Prevalence and Severity of Positional Posterior Plagiocephaly and Positional Posterior Brachycephaly in Children and Adolescents in Japan.

This study aimed to assess the prevalence, severity, and natural history of positional posterior plagiocephaly (PPP) and positional posterior brachycephaly in Japan. We conducted a cross-sectional study of pediatric patients, ranging from 0 to 15 years old, evaluated for head trauma with negative computed tomography (CT) findings. The cranial vault asymmetry index (CVAI) was calculated using CT images at the superior orbital rim. Asymmetry according to CVAI values was subcategorized as follows: mild (3.5%-7%), moderate (7%-12%), and severe (>12%). The results were analyzed according to different age groups: group 1, 2-23 months (54 patients); group 2, 2-6 years (123 patients); and group 3, 7-15 years (123 patients). Overall, 300 patients were included (109 [36.3%] girls and 191 [63.7%] boys). The overall prevalence of PPP in the 300 patients was 46.7% (140 patients). PPP prevalence decreased consistently with age group: group 1, 57.4%; group 2, 47.2%; and group 3, 41.5%. Severe asymmetry was seen in all age groups. The overall mean cephalic index (CI) was 85.2. Cephalic index scores decreased consistently with age: group 1, 87.4; group 2, 85.1; and group 3, 84.3. The prevalence of PPP in Japan was higher than that reported in other countries. Although there was an overall decrease in the prevalence and severity of PPP with increasing patient age, PPP does not necessarily resolve spontaneously in all children. Furthermore, severe asymmetry was seen across all age groups.

Duraplasty using a combination of a pedicled dural flap and collagen matrix in posterior fossa decompression for pediatric Chiari malformation type 1 with syrinx.

PURPOSE: In posterior fossa decompression for pediatric Chiari malformation type 1 (CM-1), duraplasty methods using various dural substitutes have been reported to improve surgical outcomes and minimize postoperative complications. To obtain sufficient posterior fossa decompression without cerebrospinal fluid-related complications, we developed a novel duraplasty technique using a combination of a pedicled dural flap and collagen matrix. The objective of this study was to describe the operative nuances of duraplasty using a combination of a pedicled dural flap and collagen matrix in posterior fossa decompression for pediatric CM-1. METHODS: We reviewed the clinical and radiographic records of 11 consecutive pediatric patients who underwent posterior fossa decompression with duraplasty using a combination of a pedicled dural flap and collagen matrix followed by expansile cranioplasty for CM-1. The largest area of the syrinx and the size of the posterior fossa were calculated. RESULTS: The maximum syrinx area was reduced by a mean of 68.5% ± 27.3% from preoperatively to postoperatively. Four patients (36.4%) had near-complete syrinx resolution (> 90%, grade III reduction), five (45.5%) had 50% to 90% reduction (grade II), and two (18.2%) had < 50% reduction (grade I). The posterior fossa area in the midsagittal section increased by 8.9% from preoperatively to postoperatively. There were no postoperative complications, including cerebrospinal fluid leakage, pseudomeningocele formation, or infection. CONCLUSION: Duraplasty using a combination of a pedicled dural flap and collagen matrix in posterior fossa decompression is a promising safe and effective surgical technique for pediatric CM-1 with syrinx.

Comparison of passive-scattered and intensity-modulated proton beam therapy of craniospinal irradiation with proton beams for pediatric and young adult patients with brain tumors.

