Antiseizure Medications Normalize Electroencephalographic Functional Connectivity and Power in Children With Benign Epilepsy With Centrotemporal Spikes.

BACKGROUND: The decision to treat children with benign epilepsy with centrotemporal spikes (BECTS) using antiseizure medications (ASM) is controversial. Our goal is to compare the effect of ASM treatment on the alteration of electroencephalographic (EEG) functional connectivity and power across four frequency bands in children with BECTS. METHODS: Children with BECTS with two-year follow-up were retrospectively divided into ASM versus non-ASM groups. The network properties of the EEGs as based on network-based statistic and graph theory were evaluated by the following indices: global efficiency, clustering coefficient, betweenness centrality, and nodal strength in four frequency bands (delta, theta, alpha, and beta). EEG power including absolute power (AP) and relative power (RP) was analyzed in four frequency bands. RESULTS: In children with BECTS with ASM treatment, there was no significant change in EEG connectivity across all bands before and after two years of ASM. In children with BECTS without ASM treatment, there was a significant increase of global efficiency, clustering coefficient, and nodal strength but not the betweenness centrality in the delta band after two years of follow-up. A decrease in AP in the delta and theta bands and a decrease in RP in the theta band were found in the ASM group after two years of treatment. CONCLUSIONS: Our results suggest that ASM may play a role in modulating the development of increasing overall brain connectivity and in downregulating overt synaptic activity, but not intrinsic focal connectivity, in the early years of BECTS. The changes in the EEG power indicate that ASM significantly normalized slow-wave band power.

Sporadic pediatric vestibular schwannoma: a case report in a 4-year-old boy.

Sporadic vestibular schwannomas (VSs) are rare in children. When occurred in the pediatric population, they usually appear bilaterally and are related to neurofibromatosis type 2 (NF2). The current study reports a 4-year-old boy without family history of VS or NF2 who presented with a large (5.7-cm) VS involving the right cerebellopontine angle and internal auditory canal. Through seven-staged surgical interventions and two stereotactic γ­knife radiosurgery, the disease was stabilized. At 2-year follow-up, the child had right ear hearing loss, grade IV facial palsy, and normal motor function and gait. No definite evidence of gene mutation regarding NF2 can be identified after sequence analysis and deletion/duplication testing. This case highlights the significance of considering the possibility of sporadic VSs, even in very young children. It emphasizes the importance of not overlooking initial symptoms, as they may indicate the presence of a large tumor and could potentially result in delayed diagnosis.

Contemporary Management of Pediatric Brainstem Tumors.

Brain tumors are the second most common malignancy in childhood. Around 15-20% of pediatric brain tumors occur in the brainstem. The most common type of brainstem tumor are diffuse tumors in the ventral pons, whereas focal tumors tend to arise from the midbrain, medulla, and dorsal pons. Glioma is the most common pathological entity. Contemporary management consists of surgery, radiotherapy, chemotherapy, and other adjuvant treatment. Surgical options range from biopsy to radical excision. Biopsy can be performed for diagnostic and prognostic purposes, or in the setting of clinical trials, mainly for diffuse intrinsic pontine gliomas. For focal tumors, surgeons need to carefully balance clinical outcomes against possible neurological sequelae in order to achieve maximal safe resection. Radiotherapy is essential for control of high-grade tumors and may be applied to residual or recurrent low-grade tumors. Proton therapy may provide similar efficacy and less neurotoxicity in comparison to conventional photon therapy. Oncological treatment continues to evolve from conventional chemotherapy to targeted therapy, immunotherapy, and other novel treatment methods and holds great potential as adjuvant therapy for pediatric brainstem tumors.

LOXL1-AS1 contributes to metastasis in sonic-hedgehog medulloblastoma by promoting cancer stem-like phenotypes.

