Myelomeningocele: the evolution of care over the last 50 years.

PURPOSE: Myelomeningocele (MMC) is one of the representative anomalies in the field of pediatric neurosurgery. During the 50 years of ISPN history, MMC had a tremendous changes in its incidence, clinical management and outcome with advanced understanding of its pathogenesis. We reviewed the changes in MMC during the period. METHODS: We reviewed the literature review and collected our experiences. RESULTS: During the 50 years, major changes happened in many aspects of MMC including incidence, pathoembryogenesis, folate deficiency, prevention, prenatal diagnosis, mode of delivery, treatment policy with ethical considerations, clinical treatment including fetal surgery, latex allergy, retethering, management outcome, multidisciplinary team approach, and socioeconomic and family issues. CONCLUSIONS: There was a great advance in the management and research of MMC during the 50 years. It is a monumental achievement of pediatric neurosurgeons and colleagues of the related fields.

Headache in Pediatric Moyamoya Disease after Revascularization Surgery.

INTRODUCTION: Patients with moyamoya disease (MMD) often have headaches after successful revascularization surgery. We aimed to characterize headache in surgically treated MMD patients and elucidate its clinical meaning and pathophysiology. METHODS: Headache and related symptoms were surveyed using structured questionnaires in pediatric MMD patients with follow-up for 6 months or longer after indirect revascularization surgery. Clinical information including initial presentation, surgical method, and outcome was collected from medical records. Surgical outcomes were assessed clinically and by perfusion imaging. We defined "headache associated with MMD" as the headache accompanied by a transient ischemic attack or provoked by hyperventilation. Other headaches were further classified based on the diagnostic criteria of the International Headache Society-3. We analyzed the characteristics of "headache associated with MMD" and newly developed headache after surgery. RESULTS: Among 90 participants, 65 (72.2%) had headaches within the last year before survey, including 28 (43.1%) with "headaches associated with MMD," 10 (15.3%) with probable migraines, 2 (3.1%) with infrequent episodic tension-type headaches, and 4 (6.2%) with probable tension-type headaches. Headache quality was pulsatile in 27 (41.5%) patients and pressing or tightening in 27 (41.5%) patients. Nausea or vomiting was accompanied in 30 (46.2%) patients. Headache upon awakening was reported in 37 (57.8%) patients. Headache disturbed daily life in 12 (18.5%) patients. Among the 32 (35.6%) patients who suffered headache during both the pre- and postoperative period, the headache quality was similar in 27 (84.4%) patients, and its severity decreased in 24 (75.0%) and did not change in 8 (25.0%) patients. Twelve (13.3%) patients experienced newly developed headaches after surgery. Among them, six (50.0%) were classified as having "headaches associated with MMD." They were predominantly electric shock-like or stabbing in 5 (45.6%) patients and nondisturbing in all patients. All 90 patients achieved improvement of ischemic symptoms after surgery. CONCLUSION: Headaches often persist or newly develop after revascularization surgery in MMD patients. Accompanying nausea or vomiting and occurrence upon awakening are characteristic features. Postoperative headache does not necessarily imply insufficient disease control.

Genomic analysis as a tool to infer disparate phylogenetic origins of dysembryoplastic neuroepithelial tumors and their satellite lesions.

Dysembryoplastic neuroepithelial tumor (DNET) is a low-grade brain tumor commonly associated with drug-resistant epilepsy. About half of DNETs are accompanied by tiny nodular lesions separated from the main mass. The existence of these satellite lesions (SLs) has shown a strong association with tumor recurrence, suggesting that they are true tumors. However, it is not known whether SLs represent multiple foci of progenitor tumor cell extension and migration or a multifocal development of the main DNET. This study was designed to elucidate the histopathology and pathogenesis of SLs in DNETs. Separate biopsies from the main masses and SLs with DNET were analyzed. We performed comparative lesion sequencing and phylogenetic analysis. FGFR1 K656E and K655I mutations or duplication of the tyrosine kinase domain was found in all 3 DNET patients and the main masses and their SLs shared the same FGFR1 alterations. The phylogenic analysis revealed that the SLs developed independently from their main masses. It is possible that the main mass and its SLs were separated at an early stage in oncogenesis with shared FGFR1 alterations, and then they further expanded in different places. SLs of DNET are true tumors sharing pathogenic mutations with the main masses. It is plausible that multifocal tumor development takes place in the dysplastic cortex containing cells with a pathogenic genetic alteration.

