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1.  Cytogenetic Prognostication Within Medulloblastoma Subgroups 
Shih, David J.H. | Northcott, Paul A. | Remke, Marc | Korshunov, Andrey | Ramaswamy, Vijay | Kool, Marcel | Luu, Betty | Yao, Yuan | Wang, Xin | Dubuc, Adrian M. | Garzia, Livia | Peacock, John | Mack, Stephen C. | Wu, Xiaochong | Rolider, Adi | Morrissy, A. Sorana | Cavalli, Florence M.G. | Jones, David T.W. | Zitterbart, Karel | Faria, Claudia C. | Schüller, Ulrich | Kren, Leos | Kumabe, Toshihiro | Tominaga, Teiji | Shin Ra, Young | Garami, Miklós | Hauser, Peter | Chan, Jennifer A. | Robinson, Shenandoah | Bognár, László | Klekner, Almos | Saad, Ali G. | Liau, Linda M. | Albrecht, Steffen | Fontebasso, Adam | Cinalli, Giuseppe | De Antonellis, Pasqualino | Zollo, Massimo | Cooper, Michael K. | Thompson, Reid C. | Bailey, Simon | Lindsey, Janet C. | Di Rocco, Concezio | Massimi, Luca | Michiels, Erna M.C. | Scherer, Stephen W. | Phillips, Joanna J. | Gupta, Nalin | Fan, Xing | Muraszko, Karin M. | Vibhakar, Rajeev | Eberhart, Charles G. | Fouladi, Maryam | Lach, Boleslaw | Jung, Shin | Wechsler-Reya, Robert J. | Fèvre-Montange, Michelle | Jouvet, Anne | Jabado, Nada | Pollack, Ian F. | Weiss, William A. | Lee, Ji-Yeoun | Cho, Byung-Kyu | Kim, Seung-Ki | Wang, Kyu-Chang | Leonard, Jeffrey R. | Rubin, Joshua B. | de Torres, Carmen | Lavarino, Cinzia | Mora, Jaume | Cho, Yoon-Jae | Tabori, Uri | Olson, James M. | Gajjar, Amar | Packer, Roger J. | Rutkowski, Stefan | Pomeroy, Scott L. | French, Pim J. | Kloosterhof, Nanne K. | Kros, Johan M. | Van Meir, Erwin G. | Clifford, Steven C. | Bourdeaut, Franck | Delattre, Olivier | Doz, François F. | Hawkins, Cynthia E. | Malkin, David | Grajkowska, Wieslawa A. | Perek-Polnik, Marta | Bouffet, Eric | Rutka, James T. | Pfister, Stefan M. | Taylor, Michael D.
Journal of Clinical Oncology  2014;32(9):886-896.
Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication.
Patients and Methods
Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models.
Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas.
Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.
PMCID: PMC3948094  PMID: 24493713
2.  Subgroup-Specific Prognostic Implications of TP53 Mutation in Medulloblastoma 
Journal of Clinical Oncology  2013;31(23):2927-2935.
Reports detailing the prognostic impact of TP53 mutations in medulloblastoma offer conflicting conclusions. We resolve this issue through the inclusion of molecular subgroup profiles.
Patients and Methods
We determined subgroup affiliation, TP53 mutation status, and clinical outcome in a discovery cohort of 397 medulloblastomas. We subsequently validated our results on an independent cohort of 156 medulloblastomas.
TP53 mutations are enriched in wingless (WNT; 16%) and sonic hedgehog (SHH; 21%) medulloblastomas and are virtually absent in subgroups 3 and 4 tumors (P < .001). Patients with SHH/TP53 mutant tumors are almost exclusively between ages 5 and 18 years, dramatically different from the general SHH distribution (P < .001). Children with SHH/TP53 mutant tumors harbor 56% germline TP53 mutations, which are not observed in children with WNT/TP53 mutant tumors. Five-year overall survival (OS; ± SE) was 41% ± 9% and 81% ± 5% for patients with SHH medulloblastomas with and without TP53 mutations, respectively (P < .001). Furthermore, TP53 mutations accounted for 72% of deaths in children older than 5 years with SHH medulloblastomas. In contrast, 5-year OS rates were 90% ± 9% and 97% ± 3% for patients with WNT tumors with and without TP53 mutations (P = .21). Multivariate analysis revealed that TP53 status was the most important risk factor for SHH medulloblastoma. Survival rates in the validation cohort mimicked the discovery results, revealing that poor survival of TP53 mutations is restricted to patients with SHH medulloblastomas (P = .012) and not WNT tumors.