BACKGROUND: Medulloblastomas (MBs) are one of the most common malignant brain tumor types in children. MB prognosis, despite improvement in recent years, still depends on clinical and biological risk factors. Metastasis is the leading cause of MB-related deaths, which highlights an unmet need for risk stratification and targeted therapy to improve clinical outcomes. Among the four molecular subgroups, sonic-hedgehog (SHH)-MB harbors clinical and genetic heterogeneity with a subset of high-risk cases. Recently, long non-coding (lnc)RNAs were implied to contribute to cancer malignant progression, but their role in MB remains unclear. This study aimed to identify pro-malignant lncRNAs that have prognostic and therapeutic significance in SHH-MB. METHODS: The Daoy SHH-MB cell line was engineered for ectopic expression of MYCN, a genetic signature of SHH-MB. MYCN-associated lncRNA genes were identified using RNA-sequencing data and were validated in SHH-MB cell lines, MB tissue samples, and patient cohort datasets. SHH-MB cells with genetic manipulation of the candidate lncRNA were evaluated for metastatic phenotypes in vitro, including cell migration, invasion, sphere formation, and expressions of stemness markers. An orthotopic xenograft mouse model was used to evaluate metastasis occurrence and survival. Finally, bioinformatic screening and in vitro assays were performed to explore downstream mechanisms. RESULTS: Elevated lncRNA LOXL1-AS1 expression was identified in MYCN-expressing Daoy cells and MYCN-amplified SHH-MB tumors, and was significantly associated with lower survival in SHH-MB patients. Functionally, LOXL1-AS1 promoted SHH-MB cell migration and cancer stemness in vitro. In mice, MYCN-expressing Daoy cells exhibited a high metastatic rate and adverse effects on survival, both of which were suppressed under LOLX1-AS1 perturbation. Integrative bioinformatic analyses revealed associations of LOXL1-AS1 with processes of cancer stemness, cell differentiation, and the epithelial-mesenchymal transition. LOXL1-AS1 positively regulated the expression of transforming growth factor (TGF)-ß2. Knockdown of TGF-ß2 in SHH-MB cells significantly abrogated their LOXL1-AS1-mediated prometastatic functions. CONCLUSIONS: This study proved the functional significance of LOXL1-AS1 in SHH-MB metastasis by its promotion of TGF-ß2-mediated cancer stem-like phenotypes, providing both prognostic and therapeutic potentials for targeting SHH-MB metastasis.

An Infant-Type Hemispheric Glioma With SOX5::ALK: A Novel Fusion.

Infant-type hemispheric glioma (IHG) is a rare pediatric brain tumor with variable response to chemotherapy and radiotherapy. Molecular insights into IHG can be useful in identifying potentially active targeted therapy. A male fetus was found to have congenital hydrocephalus at the gestational age of 37 weeks. Fetal MRI showed a 2.6 × 2.0-cm tumor located at the frontal horn of the left lateral ventricle, involving the left basal nuclei and thalamus. Tumor biopsy at the age of 2 days revealed an IHG consisting of spindle tumor cells with strong expression of GFAP and ALK. Targeted RNA sequencing detected a novel fusion gene of SOX5::ALK. After initial chemotherapy with cyclophosphamide, carboplatin, and etoposide for 2 cycles, the tumor size progressed markedly and the patient underwent a subtotal resection of brain tumor followed by treatment with lorlatinib, an ALK tyrosine kinase inhibitor with central nervous system (CNS) activity. After 3 months of treatment, reduction of tumor size was observed. After 14 months of treatment, partial response was achieved, and the infant had normal growth and development. In conclusion, we identified a case of congenital IHG with a novel SOX5::ALK fusion that had progressed after chemotherapy and showed partial response and clinical benefit after treatment with the CNS-active ALK inhibitor lorlatinib.

Targeting of RRM2 suppresses DNA damage response and activates apoptosis in atypical teratoid rhabdoid tumor.

