкологии

Article II.
Scope of business

1. CDNO is a specialized workplace that provides comprehensive diagnostic, therapeutic, nursing, rehabilitation, psychological, psychosocial and palliative care for pediatric patients with cancer of the central nervous system and their subsequent long-term dispensarization, especially in the following indications:

1. Benign and malignant tumors of the nervous system in pediatric patients and their complications.
2. Active search and solution of long-term consequences of cancer or oncological treatment within a long-term dispensary.
3. Search for genetic hereditary predispositions to central nervous system tumors with a follow-up program for these patients.

2. Patient care in CDNO will be at the highest current level and in compliance with all recommended standard diagnostic and therapeutic procedures.

3. CDNO forms the educational, scientific and research basis for the issue of cancer of the nervous system in pediatric patients and their subsequent lifelong dispensarization.

4. CDNO participates in undergraduate and postgraduate teaching.

5. The CDNO concept is subject to approval by the Scientific Board of the University Hospital in Motol.

Article III.
Organizational structure and management

1. CDNO is the basic organizational unit of the University Hospital in Motol and has the status of an interdisciplinary workplace - organizational units of two or more organizational units permanently performing common tasks.

2. CDNO is not a separate cost center.

3. The CDNO is obliged to properly manage the entrusted property of the University Hospital in Motol and to use it effectively as well as to take care of its reproduction, if the nature of the property allows it.

4. The head of the Center for Pediatric Neurooncology is appointed by the director of the University Hospital in Motol on the proposal of the deputy for medical and preventive care.

5. The head of the CDNO is responsible to the director of the University Hospital in Motol for the professional level of care, management and administration of the Center for Pediatric Neurooncology and comprehensively coordinates its activities.

6. In the absence of the CDNO, the head of the CDNO is fully represented by his deputy, who is appointed head of the Center for Pediatric Neurooncology.

7. The CDNO has developed its own program (including the concept), which is in accordance with the operating rules and internal legislation of the University Hospital in Motol. The program of the center forms an annex to the statute of the center.

Article IV.
Final Provisions

1. Amendments to this statute are issued by the director of the University Hospital in Motol.  

2. This statute is made in two identical copies with the validity of the original, one of which will be received by the CDNO and one by the University Hospital in Motol.

3. The statute becomes valid and effective on the day it is signed by the director of the University Hospital in Motol.

Center program (concept)

The Center for Pediatric Neurooncology is designed to provide world-class professional care for pediatric patients with nervous system cancer. This requires the staffing and technical and material equipment defined below, enabling modern diagnostics and treatment, as well as links to other specializations and active clinical and translational research. The key to ensuring quality care is the experience of the staff, which is guaranteed only with a minimum annual volume of patients with the issue. In the field of pediatric neurooncology according to European standards in the care of children with cancer, it is defined as at least 30 newly diagnosed patients per year. Only such a center should be able to perform diagnostics, surgery, treatment and long-term dispensary of pediatric neurooncology patients in the Czech Republic.

1.  Objectives of the Center for Pediatric Neurooncology

a. Comprehensive diagnostic and therapeutic care for pediatric patients with cancer of the nervous system.

b. Long-term follow-up of patients with cancer of the nervous system diagnosed or treated during childhood.

c. Active search for long-term consequences of cancer or the consequences of its treatment.

d. Routine and innovative diagnosis of genetic inherited syndromes with a predisposition to cancer and subsequent monitoring of these patients.

e. Centralization will achieve the maximum level of care for pediatric patients with oncological diseases of the nervous system, especially with rare units.

f. Centralization will lead to the effective use of available resources and the concentration of experience in the diagnosis and treatment of oncological diseases of the nervous system in pediatric patients, especially in rare units.

g. Support for international cooperation will bring the possibility of enrolling patients in studies with new diagnostic and therapeutic procedures.