Leptomeningeal Metastasis in Gliomas : Clinical Characteristics and Risk Factors.

OBJECTIVE: Our objective is to analyze the occurrence, clinical course and risk factors for glioma patients with leptomeningeal metastasis (LM) according to different metastasis patterns and clinical variables. METHODS: We retrospectively reviewed data from 376 World Health Organization (WHO) grade II-IV adult glioma patients who were treated in the National Cancer Center from 2001 to 2020. Patients who underwent surgery at other institutions, those without initial images or those with pathologically unconfirmed cases were excluded. LM was diagnosed based on magnetic resonance imaging (MRI) findings or cerebrospinal fluid (CSF) cytology. The metastasis pattern was categorized as nodular or linear according to the enhancement pattern. Tumor proximity to the CSF space was classified as involved or separated, whereas location of the tumor was dichotomized as midline, for tumors residing in the thalamus, basal ganglia and brainstem, or lateral, for tumors residing in the cerebral and cerebellar hemispheres. RESULTS: A total of 138 patients were enrolled in the study. A total of 44 patients (38%) were diagnosed with LM during a median follow-up of 9 months (range, 0-60). Among the clinical variables, tumor proximity to CSF space, the location of the tumor and the WHO grade were significant factors for LM development in univariate analysis. In multivariate analysis, the midline location of the tumor and WHO grade IV gliomas were the most significant factor for LM development. The hazard ratio was 2.624 for midline located gliomas (95% confidence interval [CI], 1.384-4.974; p=0.003) and 3.008 for WHO grade IV gliomas (95% CI, 1.379-6.561; p=0.006). CONCLUSION: Midline location and histological grading are an important factor for LM in glioma patients. The proximity to the CSF circulation pathway is also an important factor for WHO grade IV glioma LM. Patients carrying high risks should be followed up more thoroughly.

Disorders of Secondary Neurulation: Suggestion of a New Classification According to Pathoembryogenesis.

Recently, advanced knowledge on secondary neurulation and its application to the clinical experience have led to the deeper insight into the pathoembryogenesis of secondary neurulation with new classifications of the caudal spinal dysraphic entities. Here, we summarize the dynamic changes in the concepts of disordered secondary neurulation over the last two decades. In addition, we suggest our new pathoembryogenetic explanations for a few entities based on the literature and the data from our previous animal research. Disordered secondary neurulation at each phase may cause various corresponding lesions, such as (1) failed junction with the primary neural tube (junctional neural tube defect and segmental spinal dysgenesis), (2) dysgenesis or duplication of the caudal cell mass associated with disturbed activity of caudal mesenchymal tissue (caudal agenesis and caudal duplication syndrome), (3) abnormal continuity of medullary cord to the surrounding layers, namely, failed ingression of the primitive streak to the caudal cell mass (myelomeningocele), focal limited dorsal neurocutaneous nondisjunction (limited dorsal myeloschisis and congenital dermal sinus), and neuro-mesenchymal adhesion (lumbosacral lipomatous malformation), and (4) regression failure spectrum of the medullary cord (thickened filum and filar cyst, retained medullary cord and low-lying conus, terminal myelocele, and terminal myelocystocele). It seems that almost every anomalous entity of the primary neural tube may occur in the area of secondary neurulation. Furthermore, the close association of the caudal cell mass with the activity of caudal mesenchymal tissue involves a wider range of surrounding structures in secondary neurulation than in primary neurulation. Although the majority of the data are from animals and many theories are still conjectural, these changing concepts of normal and disordered secondary neurulation will provoke further advancements in our management strategies as well as in the pathoembryogenetic understanding of anomalous lesions in this area.