BACKGROUND: Atypical teratoid rhabdoid tumors (ATRT) is a rare but aggressive malignancy in the central nervous system, predominantly occurring in early childhood. Despite aggressive treatment, the prognosis of ATRT patients remains poor. RRM2, a subunit of ribonucleotide reductase, has been reported as a biomarker for aggressiveness and poor prognostic conditions in several cancers. However, little is known about the role of RRM2 in ATRT. Uncovering the role of RRM2 in ATRT will further promote the development of feasible strategies and effective drugs to treat ATRT. METHODS: Expression of RRM2 was evaluated by molecular profiling analysis and was confirmed by IHC in both ATRT patients and PDX tissues. Follow-up in vitro studies used shRNA knockdown RRM2 in three different ATRT cells to elucidate the oncogenic role of RRM2. The efficacy of COH29, an RRM2 inhibitor, was assessed in vitro and in vivo. Western blot and RNA-sequencing were used to determine the mechanisms of RRM2 transcriptional activation in ATRT. RESULTS: RRM2 was found to be significantly overexpressed in multiple independent ATRT clinical cohorts through comprehensive bioinformatics and clinical data analysis in this study. The expression level of RRM2 was strongly correlated with poor survival rates in patients. In addition, we employed shRNAs to silence RRM2, which led to significantly decrease in ATRT colony formation, cell proliferation, and migration. In vitro experiments showed that treatment with COH29 resulted in similar but more pronounced inhibitory effect. Therefore, ATRT orthotopic mouse model was utilized to validate this finding, and COH29 treatment showed significant tumor growth suppression and prolong overall survival. Moreover, we provide evidence that COH29 treatment led to genomic instability, suppressed homologous recombinant DNA damage repair, and subsequently induced ATRT cell death through apoptosis in ATRT cells. CONCLUSIONS: Collectively, our study uncovers the oncogenic functions of RRM2 in ATRT cell lines, and highlights the therapeutic potential of targeting RRM2 in ATRT. The promising effect of COH29 on ATRT suggests its potential suitability for clinical trials as a novel therapeutic approach for ATRT.

Pineal/germ cell tumors and pineal parenchymal tumors.

INTRODUCTION: Pineal region tumors (PRTs) are tumors arising from the pineal gland and the paraspinal structures. These tumors are rare and heterogeneous that account for 2.8-10.1% and 0.6-3.2% of tumors in children and in all ages, respectively. Almost all types and subtypes of CNS tumors may be diagnosed in this region. These tumors come from cells of the pineal gland (pinealocytes and neuroglial cells), ectopic primordial germ cells (PGC), and cells from adjacent structures. Hence, PRTs are consisted of pineal parenchyma tumors (PPTs), germ cell tumors (GCTs), neuroepithelial tumors (NETs), other miscellaneous types of tumors, cystic tumors (epidermoid, dermoid), and pineal cyst in addition. The symptoms of PRTs correlate to the increased intracranial cranial pressure due to obstructive hydrocephalus and dorsal midbrain compression. The diagnostic imaging studies are mainly MRI of brain (with and without gadolinium) along with a sagittal view of whole spine. Serum and/or CSF AFP/ß-HCG helps to identify GCTs. The treatment of PRTs is consisted of the selection of surgical biopsy/resection, handling of hydrocephalus, neoadjuvant and/or adjuvant therapy according to age, tumor location, histopathological/molecular classification, grading of tumors, staging, and threshold value of markers (for GCTs) in addition. METHODS: In this article, we review the following focus points: 1. Background of pineal region tumors. 2. Pineal GCTs and evolution of management. 3. Molecular study for GCTs and pineal parenchymal tumors. 4. Review of surgical approaches to the pineal region. 5. Contribution of endoscopy. 6. Adjuvant therapy (chemotherapy, radiotherapy, and combination). 7. RESULTS: In all ages, the leading three types of PRTs in western countries were PPTs (22.7-34.8%), GCTs (27.3-34.4%), and NETs (17.2-28%). In children and young adults, the leading PRTs were invariably in the order of GCTs (40-80.5%), PPTs (7.6-21.6%), NETs (2.4-37.5%). Surgical biopsy/resection of PRTs is important for precision diagnosis and therapy. Safe resection with acceptable low mortality and morbidity was achieved after 1970s because of the advancement of surgical approaches, CSF shunt and valve system, microscopic and endoscopic surgery. Following histopathological diagnosis and classification of types and subtypes of PRTs, in PPTs, through molecular profiling, four molecular groups of pineoblastoma (PB) and their oncogenic driver were identified. Hence, molecular stratified precision therapy can be achieved. CONCLUSION: Modern endoscopic and microsurgical approaches help to achieve precise histopathological diagnosis and molecular classification of different types and subtypes of pineal region tumors for risk-stratified optimal, effective, and protective therapy. In the future, molecular analysis of biospecimen (CSF and blood) along with AI radiomics on tumor imaging integrating clinical and bioinformation may help for personalized and risk-stratified management of patients with pineal region tumors.

