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. 2014 Jun;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065

ATYPICAL TERATOID RHABDOID TUMOUR

PMCID: PMC4046281
Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.1

AT-001. ATYPICAL TERATOID RHABDOID TUMOURS (ATRT): A FRENCH RETROSPECTIVE STUDY

Anne Isabelle Bertozzi 1, Caroline Munzer 1, Fanny Fouyssac 4, Nicolas Andre 6, Sergio Boetto 1, Pierre Leblond 7, Franck Bourdeaut 2, Christelle Dufour 5

Abstract

BACKGROUND: To describe therapeutic approaches in children with atypical Teratoid Rhabdoid Tumours (ATRT) in France. METHODS: Observational study including all children less than 18 years old diagnosed with ATRT in France between 2009 and 2011. RESULTS: Forty seven children were included in this retrospective study. Six patients received no curative treatment while forty-one patients had a curative project. Median age was 1.5 years (range 0-16). The disease was disseminated in 10 patients. Surgical resection was complete in 21 cases. Chemotherapy was administered in 41 children. Twenty-six patients received upfront Vincristine-Methotrexate (5g/m2 x 3) with intra-thecal Methotrexate, which was stopped in eleven patients: in four cases the disease progressed and in seven cases the toxicities were manageable. Fifteen children received different chemotherapy courses and in four of them the diseases progressed. Eight patients underwent second-look surgery. Radiotherapy was administered in 17 patients at a median time of 19 weeks (13-44) after diagnosis. High-dose chemotherapy (HDCT) was given in 9 children and maintenance therapy in 5 children, starting at respectively 35 and 42 weeks after diagnosis. Median follow-up was 26 months (0.6-47). Median time for progression was 5 months. Two-years overall survival was 32% + /-8%. Median survival was 8 months. DISCUSSION: The survival rate of children with ATRT remains poor, the addition of VM is easily manageable but its benefit remains uncertain. The disease progressed mostly before radiotherapy. Future trials should focus on the delay of radiotherapy and the benefit of HDCT.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.2

AT-002. DIAGNOSIS OF ATYPICAL TERATOID/ RHABDOID TUMOUR - SINE QUA NON IN TREATMENT PROCESS

Rajkiran K Deshpande 1, Kamalakshi G Bhat 1, Soundarya Mahalingam 1

Abstract

INTRODUCTION: Childhood atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system is a recently described entity. Diagnosis is based on distinctive light microscopy and immunohistochemical findings, coupled with molecular genetic analysis. We report this case to highlight the importance of successful treatment, although prognosis is dismal particularly among children younger than 3 years of age. CASE REPORT: 2½ years old male child presented with a history of headache for 10 days and vomiting for 3 days. Physical examination showed proximally enlarged head. Child was clinically and neurologically normal. There was no history of fever, altered sensorium, seizure, bleeding, and failure to gain weight or weight loss. INVESTIGATION: CT scan showed intracranial space occupying lesions. MRI brain revealed heterogeneously enhancing lobulated mass in left cerebellum causing significant compression of fourth ventricle resulting in proximal hydrocephalus. There was a partial rim of normal cerebellar tissue suggestive of intraaxial location. Posterior craniotomy and excision of tumor was done. Histopathological examination and tumor markers were done in the same center and were also confirmed by NIMHANS, Bangalore and TATA Memorial Hospital, Mumbai as a case of AT/RT Cerebellum Chang staging T3aM0. Histopathology of the tumor revealed small undifferentiated cells with brisk mitotic activity, papillary arrangement with rhabdoid morphology-AT/RT Grade IV. Metastatic workup was done and was negative. After surgery, child was started on chemotherapy as per AT/RT protocol. After initial chemotherapy, cranial radiation was given. Today at the age of 5½ years, child is under regular follow-up. MRI brain done after 2 years of completion of treatment is normal. To conclude we report this case of its rarity and provide an insight as to how the early diagnosis and effective use of AT/RT protocol can be very essential in successful treatment. TREATMENT: Chemotherapy was as per the AT/RT protocol. Radiotherapy dose of 54Gy/30 fractions.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.3

AT-003. LOW DOSE HISTONE DEACETYLASE INHIBITOR TREATMENT HALTS RHABDOID TUMOUR GROWTH AND INDUCES OSTEOGENESIS AND NEURONAL DIFFERENTIATION

Andrea Muscat 1, Jason Cain 3, Melissa Ferguson 1, Dean Popovski 3, Elizabeth Algar 4, Fernando J Rossello 3, Samantha Jayasekara 3, DNeil Watkins 3, Jason Hodge 2, David Ashley 1

Abstract

Rhabdoid Tumour (RT) is a rare, malignant tumour of infancy arising mainly in the kidney or CNS. RTs are highly resistant to conventional treatments and outcomes remain poor despite aggressive multimodal therapy. The sole recurrent genetic abnormality in RT is homozygous deletion or inactivation of the chromatin-remodelling gene, SMARCB1, thus providing an ideal model for exploring epigenetic therapies such as the use of histone deacetylase inhibitors (HDACi). This study investigates the effects of HDACi on cell growth and differentiation in RT cell lines and mouse xenografts and analyses resultant changes in gene expression. METHODS: In vitro based cell proliferation, cell cycle and colony forming assays were undertaken and the altered gene expression profiles upon HDACi treatment were analysed using Illumina expression beadchip arrays and quantitative real-time PCR. The effects of HDACi on RT cell differentiation, both in vitro and in a mouse xenograft tumour model, were determined and post-treatment, cells or tissue were stained with various differentiation markers. RESULTS: HDACi treatment inhibited RT cell growth and self-renewal in vitro and halted tumour growth in vivo. After 21 days of continuous, low dose treatment with HDACi LBH589, gene expression signatures and qualitative differentiation marker staining of cells or tissue showed evidence of osteoblast differentiation and bone formation, as well as neuronal differentiation. CONCLUSION: Our data suggest that low dose HDACi treatment has the potential to inhibit RT cell growth and drive differentiation. This makes differentiation therapy an exciting avenue to explore and avoids the challenges of achieving a cytotoxic response in patients. The ability of HDACi to differentiate tumour cells and reduce their ability to self-renew warrants further investigation, as it provides an appealing means of tackling the issue of tumour recurrence.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.4

