Young-Shin Ra

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21xa0% of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83xa0%; 55/66) and WNT (31xa0%; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5xa0% of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.

Importance of RNF213 polymorphism on clinical features and long-term outcome in moyamoya disease

OBJECT Moyamoya disease (MMD) is an idiopathic cerebrovascular occlusive disorder prevalent in East Asia. In the pathogenesis of MMD, the important role of genetic factors is being elucidated, and RNF213 has recently been identified as a susceptibility gene for MMD. The aim of this retrospective study was to investigate the RNF213 genotype in patients with MMD and to determine their genotype-phenotype associations. METHODS The study involved 165 Korean MMD patients from 155 unrelated families who were diagnosed with MMD at a single center from 1995 to 2013. Their demographic, radiological, and clinical findings were evaluated. Direct sequencing of the major RNF213 single nucleotide polymorphisms was performed. The association of the common RNF213 variant with MMD risk was evaluated using historical controls for comparison. Correlations between RNF213 genotype and phenotype were statistically analyzed. RESULTS The c.14429G>A (p.R4810K) variant was identified in 125 (75.8%) of 165 MMD patients. Most patients (112) were heterozygous, and 13 patients had 2 copies of the c.14429G>A variant. A novel heterozygous variant, c.12086A>G (p.Q4029R), was found in 1 additional patient. The minor allele frequency of the c.14429G>A variant was significantly higher in the MMD group (138 [41.8%] of 330 patients) than in the control group (8 [1.36%] of 588 subjects; p < 0.001). The c.14429G>A (p.R4810K) variant significantly increased the risk of MMD in Korean patients, with an OR of 52.11 (p < 0.001) compared with controls. Moreover, c.14429G>A (p.R4810K) genotypes occurred more frequently in patients with a family history of MMD. The homozygous variant was highly associated with early-onset MMD (age at onset < 5 years), cerebral infarction at diagnosis, and cognitive impairment in long-term outcome. CONCLUSIONS The findings indicate that the c.14429G>A (p.R4810K) allele of RNF213 is strongly associated with Korean patients with MMD. The homozygous c.14429G>A (p.R4810K) variant is particularly related to early-onset MMD, severe symptomatic manifestations at diagnosis, and poor prognosis. This genotypic variant may be a useful biomarker for early-onset MMD or unstable MMD with cerebral infarction, which requires early diagnosis and revascularization treatment.

Repair of a cerebrospinal fluid fistula using a muscle pedicle flap: technical case report.

OBJECTIVEAs a late complication of radiation therapy and a transoral approach, a cerebrospinal fluid (CSF) fistula between an oropharyngeal cavity and the ventral dura of the cervical spine is an extremely rare event. There are often difficulties in repairing ventral dural defects. Herein, we describe a technique that assists in feasible repair of a CSF fistula associated with ventral dural defects. CLINICAL PRESENTATIONA 36-year-old man was admitted to our institution with postnasal drip and a progressive spastic gait disturbance. Eleven years earlier, he had a recurrent chordoma of the cervical spine, which was treated by 5 open surgeries, including a transoral operation, and 6 rounds of radiation therapy. A neuroradiological examination revealed a CSF fistula between a posterior pharyngeal wall and the ventral dura of the cervical spine. INTERVENTIONWe performed a repair operation of the CSF fistula using a conventional direct posterior approach. However, we were unable to repair the fistula using a dural-substitute suturing procedure. Therefore, we used a semispinalis cervicis muscle pedicle flap. The muscle pedicle flap was brought through the dural defect in the anterior part of the posterior pharyngeal wall, to which it was fixed. It was then used to reinforce the suture line that closed the fistula and to fill the fistula tract. After posterior surgery, a transoral endoscopic approach was used to augment the muscle pedicle flap with a bovine pericardial patch graft. No postoperative complications occurred, and CSF leaking ceased after surgery. There was no CSF leakage during the 1-year follow-up period. CONCLUSIONThis novel muscle pedicle flap technique for repairing a CSF fistula can be used as an alternative to the direct “water-tight” closure of ventral cervical dural defects.

Postoperative Electroencephalogram for Follow up of Pediatric Moyamoya Disease

It is well known that the electroencephalographic finding in patients with moyamoya disease demonstrates the characteristic re-build up phenomenon a few minutes after hyperventilation. To evaluate the usefulness of an electroencephalogram (EEG) in the postoperative management of children with moyamoya disease, we studied the presence or absence of improvement in the clinical, single photon emission computed tomography (SPECT) and EEG findings, before and after surgery. Twenty-two patients, who underwent indirect revascularization surgery for moyamoya disease, were included in our study. Clinical improvement was assessed as the disappearance or decrease of a transient ischemic attack or headache. The findings on the EEG and SPECT were considered improved when the re-build up phenomenon was absent and when there was improvement in the cerebrovascular reserve as a result of the acetazolamide challenge test. The statistical correlation analysis for both clinical and EEG improvement were consistent (kappa value=0.409, p<0.05). However, the result from the clinical and SPECT improvement as well as that from EEG and SPECT improvement were not statistically significant. Our results suggest that EEG can be used as a noninvasive and simple follow-up test for moyamoya disease after indirect revascularization surgery if the hyperventilation procedure is effectively performed during EEG recording.