Brain and Spinal Tumors Originating from the Germ Line Cells.

Primary central nervous system germ cell tumors (CNS GCTs) are part of the GCTs in children and adults. This tumor entity presents with geographic variation, age, and sex predilection. There are two age peaks of incidence distribution at the first few months of life and in adolescence. CNS GCTs are heterogeneous in histopathological subtypes, locations, and tumor marker (AFP, ß-hCG) secretions. In the WHO CNS tumor classification, GCTS are classified as germinoma and nongerminomatous GCT (NGGCT) with different subtypes (including teratoma). Excluding mature teratoma, the remaining NGGCTs are malignant (NGMGCT). In teratoma, growing teratoma syndrome and teratoma with somatic-type malignancy should be highlighted. The common intracranial locations are pineal region, neurohypophysis (NH), bifocal pineal-NH, basal ganglia, and cerebral ventricle. Above 50% of intracranial GCTs (IGCTs) present obstructive hydrocephalus. Spinal tumors are rare. Age, locations, hydrocephalus, and serum/CSF titer of ß-hCG correlate with clinical manifestations. Delayed diagnosis is common in tumors arising in neurohypophysis, bifocal, and basal ganglia resulting in the increasing of physical dysfunction and hormonal deficits. Staging work-up includes CSF cytology for tumor cells and contrast-enhanced MRI of brain and spine for macroscopic metastasis before treatment commences. The therapeutic approach of CNS GCTs integrates locations, histopathology, staging, tumor marker level, and therapeutic classification. Treatment strategies include surgical biopsy/excision, chemotherapy, radiotherapy (single or combination). Secreting tumors with consistent imaging may not require histopathological diagnosis. Primary germinomas are highly radiosensitive and the therapeutic aim is to maintain high survival rate using optimal radiotherapy regimen with/without chemotherapy combination. Primary NGNGCTs are less radiosensitive. The therapeutic aim is to increase survival utilizing more intensive chemotherapy and radiotherapy. The negative prognostic factors are residue disease at the end of treatment and serum or CSF AFP level >1000 ng/mL at diagnosis. In refractory or recurrent NMGGCTs, besides high-dose chemotherapy, new therapy is necessary. Molecular profiling and analysis help for translational research. Survivors of pediatric brain tumors frequently experience cancer-related cognitive dysfunction, physical disability, pituitary hormone deficiency, and other CNS complications after cranial radiotherapy. Continuous surveillance and assessment may lead to improvements in treatment protocols, transdisciplinary interventions, after-treatment rehabilitation, and quality of life.

Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome.

BACKGROUND: The prognosis for Li-Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients. METHODS: In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated. RESULTS: The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup "SHH_3" (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received postoperative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively). CONCLUSIONS: LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients.

Feasibility and Toxicity of Interval-Compressed Chemotherapy in Asian Children and Young Adults with Sarcoma.

Twelve Asian patients with sarcoma received interval-compressed (ic-) chemotherapy scheduled every 14 days with a regimen of vincristine (2 mg/m2), doxorubicin (75 mg/m2), and cyclophosphamide (1200-2200 mg/m2) (VDC) alternating with a regimen of ifosfamide (9000 mg/m2) and etoposide (500 mg/m2) (IE), with filgrastim (5-10 mcg/kg/day) between cycles. Carboplatin (800 mg/m2) was added for CIC-rearranged sarcoma. The patients were treated with 129 cycles of ic-VDC/IE with a median interval of 19 days (interquartile range [IQR], 15-24 days. Median nadirs (IQR) were neutrophil count, 134 (30-396) × 106/L at day 11 (10-12), recovery by day 15 (14-17) and platelet count, 35 (23-83) × 109/L at day 11 (10-13), recovery by day 17 (14-21). Fever and bacteremia were observed in 36% and 8% of cycles, respectively. The diagnoses were Ewing sarcoma (6), rhabdomyosarcoma (3), myoepithelial carcinoma (1), malignant peripheral nerve sheath tumor (1), and CIC-DUX4 Sarcoma (1). Seven of the nine patients with measurable tumors responded (one CR and six PR). Interval-compressed chemotherapy is feasible in the treatment of Asian children and young adults with sarcomas.

