Pediatric Diffuse Leptomeningeal Glioneuronal Tumors: Diagnosis, Follow-up, and Treatment Options.

AIM: To highlight the diagnosis, follow-up, and treatment options for diffuse leptomeningeal glioneuronal tumor (DLGNT) by examining pediatric patients diagnosed with DLGNT by molecular pathological evaluation and next generation sequencing at our center. MATERIAL AND METHODS: In this retrospective analysis, patients diagnosed with DLGNT between January 2017 and December 2022 are outlined according to their demographic data, radiological data, pathology results, treatments, and follow-up data. RESULTS: Four patients were diagnosed with DLGNT. All the patients were male. The mean age was 6.5 years. All but one patient had symptoms of increased intracranial pressure. An open biopsy was obtained from all patients for diagnosis. Three patients received radiotherapy and chemotherapy after the diagnosis. Two patients died during their follow-up, one of them in the early postoperative period. Two patients were clinically and radiologically stable in their follow-up after treatment. CONCLUSION: Further work with larger cohorts is required to determine a common algorithm for DLGNT treatment and follow-up. This analysis may keep this entity in mind in patients with pediatric communicating hydrocephalus and may present insight into diagnosis, follow-up, and treatment options.

Preliminary findings of German-sourced ONC201 treatment in H3K27 altered pediatric pontine diffuse midline gliomas.

PURPOSE: H3K27 altered pediatric pontine diffuse midline gliomas (pDMG) have a poor prognosis, and conventional treatments offer limited benefits. However, recent advancements in molecular evaluations and targeted therapies have shown promise. The aim of this retrospective analysis was to evaluate the effectiveness of German-sourced ONC201, a selective antagonist of dopamine receptor DRD2, for the treatment of pediatric H3K27 altered pDMGs. METHODS: Pediatric patients with H3K27 altered pDMG treated between January 2016 and July 2022 were included in this retrospective analysis. Tissue samples were acquired from all patients via stereotactic biopsy for immunohistochemistry and molecular profiling. All patients received radiation treatment with concurrent temozolomide, and those who could acquire GsONC201 received it as a single agent until progression. Patients who could not obtain GsONC201 received other chemotherapy protocols. RESULTS: Among 27 patients with a median age of 5.6 years old (range 3.4-17.9), 18 received GsONC201. During the follow-up period, 16 patients (59.3%) had progression, although not statistically significant, the incidence of progression tended to be lower in the GsONC201 group. The median overall survival (OS) of the GsONC201 group was considerably longer than of the non-GsONC201 group (19.9 vs. 10.9 months). Only two patients receiving GsONC201 experienced fatigue as a side effect. 4 out of 18 patients in the GsONC201 group underwent reirradiation after progression. CONCLUSION: In conclusion, this study suggests that GsONC201 may improve OS in pediatric H3K27-altered pDMG patients without significant side effects. However, caution is warranted due to retrospective design and biases, highlighting the need for further randomized clinical studies to validate these findings.

Malignant nerve sheath tumor of oculomotor nerve in a pediatric patient.

Malignant nerve sheath tumors are extremely rare pathologies. They tend to occur within peripheral nerves and have close association of neurofibromatosis disease. Here, we present the second case of MNST of oculomotor nerve in literature. The patient was a 2-year-old girl with left sided oculomotor nerve palsy. After resection, the patient immediately had chemotherapy and radiotherapy. One year after surgery disease progressed with extensive intracranial seedings, and she passed away.

Spinal intramedullary H3K27M mutant glioma with vertebral metastasis: a case report.

A new entity of gliomas, named "diffuse midline glioma (DMG), H3K27M mutant (grade IV)," which represents a specific molecular profile, was introduced to the World Health Organization (WHO) classification 2016 of central nervous system tumors. Many midline localizations have been described for this glioma, and mainly the hypothalamus, pons, thalamus, and spinal cord are sites of predilection in pediatric and young adult patients. We report the case of spinal intramedullary DMG, H3K27M mutant (WHO grade IV), that showed an unusual presentation with multiple vertebral metastases.

Is it a new culprit? "TERT promoter mutation" in an aggressive pediatric pilocytic astrocytoma.