AT-004. ATYPICAL TERATOID/RHABDOID TUMOR CASE REPORT: A LONG-TERM SURVIOR AFTER RELAPSE TREATED WITHOUT RADIATION THERAPY

Makoto Hishii 1, Masahiro Saito 2, Hajime Arai 2

Abstract

INTRODUCTION: Central nervous system atypical teratoid / rhabdoid tumors (CNS AT/RT) are highly malignant neoplasms that occur in infants and young children. In spite of multiple treatments consisting of surgical resection, radiation therapy, and chemotherapy, the prognosis has been extremely poor. We report one case of 130 months-old boy living over 112 months after intracranial relapse and 127 months after the original diagnosis without evidence of disease. PATIENT: A 3 months-old boy developed lethargy and downward deviation of his eye balls. CT/MRI revealed a large inhomogeneous enhanced mass lesion in the right CP angle with resultant hydrocephalus. A gross-total surgical resection was performed and pathology was consistent with AT/RT supported by negative SMARCB1/IN1 staining. Therapy was begun on 6 courses systemic chemotherapy including intravenous chemotherapy with IFO, CBDCA, VP16 and intrathecal chemotherapy with MTX. MRI imaging obtained after 13 months from the end of chemotherapy revealed local tumor recurrence without CSF dissemination. A second surgery achieved a gross total resection and pathological diagnosis was same as the original diagnosis of AT/RT. 4 cycles of systemic intravenous chemotherapy with CPM, VCR, THP-ADR, CDDP were administered following the second surgery. The patient continues to be well with mild growing delay. Serial MRI imaging has been negative for residual or recurrent tumor since the second surgery. Radiation therapy has never been administered at the request of his parents. CONCLUSION: There is no accepted standard therapy for AT/RT. Radiation therapy for AT/RT patients less than 3 years old is also a controversial issue. We report a long-term survivor living 112 months after relapse who was treated without radiation therapy. In some cases, successful treatment for AT/RT patients may be possible without radiation therapy.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.5

AT-005. A SMARCB1-DEFICIENT, HIGHLY PENETRANT BRAIN TUMOUR MOUSE MODEL RECAPITULATES HUMAN ATRT

Zhi Yan Han 1, Wilfrid Richer 1, Carlo Lucchesi 1, Paul Freneaux 1, Andre Nicolas 1, Camille Grison 1, Gaelle Pierron 1, Olivier Delattre 1, Franck Bourdeaut 1

Abstract

Heterozygous invalidation of Smarcb1 leads to soft-part tumours with long latency (9months) and weak penetrance in mice (10-30%). Very few brain tumours are observed in this model. A conditional Smarcb1 inversion gives rise to highly aggressive CD8 lymphomas with a short latency (12weeks) and a full penetrance, but doesn't recapitulate human rhabdoid tumours. Hence, a highly penetrant mouse model recapitulating human ATRT is still awaited, for both cognitive purposes and preclinical therapeutics. METHODS: Given the ignorance of the cell of origin of RT, we chose to cross Rosa26CreERT2 with Smarcb1flox/flox mice in order to generate a widespread Smarcb1 inactivation. Tamoxifen was administered at various time of the mice life periods. The tumours were profiled on Affymetrix MOE420 arrays and compared to human ATRT. RESULTS: Tamoxifen administration provokes early non-tumoral death in neonates and CD8 Smarcb1-deficient lymphomas in adult mice. Interestingly, the prenatal administration leads to a new phenotype, characterized by central nervous system tumours which affect supratentorial space, cerebellum and spinal cord. The median latency was 2.5months (from few days to 5 months after birth). The tumours are undifferentiated with occasional rhabdoid phenotypes, and constantly show a loss of Smarcb1 expression. The penetrance is almost complete when tamoxifen is administered in early prenatal life. Comparison of the expression profiles with transcriptomes of human ATRTs demonstrates a convincing similarity. CONCLUSION: Conditional prenatal invalidation of Smarcb1 leads to a highly penetrant model of ATRT. This new model offers excellent conditions for preclinical therapeutic testing.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.6

AT-006. ATYPICAL TERATOID/RHABDOID TUMOURS, SERIES OF 32 CASES: CYCLIN D1 OVEREXPRESSION AND MYC GENE ALTERATIONS

Sridhar Epari 1, Nagaraj TS 1, Tejpal Gupta 2, Girish Chinnaswamy 3, Jayant Goda Sastri 2, Prakash Shetty 4, Aliasgar Moiyadi 4, Rakesh Jalali 2

