Emerging interventional treatments in the management of pediatric brain tumors.

Possibilities of new therapeutic strategies in brain tumors

<div>Abstract<p>Accurate histopathologic diagnosis is essential for providing optimal surgical management of pediatric brain tumors. Current methods for intraoperative histology are time- and labor-intensive and often introduce artifact that limit interpretation. Stimulated Raman histology (SRH) is a novel label-free imaging technique that provides intraoperative histologic images of fresh, unprocessed surgical specimens. Here we evaluate the capacity of SRH for use in the intraoperative diagnosis of pediatric type brain tumors. SRH revealed key diagnostic features in fresh tissue specimens collected from 33 prospectively enrolled pediatric type brain tumor patients, preserving tumor cytology and histoarchitecture in all specimens. We simulated an intraoperative consultation for 25 patients with specimens imaged using both SRH and standard hematoxylin and eosin histology. SRH-based diagnoses achieved near-perfect diagnostic concordance (Cohen's kappa, <i>κ</i> > 0.90) and an accuracy of 92% to 96%. We then developed a quantitative histologic method using SRH images based on rapid image feature extraction. Nuclear density, tumor-associated macrophage infiltration, and nuclear morphology parameters from 3337 SRH fields of view were used to develop and validate a decision-tree machine-learning model. Using SRH image features, our model correctly classified 25 fresh pediatric type surgical specimens into normal versus lesional tissue and low-grade versus high-grade tumors with 100% accuracy. Our results provide insight into how SRH can deliver rapid diagnostic histologic data that could inform the surgical management of pediatric brain tumors.</p><p><b>Significance:</b> A new imaging method simplifies diagnosis and informs decision making during pediatric brain tumor surgery. <i>Cancer Res; 78(1); 278–89. ©2017 AACR</i>.</p></div>

<div>Abstract<p>Accurate histopathologic diagnosis is essential for providing optimal surgical management of pediatric brain tumors. Current methods for intraoperative histology are time- and labor-intensive and often introduce artifact that limit interpretation. Stimulated Raman histology (SRH) is a novel label-free imaging technique that provides intraoperative histologic images of fresh, unprocessed surgical specimens. Here we evaluate the capacity of SRH for use in the intraoperative diagnosis of pediatric type brain tumors. SRH revealed key diagnostic features in fresh tissue specimens collected from 33 prospectively enrolled pediatric type brain tumor patients, preserving tumor cytology and histoarchitecture in all specimens. We simulated an intraoperative consultation for 25 patients with specimens imaged using both SRH and standard hematoxylin and eosin histology. SRH-based diagnoses achieved near-perfect diagnostic concordance (Cohen's kappa, <i>κ</i> > 0.90) and an accuracy of 92% to 96%. We then developed a quantitative histologic method using SRH images based on rapid image feature extraction. Nuclear density, tumor-associated macrophage infiltration, and nuclear morphology parameters from 3337 SRH fields of view were used to develop and validate a decision-tree machine-learning model. Using SRH image features, our model correctly classified 25 fresh pediatric type surgical specimens into normal versus lesional tissue and low-grade versus high-grade tumors with 100% accuracy. Our results provide insight into how SRH can deliver rapid diagnostic histologic data that could inform the surgical management of pediatric brain tumors.</p><p><b>Significance:</b> A new imaging method simplifies diagnosis and informs decision making during pediatric brain tumor surgery. <i>Cancer Res; 78(1); 278–89. ©2017 AACR</i>.</p></div>

The present article illustrates whether positron-emission tomography (PET) imaging may improve the surgical management of pediatric brain tumors (PBT) at different steps. Among 400 consecutive PBT treated between 1995 and 2005 at Erasme Hospital, Brussels, Belgium, we have studied with (18) F-2-fluoro-2-deoxy-D-glucose (FDG)-PET and/or L-(methyl-(11)C)methionine (MET)-PET and integrated PET images in the diagnostic workup of 126 selected cases. The selection criteria were mainly based on the lesion appearance on magnetic resonance (MR) sequences. Cases were selected when MR imaging showed limitations for (1) assessing the evolving nature of an incidental lesion (n = 54), (2) selecting targets for contributive and accurate biopsy (n = 32), and (3) delineating tumor tissue for maximal resection (n = 40). Whenever needed, PET images were integrated in the planning of image-guided surgical procedures (frame-based stereotactic biopsies (SB), frameless navigation-based resections, or leksell gamma knife radiosurgery). Like in adults, PET imaging really helped the surgical management of the 126 children explored, which represented about 30% of all PBT, especially when the newly diagnosed brain lesion was (1) an incidental finding so that the choice between surgery and conservative MR follow-up was debated, and (2) so infiltrative or ill-defined on MR that the choice between biopsy and resection was hardly discussed. Integrating PET into the diagnostic workup of these two selected groups helped to (1) take a more appropriate decision in incidental lesions by detecting tumor/evolving tissue; (2) better understand complex cases by differentiating indolent and active components of the lesion; (3) improve target selection and diagnostic yield of stereotactic biopsies in gliomas; (4) illustrate the intratumoral histological heterogeneity in gliomas; (5) provide additional prognostic information; (6) reduce the number of trajectories in biopsies performed in eloquent areas such as the brainstem or the pineal region; (7) better delineate ill-defined PBT infiltrative along functional cortex than magnetic resonance imaging (MRI); (8) increase significantly, compared to using MRI alone, the number of total tumor resection and the amount of tumor tissue removed in PBT for which a total resection is a key-factor of survival; (9) target the resection on more active areas; (10) improve detection of tumor residues in the operative cavity at the early postoperative stage; (11) facilitate the decision of early second-look surgery for optimizing the radical resection; (12) improve the accuracy of the radiosurgical dosimetry planning. PET imaging may improve the surgical management of PBT at the diagnostic, surgical, and post-operative steps. Integration of PET in the clinical workup of PBT inaugurates a new approach in which functional data can influence the therapeutic decision process. Although metabolic information from PET are valid and relevant for the clinical purposes, further studies are needed to assess whether PET-guidance may decrease surgical morbidity and increase children survival.