Subgroup-specific analysis reconciles prior conflicting publications and confirms that TP53 mutations are enriched among SHH medulloblastomas, in which they portend poor outcome and account for a large proportion of treatment failures in these patients.
PMCID: PMC4878050  PMID: 23835706
3.  Chiari 1.5 Malformation : An Advanced Form of Chiari I Malformation 
The Chiari 1.5 malformation is defined as a tonsillar herniation within a Chiari I malformation with additional caudal descent of the brainstem through the foramen magnum. We describe a patient with Chiari I malformation who evolved to Chiari 1.5 malformation during longitudinal follow-up. A 15-year-old girl presented with neck pain during exercise for two years. She had been diagnosed with Chiari I malformation with mild hydrocephalus after minor cervical trauma at the age of six years. At that time, she was asymptomatic. After she complained of aggravated neck pain, neuroimaging (nine years after first imaging) revealed caudal descent of the brainstem and syringomyelia in addition to progression of tonsillar herniation. Posterior fossa decompressive surgery resulted in complete resolution of neck pain. Based on neuroimaging and operative findings, she was diagnosed as Chiari 1.5 malformation. Neuroimaging performed seven months after surgery showed an increased anterior-posterior diameter of the medulla oblongata and markedly decreased syringomyelia. This case demonstrates progressive developmental process of the Chiari 1.5 malformation as an advanced form of the Chiari I malformation.
PMCID: PMC2982921  PMID: 21113370
Chiari 1.5 malformation; Asymptomatic hydrocephalus; Syringomyelia
4.  Divergent clonal selection dominates medulloblastoma at recurrence 
Morrissy, A. Sorana | Garzia, Livia | Shih, David J. H. | Zuyderduyn, Scott | Huang, Xi | Skowron, Patryk | Remke, Marc | Cavalli, Florence M. G. | Ramaswamy, Vijay | Lindsay, Patricia E. | Jelveh, Salomeh | Donovan, Laura K. | Wang, Xin | Luu, Betty | Zayne, Kory | Li, Yisu | Mayoh, Chelsea | Thiessen, Nina | Mercier, Eloi | Mungall, Karen L. | Ma, Yusanne | Tse, Kane | Zeng, Thomas | Shumansky, Karey | Roth, Andrew J. L. | Shah, Sohrab | Farooq, Hamza | Kijima, Noriyuki | Holgado, Borja L. | Lee, John J. Y. | Matan-Lithwick, Stuart | Liu, Jessica | Mack, Stephen C. | Manno, Alex | Michealraj, K. A. | Nor, Carolina | Peacock, John | Qin, Lei | Reimand, Juri | Rolider, Adi | Thompson, Yuan Y. | Wu, Xiaochong | Pugh, Trevor | Ally, Adrian | Bilenky, Mikhail | Butterfield, Yaron S. N. | Carlsen, Rebecca | Cheng, Young | Chuah, Eric | Corbett, Richard D. | Dhalla, Noreen | He, An | Lee, Darlene | Li, Haiyan I. | Long, William | Mayo, Michael | Plettner, Patrick | Qian, Jenny Q. | Schein, Jacqueline E. | Tam, Angela | Wong, Tina | Birol, Inanc | Zhao, Yongjun | Faria, Claudia C. | Pimentel, José | Nunes, Sofia | Shalaby, Tarek | Grotzer, Michael | Pollack, Ian F. | Hamilton, Ronald L. | Li, Xiao-Nan | Bendel, Anne E. | Fults, Daniel W. | Walter, Andrew W. | Kumabe, Toshihiro | Tominaga, Teiji | Collins, V. Peter | Cho, Yoon-Jae | Hoffman, Caitlin | Lyden, David | Wisoff, Jeffrey H. | Garvin, James H. | Stearns, Duncan S. | Massimi, Luca | Schüller, Ulrich | Sterba, Jaroslav | Zitterbart, Karel | Puget, Stephanie | Ayrault, Olivier | Dunn, Sandra E. | Tirapelli, Daniela P. C. | Carlotti, Carlos G. | Wheeler, Helen | Hallahan, Andrew R. | Ingram, Wendy | MacDonald, Tobey J. | Olson, Jeffrey J. | Van Meir, Erwin G. | Lee, Ji-Yeoun | Wang, Kyu-Chang | Kim, Seung-Ki | Cho, Byung-Kyu | Pietsch, Torsten | Fleischhack, Gudrun | Tippelt, Stephan | Ra, Young Shin | Bailey, Simon | Lindsey, Janet C. | Clifford, Steven C. | Eberhart, Charles G. | Cooper, Michael K. | Packer, Roger J. | Massimino, Maura | Garre, Maria Luisa | Bartels, Ute | Tabori, Uri | Hawkins, Cynthia E. | Dirks, Peter | Bouffet, Eric | Rutka, James T. | Wechsler-Reya, Robert J. | Weiss, William A. | Collier, Lara S. | Dupuy, Adam J. | Korshunov, Andrey | Jones, David T. W. | Kool, Marcel | Northcott, Paul A. | Pfister, Stefan M. | Largaespada, David A. | Mungall, Andrew J. | Moore, Richard A. | Jabado, Nada | Bader, Gary D. | Jones, Steven J. M. | Malkin, David | Marra, Marco A. | Taylor, Michael D.
Nature  2016;529(7586):351-357.
The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon–driven, functional genomic mouse model of medulloblastoma with ‘humanized’ in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.
PMCID: PMC4936195  PMID: 26760213
5.  WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma 
TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6% ± 8.7%, respectively (p < 0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89% ± 2% vs. 57.4% ± 1.8% (p < 0.01)). In contrast, β-catenin mutation sensitized TP53 mutant cells to radiation (p < 0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5% ± 1.5% in lithium treated cells vs. 56.6 ± 3% (p < 0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33% ± 8% for lithium treated cells vs. 27% ± 3% for untreated controls (p = 0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.
Electronic supplementary material
The online version of this article (doi:10.1186/s40478-014-0174-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4297452  PMID: 25539912
6.  Hypertensive Encephalopathy with Reversible Brainstem Edema 
Presented here is a 36-year-old male with arterial hypertension who developed brainstem edema and intracranial hemorrhage. Magnetic resonance scan revealed diffuse brainstem hyperintensity in T2-weighted and fluid-attenuated inversion-recovery images, with an increase in apparent diffusion coefficient values. After a reduction in blood pressure, rapid resolution of the brainstem edema was observed on follow-up. The patient's condition was thus interpreted as hypertensive brainstem encephalopathy. While many consider this a vasogenic phenomenon, induced by sudden, severe hypertension, the precise mechanism remains unclear. Prompt recognition and aggressive antihypertensive treatment in such patients are essential to prevent permanent or life-threatening neurologic injury.