Prognosis of pediatric high-grade gliomas with temozolomide treatment: a retrospective, multicenter study

PurposeWe analyzed the usefulness of initial or recurrent treatment of temozolomide (TMZ) in pediatric high-grade gliomas (HGGs).MethodsBetween 2002 and 2010, we performed surgery on 35 patients with 17 glioblastomas, 14 anaplastic astrocytomas, 3 anaplastic oligodendrogliomas, and 1 anaplastic oligoastrocytoma. The male-to-female ratio was 21:14, and the median age was 13xa0years (range, 3–18xa0years). The mean follow-up period was 15.9 (±1.8) months. As the TMZ treatment, 22 patients received the initial treatment and 13 patients at recurrence. We analyzed the prognostic significance of TMZ treatment, tumor location, extent of removal, pathology, and recurrence pattern.ResultsThe median progression-free survival (PFS) and overall survival (OS) were 9.7 (±1.4) and 17.8 (±2.5) months, respectively. Based on univariate analysis, the median PFS was 9.9 (±1.6) months in the tumors located in the cerebral hemisphere and 5.6 (±1.3) months in the diencephalon (pu2009=u20090.03). Median PFS was 12.5 (±1.7) months in the initial treatment and 6.8 (±0.8) months in the recurrent treatment (pu2009=u20090.03). The median OS was 14.9 (±2.3) months in glioblastomas and 24.4 (±4.1) months in tumors with an anaplastic pathology (pu2009=u20090.01). The median OS was 12.1 (±3.7) months in patients with cerebrospinal fluid (CSF) dissemination and 18.2 (±2.9) months in patients without CSF dissemination (pu2009=u20090.02). Grades 3 and 4 treatment-related toxicity occurred in 7.7–9xa0% of the patients.ConclusionsInitial or recurrent TMZ treatment in pediatric HGGs was safe and tolerable. Initial treatment showed improved PFS compared to recurrent treatment, and both showed similar OS.

Medullary hemangioblastoma in a child with von Hippel-Lindau disease: vascular tumor perfusion depicted by arterial spin labeling and dynamic contrast-enhanced imaging.

Medullary hemangioblastoma is very rare in children. Based on small nodular enhancement with peritumoral edema and without dilated feeding arteries on conventional MRI, hemangioblastoma, pilocytic astrocytoma, oligodendroglioma, and ganglioglioma were included in the differential diagnosis of the medullary tumor. In this case report, the authors emphasize the diagnostic value of arterial spin labeling and dynamic contrast-enhanced MRI in demonstrating vascular tumor perfusion of hemangioblastoma in a 12-year-old boy who was later found to have von Hippel-Lindau disease.

Pediatric supratentorial high-grade glioma: multicenter retrospective observational study of the Korean Society for Pediatric Neuro-Oncology

We analyzed the prognostic factors of Korean pediatric patients with supratentorial high-grade glioma (HGG). Between 1997 and 2011, 62 patients with 34 glioblastomas and 28 anaplastic gliomas were surgically operated at nine institutions. The male-to-female ratio was 33 to 29 and the median age was 12xa0years (range 1–18). The prognostic significance of tumor location, extent of removal, pathologic grade, treatment method, and pattern of recurrence was analyzed. The median progression-free survival (PFS) and overall survival (OS) were 9.3 (±0.8) and 17.8 (±1.9) months, respectively. Glioblastoma and anaplastic glioma showed OSs of 15.9 (±1.3) and 19.6 (±2.4) months, respectively. Based on the univariate analysis, gross total removal (GTR) and initial combined chemoradiotherapy improved PFS (pxa0=xa00.012 and pxa0=xa00.003) and OS (pxa0=xa00.030 and pxa0=xa00.013), respectively. Cerebrospinal fluid (CSF) dissemination showed poor OS (pxa0=xa00.001). Based on the multivariate analysis, GTR and initial combined chemoradiotherapy resulted in an improved PFS [(hazard ratio 0.360; 95xa0% CI 0.177–0.733; pxa0=xa00.005) and (hazard ratio 0.458; 95xa0% CI 0.230–0.911; pxa0=xa00.026), respectively]. GTR, initial combined chemoradiotherapy, and no CSF seeding resulted in an improved OS [(hazard ratio 0.417; 95xa0% CI 0.201–0.861; pxa0=xa00.018), (hazard ratio 0.406; 95xa0% CI 0.206–0.800; pxa0=xa00.009), and (hazard ratio 0.288; 95xa0% CI 0.148–0.563; pxa0=xa00.000), respectively]. No significant difference in PFS and OS was observed between glioblastoma and anaplastic glioma. CSF dissemination was observed in 22 patients (35.5xa0%) during total follow-up. Pediatric anaplastic glioma showed poor survival, similarly to glioblastoma. GTR and initial combined chemoradiotherapy were associated with improved survival.