Pediatric brain tumors are most common cancers in childhood and among the leading causes of death in children. Chemotherapy has been used as adjuvant (i.e. after) or neoadjuvant (i.e. before) therapy to surgery and radiotherapy for the management of pediatric brain tumors for more than four decades and gained more attention in the recent two decades. Although chemotherapy has demonstrated its effectiveness in the management of some pediatric brain tumors, failure or inactiveness of chemotherapy is commonly met in the clinics and clinical trials. Some of these failures might be attributed to the blood-brain barrier (BBB), limiting the penetration of systemically administered chemotherapeutics into pediatric brain tumors. Therefore, various strategies have been developed and used to address this issue. Herein, we review different methods reported in the literature to circumvent the BBB for enhancing the present of chemotherapeutics in the brain to treat pediatric brain tumors.

Pediatric primary brain tumors pose significant therapeutic challenges due to their aggressive nature and the critical environment of the developing brain. Traditional modalities like surgery, chemotherapy, and radiotherapy often achieve limited success in high-grade gliomas and embryonal tumors. Tumor-treating fields (TTfields), a non-invasive therapy delivering alternating electric fields, has emerged as a promising approach to disrupt tumor cell division through mechanisms such as mitotic disruption, DNA damage, and tumor microenvironment modulation. TTfields are thought to selectively target dividing tumor cells while sparing healthy, non-dividing cells. While TTfields therapy is FDA-approved for the management of glioblastoma and other cancers, its application in pediatric brain tumors remains under investigation. Preclinical studies reveal its potential in medulloblastoma and ependymoma models, while observational data suggest its safety and feasibility in children. Current research focuses on optimizing TTfields' efficacy through advanced technologies, including high-intensity arrays, skull remodeling, and integration with immunotherapies such as immune checkpoint inhibitors. Innovative device-based therapies like magnetic field-based technologies further expand the treatment possibilities. As clinical trials progress, TTfields and related modalities offer hope for addressing unmet needs in pediatric neuro-oncology, especially for tumors in challenging locations. Future directions include biomarker identification, tailored protocols, and novel therapeutic combinations to enhance outcomes in pediatric brain tumor management.

