Applications of Frameless Image-Guided Robotic Stereotactic Radiotherapy and Radiosurgery in Pediatric Neuro-Oncology: A Systematic Review

Background: CyberKnife-based robotic radiosurgery (RRS) is a widely used treatment modality for various benign and malignant tumors of the central nervous system (CNS) in adults due to its high precision, favorable safety profile, and efficacy. Although RRS is emerging in pediatric neuro-oncology, scientific evidence for treatment indications, treatment parameters, and patient outcomes is scarce. This systematic review summarizes the current experience and evidence for RRS and robotic stereotactic radiotherapy (RSRT) in pediatric neuro-oncology. Methods: We performed a systematic review based on the databases Ovid Medline, Embase, Cochrane Library, and PubMed to identify studies and published articles reporting on RRS and RSRT treatments in pediatric neuro-oncology. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were applied herein. Articles were included if they described the application of RRS and RSRT in pediatric neuro-oncological patients. The quality of the articles was assessed based on their evidence level and their risk for bias using the original as well as an adapted version of the Newcastle Ottawa Quality Assessment Scale (NOS). Only articles published until 1 August 2021, were included. Results: A total of 23 articles were included after final review and removal of duplicates. Articles reported on a broad variety of CNS entities with various treatment indications. A majority of publications lacked substantial sample sizes and a prospective study design. Several reports included adult patients, thereby limiting the possibility of data extraction and analysis of pediatric patients. RRS and RSRT were mostly used in the setting of adjuvant, palliative, and salvage treatments with decent local control rates and acceptable short-to-intermediate-term toxicity. However, follow-up durations were limited. The evidence level was IV for all studies; the NOS score ranged between four and six, while the overall risk of bias was moderate to low. Conclusion: Publications on RRS and RSRT and their application in pediatric neuro-oncology are rare and lack high-quality evidence with respect to entity-related treatment standards and long-term outcomes. The limited data suggest that RRS and RSRT could be efficient treatment modalities, especially for children who are unsuitable for surgical interventions, suffer from tumor recurrences, or require palliative treatments. Nevertheless, the potential short-term and long-term adverse events must be kept in mind when choosing such a treatment. Prospective studies are necessary to determine the actual utility of RRS and RSRT in pediatric neuro-oncology

MGMT Promoter Methylation and BRAF V600E Mutations Are Helpful Markers to Discriminate Pleomorphic Xanthoastrocytoma from Giant Cell Glioblastoma.

Giant Cell Glioblastoma (gcGBM) and Pleomorphic Xanthoastrocytoma (PXA) are rare astroglial tumors of the central nervous system. Although they share certain histomorphological and immunohistochemical features, they are characterized by different clinical behavior and prognosis. Nevertheless, few cases remain uncertain, as their histomorphological hallmarks and immunophenotypes do correspond to the typical pattern neither of gcGBM nor PXA. Therefore, in addition to the routinely used diagnostic histochemical and immunohistochemical markers like Gömöri, p53 and CD34, we analyzed if genetic variations like MGMT promoter methylation, mutations in the IDH1/2 genes, or BRAF mutations, which are actually used as diagnostic, prognostic and predictive molecular markers in anaplastic glial tumors, could be helpful in the differential diagnostic of both tumor entities. We analyzed 34 gcGBM and 20 PXA for genetic variations in the above-named genes and found distinct distributions between both groups. MGMT promoter hypermethylation was observed in 3 out of 20 PXA compared to 14 out of 34 gcGBM (15% vs. 41.2%, p-value 0.09). BRAF V600E mutations were detected in 50% of the PXA but not in any of the gcGBM (50% vs. 0%, p-value < 0.001). IDH1 R132 and IDH R172 mutations were not present in any of the PXA and gcGBM cases. Our data indicate, that in addition to the histological and immunohistochemical evaluation, investigation of MGMT promoter methylation and in particular BRAF V600E mutations represent reliable additional tools to sustain differentiation of gcGBM from PXA on a molecular basis. Based on these data specific BRAF kinase inhibitors could represent a promising agent in the therapy of PXA and their use should be emphasized

A Paucisymptomatic Neuromuscular Disease Mimicking Type III 5q-SMA With Complex Rearrangements in the SMN Gene