Abstract

INTRODUCTION: Atypical teratoid/rhabdoid tumours (ATRT) are rare malignant pediatric brain tumours, characterized by inactivation of INI 1 gene. AIM: o study the morphological and immunohistochemical spectrum including cyclin D1 overexpression and MYC gene abnormalities in ATRTs. MATERIAL AND METHODS: Evaluated for clinical, histomorphological and immunohistochemistry {for epithelial markers (AE1/AE3, EMA), myogenic markers (Smooth muscle actin [SMA] and desmin), glial fibrillary acidic protein (GFAP), p53 protein, cyclin D1, Mic-2 and MIB-1} and fluorescence in-situ hybridization (FISH) for CMYC and NMYC gene. RESULTS: Total 32 cases, showed age range of 1-22yrs (≤ 3yrs: 21, 4-6yrs: 7, 7-10yrs: 2, 10-18yrs:1, >18: 1), Male: Female ratio of 3:1 and sites were posterior fossa (n= 17; cerebellum: 15, 3rd ventricle: 2), supratentorial: 13 (hemispheric: 11; lateral ventricular: 2) and spinal: 2 (cervicomedullary: 1, D10-L2:1). One case was a transformation of an INI-1 retained glial tumour and other occurred post prophylactic cranial irradiation for acute lymphoblastic leukaemia. Histologically, rhabdoid cells (RCs) were seen in 25 (Predominant: 14, scattered: 11), primitive round cell (PRC) areas in 16, confluent necrosis in 21, fibrous areas: 7 and calcification: 3 (superimposed on necrosis: 2; dystrophic bone-like: 1). Epithelial differentiation (n = 32) was in 28 (AE1/AE3 + EMA:24/32; EMA only: 4/32), myogenic differentiation (n = 23) was seen in 9 (desmin + SMA: 1, desmin only: 4, SMA only:4), MIC-2 (n = 20) positivity in 15, p53 (n = 17) positivity in 15, and cyclin D1 overexpression (n = 27) was in 15 cases. None showed positivity for GFAP. MIB-1 labeling index (n = 21) ranged from 15% to >50% (15-30%: 12, 30-40%: 2, 40-50%:3, 50-70%:4). CMYC gene (n = 16) amplification was seen in one case and NMYC gene (n = 16) amplification in none. CONCLUSIONS: ATRTs can occur in non-infantile age group, at non-conventional sites like hemispheric, intraventricular and spinal locations, show showed frequent cyclin D1 overexpression and very rare MYC gene alterations.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.7

AT-007. NEUROCOGNITIVE EVALUATION OF LONG TERM SURVIVOR'S WITH ATYPICAL TERATOID/RHABDOID TUMOR (ATRT): THE CANADIAN REGISTRY EXPERIENCE

Taryn Fay-McClymont 1, Donna Johnston 2, Laura Janzen 3, Sharon Guger 3, Katrin Scheinemann 4, Adam Fleming 5, Chris Fryer 6, Juliette Hukin 6, Donald Mabbott 3, Annie Huang 3, Eric Bouffet 6, Lucie Lafay-Cousin 1

Abstract

Because ATRT is a rare disease of infancy carrying grim prognosis, focus on long term outcome, especially neurocognitive remain very limited. With the new era of multimodality therapy, some patients are now long term survivors. We reviewed the neuropsychological (NP) status of the survivors from the Canadian ATRT registry. Among patients diagnosed between 1995-2012, 16/72 were survivors (22%). Formal NP assessments were available in 7 patients. Four patients could not be tested (3 too young, 1 blind significantly impaired, 1 lost to follow up). Additionally 1 patient was in special education class (grade 12), one received educational assistance (grade 8), one meet academic expectation (grade 4). Data on last survivor is pending. For the 7 patients with comprehensive NP, the median age at diagnosis was 28.2 months (11.2-60.7). Four tumors were infratentorial and 3 were metastatic. Four patients underwent complete resection. All patients received post operative sequential high dose chemotherapy (Carpoplatin/Thiotepa). Five patients received intrathecal chemotherapy. Two patients underwent radiation (1focal, 1CSI). Median age at time of NP was 7.3 years (3.9-9.28). Full Scale Intellectual Quotient (FSIQ) ranged from 60 to 119 (median = 71). Simple expressive and receptive language appeared relatively preserved (low average to superior). Three most recently diagnosed patients assessed at a median time of 2.6 years (2.6-4.7) from diagnosis had average to high average scores for FSIQ, academic and visual spatial skills, visual and verbal memory. Four other diagnosed earlier tested at a median time of 5.1 years (3.3-8.3) post-diagnosis had a FSIQ ranging from 60 to 71 (median = 68). Approximately 50% of their scores were in the impaired range. Whether these findings suggest further decline overtime or reflect improvement in overall management of these recently diagnosed patients remain unclear. Nevertheless this cohort of infants appears significantly impaired at school age despite the absence of systematic radiotherapy. Larger series focusing on neurocognition are definitely needed before embracing adjuvant radiotherapy as standard of care.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.8

AT-008. THE EXPERIENCE OF TREATMENT FOR 5 ATYPICAL TERATOID/RHABDOID TUMOR UNDER 3-YEAR-OLD IN HYOGO PREFECTURAL KOBE CHILDREN'S HOSPITAL

Atsufumi Kawamura 1, Kazuki Yamamoto 1, Tatsuya Nagashima 1

Abstract

INTRODUCTION: Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system is a rare, highly malignant pediatric brain tumors, with historic median survival ranging from 6 to 11 months. This report reflects our experience at the Hyogo Prefectural Kobe Children's Hospital (Japan) of aggressive treatment to five AT/RT cases in 302 central nerve system tumor from 2007 to 2013. RESULT: All cases underwent microsurgical resection and were tried to treat with a regimen of multi-agent chemotherapy with cerebrospinal irradiation. One gross total resection and four subtotal removals were achieved. In three cases, whole brain irradiation had to be added to control tumor progression during multi-agent chemotherapy because of dissemination and progression of tumor. Two of our cases are long-term survivors that have indicated Complete Reaction (CR) to the tumor and meningeal dissemination in MRI studies for 78 and 37 months. CONCLUSION: It is very difficult to plan the regimen because of progression and dissemination in each case of AT/RT after surgical treatment. We have to adjust the time of radiotherapy in each case that would be useful for AT/RT patients to improve outcome and preserve quality of life in multimodality treatment.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.9