Myelomeningocele as an anomaly of secondary neurulation.

PURPOSE: Myelomeningocele (MMC) is the representative entity of open neural tube defects resulting from an error during primary neurulation. However, cases of MMC in the region of the secondary neural tube (below the junction of S1 and S2 vertebrae) are sometimes encountered. We aimed to analyze the clinical features of atypical "low-lying" MMC in comparison to the typical MMC and suggest possible pathoembryogenesis. METHODS: From 1986 to 2020, 95 MMC patients were treated in our institute. A retrospective review of the radiological and clinical information was performed. We defined "low-lying" MMCs as those with fascia or lamina defects below the S1-2 interspinous ligament. RESULTS: Thirty-one out of the 95 MMC patients were identified as having low-lying MMC. The percentage of low-lying MMC within the entire MMC group increased dramatically (19% from 1990 to 1999 and 48% from 2000 to 2020). Thirty-nine percent of the low-lying MMCs were associated with hydrocephalus, and 36% showed the Chiari malformation. Clean intermittent catheterization was being performed by 52% of the patients and 46% had a motor weakness. The proportions of hydrocephalus, neurological symptoms, and the number of related procedures in the low-lying MMC were substantially lower than the typical MMC in our cohort and the literature. CONCLUSIONS: We present cases of atypical MMC occurring in the region of secondary neurulation. These cases provide clues that secondary neurulation may lead to open neural defects. Future experiments with animal models supporting what we have seen in the clinics will greatly enhance the understanding of the developmental process of neurulation and the corresponding anomalies.

Complications of Endoscopic Skull Base Surgery for Sellar and Parasellar Tumors in Pediatric Population; Neurosurgical Perspectives.

Background: Advances in surgical techniques based on in-depth anatomical knowledge of the skull base have broadened the indications for endoscopic skull base surgery (ESS) with the advantage of wide and direct surgical exposure while minimizing invasiveness. However, the low incidence of the indicated diseases and narrow surgical corridors in children have limited the popularization of ESS. In addition, surgical complications and preventive interventions are not yet well known. Therefore, we retrospectively investigated the complications and prevention methods of ESS in children with a comprehensive review. Methods: We retrospectively analyzed the medical records of pediatric patients who underwent ESS for sellar and parasellar tumors at Seoul National University Children's Hospital from July 2010 to December 2020. Visual and endocrine status, extent of resection, complications, and recurrences were investigated depending on the pathology of the tumor. In addition, a comprehensive literature review regarding the complications of pediatric ESS was performed. Results: A total of 98 patients were enrolled. The median age of the patients was 12 years, and 52 patients were male. Preoperative visual disturbance was found in 53 patients, anterior pituitary function deficit in 69, and diabetes insipidus in 32. Gross total resection was attempted in 67 patients and achieved in 62 (93%). Biopsy and cyst fenestration were the goals of surgery in 26 patients, and all were achieved as planned. Regarding outcomes, visual disturbance worsened in two patients (2%), endocrine status was aggravated in 34 (35%) patients, and new-onset diabetes insipidus occurred in 27 (41%) patients. The overall surgical complication rate (other than aggravation of visual or endocrine status) was 17%. Postoperative meningitis (12%) was the most common complication, followed by cerebrospinal fluid leakage (2%), vasospasm, hemorrhage and infarction. By pathological diagnosis, craniopharyngioma had the highest complication rate of 29%. All but one patient with postoperative hemorrhage showed no permanent deficits. Conclusion: ESS in children is feasible and relatively safe. More attention and different postoperative management protocols are required in children to avoid complications, especially in craniopharyngiomas. However, the complications can be mostly managed conservatively without permanent neurologic deficits.

Occult tethered cord syndrome: a rare, treatable condition.