PURPOSE: To investigate the dose stability of craniospinal irradiation based on irradiation method of proton beam therapy (PBT). METHODS AND MATERIALS: Twenty-four pediatric and young adult brain tumor patients (age: 1-24 years) were examined. Treatment method was passive-scattered PBT (PSPT) in 8 patients and intensity-modulated PBT (IMPT) in 16 patients. The whole vertebral body (WVB) technique was used in 13 patients whose ages were younger than 10, and vertebral body sparing (VBS) technique was used for the remaining 11 patients aged 10 and above. Dose stability of planning target volume (PTV) against set-up error was investigated. RESULTS: The minimum dose (Dmin) of IMPT was higher than that of PSPT (p = 0.01). Inhomogeneity index (INH) of IMPT was lower than that of PSPT (p = 0.004). When the irradiation field of the cervical spinal cord level (C level) was shifted, the maximum dose (Dmax) was lower in IMPT, and mean dose (Dmean) was higher than PSPT as movement became greater to the cranial-caudal direction (p = 0.000-0.043). Dmin was higher and INH was lower in IMPT in all directions (p = 0.000-0.034). When the irradiation field of the lumber spinal cord level (L level) was shifted, Dmax was lower in IMPT as movement became greater to the cranial direction (p = 0.000-0.028). Dmin was higher and INH was lower in IMPT in all directions (p = 0.000-0.022). CONCLUSIONS: The PTV doses of IMPT and PSPT are robust and stable in both anterior-posterior and lateral directions at both C level and L level, but IMPT is more robust and stable than PSPT for cranial-caudal movements. TRIAL REGISTRY: Clinical Trial Registration number: No. 04-03.

Subtyping of Group 3/4 medulloblastoma as a potential prognostic biomarker among patients treated with reduced dose of craniospinal irradiation: a Japanese Pediatric Molecular Neuro-Oncology Group study.

BACKGROUND: One of the most significant challenges in patients with medulloblastoma is reducing the dose of craniospinal irradiation (CSI) to minimize neurological sequelae in survivors. Molecular characterization of patients receiving lower than standard dose of CSI therapy is important to facilitate further reduction of treatment burden. METHODS: We conducted DNA methylation analysis using an Illumina Methylation EPIC array to investigate molecular prognostic markers in 38 patients with medulloblastoma who were registered in the Japan Pediatric Molecular Neuro-Oncology Group and treated with reduced-dose CSI. RESULTS: Among the patients, 23 were classified as having a standard-risk and 15 as high-risk according to the classic classification based on tumor resection rate and presence of metastasis, respectively. The median follow-up period was 71.5 months (12.0-231.0). The median CSI dose was 18 Gy (15.0-24.0) in both groups, and 5 patients in the high-risk group received a CSI dose of 18.0 Gy. Molecular subgrouping revealed that the standard-risk cohort included 5 WNT, 2 SHH, and 16 Group 3/4 cases; all 15 patients in the high-risk cohort had Group 3/4 medulloblastoma. Among the patients with Group 3/4 medulloblastoma, 9 of the 31 Group 3/4 cases were subclassified as subclass II, III, and V, which were known to an association with poor prognosis according to the novel subtyping among the subgroups. Patients with poor prognostic subtype showed worse prognosis than that of others (5-year progression survival rate 90.4% vs. 22.2%; p < 0.0001). The result was replicated in the multivariate analysis (hazard ratio12.77, 95% confidence interval for hazard ratio 2.38-99.21, p value 0.0026 for progression-free survival, hazard ratio 5.02, 95% confidence interval for hazard ratio 1.03-29.11, p value 0.044 for overall survival). CONCLUSION: Although these findings require validation in a larger cohort, the present findings suggest that novel subtyping of Group 3/4 medulloblastoma may be a promising prognostic biomarker even among patients treated with lower-dose CSI than standard treatment.

Comparison of Craniospinal Irradiation Using Proton Beams According to Irradiation Method and Initial Experience Treating Pediatric Patients.

Purpose: This study compared craniospinal irradiation using proton beam therapy (PBT) according to irradiation method and investigated the initial effects. Methods and Materials: Twenty-four pediatric patients (1-24 years old) who received proton craniospinal irradiation were examined. Passive scattered PBT (PSPT) and intensity modulated PBT (IMPT) were used in 8 and 16 patients, respectively. The whole vertebral body technique was used for 13 patients <10 years old, and the vertebral body sparing (VBS) technique was used for the remaining 11 patients aged ≥10 years. The follow-up period was 17 to 44 (median, 27) months. Organ-at-risk and planning target volume (PTV) doses and other clinical data were examined. Results: The maximum lens dose using IMPT was lower than that using PSPT (P = .008). The mean thyroid, lung, esophagus, and kidney doses were lower in patients treated using the VBS technique compared with the whole vertebral body technique (all P < .001). The minimum PTV dose of IMPT was higher than that of PSPT (P = .01). The inhomogeneity index of IMPT was lower than that of PSPT (P = .004). Conclusions: IMPT is better than PSPT at reducing the dose to the lens. The VBS technique can decrease the doses to neck-chest-abdomen organs. The PTV coverage of IMPT is superior to that of PSPT.