The role of the pediatrician is crucial in both the diagnosis and management of pediatric brain tumors, the most common solid tumor of childhood. Awareness of the presenting signs and symptoms of brain tumors can lead to timely diagnosis, and understanding the late effects of brain tumor treatment improves long-term management of childhood brain tumor survivors.After completing this article, readers should be able to: Recognize the presenting symptoms and physical examination findings suggestive of a childhood brain tumor and how these findings depend on tumor location.Review common brain tumor pathologies affecting children.Understand how molecular genetics plays a role in the diagnosis and treatment of childhood brain tumors.Recognize the late affects associated with the treatment of childhood brain tumors.Brain tumors are the most common solid malignancy in children and represent the leading cause of pediatric cancer-related deaths. Five thousand new brain tumors are diagnosed yearly in the United States in children ages 0 to 19 years, with an incidence of approximately 6 per 100,000 children. (1) Childhood brain tumors, more than half of which are malignant, vary in terms of biology, prognosis and treatment. Presenting signs and symptoms depend on tumor location, growth rate, and presence of obstructive hydrocephalus. Making the initial diagnosis of a brain tumor can be difficult because early symptoms, such as headaches or vomiting, are nonspecific to brain tumors and more frequently are associated with other etiologies, leading to delays in diagnosis. The pediatrician plays a crucial role in the timely diagnosis of patients with brain tumors as well as recognizing late effects resulting from tumor therapies. This review summarizes the presenting features on history and physical examination, tumor classification of common tumor types, genetic brain tumor predisposition syndromes, general management strategy, and late effects of therapy.Signs and symptoms of a pediatric brain tumor can be nonspecific, insidious, intermittent, and dependent on location within the central nervous system (CNS) and the anatomical pathways affected. Although headache is the most common presenting complaint overall, it is present in only approximately one-third of the children presenting with brain tumors, and, in the absence of other symptoms or physical examination findings, is not in itself predictive of a brain tumor. Elevated intracranial pressure (ICP) is present in approximately half of all children with brain tumors. In addition to headache, it can cause nausea/vomiting, abnormalities of gait and coordination, and papilledema. Vital sign abnormalities associated with increased ICP, known as the Cushing triad (bradycardia, hypertension, abnormal respirations), are late signs of acutely increased ICP but can be absent in those with chronically elevated ICP. In young children with an open fontanelle, macrocephaly, especially when progressive, can be suggestive of hydrocephalus and a potential mass-occupying lesion. (2)Presenting symptoms depend on tumor location (Fig 1), and certain constellations of symptoms can point to specific lesion locations. Table 1 lists commonly overlooked signs and symptoms that can lead to a delayed diagnosis. Wilne et al analyzed presenting features of more than 4,000 childhood brain tumors and found that for posterior fossa tumors, three-quarters presented with nausea and vomiting, two-thirds with headache, three-fifths with abnormal gait and coordination, and one-third with papilledema. (2) In contrast, headache, nausea, and vomiting were rare in patients presenting with supratentorial tumors. Instead, seizures were present in one-third of patients, along with focal neurologic deficits such as weakness or sensory deficits on the contralateral side if there is involvement of the cortical motor or sensory regions, respectively. (2) In cases of brainstem tumors, children can present with crossed findings of ipsilateral facial weakness and contralateral hemiparesis. More than 75% of patients with brainstem tumors present with abnormal gait and coordination, whereas cranial nerve (CN) palsies are present in more than half. Headache, however, is not common in patients with brainstem tumors and is present in less than one-quarter at the time of diagnosis. Thalamic tumors can cause coordination and motor difficulties or hemiplegia. (2)Patients with pituitary tumors or optic pathway tumors often present with visual deficits. It is not uncommon for even severe visual deficits in children to go unrecognized by the patient, parents, or pediatrician. (3) Because patients with neurofibromatosis (NF) type 1 are at increased risk for optic pathway glioma, they should have yearly ophthalmology evaluations. Children with pituitary or hypothalamic tumors often present with endocrine abnormalities, such as failure to thrive, excessive thirst, or central obesity.Children with spinal cord tumors most commonly present with back pain, present at diagnosis in approximately two-thirds of cases. Spinal cord tumors may occur in extradural, intramedullary, and extramedullary intradural locations. Although some children may present with scoliosis, most will not. Spinal cord compression causes signs such as gait and coordination abnormalities, focal weakness, or bowel and bladder dysfunction. (2)A comprehensive neurologic examination (summarized in Table 2) is crucial to identify abnormalities that might be suggestive of a CNS tumor. A normal neurologic examination does not exclude the diagnosis of a brain or spinal cord tumor and must be correlated with symptoms.Patients with acute hydrocephalus can display dramatic changes in their mental status, with increased sleepiness, decreased energy, and decreased responsiveness. However, those with chronic hydrocephalus might show only subtle signs, such as slowly declining school performance.A fundoscopic examination of the optic nerve, CN II, is crucial to assess for papilledema and optic nerve pallor, which can reveal information about hydrocephalus or tumors along the optic pathways. A fundoscopic examination can be difficult in young or uncooperative children, warranting referral to ophthalmology for a dilated examination. Vision should be assessed by confrontation in the 4 quadrants of each eye because different patterns of visual field deficits will suggest varying tumor locations. In younger children, assessment of visual fields can be performed using a colorful object for central fixation and introducing a second object in the periphery and watching for the eyes to track to that object.Eye movements are controlled by CNs III, IV, and VI. The nuclei of CNs III and IV are located in the midbrain, whereas the nucleus of CN VI is in the pons, and brainstem tumors can lead to abnormalities of extraocular movements. Large pineal tumors can cause Parinaud syndrome, characterized by upgaze palsy, convergence-retraction nystagmus, and poorly reactive pupils due to compression of the rostral midbrain. Nystagmus can also be seen in patients with cerebellar tumors or optic pathway tumors.CN V, the trigeminal nerve, has 3 divisions that give sensation to the face. The trigeminal nucleus is located in the pons, as is the nucleus of CN VII (the facial nerve), which controls facial movement. Facial asymmetry or decreased facial sensation should raise concern for a mass in this region. Hearing in each ear should be assessed to look for CN VIII dysfunction.The lower CNs (CNs IX, X, XII) exit from the medulla and are involved in phonation, swallowing, and tongue movement. Palatal asymmetry, change in voice quality, or unilateral glossal atrophy raises suspicion for a medullary lesion. CN XI, the accessory nerve, has the most distal nucleus, also in the medulla, and innervates the trapezius and sternocleidomastoid musculature.Motor function, sensation, and reflexes should be assessed with special attention to comparison with the contralateral findings. Asymmetry can indicate a lesion affecting corticospinal tracts (motor), spinothalamic tracts (temperature, pain, light touch), or dorsal columns (proprioception, vibratory sense). Asymmetrical hyporeflexia can indicate lower motor neuron injury, whereas hyperreflexia and the presence of a Babinski reflex are indicative of upper motor neuron dysfunction. In acute upper motor neuron injury, reflexes may be absent.Patients with cerebellar tumors can present with a wide-based ataxic gait and difficulty with tandem gait. A hemiparetic gait can suggest a tumor involving cortical motor areas, the thalamus, or the brain stem. Patients with cerebellar or brainstem tumors may exhibit abnormal coordination, elicited by testing rapid alternating movements, finger to nose testing, or finger (pointer to thumb) and toe tapping (on the floor) or asking a child to mirror the examiner's finger as the examiner moves the finger laterally and/or vertically.Although not technically part of the neurologic examination, a skin examination is important to assess for dermatologic manifestations of underlying tumor predispositions such as NF type 1 (predisposed to low-grade gliomas [LGGs], especially in optic pathways), NF type 2 (predisposed to acoustic schwannomas and meningiomas), tuberous sclerosis complex (predisposed to subependymal giant cell tumors), or, more rarely, constitutional mismatch repair deficiency syndrome. Patients with constitutional mismatch repair deficiency syndrome have a genetic defect in genes responsible for repairing a specific type of DNA damage known as mismatch repair. Abnormalities in these genes (MLH1, MSH2, MSH5, PMS2) make it more difficult for the body to repair normally occurring DNA damage, leading to mutations and predisposing these patients to many types of cancers at an early age, including brain tumors, most commonly high-grade gliomas (HGGs). (4)The child with a suspected brain tumor might require urgent interventions. Those with unstable vital signs, altered mental status, or concern for increased ICP warrant expedited evaluation, best managed initially in the emergency department. Although magnetic resonance imaging (MRI) with and without contrast is the gold standard imaging technique for optimal visualization for brain tumors and is often needed for neurosurgical planning, in the unstable child, a computed tomographic (CT) scan may be the best initial imaging choice. CT scans can provide information regarding acute hydrocephalus, impending herniation, or acute hemorrhage, all of which represent neurosurgical emergencies. They can also show the anatomical location of a mass, lesion size, presence of hydrocephalus, and whether the mass is compressing other brain structures, thereby helping to triage and plan a timeline for MRI, surgery, or other sedated procedures. When choosing the optimal initial imaging study for a young child who would require anesthesia to complete an MRI, the relative risks of anesthesia compared with the risk of exposure to ionizing radiation from a CT scan, which could be completed without sedation, must be weighed while taking into account the degree of suspicion for an abnormality and individual risk factors specific to that patient. (5)MRI with and without contrast is generally the preferred imaging modality for diagnosis and follow-up of brain tumors. MRI allows for more detailed characterization of the tumor itself and the surrounding anatomy, with more specialized sequences for visualization of edema, relationship to CNs, blood vessels, and perfusion. Furthermore, MRI does not expose children to ionizing radiation so is preferred over CT for repeated studies, as would be needed to follow a brain tumor. Most patients with a brain tumor require a spinal MRI to evaluate for evidence of leptomeningeal disease.When a diagnosis of a brain tumor is made based on imaging, in the absence of a neurosurgical emergency, patients should be managed in concert with neuro-oncology teams preoperatively. Early neuro-oncology consultation allows for additional baseline neurologic examination, can help inform surgical planning based on the working differential diagnosis and postoperative treatment options, and facilitates an opportunity for clinical trial enrollment where presurgical consent may be required.The care of the pediatric neuro-oncology patient requires a multidisciplinary team–based approach. In addition to an excellent primary care pediatrician, this team includes neuro-oncology, neuro-surgery, neurology, neuro-radiology, radiation oncology, genetics, endocrinology, ophthalmology, audiology, neuropsychology, physical medicine and rehabilitation, palliative care, and social work.Upfront treatment of pediatric brain tumors generally includes surgery, radiotherapy, chemotherapy, or a combination of these modalities. For most tumor types, maximal safe surgical resection is pursued to obtain diagnosis and as the first step in definitive treatment. Some notable exceptions to this include tumors in eloquent locations where resection would result in significant morbidity or mortality. These locations include the brain stem, optic pathways, thalamus, internal capsule, sensory and motor cortices, visual cortex, or Broca and Wernicke areas, which are important for receptive and expressive language. In some cases, a small needle biopsy of these areas can be performed to obtain tissue for diagnostic purposes. For germ cell tumors, tumor markers can be diagnostic, obviating the need for upfront surgery. Some patients with low-grade–appearing lesions are followed with observation alone.Although some low-grade tumors can be treated with resection only, many low-grade and most high-grade tumors require additional postsurgical treatment. The standard of care for postsurgical management of pediatric brain tumors is constantly evolving based on emerging preclinical and clinical data. In many cases, enrollment in an open clinical trial is considered the standard of care. There are a variety of clinical trial consortia and cooperative groups with open protocols focused on pediatric brain tumors. A complete list of open clinical trials can be found on clinicaltrials.gov.There are more than 30 unique pathologies of CNS tumors in children. MRI characteristics of some common childhood brain tumors are shown in Fig 2. The advent of molecular genetics has enhanced our understanding of the biologic behavior of brain tumors, has changed tumor classification systems, and has had treatment implications.Medulloblastoma is the most common malignant brain tumor in children and is of embryonal origin. It generally presents as a posterior fossa mass and, due to its location, is often associated with obstructive hydrocephalus. Staging includes an MRI of the spine and a lumbar puncture looking for malignant cells in the cerebrospinal fluid (CSF). Histologically it is classified as classic, large cell anaplastic, or nodular desmoplastic. Overall, medulloblastoma has 5-year overall survival (OS) of approximately 70%. (6)Treatment depends on age at presentation, extent of resection, and presence of metastatic disease. Recent trials are accounting for molecular subtype in treatment decisions. Generally, treatment involves maximal tumor resection, craniospinal radiotherapy, and chemotherapy. Young patients undergo high-dose chemotherapy with autologous stem cell rescue to avoid or delay irradiation.Medulloblastoma has been classified into 4 principle molecular subgroups: WNT (wingless), SHH (sonic hedgehog), group 3, and group 4 (Table 3). (7) WNT-driven medulloblastomas are rarely metastatic and have the best overall prognosis, with greater than 90% OS. Current clinical trials are focused on reducing therapy in this subtype. SHH-driven tumors have a bimodal distribution presenting most commonly in infants or adolescents and young adults. They have an intermediate prognosis, although association with p53 mutations portends a poor prognosis. (9) Group 3 and group 4 tumors are known as non-WNT, non-SHH medulloblastoma subtypes. Although immunohistochemical studies can differentiate WNT and SHH medulloblastoma from the non-WNT and non-SHH medulloblastoma subtypes, other molecular methods, such as methylation studies, are needed to distinguish group 3 from group 4 tumors. Group 3 tumors can present in very young children, often have MYC amplification, are commonly metastatic at presentation, and have the poorest outcomes overall of any subgroup. Recent data suggest that group 3 tumors might benefit from intensified chemotherapy concurrent with radiotherapy. Group 4 tumors are the most common subgroup overall, presenting in children and adults and, similar to group 3 tumors, more commonly present in males than in females. (7) Group 4 tumors have an intermediate prognosis.Atypical teratoid rhabdoid tumors (ATRTs) are also embryonal tumors but can present in the posterior fossa or supratentorial region. These tumors have a very poor prognosis, with 3-year OS of approximately 25%. Survival trends improve with older age at diagnosis, with those older than 3 years faring better than younger patients. (10) Histologically, the loss of INI1, encoded by SMARCB1, is pathognomonic. Up to 35% of patients with ATRT have a germline mutation in SMARCB1 (or rarely SMARCA4), which predisposes them to the development of malignant rhabdoid tumors in other locations, most commonly the kidneys. Germline variants are more common in younger patients, and approximately two-thirds are sporadic. (11)Staging includes MRI of the brain and spine and lumbar puncture for CSF cytology. Treatment involves surgical resection, radiotherapy, and chemotherapy, with or without triple tandem autologous stem cell transplant. Recent clinical trial data showed improved survival outcomes compared with historical controls achieved with a regimen including radiotherapy for patients as young as 6 months and 3 cycles of high-dose chemotherapy with autologous stem cell rescue for all patients. (12) A meta-analysis including 130 patients with ATRT saw that survival correlated most strongly when patients were treated with regimens that included high-dose chemotherapy with autologous stem cell rescue. Treatment modalities of radiotherapy and intrathecal chemotherapy also lead to a statistically significant improvement in OS in this cohort. (10)ATRT tumors have also been classified based on molecular characteristics into 3 subgroups: ATRT–tyrosine (ATRT-TYR), ATRT–sonic hedgehog (ATRT-SHH), and ATRT–myelocytomatosis oncogene (ATRT-MYC), but further research is needed to delineate the prognostic and clinical implications of these subgroups. (13)Ependymoma represents the third most common brain tumor in children and arises from the ependymal cells lining the ventricles or the central canal of the spinal cord. Two-thirds of ependymomas present in the posterior fossa, with the remainder in the supratentorial region or spinal cord. For pediatric ependymoma as a whole, OS at 10 years is approximately 64%, but cases achieving gross total resection followed by radiotherapy fare significantly better. Molecular subtype and gain of chromosome 1q has important prognostic implications as well. (14)Ependymoma is treated with maximal surgical resection followed by focal radiotherapy, except for spinal disease, in which gross total resection without adjuvant radiotherapy can be curative. The role of chemotherapy in ependymoma remains under clinical investigation. Studies have also explored the use of postoperative chemotherapy to delay or omit radiotherapy in patients younger than 3 years, but outcomes were inferior to regimens involving radiotherapy for children older than 12 months. (15)Ependymoma has been divided into 9 molecular subgroups, with 3 subgroups for each anatomical location: spinal, supratentorial, and posterior fossa. Only 6 of the molecular subtypes generally affect children. Pediatric ependymoma of the spine is divided into the subtype and the subtype spinal subtypes have a prognosis. In the posterior fossa, patients with have a prognosis than those with and in the supratentorial those with have OS than those with and are associated with OS less than and survival of approximately are a group of tumors that including tumors the most tumors as and tumors When represent the most common brain tumor in children and can present in many anatomical locations. are less to to other of the CNS than their malignant and in some cases gross total resection can be curative. However, resection is not in certain anatomical locations, such as in the brain stem or with optic pathway common in patients with NF type have a prognosis, with OS of and survival of in a study of with follow-up of when therapy is needed for the regimen of chemotherapy with or and although other chemotherapy regimens have as well. is not in the upfront management of due to for late of the molecular of has that most are by in the most commonly variants and NF type 1 have shown pediatric and have shown in tumors. contrast to pediatric have a prognosis. include high-grade tumors brainstem tumors and of pediatric is tumors may be to surgical is followed by radiotherapy and chemotherapy for these tumors, as a Group study showed improved survival when chemotherapy to radiotherapy compared with radiotherapy specific chemotherapy regimen has as a standard of care for upfront pediatric In contrast, for tumors such as glioma, chemotherapy to radiotherapy has not been shown to survival the to OS and the OS achieved with radiotherapy open based and clinical trials are patients, to improve outcomes for these patients. studies in pediatric that the of pediatric from that of mutations and in tumors, and in tumors, the of in pediatric and a poor prognosis. are from in older children, with significantly improved are more common in children younger than 1 and under are germ cell tumors represent approximately of pediatric brain tumors and are as and germ cell tumors They most commonly in the pineal region but can also present in the thalamus, or or or both or which can be in blood and/or can cause of in the CSF but not In some cases, diagnosis can be made based on CSF and tumor whereas biopsy is when tumor markers are have a better overall prognosis, with OS greater than 90% compared with to for are commonly treated with 4 cycles of chemotherapy followed by radiotherapy to the tumor and whereas are generally treated with 6 cycles of chemotherapy alternating with and craniospinal radiotherapy in many cases, although studies are whether radiotherapy can be in patients with to associated with craniospinal radiotherapy. is a tumor from the of the and solid Histologically, they are classified as tumors and are divided into and subtypes. to their location they can and treatment for is some a more neurosurgical in an to avoid radiotherapy, and an initial resection followed by upfront radiotherapy. are germline mutations that children to specific types of childhood brain tumors in the of tumor predisposition of these is important to the primary care who follow these patients In the child who presents with a brain especially in the of other history of tumors, history of tumors at a young age, or dermatologic findings, it is important to further for these predisposition Children with a known history of predisposition might require genetic for the presence of these syndromes, and specific tumor if found to of these Furthermore, the presence of certain underlying may the of therapy for the management of a brain tumor. Table 4 summarizes germline associated with specific brain tumor the treatment of different tumor types each of the commonly treatment modalities their risks and acute risks of include and damage to structures, as well as morbidity dependent on tumor For posterior fossa syndrome affects an to of patients who undergo resection of large posterior fossa tumors. fossa syndrome is characterized by a combination of or significant with and or motor occurring within 2 of cerebellar and symptoms can months to and many are with deficits. Patients with supratentorial tumors are at greater risk for postoperative seizures and are often on Children with tumors are at increased risk for postoperative visual deficits and tumors by or at a tumor to damage is over to a total to the are without mass, that when at a point to a certain they also radiation at a lower on both the and exit side of the have mass, so the radiation is to within the the of at that the that the effects of radiotherapy are due to the radiation in both and radiotherapy, patients can skin which generally over the treatment Patients intracranial radiotherapy often headache or radiotherapy can cause due to the by the body and can the growth of the resulting in loss of in younger radiotherapy is preferred over radiotherapy, for patients who require craniospinal radiotherapy, because it to important such as the and For patients focal radiotherapy, therapy may to important or result in a significantly overall radiation on tumor the radiation field and for a plan a plan can be to evaluate relative of over based on the brain that would a with each to the use of therapy are the of radiotherapy