PURPOSE: Occult tethered cord syndrome (OTCS) is an entity that shows tethered cord syndrome (TCS) with normal spinal MRI findings. The definition and treatment of OTCS have been controversial since first proposal. The purpose of this study was to evaluate the existence, prevalence, histological characteristics, and surgical outcomes of OTCS. METHODS: We retrospectively analyzed patients who underwent untethering surgery for OTCS from January 2010 to December 2019. Inclusion criteria were (1) clinical manifestation of TCS; (2) supported by urodynamic study (UDS) or electromyography/nerve conduction study; (3) no structural lesions in the urological tract or spinal cord, and no developmental delay; and (4) postoperative follow-up for > 6 months. Sectioned fila from OTCS patients were histologically compared with those from cases of thickened filum or low-lying conus. RESULTS: Five (four female, one male) of 439 patients (1.1%) who underwent untethering surgeries for occult spinal dysraphism corresponded to OTCS. Mean age at the time of surgery was 16 years (7-22 years). Mean postoperative follow-up duration was 45 months (15-114 months). The main symptom was urinary dysfunction in four patients and leg pain in one. All patients had detrusor-sphincter dyssynergia. Fila from OTCS patients revealed increased fibrous tissue as in TCS patients. Four patients showed postoperative improvement and one with preoperative static course had no improvement. CONCLUSIONS: This study suggests that OTCS is a definitely existing entity although rare. OTCS is curable when timely treatment is given. Sudden onset with rapid progression of symptom seems the best indication for surgery.

Experimental Assessment of Leptomeningeal Metastasis Diagnosis in Medulloblastoma Using Cerebrospinal Fluid Metabolomic Profiles.

Diagnosing leptomeningeal metastasis (LM) in medulloblastoma is currently based on positive cerebrospinal fluid (CSF) cytology or magnetic resonance imaging (MRI) finding. However, the relevance of discordant results has not been established. We evaluated the diagnostic potential of CSF metabolomic profiles in the medulloblastoma LM assessment. A total of 83 CSF samples from medulloblastoma patients with documented MRI and CSF cytology results at the time of sampling for LM underwent low-mass ions (LMIs) analysis using liquid chromatography-mass spectrometry. Discriminating LMIs were selected by a summed sensitivity and specificity (>160%) and LMI discriminant equation (LOME) algorithms, evaluated by measuring diagnostic accuracy for verifying LM groups of different MRI/cytology results. Diagnostic accuracy of LM in medulloblastoma was 0.722 for cytology and 0.889 for MRI. Among 6572 LMIs identified in all sample, we identified 27 discriminative LMIs differentiating MRI (+)/cytology (+) from MRI (-)/cytology (-). Using LMI discriminant equation (LOME) analysis, we selected 9 LMIs with a sensitivity of 100% and a specificity of 93.6% for differentiating MRI (+)/cytology (+) from MRI (-)/cytology (-). Another LOME of 20 LMIs significantly differentiated sampling time relative to treatment (p = 0.007) and the presence or absence of LM-related symptoms (p = 0.03) in the MRI (+)/cytology (-) group. CSF metabolomics of medulloblastoma patients revealed significantly different profiles among LM diagnosed with different test results. We suggest that LM patients could be screened by appropriately selected LOME-generated LMIs to support LM diagnosis by either MRI or cytology alone.

Caudal duplication syndrome: a literature review and reappraisal of its pathoembryogenesis.