PMCID: PMC3809442  PMID: 24175031
Brain stem; Edema; Encephalopathy; Hypertension
7.  Subgroup specific structural variation across 1,000 medulloblastoma genomes 
Northcott, Paul A | Shih, David JH | Peacock, John | Garzia, Livia | Morrissy, Sorana | Zichner, Thomas | Stütz, Adrian M | Korshunov, Andrey | Reimand, Juri | Schumacher, Steven E | Beroukhim, Rameen | Ellison, David W | Marshall, Christian R | Lionel, Anath C | Mack, Stephen | Dubuc, Adrian | Yao, Yuan | Ramaswamy, Vijay | Luu, Betty | Rolider, Adi | Cavalli, Florence | Wang, Xin | Remke, Marc | Wu, Xiaochong | Chiu, Readman YB | Chu, Andy | Chuah, Eric | Corbett, Richard D | Hoad, Gemma R | Jackman, Shaun D | Li, Yisu | Lo, Allan | Mungall, Karen L | Nip, Ka Ming | Qian, Jenny Q | Raymond, Anthony GJ | Thiessen, Nina | Varhol, Richard J | Birol, Inanc | Moore, Richard A | Mungall, Andrew J | Holt, Robert | Kawauchi, Daisuke | Roussel, Martine F | Kool, Marcel | Jones, David TW | Witt, Hendrick | Fernandez-L, Africa | Kenney, Anna M | Wechsler-Reya, Robert J | Dirks, Peter | Aviv, Tzvi | Grajkowska, Wieslawa A | Perek-Polnik, Marta | Haberler, Christine C | Delattre, Olivier | Reynaud, Stéphanie S | Doz, François F | Pernet-Fattet, Sarah S | Cho, Byung-Kyu | Kim, Seung-Ki | Wang, Kyu-Chang | Scheurlen, Wolfram | Eberhart, Charles G | Fèvre-Montange, Michelle | Jouvet, Anne | Pollack, Ian F | Fan, Xing | Muraszko, Karin M | Gillespie, G. Yancey | Di Rocco, Concezio | Massimi, Luca | Michiels, Erna MC | Kloosterhof, Nanne K | French, Pim J | Kros, Johan M | Olson, James M | Ellenbogen, Richard G | Zitterbart, Karel | Kren, Leos | Thompson, Reid C | Cooper, Michael K | Lach, Boleslaw | McLendon, Roger E | Bigner, Darell D | Fontebasso, Adam | Albrecht, Steffen | Jabado, Nada | Lindsey, Janet C | Bailey, Simon | Gupta, Nalin | Weiss, William A | Bognár, László | Klekner, Almos | Van Meter, Timothy E | Kumabe, Toshihiro | Tominaga, Teiji | Elbabaa, Samer K | Leonard, Jeffrey R | Rubin, Joshua B | Liau, Linda M | Van Meir, Erwin G | Fouladi, Maryam | Nakamura, Hideo | Cinalli, Giuseppe | Garami, Miklós | Hauser, Peter | Saad, Ali G | Iolascon, Achille | Jung, Shin | Carlotti, Carlos G | Vibhakar, Rajeev | Ra, Young Shin | Robinson, Shenandoah | Zollo, Massimo | Faria, Claudia C | Chan, Jennifer A | Levy, Michael L | Sorensen, Poul HB | Meyerson, Matthew | Pomeroy, Scott L | Cho, Yoon-Jae | Bader, Gary D | Tabori, Uri | Hawkins, Cynthia E | Bouffet, Eric | Scherer, Stephen W | Rutka, James T | Malkin, David | Clifford, Steven C | Jones, Steven JM | Korbel, Jan O | Pfister, Stefan M | Marra, Marco A | Taylor, Michael D
Nature  2012;488(7409):49-56.
Medulloblastoma, the most common malignant pediatric brain tumour, is currently treated with non-specific cytotoxic therapies including surgery, whole brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, prior attempts to identify targets for therapy have been underpowered due to small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup enriched. The most common region of focal copy number gain is a tandem duplication of the Parkinson’s disease gene SNCAIP, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1 that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGFβ signaling in Group 3, and NF-κB signaling in Group 4 suggest future avenues for rational, targeted therapy.
PMCID: PMC3683624  PMID: 22832581
8.  Prognostic classification of pediatric medulloblastoma based on chromosome 17p loss, expression of MYCC and MYCN, and Wnt pathway activation 
Neuro-Oncology  2011;14(2):203-214.
Pediatric medulloblastoma is considered a highly heterogeneous disease and a new strategy of risk stratification to optimize therapeutic outcomes is required. We aimed to investigate a new risk-stratification approach based on expression profiles of medulloblastoma cohorts. We analyzed gene expression profiles of 30 primary medulloblastomas and detected strong evidence that poor survival outcome was significantly associated with mRNA expression profiles of 17p loss. However, it was not supported in independent cohorts from previously published data (n = 100). We speculated that this discrepancy might come from complex conditions of two important prognostic determinants: loss of tumor suppressors (chromosome 17p) and high expression of oncogenes c-myc (MYCC) or N-myc (MYCN). When patients were stratified into 5 or 7 subgroups based on simultaneous consideration of these 2 factors while defining the Wnt group as independent, obviously different survival expectancies were detected between the subgroups. For instance, predicted 5-year survival probabilities ranged from 19% to 81% in the 5 subgroups. We also found that age became a significant prognostic marker after adjusting for 17p, MYCC, and MYCN status. Diminished survival in age <3 years was more substantial in subgroups with high expression of MYCC, MYCN, or 17p loss but not in other subgroups, indicating that poor survival outcome might be synergistically affected by these 3 factors. Here we suggest a more tailored subgrouping system based on expression profiles of chromosome 17p, MYCC, and MYCN, which could provide the basis for a novel risk-stratification strategy in pediatric medulloblastoma.