AT-009. IMPROVED 5-YEAR OVERALL SURVIVAL IN 23 PATIENTS WITH AT/RT TREATED ACCORDING TO THE RHABDOID 2007 REGIMEN OF THE EU-RHAB REGISTRY

Kerstin Bartelheim 1, Martin Benesch 2, Jochen Büchner 3, Joachim Gerß 4, Martin Hasselblatt 5, Rolf-Dieter Kortmann 6, Gudrun Fleischack 7, Eduardo Quiroga 8, Harald Reinhard 9, Reinhard Schneppenheim 10, Angela Seeringer 1, Reiner Siebert 11, Beate Timmermann 12, Monika Warmuth-Metz 13, Irene Schmid 14, Michael C Frühwald 1

Abstract

PURPOSE: AT/RT are aggressive malignancies of infancy and early childhood characterized by an unfavorable outcome and SMARCB1 (INI1, hSNF5) mutation. A consensus therapy regimen termed Rhabdoid 2007 was established in order to standardize treatment, to optimize the frequency and quality of genetic testing, neuropathology, CSF and neuroradiology review and to establish centralized clinical counseling. PATIENTS AND METHODS: From 2005 to 2009 Rhabdoid 2007 recommended 9 courses of alternating VCD and ICE with intrathecal methotrexate (before radiotherapy only) and focal radiotherapy (CSI for age> 3years and M+ disease). 31 patients were registered. 8 patients received high dose chemotherapy (HDCT) with autologous stem cell transplantation at the treating institutions choice. Data of 23 patients without HDCT were therfore analyzed separately. RESULTS: Patients presented at diagnosis with the following ages: 35% <1y (n = 8), 35% 1-3y (n = 8) and 30% >3y (n = 7). Metastases at diagnosis were present in four patients (17%). Central neuropatholoyl review was performed in all patients and molecular genetic analysis for germ line mutations was obtained in 15 patients (65%). Four patients with germ line mutations were identified. Statistical analysis demonstrated an association of prolonged survival with age >3 years at diagnosis, achievement of a complete remission and radiotherapy. 5-year overall and event-free survival were 52% (± 0.10) and 48% (± 0.10) respectively. No treatment-related death occurred. CONCLUSION: The treatment recommendation of Rhabdoid 2007 is feasible and achieved improvement of overall survival in patients with AT/RT when compared to historic cohorts. The established reference structures as well as the central data accrual of the European registry, EU-RHAB, offer an ideal basis for phase I/II clinical trials in this rare entity. Supported by the “Deutsche Kinderkrebsstiftung”, “Gesellschaft für Kinderkrebsforschung GKKF” and “Elterninitiative Horizonte, Weseke”.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.10

AT-010. LONGTERM REMISSION OF HIGH RISK AT/RT DESPITE INOPERABILITY AND WIDESPREAD METASTASIS - THE EU-RHAB STRATEGY

Michael C Frühwald 1, Kerstin Bartelheim 1, Angela Seeringer 1, Kornelius Kerl 2, Rolf-Dieter Kortmann 3, Monika Warmuth-Metz 4, Martin Hasselblatt 5, Reinhard Schneppenheim 6, Reiner Siebert 7, Thomas Klingebiel 8

Abstract

INTRODUCTION: Young age, incomplete resection and metastatic disease are established factors defining a high risk group among children with AT/RT. Affected patients almost inevitably take a fatal course and some question the justification of a therapeutic approach in these patients altogether. CASE PRESENTATION: Our patient presented at 2.5 years with a history of 4 weeks of intermittent fasting vomiting and weight loss. Imaging revealed extensive tumor masses and leptomeningeal metastases to the left trigonum and temporal region plus (supra- and infratentorial) spinal nodular seeding reaching the cauda equina (M3b). Following biopsy diagnosis of an inoperable AT/RT stage M3 was made. No germ line mutation was detected (Sequencing, MLPA, FISH). Molecular evaluation of the tumor showed a homozyous c.601C > T p.R201X mutation. Therapy was initiated according to the EU-RHAB proposal with 6 courses of biweekly alternating cycles of DOX, ICE, VCA including i.ventr. MTX. A significant tumor reduction and regression of ependymal and leptomeningeal seeding was achieved. Subsequently high dose chemotherapy with carboplatinum, thiotepa, i. ventr. MTX followed by stem cell transplantation was applied. At the age of 35 months the patient received craniospinal radiation with 35.2 Gy and a boost up to 55 Gy to the primary tumor region left temporal. This intensive therapy resulted in remission with questionable residuals up to 3 years after diagnosis. The patient remains in stable condition with rather limited side effects. CONCLUSION: Despite inoperable M3 disease with massive tumor burden a considerable tumor regression and prolonged survival may be achieved with intensive therapy even in very young patients with AT/RT. EU-RHAB is supported by the Deutsche Kinderkrebsstiftung and the Gesellschaft für Kinderkrebsforschung - GKKF.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.11

AT-011. ATYPICAL TERATOID/RHABDOID TUMORS (ATRT): TREATMENT EFFORTS AT KING FAISAL SPECIALIST HOSPITAL AND RESEARCH CENTRE, RIYADH, SAUDI ARABIA

Amani Al-Kofide 1, Yasser Khafaga 1, Hindi Al-Hindi 1, M Dababo 1, Anwar Ul-Haq 1, M Anas 1, Mary Grace Barria 1, Khawar Siddiqui 1, Maher Hassounah 1, Mouhab Ayas 1, Essam Al-Shail 1