INTRODUCTION: The term caudal duplication syndrome (CDS) was first introduced for complex anomalies of the distal caudal end of the trunk. The pathoembryogenesis of CDS is yet unknown, although a few theories have been proposed. We reviewed the previously proposed pathoembryogenetic theories and suggested a new perspective through the common clinical characteristics shown in CDS cases reported in the literature. METHODS: We conducted a systematic literature search of the online database PubMed from October 1993 to October 2020, using the search term "caudal duplication syndrome", according to the first mention of this entity. A total of 17 articles with 23 patients were reviewed. RESULTS: The most common manifestations were the duplication of the distal colon, genitourinary organs, and lower spine. Specifically, the duplicated bladders or uteri contacted their counterpart through a septum, and the duplicated bowels ran parallel. More caudal structures, such as the urethra or anus, were formed separately. The duplication seems to be a result of division by an intervening septum or structure in each part. In addition, duplication was not limited to the structures formed from the caudal cell mass (CCM), such as the distal spine and spinal cord, but also included hindgut structures. Moreover, anomalies involving caudal mesenchymal defects were also present. Considering clinical manifestations that are related to all three germ layers and seemingly the overseptation of these germ layers in CDS patients, with supporting data from animal experiments, events such as late-stage errors involving Hensen's node/the primitive streak and the duplication of the CCM with the hyperplasia of the abnormally located central caudal mesenchyme are probable pathoembryogenetic mechanisms for CDS. The "leakage" of the normal growth power of the caudal mesenchyme into the intervening midline space between the two CCMs and consequent weak lateral and caudal pushes of the caudal mesenchyme may explain the association of caudal agenesis or its related anomalies with CDS. CONCLUSION: We propose a theory that by a molecular interaction, an insult causes late gastrulation phase problems, resulting in ectopic primitive streak formation, and therefore, a duplication of the CCM is induced. Subsequently, the overactivity of abnormally positioned midline mesenchyme between the two CCMs may divide the hindgut derivatives by a central septum. Underactive lateral and caudal pushes of the caudal mesenchyme may lead to an association of features shown in caudal agenesis.

Disorders of Secondary Neurulation : Mainly Focused on Pathoembryogenesis.

Recent advancements in basic research on the process of secondary neurulation and increased clinical experience with caudal spinal anomalies with associated abnormalities in the surrounding and distal structures shed light on further understanding of the pathoembryogenesis of the lesions and led to the new classification of these dysraphic entities. We summarized the changing concepts of lesions developed from the disordered secondary neurulation shown during the last decade. In addition, we suggested our new pathoembryogenetic explanations for a few entities based on the literature and the data from our previous animal research. Disordered secondary neurulation at each phase of development may cause corresponding lesions, such as failed junction with the primary neural tube (junctional neural tube defect and segmental spinal dysgenesis), dysgenesis or duplication of the caudal cell mass associated with disturbed activity of caudal mesenchymal tissue (caudal agenesis and caudal duplication syndrome), failed ingression of the primitive streak to the caudal cell mass (myelomeningocele), focal limited dorsal neuro-cutaneous nondisjunction (limited dorsal myeloschisis and congenital dermal sinus), neuro-mesenchymal adhesion (lumbosacral lipomatous malformation), and regression failure spectrum of the medullary cord (thickened filum and filar cyst, low-lying conus, retained medullary cord, terminal myelocele and terminal myelocystocele). It seems that almost every anomalous entity of the primary neural tube may occur in the area of secondary neurulation. Furthermore, the close association with the activity of caudal mesenchymal tissue in secondary neurulation involves a wider range of surrounding structures than in primary neurulation. Although the majority of the data are from animals, not from humans and many theories are still conjectural, these changing concepts of normal and disordered secondary neurulation will provoke further advancements in our management strategies as well as in the pathoembryogenetic understanding of anomalous lesions in this area.

A boy with a congenital cerebellar mass.

PURPOSE: Tumorigenesis of medulloblastoma is believed to be associated with granule cell progenitor neurogenesis of the cerebellum. Nevertheless, congenital medulloblastomas are rarely found. Here, we report a case of congenital medulloblastoma that showed spontaneous albeit transient regression. METHODS: A one-month-old baby presented with abnormal antenatal and postnatal imaging findings. Upon ultrasonography at 26 weeks of gestational age, Dandy-Walker malformation with vermian hypoplasia and cystic change was suspected. Brain MRI at 1 week after birth revealed gadolinium-enhancing lesions in the cerebellum with apparent infiltrative features along the cerebellar folia accompanied by three independent cysts in the upper and inferolateral sides of the lesion. Serial MRIs taken up to 5 months of age showed a decrease in the size and extent of enhancing solid portions. The baby did not show any abnormal signs or developmental delay. MRI at the age of 7 months showed enlargement of the lesion, and surgery was performed. RESULTS: The lesion was diagnosed as medulloblastoma with histologically extensive nodularity (MBEN), genetically SHH-activated and TP53-wildtype. CONCLUSION: This case provides an unusual chance of observing an early phase of medulloblastoma development and raises a suspicion that medulloblastoma may initiate itself very early in cerebellar organogenesis and progress later at a certain time of postnatal development.