Clinical and Molecular Features in Medulloblastomas Subtypes in Children in a Cohort in Taiwan.

Medulloblastoma (MB) was classified into four molecular subgroups: WNT, SHH, group 3, and group 4. In 2017, 12 subtypes within 4 subgroups and 8 subtypes within non-WNT/non-SHH subgroups according to the differences of clinical features and biology were announced. In this study, we aimed to identify the heterogeneity of molecular features for discovering subtype specific factors linked to diagnosis and prognosis. We retrieved 70 MBs in children to perform RNA sequencing and a DNA methylation array in Taiwan. Integrated with clinical annotations, we achieved classification of 12 subtypes of pediatric MBs in our cohort series with reference to the other reported series. We analyzed the correlation of cell type enrichment in SHH MBs and found that M2 macrophages were enriched in SHH ß, which related to good outcomes of SHH MBs. The high infiltration of M2 macrophages may be an indicator of a favorable prognosis and therapeutic target for SHH MBs. Furthermore, C11orf95-RELA fusion was observed to be associated with recurrence and a poor prognosis. These results will contribute to the establishment of a molecular diagnosis linked to prognostic indicators of relevance and help to promote molecular-based risk stratified treatment for MBs in children.

Adrenal Crisis Mimicking COVID-19 Encephalopathy in a Teenager with Craniopharyngioma.

There is an increasing number of reported cases with neurological manifestations of COVID-19 in children. Symptoms include headache, general malaise, ageusia, seizure and alterations in consciousness. The differential diagnosis includes several potentially lethal conditions including encephalopathy, encephalitis, intracranial hemorrhage, thrombosis and adrenal crisis. We report the case of a 17-year-old boy with a positive antigen test of COVID-19 who presented with fever for one day, altered mental status and seizure, subsequently diagnosed with adrenal insufficiency. He had a history of panhypopituitarism secondary to a suprasellar craniopharyngioma treated with surgical resection; he was treated with regular hormone replacement therapy. After prompt administration of intravenous hydrocortisone, his mental status returned to normal within four hours. He recovered without neurologic complications. Adrenal insufficiency can present with neurological manifestations mimicking COVID-19 encephalopathy. Prompt recognition and treatment of adrenal insufficiency, especially in patients with brain tumors, Addison's disease or those recently treated with corticosteroids, can rapidly improve the clinical condition and prevent long-term consequences.

Outcomes of intracranial non-germinomatous germ cell tumors: a retrospective Asian multinational study on treatment strategies and prognostic factors.

PURPOSE: Non-germinomatous germ cell tumors (NGGCTs) are rare pediatric conditions. This multicenter study using Asian multinational patient data investigated treatment outcomes and prognostic factors for NGGCTs. METHODS: Medical records of 251 patients with NGGCTs treated from 1995 to 2015 were retrospectively analyzed from participating centers in Asian countries (Korea, Taiwan, Singapore, and Japan). RESULTS: The median follow up was 8.5 years (95% CI 7.8-9.9). In the total cohort, 5-year event-free survival (EFS) and overall survival (OS) rates were 78.2% and 85.4%, respectively. In 17.9% of the patients, diagnosis was determined by tumor markers alone (alpha-fetoprotein ≥ 10 ng/mL (Korea) or > 25 ng/mL (Taiwan and Singapore), and/or ß-human chorionic gonadotropin (ß-hCG) ≥ 50 mIU/mL). Patients with immature teratomas and mature teratomas comprised 12.0% and 8.4%, respectively. The 5-year EFS rate was higher in patients with histologically confirmed germinoma with elevated ß-hCG (n = 28) than those in patients with malignant NGGCTs (n = 127). Among malignant NGGCTs, patients with choriocarcinoma showed the highest 5-year OS of 87.6%, while yolk sac tumors showed the lowest OS (68.8%). For malignant NGGCT subgroups, an increase in serum ß-hCG levels by 100 mIU/mL was identified as a significant prognostic factor associated with the EFS and OS. CONCLUSION: Our result shows excellent survival outcomes of overall CNS NGGCT. However, treatment outcome varied widely across the histopathologic subgroup of NGGCT. Hence, this study suggests the necessity for accurate diagnosis by surgical biopsy and further optimization of diagnosis and treatment according to the histopathology of NGGCTs. Future clinical trials should be designed for individualized treatments for different NGGCTs subsets.