Advanced MRI for Pediatric Brain Tumors with Emphasis on Clinical Benefits

Conventional anatomic brain MRI is often limited in evaluating pediatric brain tumors, the most common solid tumors and a leading cause of death in children. Advanced brain MRI techniques have great potential to improve diagnostic performance in children with brain tumors and overcome diagnostic pitfalls resulting from diverse tumor pathologies as well as nonspecific or overlapped imaging findings. Advanced MRI techniques used for evaluating pediatric brain tumors include diffusion-weighted imaging, diffusion tensor imaging, functional MRI, perfusion imaging, spectroscopy, susceptibility-weighted imaging, and chemical exchange saturation transfer imaging. Because pediatric brain tumors differ from adult counterparts in various aspects, MRI protocols should be designed to achieve maximal clinical benefits in pediatric brain tumors. In this study, we review advanced MRI techniques and interpretation algorithms for pediatric brain tumors.

Long-Term Results Following Surgical Resection of Chordomas in the Craniocervical Junction and the Upper Cervical Spine: Review of 12 Consecutive Cases

BACKGROUNDnSince chordoma is refractory to chemotherapy and conventional radiotherapy, radical surgical resection is mandatory. However, it is surgically demanding in the craniocervical junction (CCJ) and upper cervical spine.nnnOBJECTIVEnTo analyze long-term surgical results of cervical chordomas.nnnMETHODSnWe retrospectively reviewed 12 consecutive patients who underwent surgical treatment for CCJ or upper cervical chordomas from 2001 to 2009 in 2 academic institutions. We analyzed the progression-free survival and overall survival and compared the results between gross total resection (GTR) cases and partial resection (PR). Complications were analyzed by comparing primary and recurrent tumor. We also delineated the type of radiotherapy.nnnRESULTSnOf the 12 patients, 5 underwent GTR and 7 underwent PR. GTR of the tumor was achieved by intralesional piecemeal removal. No recurrence occurred in the GTR group. PR group had 6 cases of regrowth (85.7%). Ten patients (83.3%) underwent any kind of radiation therapy. There were 3 (60%) patients in the GTR group and 7 (100%) in the PR group. Compared to PR, GTR revealed a better 3-yr progression-free survival rate (100% vs 14.3%) as well as a better 3-yr overall survival rate (100% vs 71.4%). Surgical complication rate (40% for GTR vs 42.9% for PR) was not significantly different between the groups. The surgical complication rates of primary and revision surgery were 25% and 75%, respectively. Complication associated with radiation occurred in 2 patients.nnnCONCLUSIONnGross total intralesional piecemeal resection with perioperative radiation therapy is an acceptable strategy for CCJ and the upper cervical chordoma management.

Neurocognitive Function and Health-Related Quality of Life in Pediatric Korean Survivors of Medulloblastoma

The neurocognitive function and quality of life of 58 Korean survivors of childhood medulloblastoma were assessed after surgery, cranial radiation and chemotherapy. All patients were evaluated with a battery of neurocognitive function tests and the Pediatric Functional Assessment of Cancer Therapy-Brain Tumor Survivors, which consists of self-report questionnaires on quality of life. The mean full-scale intelligence quotient (IQ), verbal IQ, and performance IQ scores were 90.2, 97.1, and 84.16, respectively. The mean memory quotient (MQ) score was 86.78, which was within 1 standard deviation of the average score of 100. Processing speed, attention, and executive function showed mild to moderate deficits. Intelligence, memory, executive function, visuospatial function, and simple motor function were significantly lower in the patients diagnosed before 8 years of age compared with those diagnosed after 8. The cognitive deficits in the patients diagnosed at younger ages might be related to earlier exposure to craniospinal irradiation and chemotherapy. The patient and parent proxy evaluations of attention, fine motor function, and quality of life did not differ. We found significant neurocognitive changes in a wide range of neurocognitive functional domains in Korean survivors of childhood medulloblastoma. Long-term follow-up studies of survivors of childhood medulloblastoma beginning at the time of their first diagnosis are required to better understand the deficits exhibited by survivors of childhood medulloblastoma, so that intervention strategies and treatment refinements that reduce the long-term neurocognitive decline can be developed.