PMCID: PMC3266382  PMID: 22090452
chromosome 17p; medulloblastoma; MYC; MYCN; prognosis; Wnt
9.  Desmoplastic Fibroma of the Cranium in a Young Man 
Desmoplastic fibroma, which develops predominantly in long bones and the mandible, is a rare and benign but locally aggressive tumor. Desmoplastic fibroma of the cranium is extremely rare. We report a case of desmoplastic fibroma of the frontal bone in a young man. Because of its locally aggressive behavior, complete surgical excision with a safety margin is essential.
PMCID: PMC3550427  PMID: 23346331
Desmoplastic fibroma; Frontal bone; Skull
10.  Indirect revascularization surgery for moyamoya disease in children and its special considerations 
Korean Journal of Pediatrics  2012;55(11):408-413.
Moyamoya disease (MMD) is the most common pediatric cerebrovascular disease in Far Eastern countries. In children, MMD frequently manifests as ischemic symptomatology. Cerebral perfusion gradually decreases as the disease progresses, which often leads to cerebral infarction. The benefits of revascularization surgery, whether direct or indirect, have been well established in MMD patients with ischemic symptoms. In adults, the increase in cerebral blood flow achieved with indirect revascularization is often unsatisfactory, and direct revascularization is usually feasible. In children, however, direct revascularization is frequently technically not feasible, whereas the response to indirect revascularization is excellent, although 1 or 2 weeks are required for stabilization of symptoms. The authors describe surgical procedures and perioperative care in indirect revascularization for MMD. In addition, special considerations with regard to very young patients, patients with recent cerebral infarction, and patients with hyperthyroidism are discussed.
PMCID: PMC3510269  PMID: 23227059
Moyamoya disease; Child; Surgery
11.  Cerebrospinal fluid M staging for medulloblastoma: Reappraisal of Chang's M staging based on the CSF flow 
Neuro-Oncology  2010;13(3):334-344.
Tumor seeding is a strong negative prognostic factor for patients with medulloblastoma. Because Chang's M staging is based primarily on CT and myelographic findings and might be contradictory to the direction of normal cerebrospinal fluid (CSF) flow, seeding patterns and appropriate staging of medulloblastoma need to be revisited in patients diagnosed in the MRI era. We retrospectively reviewed the clinical and radiological data of 86 patients with a diagnosis of medulloblastoma who were treated in the MRI era. The presence of seeding in each subarachnoid space compartment and the patterns of seeding were analyzed in correlation with patient survival data. Thirty-four patients had gross seeding on perioperative MRI. Thirty-two patients had seeding in the spinal compartment. Sixteen and 12 patients had seeding in the infratentorial and supratentorial compartments, respectively. There was an apparent hierarchy of seeding (ie, from seeding in the spinal compartment up to the supratentorial compartment). Patients with seeding in the spinal compartment had longer progression-free survival (P = .038) and a tendency toward better overall survival (P = .053) compared with patients with seeding in intracranial compartments. We modified Chang's M staging based on the CSF flow and termed this approach “CSF M staging.” CSF M staging for medulloblastoma, in which intracranial seeding occupies a higher rank than spinal seeding, was a better predictor of patient prognosis. This modified staging method may be applied to metastatic staging of brain tumors located in the fourth ventricle.
PMCID: PMC3064600  PMID: 21134897
cerebrospinal fluid, medulloblastoma; prognosis; seeding; staging
12.  Therapeutic efficacy and safety of TRAIL-producing human adipose tissue–derived mesenchymal stem cells against experimental brainstem glioma 
Neuro-Oncology  2010;13(1):61-69.