Despite increased understanding of molecular changes in brain tumorigenesis and successful establishment of mouse brain tumor models, the prognosis for brain cancer has improved only slightly over the past several decades. In November 2007, members of the brain tumor mouse models community convened to discuss how to effectively leverage mouse models to better understand brain tumorigenesis and discover targets for therapy. Discussions focused on identification of molecular targets and cell lineage, microenvironment, and genomic contributions to tumor development and maintenance. Herein, we present recommendations for optimizing mouse models to achieve better outcomes for brain tumor patients. Since the first National Cancer Institute (NCI) Mouse Models of Human Cancer Consortium (MMHCC) meeting in 2000 (1), many mouse models of brain cancer have been developed, and the field has progressed from generating models to using models to gain insights into the cellular and molecular pathogenesis of brain tumors. In November 2007, an international meeting sponsored by the MMHCC and the Office of Rare Diseases convened to discuss the current status of mouse brain tumor modeling and make recommendations for exploiting these models to address fundamental questions in brain tumor biology (for participants, see Supplemental Appendix). A major theme of the meeting was the growing appreciation of the complexity of brain tumors (Supplementary Fig. S1). Development of the central nervous system (CNS) requires ordered and tightly regulated signals that instruct cells to grow, die, mature, and move at the right time and place. Tumors of the nervous system form as a result of mutations that co-opt these signals to promote inappropriate proliferation, survival, differentiation, and migration – the hallmarks of cancer (2). Because brain tumorigenesis may reflect improper responses to instructions important for normal brain development, a more integrated view of brain cancer is needed. A central focus of the meeting was how to apply lessons and techniques from developmental biology to the study of brain tumorigenesis. At the molecular level, the signaling pathways important for brain tumorigenesis are multiple, not necessarily linear, with feedback mechanisms that must be taken into account when designing molecularly targeted interventions. At the cellular level, brain tumors are heterogeneous, composed of tumor stem cells and differentiated tumor cells with different characteristics and susceptibilities to therapy. At the level of the organ, brain tumors co-evolve with their environment, with stromal cells and factors in the surrounding microenvironment being important for tumor maintenance and progression, offering additional targets for intervention. Finally at the organism level, genetic variations between individuals can dictate how tumors initiate, progress, and respond to treatment. Mouse models allow researchers to rigorously test hypotheses developed from examining human tumors using genetic manipulation and controlling specific variables (e.g., environmental influences) to better understand the roles of different pathways, cell types, stromal factors, and genetic variation. Searching for Achilles’ Heel in the Brain -- Targeting Molecular Pathways in Tumors The topic of molecular targets for brain tumors was led by Drs. Marco Giovannini (INSERM, Paris, France) and Martine Roussel (St. Jude Children’s Research Hospital, Memphis, TN), and focused on the characterization of specific molecular targets and signaling pathways, as well as development of effective drug delivery methods in preclinical mouse models. Several experts discussed loss or constitutive activation of key tumor suppressors and oncogenes, respectively, with an emphasis on PI3K/PTEN and RB/TRP53/INK4A-ARF tumor suppressor pathways. Dr. Suzanne Baker (St. Jude Children’s Research Hospital, Memphis, TN) discussed the importance of feedback inhibition in signaling pathways, and the need to test putative targets, such as intermediates in the PI3K/PTEN/S6/mTOR pathway, in different contexts to determine whether targeting the pathway is likely to be universally successful, or successful only in certain contexts. Because molecular signaling pathways can branch and activate compensatory signaling pathways, inhibition of specific targets (e.g., mTOR) can actually lead to release of inhibition of certain branches of the pathway, culminating in increased tumor growth. Similarly, Dr. Terry Van Dyke (National Cancer Institute-Frederick, MD/University of North Carolina, Chapel Hill, NC) presented intriguing data on the levels of EGFR expression in accelerating or inhibiting Ras-driven brain tumors. In addition to their use in identifying important molecular targets and understanding interactions between signaling pathways, mouse models can be powerful tools for developing drug delivery approaches and high-throughput evaluation of targets and therapies. Dr. Martine Roussel discussed micro-RNA as an additional layer of complexity, whereby many pathways may be altered by loss of expression or misexpression of a single micro-RNA (3). Dr. John Ohlfest (University of Minnesota, Minneapolis, MN) presented a novel approach to generate humanized spontaneous gliomas using transposons expressing human proteins in neonatal mouse brains (manuscript submitted). Because the resulting tumor-bearing mice are immune-competent expressing human proteins, this model can be used to test immunotherapies. Dr. Alain Charest (Tufts University, Boston, MA) discussed the use of nanoparticles for effective delivery of siRNAs to treat GBM in mice.