Cystic retained medullary cord in an intraspinal J-shaped cul-de-sac: a lesion in the spectrum of regression failure during secondary neurulation.

INTRODUCTION: Retained medullary cord (RMC) is thought to be a product of arrested secondary neurulation during the regression phase. A cord-like structure with a caudal non-functional part ends at the cul-de-sac. If the arrest occurs at the cavitation phase of secondary neurulation, the medullary cord has a cystic portion making "RMC of cystic type." CLINICAL PRESENTATION: We report a case of a 4-month-old girl who had a low-lying conus with an extradural-looking dorsal cyst. Preoperative diagnosis was RMC with a lumbosacral extradural cyst such as an arachnoid cyst. At surgery, we found that the extradural cyst was an extension of dural sac with the caudal portion of the cystic RMC inside. The RMC was untethered and the dural sac was reconstructed. The histopathologic examination revealed findings compatible with cystic RMC attached to the cul-de-sac. CONCLUSIONS: We regard this case as an intermediate form between the typical RMC in which is regarded as regression arrest occurred after the terminal balloon collapsed and the medullary cord detached from the skin to the normal cul-de-sac, and the terminal myelocystocele which is considered the result of arrest at the phase of the persisted terminal balloon attached to the skin.

Combined unilateral coronal-lambdoid suture synostosis: surgical outcome of suturectomy and postoperative helmet therapy.

INTRODUCTION: Nonsyndromic, multi-suture craniosynostosis is not common, especially those involving unilateral coronal and lambdoid sutures. Based on the experience on 6 cases, we analyzed the skull morphology of combined unilateral coronal-lambdoid suture synostosis and evaluated the surgical outcome of suturectomy. METHODS: Patients who underwent an operation for craniosynostosis in Seoul National University Children's Hospital from 2010 to 2018 were reviewed. For qualitative analysis of the surgical outcome, five typical morphologic characteristics (ipsilateral superior orbital rim deviation, deviation of the nasal ridge, ipsilateral frontal flattening, contralateral parietal bulging, ipsilateral occipitomastoid bulging) in unilateral coronal-lambdoid suture synostosis were evaluated based on medical photos, plain skull radiographs, and CT scans. For quantitative analysis, three parameters (nasal root deviation, orbital asymmetry, posterior skull base deviation) were measured. RESULTS: Among 316 patients with craniosynostosis, 41 patients had nonsyndromic, multi-suture synostosis. There were 6 unilateral coronal-lambdoid suture synostosis patients who were all treated with suturectomy. Qualitative evaluation of the postoperative outcome revealed that the nasal root and orbital rim deviations and the contralateral occipitomastoid bulging showed satisfactory improvements. However, ipsilateral frontal flattening and contralateral parietal bulging were improved but still present in most cases. Quantitative, craniometric analysis supported the qualitative outcomes. The nasal ridge deviation angle was corrected from 7.04 to 1.79 degrees. The posterior skull base deviation angle improved from 6.29 to 3.55 degrees. CONCLUSION: Unilateral coronal-lambdoid suture synostosis suturectomy followed by helmet therapy resulted in favorable outcomes, although the correction of frontal flattening was less satisfactory than the other measures. Considering the minimal invasiveness of the treatment, suturectomy may be a viable option for these patients.

Extracellular vesicle-associated miR-135b and -135a regulate stemness in Group 4 medulloblastoma cells by targeting angiomotin-like 2.