Pediatric intraparenchymal meningioma in the basal ganglia treated with gross total resection: a case report and review of the literature.

INTRODUCTION: Intraparenchymal meningiomas in the basal ganglia are extremely rare, and to the best of our knowledge, only three case reports have been published to date. Owing to concerns regarding major vessels, gross total resection (GTR) is difficult to achieve; therefore, subtotal resection and radiation therapy are often chosen as treatment options. We present a pediatric case with an intraparenchymal meningioma in the left basal ganglia that was successfully treated with GTR. We also reviewed the relevant literature to discuss the pathogenesis, radiological findings, and treatment methods of this rare disease. CASE REPORT: A 4-year-old girl presented with progressive right facial paralysis, aphasia, and right incomplete hemiplegia. Imaging revealed a mass lesion in the left basal ganglia and unilateral obstructive hydrocephalus. Neuroendoscopic septostomy, tumor biopsy, and cerebrospinal fluid reservoir placement were performed, and the initial pathological diagnosis was suspected glioma. Thus, craniotomy was performed to remove the tumor, which was white, elastic, and well-defined. Intraoperative rapid pathology revealed a meningioma. Postoperatively, the patient experienced transient worsening of the right incomplete hemiplegia, which subsequently improved. The final pathological diagnosis was a fibrous meningioma. CONCLUSION: Surgery for intraparenchymal meningiomas in the basal ganglia is challenging owing to the proximity of major blood vessels; however, GTR may be preferable to subtotal resection, considering the possibility of recurrence. Even in cases of intraparenchymal tumors, it is important to consider meningioma as a differential diagnosis and to carefully plan the appropriate treatment.

Epidural Spinal Cord Compression as the Presenting Manifestation of Acute Myeloid Leukemia: A Case Report and Literature Review.

We herein report a rare case of spinal cord compression due to epidural involvement of acute myeloid leukemia (AML). A 14-year-old boy presented with a 7-day history of back pain, paraplegia and hypoesthesia. Contrast-enhanced computed tomography revealed an epidural mass. Emergency laminectomy and resection of the mass were performed. Histopathologically, the resected mass was comparable to an extramedullary mass of AML. Chemotherapy was initiated, and complete remission was achieved. Neurological sequelae remained after the treatment. Based on the present and previous reports, spinal cord compression from epidural AML involvement may progress rapidly.

A common deletion at BAK1 reduces enhancer activity and confers risk of intracranial germ cell tumors.

Intracranial germ cell tumors (IGCTs) are rare brain neoplasms that mainly occur in children and adolescents with a particularly high incidence in East Asian populations. Here, we conduct a genome-wide association study (GWAS) of 133 patients with IGCTs and 762 controls of Japanese ancestry. A common 4-bp deletion polymorphism in an enhancer adjacent to BAK1 is significantly associated with the disease risk (rs3831846; P = 2.4 × 10-9, odds ratio = 2.46 [95% CI: 1.83-3.31], minor allele frequency = 0.43). Rs3831846 is in strong linkage disequilibrium with a testicular GCTs susceptibility variant rs210138. In-vitro reporter assays reveal rs3831846 to be a functional variant attenuating the enhancer activity, suggesting its contribution to IGCTs predisposition through altering BAK1 expression. Risk alleles of testicular GCTs derived from the European GWAS show significant positive correlations in the effect sizes with the Japanese IGCTs GWAS (P = 1.3 × 10-4, Spearman's ρ = 0.48). These results suggest the shared genetic susceptibility of GCTs beyond ethnicity and primary sites.

Repair of refractory postoperative cerebrospinal fluid leakage using a reversed dermis flap in a pediatric lipomyelomeningocele patient.