Mesenchymal stem cells (MSCs) have an extensive migratory capacity for gliomas, which is comparable to that of neural stem cells. Among the various types of MSCs, human adipose tissue-derived MSCs (hAT-MSC) emerge as one of the most attractive vehicles for gene therapy because of their high throughput, lack of ethical concerns, and availability and ease of isolation. We evaluated the therapeutic potential and safety of genetically engineered hAT-MSCs encoding the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) against brainstem gliomas. Human AT-MSCs were isolated from human fat tissue, characterized, and transfected with TRAIL using nucleofector. The therapeutic potential of TRAIL-producing hAT-MSCs (hAT-MSC.TRAIL) was confirmed using in vitro and in vivo studies. The final fate of injected hAT-MSCs was traced in long-survival animals. The characterization of hAT-MSCs revealed the expression of MSC-specific cell-type markers and their differentiation potential into mesenchymal lineage. Short-term outcomes included a 56.3% reduction of tumor volume (P < .001) with increased apoptosis (3.03-fold, P < .05) in animals treated with hAT-MSC.TRAIL compared with the control groups. Long-term outcomes included a significant survival benefit in the hAT-MSC.TRAIL-treated group (26 days of median survival in the control group vs 84 days in the hAT-MSC.TRAIL-treated group, P < .0001), without any evidence of mesenchymal differentiation in vivo. Our study demonstrated the therapeutic efficacy and safety of nonvirally engineered hAT-MSCs against brainstem gliomas and showed the possibility of stem-cell–based targeted gene therapy for clinical application.
PMCID: PMC3018907  PMID: 21062796
adipose tissue-derived mesenchymal stem cells; antitumor effect; brainstem glioma; tumor necrosis factor-related apoptosis-inducing ligand
13.  Efficacy of High-dose Chemotherapy and Autologous Stem Cell Transplantation in Patients with Relapsed Medulloblastoma: A Report on The Korean Society for Pediatric Neuro-Oncology (KSPNO)-S-053 Study 
Journal of Korean Medical Science  2010;25(8):1160-1166.
The efficacy and toxicity of high-dose chemotherapy and autologous stem cell transplantation (HDCT/ASCT) were investigated for improving the outcomes of patients with relapsed medulloblastoma. A total of 15 patients with relapsed medulloblastoma were enrolled in the KSPNO-S-053 study from May 2005 to May 2007. All patients received approximately 4 cycles of salvage chemotherapy after relapse. Thirteen underwent HDCT/ASCT; CTE and CM regimen were employed for the first HDCT (HDCT1) and second HDCT (HDCT2), respectively, and 7 underwent HDCT2. One transplant related mortality (TRM) due to veno-occlusive disease (VOD) occurred during HDCT1 but HDCT2 was tolerable with no further TRM. The 3-yr overall survival probability and event-free survival rates ±95% confidence intervals (CI) were 33.3±12.2% and 26.7% ±11.4%, respectively. When analysis was confined to only patients who had a complete response (CR) or partial response (PR) prior to HDCT, the probability of 3-yr overall survival rates ±95% CI was 40.0±15.5%. No patients with stable disease (SD) or progressive disease (PD) survived. Survival rates from protocol KSPNO-S-053 are encouraging and show that tumor status prior to HDCT/ASCT is an important factor to consider for improving survival rates of patients with relapsed medulloblastoma.
PMCID: PMC2908784  PMID: 20676326
Recurrence; Medulloblastoma; Transplantation, Autologous; Tandem; Hematopoietic Stem Cell Transplantation
14.  Reduced-dose craniospinal radiotherapy followed by high-dose chemotherapy and autologous stem cell rescue for children with newly diagnosed high-risk medulloblastoma or supratentorial primitive neuroectodermal tumor 
The Korean Journal of Hematology  2010;45(2):120-126.
In this study, we investigated the effects of reduced-dose craniospinal radiotherapy (CSRT) followed by tandem high-dose chemotherapy (HDCT) with autologous stem cell rescue (ASCR) in children with a newly diagnosed high-risk medulloblastoma (MB) or supratentorial primitive neuroectodermal tumor (sPNET).