Influence of Acoustic Parameters and Sonication Schemes on Transcranial Blood-Brain Barrier Disruption Induced by Pulsed Weakly Focused Ultrasound.

Pulsed ultrasound combined with microbubbles use can disrupt the blood-brain barrier (BBB) temporarily; this technique opens a temporal window to deliver large therapeutic molecules into brain tissue. There are published studies to discuss the efficacy and safety of the different ultrasound parameters, microbubble dosages and sizes, and sonication schemes on BBB disruption, but optimal the paradigm is still under investigation. Our study is aimed to investigate how different sonication parameters, time, and microbubble dose can affect BBB disruption, the dynamics of BBB disruption, and the efficacy of different sonication schemes on BBB disruption. Method: We used pulsed weakly focused ultrasound to open the BBB of C57/B6 mice. Evans blue dye (EBD) was used to determine the degree of BBB disruption. With a given acoustic pressure of 0.56 MPa and pulse repetitive frequency of 1 Hz, burst lengths of 10 ms to 50 ms, microbubbles of 100 µL/kg to 300 µL/kg, and sonication times of 60 s to 150 s were used to open the BBB for parameter study. Brain EBD accumulation was measured at 1, 4, and 24 h after sonication for the time-response relationship study; EBD of 100 mg/kg to 200 mg/kg was administered for the dose-response relationship study; EBD injection 0 to 6 h after sonication was performed for the BBB disruption dynamic study; brain EBD accumulation induced by one sonication and two sonications was investigated to study the effectiveness on BBB disruption; and a histology study was performed for brain tissue damage evaluation. Results: Pulsed weakly focused ultrasound opens the BBB extensively. Longer burst lengths and a larger microbubble dose result in a higher degree of BBB disruption; a sonication time longer than 60 s did not increase BBB disruption; brain EBD accumulation peaks 1 h after sonication and remains 81% of the peak level 24 h after sonication; the EBD dose administered correlates with brain EBD accumulation; BBB disruption decreases as time goes on after sonication and lasts for 6 h at least; and brain EBD accumulation induced by two sonication increases 74.8% of that induced by one sonication. There was limited adverse effects associated with sonication, including petechial hemorrhages and mild neuronal degeneration. Conclusions: BBB can be opened extensively and reversibly by pulsed weakly focused ultrasound with limited brain tissue damage. Since EBD combines with albumin in plasma to form a conjugate of 83 kDa, these results may simulate ultrasound-induced brain delivery of therapeutic molecules of this size scale. The result of our study may contribute to finding the optimal paradigm of focused ultrasound-induced BBB disruption.

Enrichment of Tumor-Infiltrating B Cells in Group 4 Medulloblastoma in Children.

Medulloblastoma (MB) is the most common malignant brain tumor in children. It is classified into core molecular subgroups (wingless activated (WNT), sonic hedgehog activated (SHH), Group 3 (G3), and Group 4 (G4)). In this study, we analyzed the tumor-infiltrating immune cells and cytokine profiles of 70 MB patients in Taiwan using transcriptome data. In parallel, immune cell composition in tumors from the SickKids cohort dataset was also analyzed to confirm the findings. The clinical cohort data showed the WNT and G4 MB patients had lower recurrence rates and better 5-year relapse-free survival (RFP) compared with the SHH and G3 MB patients, among the four subgroups of MB. We found tumor-infiltrating B cells (TIL-Bs) enriched in the G4 subgroups in the Taiwanese MB patients and the SickKids cohort dataset. In the G4 subgroups, the patients with a high level of TIL-Bs had better 5-year overall survival. Mast cells presented in G4 MB tumors were positively correlated with TIL-Bs. Higher levels of CXCL13, IL-36γ, and CCL27 were found compared to other subgroups or normal brains. These three cytokines, B cells and mast cells contributed to the unique immune microenvironment in G4 MB tumors. Therefore, B-cell enrichment is a G4-subgroup-specific immune signature and the presence of B cells may be an indicator of a better prognosis in G4 MB patients.