dren. They are thus a leading cause of death, disability, and heartache. Nevertheless, the news over the last decade has been hopeful. Through coordinated national and international studies, largely led by the Children’s Oncology Group, the prognosis has dramatically improved for many of these lesions, especially primitive neuroectodermal tumors and germ cell tumors. We have been steadily moving in the direction of more efficacious and less toxic therapies, and this has allowed us to save lives. The role of the neurosurgeon in the management of pediatric brain tumors is large. Only the neurosurgeon can make the diagnosis in the safest and surest fashion and effect the most appropriate resection. In many of these diseases, the extent of the resection directly impacts prognosis. Only the surgeon can apply the appropriate tools and judgment to address these entities. In the pediatric brain tumor section of the current edition of Neurosurgical Focus, these issues of relevance for the neurosurgeon are addressed. New technology has facilitated the management of brain tumors in children. The first three papers, by Drs. Souweidane, Li, and Luther, explore the use of endoscopic surgical techniques to address pediatric brain tumors and concomitant hydrocephalus. The paper by Dr. Krieger, et al., explores the use of magnetic resonance spectroscopy as a surgical adjuvant. Diseaseand site-specific approaches have facilitated the management of these tumors. Dr. Sandberg, et al., explore surgical outcomes for dysembryoplastic neuroepithelial tumors in terms of disease and seizure control. The paper by Dr. Jagannathan and colleagues discusses state of the art management strategies for sellar tumors. Drs. Komotar and Chen discuss the recently described entities of pilomyxoid astrocytomas and atypical teratoid/rhabdoid tumors, respectively. Accurate understanding of subtypes of tumors allows us to evaluate treatments and outcomes more appropriately. The debate over the management of craniopharyngiomas is not likely to end soon. The papers of Drs. Liu and Aryan describe logical approaches to this challenging disease entity. Last, the paper by Dr. Lee explores an experimental model for evaluating pediatric tumors. It is only through continued study that we will advance our field. Neurosurg Focus 18 (6a):Introduction, 2005