Abstract

The study was designed to describe clinical features, therapeutic approaches and prognostic variables in patients with ATRT treated at King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. Patients registered at our institution from 1989 to 2014 with confirmed pathology were identified and their medical charts were reviewed. Out of 68 patients identified from 1989-2014, 46 had confirmed pathology of ATRT and full clinical data available for analysis. Median age at diagnosis was 1.9years (0.03-24.1) and (54.3%,25) were boys. 67.4%(31) were younger than 3 years. 41.3%(19) had their tumor location as infratentorial, 30.4%(14) supratentorial, 4.3%(2) spine and 23.9%(11) at other locations. 56.5%(26) had vomiting followed by 23.9%(11) headache and 19.6%(9) ataxia at presentation. 65.2%(30) had local disease with 21.7%(10) disseminated to spine, 11%(5) to CSF and 2.2%(1) to brain. All patients underwent surgical resection; 68.9%(31 of 45, one patient excluded due to short follow-up) received subsequent chemotherapy on standard Malignant Rhomboid Tumor Protocol (23, 74.2%) followed by Rhabdomyosarcoma Stage IV Protocol (3, 9.7%). 42%(19 of 45) received radiotherapy; 36.8%(7 of 19) were younger than 3 years. Median Overall Survival (OS) was 1.31 ± 0.083 years while median Event Free Survival (EFS) was 0.74 ± 0.131 years. Our treatment failure rate was 62.2% (28 of 45 PD) with 75% in disseminated compared to 55.2% in local disease. Two-year EFS was significantly better in children with local than those with disseminated disease (24.6% ± 10.3% vs. 0%, p-value = 0.048). No other clinical characteristics were predictive of survival. 53.3%(24) were alive at last update, 15 had progressive disease with 5 on palliative care, 4 with Stable Disease, 2 in CR and for remaining 3 disease response could not be evaluated. Five year OS was 33.3% ± 10% and EFS was 11.5% ± 6.1%. Children with ATRT have a poor prognosis. Extent of disease played a significant role affecting EFS of our patient population.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.12

AT-012. HIPPO SIGNALING IS ESSENTIAL FOR THE PHENOTYPE ASSOCIATED WITH snr1 LOSS IN DROSOPHILA MELANOGASTER AND INVOLVED IN THE BIOLOGY OF SMARCB1-DEFICIENT ATYPICAL TERATOID/RHABDOID TUMORS

Martin Hasselblatt 1, Astrid Jeibmann 1, Kristin Eikmeier 1, Anna Linge 1, Pascal Johann 2, Björn Koos 3, Kerstin Bartelheim 4, Marcel Kool 2, Stefan M Pfister 2, Michael C Frühwald 4, Werner Paulus 1

Abstract

SMARCB1 (hSNF5/INI1) is a member of the evolutionarily conserved SWI/SNF chromatin remodeling complex, which plays an important role in the biology of atypical teratoid/rhabdoid tumors (AT/RT). Little is known, however, on pathways involved in the oncogenic effects of SMARCB1 inactivation, which might also represent targets for treatment. We here report a comprehensive study in Drosophila melanogaster, which establishes a functional role for several genes not yet associated with loss of snr1, the fly homolog of SMARCB1. Crossing snr1 knockdown flies with strains expressing specific RNAis shifted the lethal phenotype associated with snr1 knockdown in 70/1015 screened candidate genes, including hippo pathway members merlin, kibra and expanded. Furthermore, silencing of the human homologs NF2, WWC1 and FRMD6 as well as pharmacological inhibition of YAP1, the main effector of the hippo pathway, decreased proliferation of human rhabdoid tumor cells. In human AT/RT samples, YAP1 over-expression was associated with significantly shorter progression-free survival and overall survival. Highlighting the role of hippo signaling in SMARCB1-deficiency, the biology and possibly therapy of AT/RT, our results demonstrate that fly models can be employed for the identification of clinically relevant pathways in human cancer. Supported by IZKF Münster (Ha3/016/11).

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.13

AT-013. GENETIC ALTERATIONS OF SMARCA4 IN ATYPICAL TERATOID/RHABDOID TUMOURS (AT/RT) ARE ASSOCIATED WITH HIGHER FREQUENCY OF GERM LINE ALTERATIONS AND SHORTER SURVIVAL AS COMPARED TO SMARCB1 DEFICIENT AT/RT

Martin Hasselblatt 1, Ulrich Schüller 2, Reimar Junckerstorff 3, Marc K Rosenblum 4, Ali H Alassiri 5, Sabrina Rossi 6, Kerstin Bartelheim 7, Irene Schmid 8, Nick Gottardo 9, Helen Toledano 10, Elisabetta Viscardi 11, Leora Witkowski 12, Inga Nagel 13, Florian Oyen 14, William D Foulkes 12, Werner Paulus 1, Reiner Siebert 13, Reinhard Schneppenheim 14, Michael C Frühwald 7

Abstract

Atypical teratoid/rhabdoid tumors (AT/RT) are malignant brain tumors affecting young children. The vast majority is characterized by inactivating mutations of the SMARCB1 gene (hSNF5/INI1). Not all AT/RT, however, can be linked to genetic alterations of SMARCB1. In seven children harboring aggressive brain tumors with rhabdoid phenotype showing retained (normal) SMARCB1 protein expression, genetic alterations of SMARCA4, another member of the chromatin modeling complex, could be identified. Six tumors displayed inactivating mutations with loss of SMARCA4 protein expression. In one case with retained SMARCA4 expression, a homozygous missense mutation (c.2335G > A) resulting in an amino acid exchange in the ATP binding region of the ATPase domain could be identified. Interestingly, as compared to 33 SMARCB1 deficient AT/RT from the European Rhabdoid Tumor Registry (EURHAB), the proportion of germ line alterations was significantly higher in SMARCA4 mutated AT/RT (4/5 vs. 9/33, χ2 = 5.364, P = 0.02). Furthermore, overall survival was significantly shorter in SMARCA4 mutated AT/RT as compared to SMARCB1 mutated AT/RT [3 months (0-8 months) vs. 24 months (16-32 months); median (95% confidence intervals), Log-Rank-Test P < 0.001]. In conclusion, genetic alterations of the SMARCA4 gene in atypical teratoid/rhabdoid tumors (AT/RT) are associated with a higher frequency of germ line alterations and shorter survival as compared to SMARCB1 deficient AT/RT. These results should prompt routine screening of pediatric brain tumors for SMARCA4 alterations as well as genetic counseling of affected families. Supported by IZKF Münster (HA3/016/11), KinderKrebsInitiative Buchholz/Holm-Seppensen and Fördergemeinschaft Kinderkrebszentrum Hamburg e.V.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.14