2.  Internal organization (structure) and management of the activities of the Center for Pediatric Neurooncology

a. CDNO is an interdisciplinary department covering the fields of diagnosis and treatment of cancer of the central nervous system diagnosed in childhood, in particular the following departments:

1. Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and Motol University Hospital

2. Department of Pediatric Neurology, 2nd Faculty of Medicine, Charles University and Motol University Hospital

3. Department of Neurosurgery for Children and Adults, 2nd Faculty of Medicine, Charles University and Motol University Hospital

4. Department of Pediatrics, 2nd Medical Faculty, Charles University and University Hospital Motol

5. Department of Imaging Methods, 2nd Faculty of Medicine, Charles University and Motol University Hospital

6. Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University and Motol University Hospital

7. Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University and Motol University Hospital

8. Department of Anaesthesiology, Resuscitation and Intensive Care Medicine, 2nd Medical Faculty, Charles University and University Hospital Motol

9. Department of Rehabilitation and Sports Medicine, 2nd Faculty of Medicine, Charles University and Motol University Hospital

1. Department of Radiotherapy, Department of Oncology, 2nd Medical Faculty, Charles University and University Hospital Motol
2. Department of Clinical Psychology, Motol University Hospital
3. Other workplaces are involved in the diagnostic-therapeutic process on the basis of current needs.

b. The individual clinics and institutes work closely together during the diagnostic, therapeutic and dispensary phases of the treatment process.

c. Individual clinics and institutes strictly adhere to the latest diagnostic and treatment protocols in accordance with the principles of "lege artis" and "evidence-based medicine".

d. Individual clinics and institutes are fully responsible for adequate education of the patient and his / her legal representative in connection with the diagnostic-therapeutic process and for signing informed consent.

e. Patient care is coordinated through regular joint seminars and continuous consular availability.

f. Long-term follow-up is ensured by clinical monitoring by an oncologist and neurologist and regular imaging examinations. According to the development of late consequences, specialists in the field of endocrinology, neurology, otorhinolaryngology, obesitology and dentistry of the 2nd Medical Faculty of Charles University and the Motol University Hospital also take part in further care. Adult patients at risk of post-treatment infertility are monitored at the Institute of Biology and Medical Genetics of the 2nd Medical Faculty of Charles University and the Motol University Hospital.

g. The workplaces mentioned in point 2a are mainly involved in the dispensary.

h. Long-term patient care is provided within the Motol University Hospital in cooperation with the Department of Neurosurgery for Children and Adults of the 2nd Medical Faculty of Charles University and the Motol University Hospital, the Department of Neurology of the 2nd Medical Faculty of Charles University and the Motol University Hospital and the Department of Oncology of the 2nd Medical Faculty of Charles University and the Motol University Hospital.

3. The catchment area of ​​the Center for Pediatric Neurooncology

a. CDNO does not have a defined catchment area, it accepts and dispensaries monitors patients from all over the Czech Republic.

b. In case of interest, CDNO also accepts and dispensaries monitors foreign patients (whether with care paid for by their health insurance or self-paying).

4. Staffing of the Center for Pediatric Neurooncology

a. Head of CDNO - a doctor with specialized competence in the field of Pediatric Oncology and Hematology with at least 5 years of experience in the indication and planning of treatment of central nervous system cancers, in the scope of full-time (1,0).

b. Deputy Head of CDNO - a doctor with specialized qualifications in the field of Pediatric Oncology and Hematology or Neurosurgery or Pediatric Neurology with at least 5 years of experience in indicating and planning treatment of central nervous system cancers, full-time (1,0).

c. Physicians from the establishments listed in point 2a with appropriate specialized competence in the field, of which at least two have at least 5 years of experience focused on pediatric patients and a minimum working time of 0,5. The total number of working hours of physicians from the workplaces named in point 2a involved in the activities of the CDNO (with and without specialization in the field) will be at least 5,0.

d. Other staff of the center:

1. Physician with specialized competence in the field of Child Psychiatry; at least 0,1 working hours.

2. Physician with specialized competence in the field of pediatric endocrinology and diabetology; at least 0,2 working hours.

3. Clinical anthropologist; at least 0,5 working hours.

4. Physiotherapist; at least 1,0 working hours.

5. Occupational Therapist; at least 0,5 working hours.

6. Clinical speech therapist; at least 0,2 working hours.

7. Health and social worker; at least 0,2 working hours.

8. Nutritional therapist; at least 0,2 working hours.

e. Patients and midwives are also involved in the treatment of patients. Secondary medical staff is dedicated to the care of a pediatric patient with adequate specialized education (University degree in medical care, completion of specialized education in the field of Nurse).

f. A dedicated administrative staff member participates in the coordination of the dispensary, who ensures the necessary imaging and clinical monitoring at regular intervals; at least 0,5 working hours.