Accurate histopathologic diagnosis is essential for providing optimal surgical management of pediatric brain tumors. Current methods for intraoperative histology are time- and labor-intensive and often introduce artifact that limit interpretation. Stimulated Raman histology (SRH) is a novel label-free imaging technique that provides intraoperative histologic images of fresh, unprocessed surgical specimens. Here we evaluate the capacity of SRH for use in the intraoperative diagnosis of pediatric type brain tumors. SRH revealed key diagnostic features in fresh tissue specimens collected from 33 prospectively enrolled pediatric type brain tumor patients, preserving tumor cytology and histoarchitecture in all specimens. We simulated an intraoperative consultation for 25 patients with specimens imaged using both SRH and standard hematoxylin and eosin histology. SRH-based diagnoses achieved near-perfect diagnostic concordance (Cohen's kappa, κ > 0.90) and an accuracy of 92% to 96%. We then developed a quantitative histologic method using SRH images based on rapid image feature extraction. Nuclear density, tumor-associated macrophage infiltration, and nuclear morphology parameters from 3337 SRH fields of view were used to develop and validate a decision-tree machine-learning model. Using SRH image features, our model correctly classified 25 fresh pediatric type surgical specimens into normal versus lesional tissue and low-grade versus high-grade tumors with 100% accuracy. Our results provide insight into how SRH can deliver rapid diagnostic histologic data that could inform the surgical management of pediatric brain tumors.Significance: A new imaging method simplifies diagnosis and informs decision making during pediatric brain tumor surgery. Cancer Res; 78(1); 278-89. ©2017 AACR.