Spinal muscular atrophy is an autosomal-recessive neuromuscular disorder, causing progressive proximal weakness and atrophy of the voluntary muscles. More than 96% of the spinal muscular atrophy patients show a homozygous absence of exons 7 and 8, or exon 7 only, in SMN1, the telomeric copy of the SMN gene. We report a young male patient with neurogenic symptoms and sparse muscle fiber atrophy, suggestive of a mild form of type III spinal muscular atrophy. He was found to be a carrier of intragenic mutations in both copies of the SMN gene, exhibiting a homozygous duplication of exons 7 and 8 in SMN1 and a homozygous deletion of exon 8 as well as a heterozygous deletion of exon 7 in SMN2. However, an intact full-length SMN1 complementary deoxyribonucleic acid was identified, and SMN protein levels in a muscle specimen were identical to that of a healthy control, formally excluding the diagnosis of spinal muscular atrophy III

<i>MGMT</i> Promoter Methylation and <i>BRAF</i> V600E Mutations Are Helpful Markers to Discriminate Pleomorphic Xanthoastrocytoma from Giant Cell Glioblastoma

<div><p>Giant Cell Glioblastoma (gcGBM) and Pleomorphic Xanthoastrocytoma (PXA) are rare astroglial tumors of the central nervous system. Although they share certain histomorphological and immunohistochemical features, they are characterized by different clinical behavior and prognosis. Nevertheless, few cases remain uncertain, as their histomorphological hallmarks and immunophenotypes do correspond to the typical pattern neither of gcGBM nor PXA. Therefore, in addition to the routinely used diagnostic histochemical and immunohistochemical markers like Gömöri, p53 and CD34, we analyzed if genetic variations like <i>MGMT</i> promoter methylation, mutations in the <i>IDH1/2</i> genes, or <i>BRAF</i> mutations, which are actually used as diagnostic, prognostic and predictive molecular markers in anaplastic glial tumors, could be helpful in the differential diagnostic of both tumor entities. We analyzed 34 gcGBM and 20 PXA for genetic variations in the above-named genes and found distinct distributions between both groups. <i>MGMT</i> promoter hypermethylation was observed in 3 out of 20 PXA compared to 14 out of 34 gcGBM (15% vs. 41.2%, p-value 0.09). <i>BRAF</i> V600E mutations were detected in 50% of the PXA but not in any of the gcGBM (50% vs. 0%, p-value < 0.001). <i>IDH1</i> R132 and <i>IDH</i> R172 mutations were not present in any of the PXA and gcGBM cases. Our data indicate, that in addition to the histological and immunohistochemical evaluation, investigation of <i>MGMT</i> promoter methylation and in particular <i>BRAF</i> V600E mutations represent reliable additional tools to sustain differentiation of gcGBM from PXA on a molecular basis. Based on these data specific BRAF kinase inhibitors could represent a promising agent in the therapy of PXA and their use should be emphasized.</p></div

gcGBM: Patients, histology, immunohistochemical and molecular markers.

<p>gcGBM: Patients, histology, immunohistochemical and molecular markers.</p

Comparative marker distribution in gcGBM and PXA.

<p>Comparative marker distribution in gcGBM and PXA.</p

PXA and PXA-A: Patients, histology, immunohistochemical and molecular markers.

<p>PXA and PXA-A: Patients, histology, immunohistochemical and molecular markers.</p

“Borderline Case” demonstrating that MGMT and BRAF are helpful additional molecular markers to differentiate PXA from gcGBM.

<p><b>A</b> Tumor specimen of a 51-years old female patient, located in the right parietal region: T1-weighted, contrast-enhanced MRI scan shows a well-circumscribed, vascularized and in-homogeneously contrasted tumor, suspicious for focal necrosis. <b>B</b> HE staining displays a pleomorphic astroglial tumor with giant cells, elevated mitotic activity and palisading necrosis. <b>C</b> Reticulin fiber dispositions are present around the vessel walls, while <b>D</b> CD34 expression is limited to the vessels. <b>E</b> As the proliferative index additionally accounts for 20% the tumor was initially classified as giant cell glioblastoma (WHO grade IV). <b>F</b> Pyrogram indicating a significant <i>MGMT</i> hypermethylation and G <i>BRAF</i> V600E mutation. For that reason the tumor was finally classified as PXA with anaplastic features (analogues to grade III).</p

MGMT and BRAF V600 analysis in gcGBM and PXA.

<p><b>A</b> Hypermethylation of <i>MGMT</i> was detected in 2 PXA (10%) and 14 gcGBM (41,2%). <b>B</b> 5 PXA and 6 PXA-A (55%) reveal V600E mutations in the <i>BRAF</i> gene, while being absent in gcGBM.</p