Compassionate Treatment of Brainstem Tumors with Boron Neutron Capture Therapy: A Case Series.

Brainstem tumors are heterogenous and cancerous glioma tumors arising from the midbrain, pons, and the medulla that are relatively common in children, accounting for 10% to 20% of all pediatric brain tumors. However, the prognosis of aggressive brainstem gliomas remains extremely poor despite aggressive treatment with chemotherapy and radiotherapy. That means there are many life-threatening patients who have exhausted all available treatment options and are beginning to face end-of-life stage. Therefore, the unique properties of highly selective heavy particle irradiation with boron neutron capture therapy (BNCT) may be well suited to prolong the lives of patients with end-stage brainstem gliomas. Herein, we report a case series of life-threatening patients with end-stage brainstem glioma who eligible for Emergency and Compassionate Use, in whom we performed a scheduled two fractions of salvage BNCT strategy with low treatment dosage each time. No patients experienced acute or late adverse events related to BNCT. There were 3 patients who relapsed after two fractionated BNCT treatment, characterized by younger age, lower T/N ratio, and receiving lower treatment dose. Therefore, two fractionated low-dose BNCT may be a promising treatment for end-stage brainstem tumors. For younger patients with low T/N ratios, more fractionated low-dose BNCT should be considered.

Bifocal lesions have a poorer treatment outcome than a single lesion in adult patients with intracranial germinoma.

Intracranial germinoma (IG) rarely occurs in adults. Its optimal treatment strategy is unclear. We evaluated the outcomes of radiotherapy in adults with intracranial germinoma. Data of 29 adult patients (age, 18-52 years; median age, 24.3 years) with IG treated with radiotherapy at Taipei Veterans General Hospital were retrospectively reviewed. They were followed up for a median time of 5.9 years (range, 1.0-12.8 years). We used the Kaplan-Meier method to estimate the progression-free survival (PFS) and overall survival (OS), and univariate and multivariate Cox proportional hazards regression models to identify the factors affecting PFS. PFS and OS were compared between adult and pediatric patients with IG. The 1-, 3-, and 5-year PFS rates were 96.6%, 85.8%, and 77.8%, respectively, in the adult patients, and the OS rate were all 100%. Seven patients (24.1%) experienced recurrence, and in six of them, salvage therapy successfully controlled the disease. Two patients (6.9%) died after 5 years of follow-up due to disease progression and central pontine myelinolysis. In the univariate and multivariate Cox analysis, bifocal lesions had a significantly lower PFS than those with single lesions (p = 0.008). Kaplan-Meier survival analysis showed that adult patients had a poorer PFS (p = 0.06) and OS (p = 0.025) than pediatric patients. Our study showed bifocal lesions were associated with lower PFS than a single lesion among adult IG patients, and adult IG patients tended to have poorer PFS and OS compared to pediatric IG patients. For adult patients with bifocal IG, we recommend treatment with craniospinal irradiation, whole ventricle irradiation (WVI) with chemotherapy, or frequent spine images follow-up for patients who received only WVI.

Atypical Teratoid/Rhabdoid Tumor in Taiwan: A Nationwide, Population-Based Study.