Purpose of ReviewOver the last years, our understanding of the molecular biology of pediatric brain tumors has vastly improved. This has led to more narrowly defined subgroups of these tumors and has created new potential targets for molecularly driven therapies. This review presents an overview of the latest advances and challenges of implementing targeted therapies into the clinical management of pediatric brain tumors, with a focus on gliomas, craniopharyngiomas, and medulloblastomas.Recent FindingsPediatric low-grade gliomas (pLGG) show generally a low mutational burden with the mitogen-activated protein kinase (MAPK) signaling presenting a key driver for these tumors. Direct inhibition of this pathway through BRAF and/or MEK inhibitors has proven to be a clinically relevant strategy. More recently, MEK and IL-6 receptor inhibitors have started to be evaluated in the treatment for craniopharyngiomas. Aside these low-grade tumors, pediatric high-grade gliomas (pHGG) and medulloblastomas exhibit substantially greater molecular heterogeneity with various and sometimes unknown tumor driver alterations. The clinical benefit of different targeted therapy approaches to interfere with altered signaling pathways and restore epigenetic dysregulation is undergoing active clinical testing. For these multiple pathway-driven tumors, combination strategies will most likely be required to achieve clinical benefit.SummaryThe field of pediatric neuro-oncology made tremendous progress with regard to improved diagnosis setting the stage for precision medicine approaches over the last decades. The potential of targeted therapies has been clearly demonstrated for a subset of pediatric brain tumors. However, despite clear response rates, questions of sufficient blood-brain barrier penetration, optimal dosing, treatment duration as well as mechanisms of resistance and how these can be overcome with potential combination strategies need to be addressed in future investigations. Along this line, it is critical for future trials to define appropriate endpoints to assess therapy responses as well as short and long-term toxicities in the growing and developing child.