Recent advances in the genomic study have revolutionized the discovery of molecular biomarkers in glioma not only to aid in targeted therapy but also to prognosticate character of tumor and outcome of a patient.The usually benign nature of pilocytic astrocytoma (PA) can now be challenged with the discovery of genomic alterations that could promote more aggressive clinical behavior. CDKN2A deletion and ATRX gene inactivation or mutation have been the most common molecular alterations in worse prognosis.We will discuss a case of pilocytic astrocytoma showing the progressive recurrence with pilomyxoid features and the presence of TERT promoter mutation.

Current Clinical Practice About Pediatric Midline Gliomas in the Scope of Molecular Era.

AIM: To share our clinical experience with surgical and adjuvant treatment strategies followed during the treatment of midline gliomas. MATERIAL AND METHODS: Pediatric patients with midline gliomas who underwent surgery in our clinic between March 2016 and November 2019 were included. Tissue samples were obtained through surgical excision, open biopsy, or stereotactic biopsy. All samples were analyzed for ATRX, BRAFV600E, IDH1/2, H3K27M, and H3G34R mutations, EGFR and PGFRA amplifications, and PTEN loss. RESULTS: There were 7 (43.8%) female and 9 (56.2%) male pediatric patients in the study. Eight patients had thalamic, 5 patients had pontine, 2 patients had medulla oblongata and one patient had brachium pontis tumors. Presenting symptoms were headache, disequilibrium, ophthalmoplegia, and panic attack. Eleven tumors showed H3K27M mutation and were diagnosed as diffuse midline gliomas. BRAFV600E, ATRX mutations, PTEN loss, and EGFR amplifications were other molecular alterations detected within tumor samples. Patients with H3K27M mutant tumors had a shorter life span. Five patients were enrolled in an ONC201 trial. CONCLUSION: Although most midline gliomas are not amenable to gross total excision, obtaining tissue samples is mandatory for determining patients? exact diagnoses, tailored treatment plans, and eligibility for clinical trials. Stereotactic biopsy for midline gliomas is a safe and effective method.

Is H3K27me3 status really a strong prognostic indicator for pediatric posterior fossa ependymomas? A single surgeon, single center experience.

PURPOSE: Posterior fossa ependymomas (PFE) are among the most frequently occurring solid tumors in children. Their definitive treatment is surgical excision and adjuvant radio-chemotherapy. This study aimed to investigate prognostic effects of age, H3K27me3 status, extent of resection, radiation treatment (RT), Ki67 index, WHO grade, and ATRX and H3K27M mutations in PFE patients. METHODS: This retrospective study included 42 pediatric patients with PFE who had undergone operation at our institution between 1996 and 2018. Patient demographics and treatment information were obtained from patient notes. Information on radiological location of tumors (median vs paramedian), extent of tumor resection, and recurrence was obtained from preoperative and postoperative magnetic resonance imaging. Formalin-fixed paraffin-embedded tumor samples were evaluated for H3K27me3 immunostaining, Ki67 index, WHO grades, and ATRX and H3K27M mutations. Tumor samples with global reduction in H3K27me3 were grouped as posterior fossa ependymoma group A (PFA) and those with H3K27me3 nuclear immunopositivity as posterior fossa ependymoma group B (PFB). We evaluated the cohort's 5-year progression-free survival (PFS) and overall survival (OS). RESULTS: There were 20 (47.6%) female and 22 (52.4%) male patients in the cohort. The mean age of patients was 4.4 (range, 0.71-14.51) years. Overall, tumors in 31 (73.8%) and 11 (26.2%) patients were found to be PFA and PFB, respectively. There was no statistically significant age or sex difference between PFA and PFB. All patients received chemotherapy, whereas only 28 (66.6%) received RT. The WHO grades of PFA were statistically higher than those of PFB. There was no significant difference between PFA and PFB in terms of extent of resection, disease recurrence, and survival parameters. Nine of 42 tumor samples had ATRX mutations. One patient with PFA showed H3K27M mutation. Age, WHO grade, H3K27me3 status, and RT had no effect on patients' PFS and OS. Patients with total surgical excisions had significantly better PFS and OS rates. Those with Ki67 < 50% also had better OS rates. CONCLUSIONS: Determining H3K27me3 status by immunohistochemistry is a widely accepted method for molecular subgrouping of PFEs. Most of the reports in the literature state that molecular subgroups of PFEs have significantly different clinical outcomes. However, in our present series, we have shown that the extent of surgical excision is still the most important prognostic indicator in PFEs. We also conclude that the prognostic effect of H3K27me3 status-based molecular subgrouping may be minimized with a more aggressive surgical strategy followed in PFAs.