INTRODUCTION: Cerebrospinal fluid (CSF) leak and pseudomeningocele are common complications after surgery for spinal dysraphism. CASE REPORT AND TECHNIQUE: We report a 6-month-old girl with a lumbosacral lipomyelomeningocele and accessory lower limb who developed a refractory cerebrospinal fluid leak and pseudomeningocele after lipomyelomeningocele repair and removal of the accessory limb. The pseudomeningocele was successfully repaired using a reversed dermis flap made from excess skin that covered the meningocele. CONCLUSION: This technique can be performed without using synthetic material or an additional surgical incision.

The comparison of acute toxicities associated with craniospinal irradiation between photon beam therapy and proton beam therapy in children with brain tumors.

INTRODUCTION: This study aimed to evaluate acute toxicities associated with irradiation between the X-CSI (photon beam craniospinal irradiation) and P-CSI (proton beam craniospinal irradiation) groups in children with brain tumors. METHODS: Sixty-two consecutive patients who received initial craniospinal irradiation (CSI) for brain tumors in our center between January 1, 2011 and May 31, 2021, were included in the study. Acute toxicities were retrospectively evaluated during CSI using Common Terminology Criteria for Adverse Events version 5.0. Maximum grades of fatigue, headache, insomnia, nausea, vomiting, dermatitis, constipation, abdominal pain, oropharyngeal mucositis, and hematological toxicities were evaluated. RESULTS: Thirty-six patients received X-CSI, and 26 patients received P-CSI. The median dose of CSI was 18.0 Gy in the X-CSI group and 23.4 Gy (relative biological effectiveness) in the P-CSI group (p < 0.001). The P-CSI group had a lower incidence of more than grade 2 nausea (11.5% vs. 69.4%, p = 0.008) and vomiting (7.7% vs. 38.8%, p < 0.001), compared with the X-CSI group. Multivariate logistic regression analysis with adjustments for potential confounding factors of doses of CSI showed that proton radiation therapy was associated with a marked reduced risk of more than grade 2 nausea and vomiting during CSI (adjusted odds ratio, 0.050; 95% confidential interval, 0.011-0.24; p < 0.001). CONCLUSION: The present study suggests that P-CSI reduces the acute gastrointestinal toxicities associated with irradiation.

Poorly Differentiated Chordoma of the Clivus With Loss of SMARCB1 Expression in a Pediatric Patient: A Case Report.

Poorly differentiated chordoma (PDC) is a rare, aggressive subtype of chordoma. A two-year-old girl presented with cervical pain, limb paralysis and respiratory failure. Magnetic resonance imaging and positron emission tomography-computed tomography revealed a tumor compressing the pons at the clivus and osteoblastic metastatic lesions of the left upper arm and right iliac bone. Her tumors shrank substantially after treatment with chemotherapy and proton beam therapy. Our initial diagnosis was an atypical teratoma/rhabdoid tumor, but final diagnosis of PDC was made on the basis of the immunohistochemical expression of brachyury. In addition, the detection of SMARCB1/INI1 mutation confirmed the diagnosis of PDC.

Proton beam therapy for children and adolescents and young adults (AYAs): JASTRO and JSPHO Guidelines.

Children and adolescents and young adults (AYAs) with cancer are often treated with a multidisciplinary approach. This includes use of radiotherapy, which is important for local control, but may also cause adverse events in the long term, including second cancer. The risks for limited growth and development, endocrine dysfunction, reduced fertility and second cancer in children and AYAs are reduced by proton beam therapy (PBT), which has a dose distribution that decreases irradiation of normal organs while still targeting the tumor. To define the outcomes and characteristics of PBT in cancer treatment in pediatric and AYA patients, this document was developed by the Japanese Society for Radiation Oncology (JASTRO) and the Japanese Society of Pediatric Hematology/Oncology (JSPHO).

Pediatric takotsubo syndrome caused by hydrocephalus after posterior fossa tumor surgery.

Takotsubo syndrome (TTS) can develop after intense physical or emotional stress and is uncommon in children. We report a 2-year-old girl who developed TTS caused by acute hydrocephalus after posterior fossa tumor resection and required mechanical ventilation and administration of vasopressor/inotropic agents. Her cardiac function gradually recovered over the course of 2 weeks. Hydrocephalus after posterior fossa surgery can cause compression of the medulla oblongata, resulting in solitary nucleus dysfunction and TTS, a potentially life-threatening complication.