5. Material and technical equipment of the Center for Pediatric Neurooncology

a. Spatial security

1. The CDNO shall use the bed capacities of the workplaces mentioned in point 2a.

2. The patient is directed to a workplace that requires his current state of health.

3. The inpatient workplaces listed in point 2a shall always have at least 3 beds in the standard ward and 1 intensive care bed for the needs of the CDNO.

4. A dedicated outpatient clinic is available within the CDNO workplaces, where outpatient examinations and dispensary inspections take place.

b. Instrumentation and technical equipment

1. Computed tomography (CT), magnetic resonance imaging (MRI) and other imaging methods are available for CDNO diagnostic needs.

2. Examination by positron emission tomography is routinely available in cooperation with the PET Center of the Homolka Hospital.

3. A hospital laboratory complement is available for CDNO.

4. Blood derivatives are available continuously for CDNO.

5. CDNO freely has the existing instrumentation and space equipment of individual workplaces according to the current situation.

6. Perioperative histological examination is available for CDNO.

7. The basic processing of tumor tissue samples takes place directly in the operating room with the possibility of deep freezing in the laboratory within 20 minutes of collection.

8. Frozen samples and samples in paraffin blocks are in the Laboratory of Molecular Pathology - LaMPa (Department of Pathology and Molecular Medicine, 2nd Faculty of Medicine, Charles University and Motol University Hospital) and Laboratory of Solid Tumors - LBSN (Department of Pediatric Hematology and Oncology, 2nd Faculty of Medicine, Charles University and Motol University Hospital) processed and frozen as standard according to the procedures established at the Institute of Pathology and Molecular Medicine and the Department of Pediatric Hematology and Oncology, which correspond to good laboratory practice. Samples that are used within the CDNO are not stored separately and exclusively, but are classified, processed and stored as established for other samples received by these laboratories. Sample names are anonymized in LBSN by an alphanumeric code that does not contain any alphanumeric series of first name, last name, date of birth, and birth number, so it is not possible to trace a patient based on this information. The sample code thus does not contain GDPR sensitive data. At the Institute of Pathology and Molecular Medicine, isolated nucleic acid samples are identified by an isolation number and surname, but the samples are treated according to GDPR rules. GDPR sensitive data is stored in an isolated database or hospital system and is provided with a password. These databases are accessible in the laboratories on FNM computers in locked rooms, to which only FNM employees have access. The samples themselves are then placed in freezers at -20 ^oC and -80 ^oC, or in liquid nitrogen. These freezers and liquid nitrogen containers are located in closed rooms, to which only FNM employees have access. The storage of paraffin-embedded samples is governed by a standard procedure that is part of the accreditation of the Department of Pathology and Molecular Medicine.

9. Immunohistochemical methods follow the basic histopathological examination.

1. Simultaneously or subsequently with the histological examination, a molecular biological examination takes place, which is ensured by mutual cooperation of the Laboratory of Molecular Pathology (Department of Pathology and Molecular Medicine, 2nd Medical Faculty, Charles University and Motol University Hospital) and the Laboratory of Solid Tumors (Department of Pediatric Hematology and Oncology ). These laboratories are fully equipped for molecular biological examinations of CNS tumors. The laboratories have a bioinformatics that provides bioinformatics analyzes for next-generation sequencing. The molecular biological methods we use to diagnose CNS tumors include:

a. PCR and RT-PCR, or ddPCR

b. FISH

c. Direct sequencing method

d. MLPA

e. Next generation sequencing (NGS) at the DNA and RNA level

f. SNParray and methylation SNParray

g. Fragmentation analysis

1. In indicated cases, examination of germinal pathogenic variants (hereditary tumor predispositions) is available.

a. Patients for examination of hereditary tumor predispositions are recommended by an oncologist based on the type of tumor, family history and other circumstances (therapeutic purposes).

b. Molecular examination is preceded by consultation with a clinical geneticist.

c. Laboratory testing options include, but are not limited to:

1. Targeted examination by sequencing methods according to Sanger and MLPA.

2. If necessary, in STATIM mode, results in genes TP53 a SMARCB1 we guarantee the examination within 10 working days.

3. Massively parallel sequencing method - in case of suspected heterogeneous etiology, cooperating service laboratories provide.