AT-014. IMPACT OF HIGH DOSE CHEMOTHERAPY ON SURVIVAL OF NEWLY DIAGNOSED PATIENTS WITH ATYPICAL TERATOID RHABDOID TUMOUR (ATRT) - A SYSTEMATIC REVIEW AND RE-ANALYSIS OF MULTIMODAL THERAPY

Dominik Schrey 1, George Malietzis 2, Susan Chi 3, Christelle Dufour 4, Lucie Lafay-Cousin 5, Lynley Marshall 1, Fernando Carceller 1, Lucas Moreno 1, Stergios Zacharoulis 1

Abstract

BACKGROUND AND OBJECTIVES: ATRT is a highly malignant tumour associated with grim prognosis. There is currently no consensus on optimal treatment. High dose chemotherapy with stem-cell-rescue (HD-SCR) was introduced to consolidate and improve outcome. However its benefit remains unclear and controversial. The main objective of this systematic review was to evaluate the impact of HD-SCR on Progression Free Survival (PFS) and Overall Survival (OS). METHODS: A PubMed literature review was performed with MeSH term "atypical teratoid rhabdoid tumour". Reviews and articles including non CNS-rhabdoid tumors or adult patients were excluded. Age at diagnosis, extend of surgery, staging (M0/M+), treatment with intrathecal chemotherapy (IT), use of radiotherapy, use of HD-SCR were extracted. Individual authors were contacted to complete missing data. RESULTS: Overall 359 papers were identified. Twenty-eight met inclusion criteria and were further evaluated. Three hundred and thirty two patients were analysed. Median age at diagnosis was 37 months (1 -231). Median PFS and OS for all patients were respectively 18 months and 33 months. Data on HD-SCR were available for 203 patients. Fifty eight (28.5%) underwent HD-SCR using various regimen of chemotherapy. Multivariate Cox analysis showed a significant favourable HR for OS/PFS for patients who received HD-SCR (OS: 0.529 (0.331-0.845);p = 0.008; PFS: 0.613(0.406-0.927);p = 0,02). Radiotherapy did also significantly impact OS (HR: 0.403 (0.247-0.656;p < 0.001)) and PFS (HR: 0.640 (0.438-0.935;p = 0.021). Incomplete surgical resection had significant negative impact on OS with HR of 1.665 (1.057-2.623;p = 0.028), but not PFS. The use of IT did not impact significantly on OS with HR 0.555 (0.294-1.048;p = 0.069), but a trend was observed. CONCLUSION: This systematic review allowed analysing a large dataset of children with ATRT. Data suggests that patients with newly diagnosed ATRT may benefit from HD-SCR. Surgery and use of radiation also seem to have impact on PFS/OS. Prospective randomised trials will be needed to confirm these findings.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.15

AT-015. INFLUENCE OF miRNAs IN ATYPICAL TERATOID RHABDOID TUMORS

Ratan Bhardwaj 1, Madhavi Chakravadhanula 1, Victor Ozals 1, Chris Hampton 1, Raghu Metpally 1

Abstract

Atypical Teratoid Rhabdoid Tumors (ATRTs) are aggressive tumors with significantly worse survival than other tumors in the field of pediatric neuro-oncology. In recent years, genome sequencing technologies have revealed that the mammalian transcriptome includes large numbers of non-coding RNAs (ncRNAs) such as, microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs), and long non-coding RNAs (lncRNAs). Studies have shown that miRNA can function as tumor suppressors or oncogenes. Loss of SMARCB1 may cause epigenetic modifications in ATRTs. We hypothesize that understanding the interactions of these ncRNAs either among the known groups or with chromatin remodeling proteins such as Polycomb Repressor Complex proteins, will shed light on some aspects of epigenetic modifications in ATRT. Transcriptome analyses were first performed to study the miRNA expression profiles in 20 ATRT patient samples and 3 patient derived primary cell lines, on the Nanostring platform and the Ilumina platform. These results may improve our understanding of epigenetic modifications in ATRT which may lead us toward discovery of novel therapeutics.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.16

AT-016. INCIDENCE AND OUTCOME IN SMALL CHILDREN WITH ATYPICAL TERATOID RHABDOID TUMOR (ATRT) IN THE SWEDISH NATIONAL REGISTRY FOR CNS TUMORS IN CHILDREN