CNS Low-grade Diffusely Infiltrative Tumors With INI1 Deficiency, Possessing a High Propensity to Progress to Secondary INI1-deficient Rhabdoid Tumors.

Atypical teratoid/rhabdoid tumors (AT/RTs) are highly malignant tumors of the central nervous system that predominantly occur in infants, and are characterized by the presence of rhabdoid cells and inactivation of INI1 or (rarely) BRG1. Most AT/RT are identified as primary tumors; however, rare AT/RT or INI1-deficient RTs arising from other primary tumors have been reported. Here, we report 3 cases of hitherto unclassifiable low-grade tumors with loss of INI1 nuclear expression, for which we propose the designation of central nervous system low-grade diffusely infiltrative tumors with INI1 deficiency (CNS LGDIT-INI1), 2 of which progressed to secondary RT. All 3 CNS LGDIT-INI1 exhibited a similar histology: diffusely distributed small tumor cells with round to oval or irregular nuclei and scant cytoplasm were admixed with degenerative neurons and large reactive astrocytes in an edematous, myxoid, or collagenous background. Mitotic figures were absent. Immunohistochemistry revealed that the tumor cells in all 3 CNS LGDIT-INI1 and 2 RT were negative for INI1. Genetically, total or partial homozygous deletions of the INI1 gene were detected in all CNS LGDIT-INI1 and RT excluding 1 CNS LGDIT-INI1 without sufficient DNA quality and quantity. Despite the loss of INI1 expression, these low-grade lesions were clearly distinguishable from AT/RT by their low proliferative activity, diffusely infiltrative growth pattern, and lack of rhabdoid cells and polyphenotypic immunoreactivity. In conclusion, CNS LGDIT-INI1 may represent a rare group of tumors that are clinically indolent but have a high propensity to progress to RT.

Management and problems of prolonged survival with hydranencephaly in the modern treatment era.

PURPOSE: Hydranencephaly is a rare condition that occurs during embryogenesis after neurogenesis and is characterized by the near complete absence of the cerebral hemispheres. In general, patients with hydranencephaly have been considered to have a markedly reduced life expectancy. We present 4 patients with hydranencephaly who have survived for over 5 years. The management and problems encountered in these cases are discussed. METHODS: A retrospective review was conducted at our institution. Medical charts and radiographic studies were reviewed. Data including age at follow-up, sex, clinical complications, and surgical procedures were recorded. RESULTS: Six patients were radiologically diagnosed with hydranencephaly during the period from January 2000 to December 2012. Two patients were excluded from our study: one because of death from pneumonia at 1 year of age and another because of transfer to another hospital. Four patients (3 males and 1 female) were included in the analysis. All 4 patients underwent ventriculoperitoneal shunt (VPS) placement and shunt revision. VPS infection occurred in 3 of 4 cases, and bloody cerebrospinal fluid (CSF) was observed in 2 of 4 cases. One patient underwent successful choroid plexus cauterization (CPC) and shunt removal after shunt infection. CONCLUSIONS: Prolonged survival with hydranencephaly is not unusual in the modern treatment era. CSF shunt problems, such as recurring shunt malfunction and shunt infection, represent one of the major problems, and avoiding CSF shunt with CPC is particularly desirable in patients with hydranencephaly.

Microsurgical confirmation of parenchymal contamination of hair in a pediatric patient with a penetrating head injury.

Penetrating head injuries are rare, but can cause severe morbidity in children. In particular, penetrating head trauma with a wooden foreign body is considered to be likely to cause central nervous system infections because of its porosity and softness. However, actually confirming minute contaminations, such as skin debris or hair, in the brain parenchyma is rare. We report the case of a 2-year-old boy who presented with a penetrating head injury by a chopstick. During surgical removal of the chopstick, intraparenchymal hair contamination was confirmed under a surgical microscope. The postoperative course of the patient was uneventful. After 13 months of follow-up without any infectious events, the patient remains well and asymptomatic. The findings in the present case demonstrate that in the case of a penetrating head trauma with a wooden foreign body, surgical removal and active debridement should be the treatment of first choice.

Presacral malignant teratoid neoplasm in association with pathogenic DICER1 variation.