Changes in Callosal Angle After Successful Endoscopic Third Ventriculostomy Procedure in Pediatric Patients.

AIM: To determine whether callosal angle (CA) measurement, a diagnostic and prognostic tool used for normal-pressure hydrocephalus in adults, is a reliable radiological parameter for evaluating endoscopic third ventriculostomy (ETV) outcomes in pediatric patients. MATERIAL AND METHODS: Forty-seven pediatric patients with hydrocephalus who underwent successful ETV in our clinic between 2011 and 2015 were included in this study. Preoperative and postoperative three-month CA, lateral ventricle frontal horn (LVFH) width, Evans' index (EI), and frontal-occipital horn ratio (FOR) parameters were recorded, with changes analyzed using a paired-samples t-test. RESULTS: There were 29 male and 18 female patients included within the cohort. For mean preoperative values, LVFH width was 58.8 ± 14.9 mm, EI was 0.43 ± 0.09, FOR was 0.51 ± 0.74, and CA was 78.5° ± 36.4°. Separately, for mean postoperative values, LVFH width was 54 ± 14.2 mm, EI was 0.39 ± 0.09, FOR was 0.47 ± 0.07, and CA was 104.5° ± 32.6°. The CA was increased and the LVFH width, EI, and FOR were decreased in all patients within three months after surgery. The postoperative three-month change in CA was higher than those observed in the other parameters. CONCLUSION: Changes in CA after successful ETV were dramatically higher than those in the other ventricular parameters. For this reason, we suggest CA be used as a radiological criterion during early radiological follow-up of patients after ETV.

Management of mature pineal region teratomas in pediatric age group.

PURPOSE: Mature pineal region teratomas differ from other pineal tumors in terms of their characteristic radiological appearance and their clinical outcome after gross total excision. Our aim is to share our clinical experience and treatment outcomes in pediatric patients with mature pineal region teratoma. METHODS: In this retrospective study, we reviewed clinical, radiological, and surgical data of ten patients who had radiologically predicted diagnosis of pineal region teratoma and pathologically confirmed diagnosis of mature pineal region teratoma between years 2004 and 2017 in our clinic. Statistical analysis was performed with SPSS 20. RESULTS: All patients were male. Ages of patients ranged between 5 and 17 (median age was 9.5). All of them presented with headache. Magnetic resonance imaging showed characteristic appearance of teratomas with variable degree of hydrocephalus. All patients had negative results for AFP and b-HCG levels. All patients had gross total resection of pineal tumor through occipital transtentorial approach with no permanent neurological deficit. Pathological results of all tumor samples were consistent with mature teratoma. None of them had adjuvant chemotherapy or radiotherapy. Follow-up periods ranged between 3 and 170 months (median follow-up period was 60.5 months). All patients are alive with no tumor recurrence. CONCLUSIONS: Pediatric mature pineal region teratomas are benign tumors with characteristic MRI appearance and negative tumor markers. Their definitive treatment is gross total surgical excision. Occipital transtentorial approach is a safe procedure for treatment of pediatric mature pineal teratomas.

In Vitro Effects of Mesenchymal Stem Cells and Various Agents on Apoptosis of Glioblastoma Cells.

AIM: To investigate a new anti-tumor treatment method using stem cells transfected with specific genes and proteins that induce apoptosis in tumor cells. MATERIAL AND METHODS: We used glioblastoma (GBM) cells and human adipose tissue-derived mesenchymal stem cells (ADMSCs) in this study. The AD-MSCs were transfected with the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). To overcome apoptosis resistance in tumor cells, we used suberoylanilide hydroxamic acid (SAHA) as the histone deacetylase inhibitor and embelin as the X-linked inhibitor of apoptosis protein (XIAP). In addition, we silenced the XIAP gene on GBM cells with the shXIAP plasmid. Following the determination of half-maximal effective concentration (EC50%) doses of SAHA and embelin, GBM cells were incubated with them for 24 hours. XIAP-silenced and XIAP-non-silenced GBM cells were cultured with TRAIL-nontransfected and TRAIL-transfected stem cells for 24 hours. Viability and cell cycle analysis of all groups were determined using annexin V/propidium iodide and cell cycle method via flow cytometry. RESULTS: TRAIL-transfected AD-MSCs, XIAP silencing, embelin, and SAHA induced apoptosis in GBM cells and decreased their proliferation, whereas TRAIL-non-tranfected AD-MSCs did not. CONCLUSION: Engineered stem cell therapies and molecular studies show promise in developing combination therapies for effective treatment of GBM.