Pernilla Grillner 1, Jurate Asmundsson 2, Bengt Gustavsson 3, Stefan Holm 1

Abstract

Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant CNS tumor with rhabdoid features predominantly diagnosed in children less than 3 years old. Ninety percent of ATRT cases are diagnosed in children ≤5 years of age. The true incidence is not known, but is estimated to be 10% of CNS tumors in children under 2 years. The tumor is a relatively newly recognized entity and has been possible to diagnose during the last 10 years. In the WHO classification (2000), ATRT was introduced as a diagnosis and the lack of INI1/SNF5 gene product as a new specific marker for this tumor entity. It has histopathological similarities with medulloblastoma and primitive neuroectodermal tumors (PNETs). These tumors do not, however, involve INI1/SNF5 (SMARCB1) gene mutations. It has a low overall survival, but the prognosis has improved with multimodal treatmentprotocols including surgery, chemotherapy, and radiotherapy. In the Swedish registry for CNS tumors in children, we find 1.4 % of children ≤ 4 years diagnosed with ATRT between 1992 and 2012. It is likely that there are undiagnosed cases in the registry. The present study investigate the incidence of ATRT in children from 1992-2012 in this registry, by re-examination and staining for immunoreactivity of INI1 on tumour material from 210 patients diagnosed with medulloblastoma, PNET, choroid plexus tumors or tumors with mixed tissue types. We will also report outcome for the patients diagnosed with ATRT. Describing the incidence and outcome of ATRT in the Swedish material contribute to the knowledge of this tumor type that still has a very poor prognosis. Results can be used to correlate treatment vs survival and neurological outcome in this patient category, and contribute to the development of new therapies with increased survival and reduced lateeffects. This work also contribute to the accuracy of the Swedish registry.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.17

AT-017. ATYPICAL TERATOID/RHABDOID TUMOUR IS A HETEROGENEOUS ENTITY THAT COMPRISES SUBGROUPS WITH DISTINCT MOLECULAR PROFILES

Pascal D Johann 1, Andrey Korshunov 2, Marina Ryzhova 3, Kornelius Kerl 4, Till Milde 5, Olaf Witt 5, David TW Jones 1, Volker Hovestadt 1, Amar Gajjar 7, Martin Hasselblatt 8, Michael Frühwald 9, Stefan Pfister 1, Marcel Kool 1

Abstract

Atypical Teratoid/Rhabdoid Tumours (AT/RT) represent an important subgroup of pediatric brain tumours that is often associated with hereditary cancer predisposition syndromes. While SMARCB1/SMARCA4 mutations and the consequent loss of INI-1/BRG1 protein expression represent diagnostically used molecular features in AT/RT, these tumours seem to lack other recurrent genomic aberrations, pointing to an important role of the epigenome in tumorigenesis. To study this, we subjected a cohort of 71 AT/RTs to genome-wide DNA methylation profiling using Illumina 450k arrays and additionally analysed these samples for gene expression using Affymetrix 133plus2.0 arrays. Unsupervised cluster analyses of both methylation and expression data identified three distinct subgroups, characterized by different methylation patterns and pathways implicated in cancer, such as the Sonic Hedgehog signalling pathway, which is activated in only one of the subgroups. Additional differences in the expression of relevant molecular targets (such as Histone deacetylase inhibitors and DNA methyltransferases) could be detected between the groups. In 22 samples for which matching expression and methylation profiles were available, a high correlation was observed between the subgroups defined by gene expression and methylation profiles respectively. In order to better understand the biology of this aggressive disease and to characterize each of these distinct molecular subgroups, we are currently analysing a cohort of 24 AT/RT using whole-genome sequencing, whole-genome bisulfite sequencing, RNA-sequencing, and ChIP-sequencing for various histone marks and other important enhancer elements (such as Brd4 and EZH2) in AT/RT tumorigenesis. Integrating this data will give us a comprehensive landscape of the AT/RT (epi)genome, which may pave the way to novel therapeutic strategies and potentially patient stratification.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.18

AT-018. CHARACTERISING CRITICAL PATHWAYS IN ATRT TUMOURIGENESIS: A GENOME-WIDE ANALYSIS OF PRIMARY TUMOURS AND FUNCTIONAL GENOMIC MODELS

Martina Finetti 1, Alicia del Carpio Pons 1, Matthew Selby 1, Amanda Smith 1, Stephen Crosier 1, James Wood 1, Benjamin Skalkoyannis 1, Simon Bailey 1, Steven Clifford 1, Daniel Williamson 1

Abstract

Rhabdoid tumours are rare aggressive tumours of early childhood which may occur at any location in the body; most frequently in the CNS (ATRT - Atypical Teratoid Rhabdoid Tumours) and kidney. >90% of Rhabdoid tumours have biallelic inactivation of SMARCB1; a core subunit of the SWI/SNF complex. Inactivation of SMARCB1 provokes widespread chromatin remodelling and affects the expression of many hundreds of downstream genes/pathways. Understanding which of these downstream effects is critical to ATRT tumourigenesis will allow us to rationally predict how loss of SMARCB1 may be counteracted therapeutically. We performed RNA-seq and 450K-methylation array on primary rhabdoid tumorus (n > 30) and on 4 rhabdoid tumour cell lines in which lentivirus was used to re-express SMARCB1. Integrative bioinformatics analyses were performed to cross-reference results from our functional models with primary ATRT and define key biological effects. We show that whilst Rhabdoid tumours have a common and characteristic biology they show distinct sub-grouping of their expression and methylation profiles by location; ATRT are distinguishable from extra-cranial Rhabdoid Tumours. We show that loss of SMARCB1 leads not only to deregulated expression of hundreds of genes, but also expression of aberrant isoforms, switches in promoter usage and expression of novel transcripts. We show that genome-wide methylation patterns are altered by SMARCB1 loss with consequent changes in expression. We have critically analysed the genomic changes downstream of SMARCB1 loss to isolate pathways which are potentially critical downstream targets in ATRT. Using next generation sequencing and chromatin immunoprecipitation we are developing a high-resolution picture of the downstream consequences of SMARCB1 loss to both the transcriptome and methylome, these results are being cross-referenced and verified in primary ATRT. This will provide an excellent resource to isolate, from amongst the many hundreds of possible downstream effects, key tumourigenic pathways or events which may be ultimately targetable therapeutically.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.19