We report two malignant sacrococcygeal tumors in infants that were associated with pathogenic DICER1 variation. These tumors were composed of primitive neuroepithelium, embryonal rhabdomyosarcoma, and cartilage and initially diagnosed as immature teratomas. One child developed intracranial metastasis and died. The second child underwent surgery and chemotherapy and achieved complete remission. This child subsequently developed five additional DICER1-associated neoplasms by age nine. Genetic analysis revealed that both tumors harbored biallelic pathogenic DICER1 variation. We believe these cases represent another novel subtype of DICER1-associated tumor. This new entity, which we propose to call DICER1-associated presacral malignant teratoid neoplasm, may be difficult initially to distinguish from immature teratoma, but recognizing it as an entity can prompt appropriate classification as an aggressive malignancy and facilitate appropriate genetic counseling, DICER1 germline variant testing, screening, and education.

Significance of molecular classification of ependymomas: C11orf95-RELA fusion-negative supratentorial ependymomas are a heterogeneous group of tumors.

Extensive molecular analyses of ependymal tumors have revealed that supratentorial and posterior fossa ependymomas have distinct molecular profiles and are likely to be different diseases. The presence of C11orf95-RELA fusion genes in a subset of supratentorial ependymomas (ST-EPN) indicated the existence of molecular subgroups. However, the pathogenesis of RELA fusion-negative ependymomas remains elusive. To investigate the molecular pathogenesis of these tumors and validate the molecular classification of ependymal tumors, we conducted thorough molecular analyses of 113 locally diagnosed ependymal tumors from 107 patients in the Japan Pediatric Molecular Neuro-Oncology Group. All tumors were histopathologically reviewed and 12 tumors were re-classified as non-ependymomas. A combination of RT-PCR, FISH, and RNA sequencing identified RELA fusion in 19 of 29 histologically verified ST-EPN cases, whereas another case was diagnosed as ependymoma RELA fusion-positive via the methylation classifier (68.9%). Among the 9 RELA fusion-negative ST-EPN cases, either the YAP1 fusion, BCOR tandem duplication, EP300-BCORL1 fusion, or FOXO1-STK24 fusion was detected in single cases. Methylation classification did not identify a consistent molecular class within this group. Genome-wide methylation profiling successfully sub-classified posterior fossa ependymoma (PF-EPN) into PF-EPN-A (PFA) and PF-EPN-B (PFB). A multivariate analysis using Cox regression confirmed that PFA was the sole molecular marker which was independently associated with patient survival. A clinically applicable pyrosequencing assay was developed to determine the PFB subgroup with 100% specificity using the methylation status of 3 genes, CRIP1, DRD4 and LBX2. Our results emphasized the significance of molecular classification in the diagnosis of ependymomas. RELA fusion-negative ST-EPN appear to be a heterogeneous group of tumors that do not fall into any of the existing molecular subgroups and are unlikely to form a single category.

Endoscopic third ventriculostomy for hydrocephalus in osteopetrosis: a case report and review of the literature.

INTRODUCTION: There are very few reports in the literature associating in hydrocephalus in osteopetrosis. As a complication of shunt procedure, there are two reports on shunt malfunction due to osseous overgrowth at the burr hole in patients with osteopetrosis. We herein report a case of osteopetrosis with hydrocephalus that was successfully treated with endoscopic third ventriculostomy (ETV). CASE REPORT: At 5 months of age, a male patient presented with developmental delay. Head computed tomography (CT) demonstrated triventricular hydrocephalus with a cerebellar tonsillar herniation. At 7 months of age, he underwent suboccipital decompression with decompression of the foramen magnum. The hydrocephalus did not improve postoperatively, and the patient was transferred to our hospital. At 12 months of age, the hydrocephalus was successfully treated with ETV. The postoperative period was uneventful. Postoperative CT demonstrated an improvement in the ventricle size. CONCLUSIONS: The etiology of hydrocephalus in osteopetrosis is not completely understood; however, there have been several reports in which ETV was effective. ETV should be considered the treatment of choice for hydrocephalus in osteopetrosis, as it avoids the characteristic shunt complications that can occur in patients with osteopetrosis.