Acute Obstructive Hydrocephalus due to a Giant Posterior Cerebral Artery Aneurysm in a Pediatric Patient.

INTRODUCTION: Intracranial aneurysms are very rare in children. Although subarachnoidal hemorrhage (SAH) is by far the most common presentation of aneurysms in the majority of the pediatric case series, it is not rare for an unruptured aneurysm to present with a mass effect. Acute hydrocephalus is a common finding following aneurysmal SAH. However, this malady may develop even in the absence of SAH but secondary to direct obstruction by a giant aneurysm. This situation is extremely rare in children, with only a few known case reports in the literature. CASE REPORT: We report the case of a 10-year-old girl who presented with signs and symptoms of acute hydrocephalus; further radiological evaluation revealed obstructive hydrocephalus and a giant posterior cerebral artery aneurysm. Following endovascular treatment of the aneurysm, hydrocephalus was completely resolved, and the patient was symptom free. CONCLUSION: Although they are very rare, giant intracranial aneurysms must be kept in mind during the differential diagnosis of pediatric acute hydrocephalus cases. Hydrocephalus may resolve spontaneously after the successful treatment of these aneurysms.

Malignant triton tumor of trigeminal nerve-case report.

INTRODUCTION: Here we are presenting a unique case of malignant triton tumor of the trigeminal nerve in a 4-year-old boy who presented with diplopia and ptosis. INTERVENTION: Near total excision of the tumor was performed, and adjuvant chemotherapy and radiotherapy were administered. RESULTS: The patient is in good health and has no evidence of clinical and radiological tumor recurrence for 22  months.

Hypothalamic hamartoma presenting with infantile spasms.

BACKGROUND: Hypothalamic hamartomas (HH) generally present with gelastic seizures. It is very unusual for a pediatric patient with HH to present with infantile spasms (IS). CASE PRESENTATION: Here we present a 6-month-old boy diagnosed with IS whose brain magnetic resonance imaging (MRI) showed an 18 × 18 × 16 mm mass in the hypothalamus. His seizures did not respond to antiepileptic treatment with vigabatrin and valproic acid. He had disconnective surgery for HH. Immediately postoperatively, his seizures subsided and he has now been seizure-free for 2 years. CONCLUSION: Although hypothalamic hamartomas generally present with gelastic seizures, they should also be considered in the differential diagnosis of infantile spasms.

Diffusion tensor imaging of cervical spinal cord: A quantitative diagnostic tool in cervical spondylotic myelopathy.

BACKGROUND: Diffusion tensor imaging (DTI) is a novel magnetic resonance imaging (MRI) technique potentially able to evaluate the microscopic structural organization of white matter fibers. AIM: This study aimed to compare fractional anisotropy (FA) and apparent diffusion coefficient (ADC) values obtained by DTI in stenotic versus nonstenotic cervical spinal segments of patients with clinical and neurological evidence of cervical spondylotic myelopathy (CSM). MATERIALS AND METHODS: This prospective study included 21 patients with CSM but without T2 changes on conventional MRI. Diffusion tensor (DT) images from the stenotic and nonstenotic segments of the subjects were obtained. FA and ADC values were estimated and compared with stenotic versus nonstenotic segments. STATISTICAL ANALYSIS: Paired t-test was used [Statistical Package for the Social Sciences (SPSS) 12.0]. RESULTS: In the most stenotic segments, the mean FA value was significantly lower (0.4228 ± 0.1090 vs 0.6884 ± 0.0075, P < 0.001) and the mean ADC value was significantly higher (1.312 ± 0.2405 vs 0.9183 ± 0.1477, P < 0.001) when compared to nonstenotic segments. In addition, there was a negative correlation between FA and ADC values (r = 0.63, P = 0.002). CONCLUSIONS: DTI of the cervical spine seems to be a promising novel imaging modality in patients with CSM. ADVANCES IN KNOWLEDGE: DTI may offer increased diagnostic sensitivity as compared to standard MRI and enables earlier detection of the disease.