BACKGROUND: Extracellular vesicles (EVs) secreted by tumours, including exosomes, are important factors that regulate cell-cell interactions in oncogenesis. Although EV studies are ongoing, the biological understanding of EV-miRNAs derived from brain tumour spheroid-forming cells (BTSCs) of medulloblastoma is poor. PURPOSES: We explored the specific cellular miRNAs and EV-miRNAs in medulloblastoma BTSCs to determine their potential biological function. METHODS: Bulk tumor cells (BTCs) and BTSCs were cultured under different conditions from medulloblastoma tissues (N = 10). RESULTS: Twenty-four miRNAs were simultaneously increased in both cells and EVs derived from BTSCs in comparison to BTCs. After inhibition of miR-135b or miR135a which were the most significantly increased in BTSCs, cell viability, self-renewal and stem cell marker expression decreased remarkably. Through integrated analysis of mRNAs and miRNAs data, we found that angiomotin-like 2 (AMOTL2), which was significantly decreased, was targeted by both miR-135b and miR-135a. STAT6 and GPX8 were targeted only by miR-135a. Importantly, low expression of AMOTL2 was significantly associated with overall poor survival in paediatric Group 3 and Group 4 medulloblastoma patients. CONCLUSION: Our results indicated that inhibition of miR-135b or miR-135a leads to suppress stemness of BTSC through modulation of AMOTL2.

Disulfiram potentiates the anticancer effect of cisplatin in atypical teratoid/rhabdoid tumors (AT/RT).

Atypical teratoid/rhabdoid tumor (AT/RT) is the most malignant tumor of the central nervous system that generally occurs in young children. Despite the use of intensive multimodal therapy for AT/RT, the prognosis is still poor. The brain tumor initiating cells in AT/RT cells has been suggested as one of the challenges in AT/RT treatment. These cells have high expression of aldehyde dehydrogenase (ALDH). We investigated the combination effect of the ALDH inhibitor, disulfiram and cisplatin in the treatment of AT/RT cells. Isobologram analysis revealed that the combination therapy synergistically increases AT/RT cell death. The enzyme activity of ALDH AT/RT cells was effectively reduced by the combination therapy. We proposed that the synergistic augmentation occurs, at least partially through an increase in cleaved Poly (ADP-ribose) polymerase (PARP)-dependent apoptosis mediated by activating transcription factor 3 (ATF3). In the AT/RT mouse model, the combination therapy decreased tumor volume and prolonged survival. Immunofluorescence assay in mouse brain tissues were consistent with the expression of ATF3 and cleaved PARP. Our study demonstrates enhanced anti-cancer effect of combination therapy of disulfiram and cisplatin. This combination might provide a viable therapeutic strategy for AT/RT patients.

Long-Term Outcomes of Indirect Bypass for 629 Children With Moyamoya Disease: Longitudinal and Cross-Sectional Analysis.

Background and Purpose- In pediatric moyamoya disease, there are few reports on the efficacy of surgical intervention for stroke prevention. We evaluated the long-term outcomes of indirect bypass surgery on a relatively large number of children with moyamoya disease in a single center. Methods- From August 1988 to December 2012, 772 children underwent indirect bypass surgery. This study included 629 patients who were followed up for >5 years, excluding patients with moyamoya syndrome. The mean clinical follow-up duration was 12 years (range, 5-29 years). Cross-sectional analysis was performed based on either Karnofsky Performance Scale or Lansky Play Performance Scale to evaluate overall clinical outcomes and factors associated with unfavorable outcomes. To analyze the longitudinal effect of surgery, the annual risk of symptomatic infarction or hemorrhage on the operated hemisphere after indirect bypass surgery was calculated with a person-year method, and the event-free survival rate was evaluated using the Kaplan-Meier method. Results- The overall clinical outcome was favorable in 95% of the patients. The annual risks of symptomatic infarction and hemorrhage on the operated hemispheres were 0.08% and 0.04%, respectively. Furthermore, the 10-year event-free survival rates for symptomatic infarction and hemorrhage were 99.2% and 99.8%. Conclusions- Indirect bypass surgery could provide satisfactory long-term improvement in overall clinical outcome and prevention of recurrent stroke in children with moyamoya disease.