1. In case of diagnostic ambiguities, CDNO has the opportunity to consult our results abroad; or, if the examination is not introduced in our country, sending the material for further examinations to a foreign workplace.

6. Financial support of the Center for Pediatric Neurooncology

a. Patient care is reported to health insurance companies.

b. CDNO actively participates in grant projects of the European Union, the Ministry of Health, the Agency for Health Research, Charles University and other institutions.

7. Control activities of the Center for Pediatric Neurooncology

a. The CDNO regularly monitors the following indicators of the quality of health care provided and regularly as of 1.6. publishes the results for the previous year.

b. CDNO quality and performance indicators:

1. Number of pediatric patients with newly diagnosed CNS cancer in the past year.

2. Number of performed neurosurgical procedures for cancer.

3. Mortality within 30 days of the operation.

4. Repeated admission within 30 days of surgery.

5. Number of patients operated for recurrence of the underlying disease in the past year.

c. Data collection:

1. The CDNO primarily collects data in a prospective manner.

2. For the needs of scientific studies, a retrospective analysis of a certain issue is also permissible.

3. The data shall be stored in dedicated databases which shall be managed in accordance with Regulation (EU) 2016/679 of the European Parliament and of the Council.

8. Scientific and research activities of the Center for Pediatric Neurooncology

a. CDNO is actively involved in basic and clinical research.

b. The CDNO prospectively monitors treated patients through a dedicated database.

c. CDNO actively participates in mono- and multicentre scientific studies at the national and international levels.

d. CDNO actively seeks to obtain grant funds from the European Union, the Ministry of Health, the Agency for Health Research, Charles University, the 2nd Faculty of Medicine, Charles University and other institutions.

e. The results of CDNO's scientific activities are presented in the form of lectures, expert articles and other scientific results.

9. Cooperation of the Center for Pediatric Neurooncology with other departments of the Faculty of Medicine and the 1st and 2nd Medical Faculty of Charles University

a. CDNO cooperates with other departments of FN Motol, 1st Faculty of Medicine and 2nd Faculty of Medicine, Charles University according to the current situation and condition of the patient, in order to meet the principles of "lege artis" and "evidence-based medicine".

b. CDNO is actively deepening existing cooperation and looking for opportunities to establish new ones with other workplaces.

10. Cooperation with other medical facilities, professional societies, organizations, etc.

a. Proton Therapy Czech (PTC) using proton radiotherapy in children.

b. Department of Pediatric Oncology, University Hospital Brno - cooperation on international protocols, creation of common national approaches to the diagnosis and treatment of pediatric brain tumors

11. International cooperation of individual workplaces forming the CDNO

The CDNO is integrated into international cooperation with the following entities through individual workplaces:

a. CDNO is part of the European Reference Network on Pediatric Cancer (hemato-oncology).

b. CDNO is part of the International Society for Pediatric Oncology (SIOP). Within the SIOP, the center participates in international phase III clinical trials within the optimization of treatment for individual diagnoses.

c. The CDNO is part of the Innovative Therapies for Childhood Cancer (ITCC), which has access to the latest treatments in Phase I and II clinical trials.

d. INFORM - molecular diagnostics and target search in patients with unfavorable prognosis.

e. EpiCARE (European Reference Network for Rare and Complex Epilepsy).

f. CDNO is actively deepening existing cooperation and looking for opportunities to establish new ones with other workplaces at the international level.

12. Development concept, future changes in the scope of care, event. investment plans

a. Promotion of CDNO within the Czech Republic and internationally through the media, internet, social networks and other media.

b. The CDNO is not a closed unit and is open to admission to other clinics and institutes.

c. CDNO is actively working on the introduction of new histopathological and molecular genetic diagnostic methods.

d. CDNO is actively working to acquire new and upgrade existing equipment needed in the diagnostic-therapeutic process.

e. CDNO seeks recognition of the center at the national level as a reference workplace for pediatric neurooncology.

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Department of Pediatric Hematology and Oncology, 2nd Medical Faculty, Charles University and Motol University Hospital