Hereditary spastic paraplegia with recessive trait caused by mutation in KLC4 gene.

We report an association between a new causative gene and spastic paraplegia, which is a genetically heterogeneous disorder. Clinical phenotyping of one consanguineous family followed by combined homozygosity mapping and whole-exome sequencing analysis. Three patients from the same family shared common features of progressive complicated spastic paraplegia. They shared a single homozygous stretch area on chromosome 6. Whole-exome sequencing revealed a homozygous mutation (c.853_871del19) in the gene coding the kinesin light chain 4 protein (KLC4). Meanwhile, the unaffected parents and two siblings were heterozygous and one sibling was homozygous wild type. The 19 bp deletion in exon 6 generates a stop codon and thus a truncated messenger RNA and protein. The association of a KLC4 mutation with spastic paraplegia identifies a new locus for the disease.

Deep brain stimulation as treatment for dystonic storm in pantothenate kinase-associated neurodegeneration syndrome: case report of a patient with homozygous C.628 2 T > G mutation of the PANK2 gene.

Pantothenate kinase-associated neurodegeneration (PKAN) syndrome is an autosomal-recessive neurodegenerative disease that causes progressive generalized dystonia. Currently, the disorder remains pharmacologically intractable. Herein we report the first case in which deep brain stimulation helped to relieve dystonic storm in a patient with PKAN syndrome who had homozygous c.628 2 T > G mutation of the PANK2 gene. A 10-year-old boy with PKAN disease presented with dystonic storm and was admitted to the emergency department. Examination revealed generalized dystonia and impaired breathing due to involvement of the respiratory muscles. The patient underwent surgery for bilateral globus pallidus internus deep brain stimulation. The patient showed marked response to treatment.

Neural tube defect family with recessive trait linked to chromosome 9q21.12-21.31.

PURPOSE: Meningomyelocele is one of the most common and socioeconomically, psychologically, and physically debilitating neurodevelopmental diseases. A few chromosomal locus and genes have been identified as responsible for the disease; however, clear evidence still needs to be produced. This study aimed to show evidence of a strong genetic linkage in a novel chromosomal locus in a family with this neural tube defect. METHODS: We identified a neural tube defect family in eastern Turkey, where two of six offspring had operations due to thoracolumbar meningomyelocele. The parents were of a consanguineous marriage. We collected venous blood from six offspring of the family. Whole genome linkage analysis was performed in all offspring. RESULTS: A theoretical maximum logarithm of an odds score of 3.16 was identified on chromosome 9q21.12-21.31. This result shows a strong genetic linkage to this locus. CONCLUSIONS: Our results identified a novel chromosomal locus related to meningomyelocele and provide a base for further investigations toward the discovery of a new causative gene.

Accessory lower limb associated with spina bifida: case report.

PURPOSE: Heterotopic redundancies, such as an accessory limb associated with spina bifida, are extremely rare anomalies. There are 12 cases of accessory limb associated with spinal bifida in literature. This report aims a detailed description of the additional case and an analysis of the findings in light. METHODS: A male baby was born at 40 weeks of gestation and was referred to the neurosurgery clinic with a diagnosis of accessory lower limb. On physical examination, the dorsal meningocele was located at the lumbosacral region and there was accessory lower limb on it. There was no open neural placode. RESULTS: The accessory limb was excised on postnatal day 3. CONCLUSIONS: Dysraphic appendages are rare and complicated anomalies. They should be investigated carefully, and all of the lesions must be repaired for babies' quality of life.

Bubble over the head: Adeloye-Odeku disease in a Turkish child-case report.

Adeloye-Odeku disease is composed of dermoid cyst over anterior fontanelle, first described in 1971. We present an 11-year-old girl with a soft, fluctuant swelling over bregma. The lesion content was isointense to cerebrospinal fluid on both T2W and FLAIRW images. There was a lytic area under the lesion, seen on CT. The lesion was totally excised. Histopathology confirmed the diagnosis. The case was unique; because a fibrous band was observed extending to superior sagittal sinus and it has never been reported before. Although lesions are sub-aponeurotic, because of this kind of fibrous band, a thorough examination with neuroimaging tools is very important for planning of surgery.