Brain tumors are the most common solid tumors in children and a leading cause of cancer-related mortality in children worldwide. Data on the epidemiology and management of pediatric brain tumors in Uganda are limited. We aimed to assess the clinicopathological profile and management of pediatric brain tumors at the national oncology center in Uganda since the inception of weekly multidisciplinary meetings. Records of children younger than19 years diagnosed with primary brain tumors at Uganda Cancer Institute between 2017 and 2021 were retrospectively reviewed. Patient and tumor characteristics were collected with multidisciplinary team management treatment plans for analysis. There were 35 patients evaluated, most of whom were males (57.1%). Craniopharyngioma (n = 9, 25.7%) was the most common brain tumor, followed by astrocytoma (n = 5, 14.2%) and medulloblastoma (n = 4, 11.4%). Management included surgical resection in 28.5% of patients, chemotherapy (28.6%), radiotherapy (17.1%) and palliative care (20.0%). Over the last five years, there were increasing trends in the number of cases discussed in the multidisciplinary team and the number for whom the multidisciplinary management decisions were implemented. The majority (n = 18, 51.4%) of the children with brain tumors were alive and active in care, 34.2% abandoned treatment/lost to follow-up, and 8.6% died. The relative distribution of pediatric brain tumors types in Uganda Cancer Institute differs slightly from international reports, and there has been a notable increase in the number of cases over the years. Implementing multidisciplinary management decisions benefited patients and decreased abandonment and patient loss to follow-up.

INTRODUCTION Radiation has a significant role in the management of pediatric brain tumors. Secondary complications to irradiation can include vascular malformations such as cavernous malformations, brain atrophy, necrosis, and demyelination. Although recognized as a potential complication, the pathogenesis and natural history of radiation induced cavernous malformations continues to be defined. We present a retrospective, single institution study of 138 patients who underwent cerebral radiotherapy as part of their comprehensive pediatric brain tumor management. METHODS Institutional review board permission was obtained and a retrospective review of all available patients with a pediatric brain tumor at our institution was completed. Patients who underwent radiotherapy and developed cavernous malformations were selected and the initial tumor type, frequency, and the radiological as well as clinical history were recorded and analyzed. RESULTS >From 1980–2005, 134 patients received radiotherapy for a pediatric brain tumor. Of this cohort, 28 patients (21%) subsequently developed at least one cerebral cavernous malformation. 21 of the patients had multiple cavernomas while only 7 were solitary. 15 patients were male. The mean time until discovery was 13.5 years. The tumor biology included 14 gliomas, 9 medulloblastomas, and 1 ependymoma. 14 patients received chemotherapy and all received at least short term corticosteroids. One patient required surgical excision of a cavernous malformation for repeated symptomatic hemorrhages. CONCLUSION Cavernous malformations are a frequent long term sequalae of pediatric radiotherapy. Although common, they are rarely associated with neurological complications even decades later and are largely discovered asymptomatically during routine surveillance screening of their primary disease. Future research in our database will be focused on establishing the relationship of radiation dose, age at irradiation, localization of radiotherapy, chemotherapy, anti-epileptics, and other medications on radiation induced cavernous malformations with the hope of identifying modifiable risk factors for clinical decision making application in a prospective fashion.

CNS tumors are the most common solid tumor of childhood. This article will review current treatments for pediatric brain tumors; low-grade gliomas, high-grade gliomas, medulloblastomas and ependymomas. It will also highlight the treatments that are used for brain tumors in very young children and in children with recurrent brain tumors. The management of recurrent pediatric brain tumors unresponsive to standard therapy will be discussed. The agents used in this setting are mainly biological modifiers, which attempt to provide molecularly targeted therapy. Future directions of therapy for pediatric brain tumors are described. Future treatment paradigms will need to consider examining the use of multiple biological modifiers. Similarly, these agents will need to be examined in combination with cytotoxic chemotherapy. Finally, the future direction of pediatric neuro-oncology and the focus of the field as it battles pediatric brain tumors is discussed.

MRI is the current gold standard imaging technique for diagnostic evaluation and monitoring of pediatric CNS tumors, however MRI measures are unable to fully relate to tumor biology and molecular stratification. Circulating in blood and cerebrospinal fluid (CSF), miRNAs are an abundant and stable nucleic acid which can be utilized as a tumor biomarker. Relating miRNA biomarkers and radiological tumor measurements may provide improved diagnostic and monitoring tools for pediatric brain tumors. Using a cohort of 54 pediatric brain tumors including low grade glioma, ependymoma, germ cell tumor, medulloblastoma, atypical teratoid rhabdoid tumor and high-grade glioma we attempted to combine MRI findings and circulating miRNA data. The miRNA expression was profiled in 33 CSF and 52 plasma samples using the HTG EdgeSeq platform. Clinically acquired, multi-parametric MRI scans at time-points close in proximity to liquid biopsy collection were collected retrospectively and used to generate volumetric tumor segmentations. We identified unique miRNA targets significantly correlated with MRI features, clinical findings, and patient outcomes. In both CSF and plasma, miRNA expression was identified to correlate with diagnosis and clinical features including tumor grade and survival status (p < 0.05). In CSF, miRNA expression was correlated with MRI measurements including cystic core volume, non-enhancing tumor volume, leptomeningeal disease, tumor size and location (p < 0.05). Combination of miRNA targets and radiomic tumor measurements improved diagnostic predictions between low- and high-grade tumors. In plasma, miRNA expression was correlated with MRI measurements including cystic core volume, location, and leptomeningeal disease (p < 0.05). These results demonstrate utility of miRNAs as a pediatric brain tumor biomarker which combined with imaging features can improve minimally to non-invasive diagnostics and management of pediatric brain tumors.