Between March 2005 and April 2007, patients older than 3 years with a newly diagnosed high-risk MB or sPNET were enrolled. The patients received two cycles of pre-RT chemotherapy consisting of cisplatin, etoposide, vincristine, and cyclophosphamide (cycle A), and carboplatin, etoposide, vincristine, and ifosphamide (cycle B), followed by CSRT with 23.4 Gy and local RT with 30.6 Gy. After four cycles of post-RT chemotherapy (cycles A, B, A, and B), tandem double HDCT with ASCR was performed.
A total of 13 patients (MB=11, sPNET=2) were enrolled. Of these, one patient progressed, one patient died of septic shock after the second cycle of B, and one patient relapsed after the third cycle of B. The 3-year event-free survival (EFS) rate of the patients intended for HDCT was 76.9%, whereas the 3-year EFS rate of the patients who received HDCT was 100%. No treatment-related mortality occurred during HDCT.
Although the follow-up period was short and the patient cohort was small in size, the results of this study are encouraging. The limited toxicity and favorable EFS rate observed in children treated with reduced-dose CSRT followed by HDCT and ASCR warrant further exploration in a larger study population.
PMCID: PMC2983022  PMID: 21120191
Radiotherapy; High-dose chemotherapy; Autologous stem cell transplantation; Medulloblastoma; Supratentorial primitive neuroectodermal tumor; Children
15.  Association of HLA-DR and -DQ Genes with Familial Moyamoya Disease in Koreans 
Moyamoya disease (MMD) is an uncommon cerebrovascular disorder, characterized by progressive occlusion at the terminal portion of the internal carotid artery. Incidence of the disease is high in East Asia and familial MMD accounts for about 15% of the disease. Although the pathogenesis is unknown, association of HLA class I or II alleles with MMD has been reported with conflicting results. We investigated whether there is a difference in HLA class II association between familial and non-familial forms of the disease.
A total of 70 Korean children with MMD, including 16 familial cases (10 probands), and 207 healthy controls were studied. Among familial cases, only 10 probands were used for the HLA frequency analysis. High resolution HLA-DRB1 and DQB1 genotyping was performed using polymerase chain reaction (PCR)-sequence specific oligonucleotide hybridization and PCR-single strand conformation polymorphism methods.
The phenotype frequencies of HLA-DRB1*1302 (70.0%) and DQB1*0609 (40.0%) were significantly increased in familial MMD compared to both controls [vs. 15.5%, corrected p (pc) = 0.008, odds ratio (OR) = 12.76; vs. 4.3%, pc = 0.02, OR = 14.67] and non-familial MMD patients (vs. 14.8%, pc = 0.02, OR = 13.42; vs. 1.9%, pc = 0.02, OR = 35.33). The frequencies of DRB1 and DQB1 alleles in non-familial MMD patients were not significantly different from those in controls.
Our findings suggest that the genetic polymorphism of HLA class II genes or other closely linked disease relevant gene(s) could be a genetic predisposing factor for familial MMD.
PMCID: PMC2803272  PMID: 20062572
Moyamoya disease; Familial; HLA-DR; HLA-DQ
16.  Primary intracranial atypical teratoid/rhabdoid tumor in a child: a case report. 
Journal of Korean Medical Science  2002;17(5):723-726.
Rhabdoid tumors of the central nervous system are rare malignancies. Primary central nervous system atypical teratoid/rhabdoid tumors (ATT/RhTs) mostly occur during early childhood and are almost invariably fatal. These tumors show similar histological and radiological features to primitive neuroectodermal tumormedulloblastoma (PNET-MB) but have different biological behaviors. We report a case of primary intracranial ATT/RhT in the posterior cranial fossa of a child. Preoperative radiological diagnosis was PNET-MB, but pathological diagnosis is ATT/ RhT. The case involved a 16-month-old baby boy who presented with severe headache, vomiting, and gait disturbance. He was treated by surgical resection, chemotherapy, and radiotherapy. Despite aggressive therapy, he died 19 months after diagnosis. Clinical, radiological, and histopathological features of primary intracranial ATT/RhT are discussed with a special emphasis on the differential diagnosis from PNET-MB.
PMCID: PMC3054946  PMID: 12378033

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