BACKGROUND: Atypical teratoid/rhabdoid tumor (AT/RT) is a rare, highly aggressive embryonal brain tumor most commonly presenting in young children. METHODS: We performed a nationwide, population-based study of AT/RT (ICD-O-3 code: 9508/3) in Taiwan using the Taiwan Cancer Registry Database and the National Death Certificate Database. RESULTS: A total of 47 cases (male/female = 29:18; median age at diagnosis, 23.3 months (IQR: 12.5-87.9)) were diagnosed with AT/RT between 1999 and 2014. AT/RT had higher prevalence in males (61.70%), in children < 36 months (55.32%), and at infratentorial or spinal locations (46.81%). Survival analyses demonstrated that patients ≥ 3 years of age (n = 21 (45%)) had a 5y-OS of 41% (p < 0.0001), treatment with radiotherapy only (n = 5 (11%)) led to a 5y-OS of 60%, treatment with chemotherapy with or without radiotherapy (n = 27 (62%)) was associated with a 5y-OS of 45% (p < 0.0001), and patients with a supratentorial tumor (n = 11 (23%)) had a 5y-OS of 51.95%. Predictors of better survival on univariate Cox proportional hazard modeling and confirmed with multivariate analysis included older age (≥1 year), supratentorial sites, and the administration of radiotherapy, chemotherapy, or both. Gender had no effect on survival. CONCLUSION: Older age, supratentorial site, and treatment with radiotherapy, chemotherapy, or both significantly improves the survival of patients with AT/RT.

Giant cystic hypothalamic hamartoma in an infant associated with persistent syndrome of inappropriate antidiuretic hormone secretion.

BACKGROUND: A giant hypothalamic hamartoma (GHH) is a rare congenital malformation only reported in a few cases in the literature and is often associated with precocious puberty, gelastic seizures, or less commonly, Pallister-Hall syndrome. Persistent syndrome of inappropriate antidiuretic hormone secretion (SIADH) is very rare in infancy, and most patients with GHH do not develop persistent SIADH, usually only transient electrolyte disturbances postoperatively. Previous cases of GHH have not been associated with persistent derangements in antidiuretic hormone levels. CASE DESCRIPTION: A 7-month-old male infant presented to our hospital with a history of an intracranial cystic lesion diagnosed at 23 weeks gestational age (GA), later impressed as a solid-cystic mass at 37 weeks GA by ultrasound prenatally. Postnatal MRI after birth showed a large mass with a dorsal cyst occupying the hypothalamus, causing hydrocephalus and brainstem compression. The patient started to have subtle seizures on the seventh day after birth and eventually developed dacrystic seizures. Hyponatremia with persistent SIADH was observed at 3 months of age before surgery. He received long-term oral sodium supplementation, polytherapy of anti-epileptic medications, ventriculocystostomy for progressive enlargement of the cystic cavity, and later surgical treatment for disconnection and partial resection which confirmed a histological diagnosis of hypothalamic hamartoma. CONCLUSION: In this case study, we present a novel association of GHH with persistent SIADH and a rare presentation of a cystic component at the dorsal part of the tumor. Clinicians should be aware of this potential endocrine derangement and provide emergent treatment.

Characteristics and outcomes of second cancers in patients with childhood cancer: A report from the Taiwan Pediatric Oncology Group.

BACKGROUND: Patients with childhood cancer are at increased risk for the development of second cancers. METHODS: A national multicenter survey of second cancers conducted by the Taiwan Pediatric Oncology Group retrieved retrospective data from the database at the Children Cancer Foundation in Taiwan beginning in 1995. The characteristics of second cancers and associations of patient demographic and clinical characteristics with time to death due to a second cancer were analyzed. RESULTS: We examined the records of 8782 patients with a primary cancer diagnosed between January 1, 1995 and December 31, 2013, and a total of 99 patients with a second cancer were identified. The most common type of second cancer was acute myeloid leukemia (n = 35), followed by acute lymphoblastic leukemia (n = 15), central nervous system (CNS) tumors (n = 15), and sarcomas (n = 10). Secondary hematological malignancies occurred earlier than other secondary cancers. The frequencies of second CNS tumors and second bone cancers and sarcomas were notably increased when prior radiation doses increased from zero, low dose to high dose. The overall 5-year survival of patients with a second cancer was poor (33.7%). Multivariate survival analysis revealed that the year of primary diagnosis ≤2002, secondary hematological malignancies, and age at second cancer diagnosis ≤9.3 years or >26.8 years increased the risk of death following second cancer. CONCLUSION: Children who develop a second cancer have an unfavorable outcome. Early detection and improved treatment for second cancers are needed.