AT-019. TREATMENT OPTIONS AND CLINICAL OUTCOME IN INFANTS WITH AT/RT

Angela Seeringer 1, Kerstin Bartelheim 1, Kornelius Kerl 2, Martin Hasselblatt 3, Stefan Rutkowski 4, Beate Timmermann 5, Rolf Dieter Kortmann 6, Reinhard Schneppenheim 4, Monika Warmuth-Metz 8, Joachim Gerß 9, Reiner Siebert 10, Norbert Graf 7, Joachim Boos 2, Karsten Nysom 11, Michael C Frühwald 1

Abstract

PURPOSE: The specifics of a developing organism and the aggressive nature of AT/RT are main reasons for the poor prognosis of these tumors especially in the vulnerable age group below 1 year. Here, we report first results of a consensus treatment regimen proposed by EU-RHAB including multidrug chemotherapy, in selected cases high dose chemotherapy (HDCT) and radiotherapy (RT). PATIENTS AND METHODS: Until January 2014, we registered 53 infants with AT/RT (46 AT/RT, 4 MRT + AT/RT, 3 RTK + AT/RT). The recommended EU-RHAB multidrug chemotherapy comprises 9 courses of alternating Dox, VCA, and ICE with intrathecal methotrexate (MTX) followed by radiotherapy (RT) in an age appropriate manner. 33 patients received intrathecal MTX, 18 patients radiotherapy (median age at RT = 16 months) and 13 high dose chemotherapy (HDCT) with autologous stem cell transplantation. RESULTS: Out of 53 infants, 11 (21 %) presented with a tumor at birth (congenital tumors). We identified 14 patients (26 %) with germ line mutations and 13 infants (25 %) presented with metastases at diagnosis. Radiotherapy and high dose chemotherapy were associated with improved 2y-OS rates. (2y-OS 18% without RT, 55 % with RT; HDCT: 2y-OS: with HDCT 65 %, without: 38 %. 9 patients received RT + HDCT with a 2y-OS of 67 %). No toxic death occurred We will discuss reasons for potential bias in patient selection for radiotherapy and HDCT. CONCLUSION: Intensive multimodal therapy according to the EU-RHAB recommendations is feasible in infants with AT/RT and may improve overall survival. Supported by the “Deutsche Kinderkrebsstiftung”, “Gesellschaft für Kinderkrebsforschung GKKF” and “Elterninitiative Horizonte”.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.20

AT-020. ARSENIC TRIOXIDE INHIBITS TUMOR CELL GROWTH IN MALIGNANT RHABDOID TUMOR CELL IN VITRO AND IN VIVO BY TARGETING OVEREXPRESSED Gli1

Kornelius Kerl 1, Natalia Moreno 1, Till Holsten 1, Julia Ahlfeld 3, Julius Mertins 1, Marc Hotfilder 2, Marcel Kool 4, Kerstin Bartelheim 5, Sabine Schleicher 6, Rupert Handgretinger 6, Michael Frühwald 5, Michael Meisterernst 1

Abstract

PURPOSE: Sonic hedgehog pathway (SHH) has been implicated in tumorigenesis and maintenance of tumor progenitor cells. In a subgroup of rhabdoid tumors SHH is activated downstream of the receptors smo and ptch. SMARCB1/INI1 directly controls the expression of Gli1 indicating that loss of INI1 may induce deregulation of Gli1. Small molecular inhibitors specifically targeting Gli1 (e.g. GANT 61), have been evaluated in preclinical studies, but are not available for clinical purposes yet. Arsenic trioxide targets Gli expression and inhibits proliferation of smo-receptor resistant SHH-activated medulloblastoma in vitro and in vivo. METHODS: We used arsenic trioxide and genetic approaches (siRNA) to target GLI in rhabdoid tumors in vitro and in vivo. Inhibition of rhabdoid tumor proliferation, cell cycle changes and apoptosis were measured in vitro by using MTT-tests and FACS analysis. To detect in vivo effects of ATO on rhabdoid tumor cell growth mouse xenograft models were used. RESULTS: In vitro rhabdoid tumor cell lines are highly sensitive to arsenic trioxide, inducing apoptosis in low dose (about 1 µM). Targeting Gli1 by siRNA in rhabdoid tumor cell lines inhibited cell proliferation and induced apoptosis. In vivo arsenic trioxide inhibited tumor growth of rhabdoid tumor xenograft mice. Rhabdoid tumors showed necrosis after ATO treatment in xenograft mouse models. Gli1 expression, which is deregulated in rhabdoid tumors by loss of INI1, is suppressed by ATO in vitro and in vivo. CONCLUSION: We demonstrate that ATO might be an interesting new therapeutic option for the treatment of SHH activated rhabdoid tumors by targeting overexpressed Gli1.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.21

AT-021. LOSS OF SMARCB1 PROTEIN IMPAIRS CEREBELLAR DEVELOPMENT

Kornelius Kerl 1, Christin Schmidt 2, Julia Ahlfeld 3, Natalia Moreno 1, Stefanie Dittmar 1, Stefan Pfister 2, Michael Frühwald 4, Marcel Kool 2, Michael Meisterernst 1, Ulrich Schüller 3

Abstract

PURPOSE: SMARCB1 (INI1) is a well known tumor suppressor genes that are crucially involved in the formation of malignant rhabdoid tumors, such as atypical rhabdoid/teratoid tumors (AT/RTs). AT/RTs typically affect infants and occur at all sites of the central nervous system, but are particularly frequent in the cerebellum. Here, granule neurons and its progenitor cells represent the most abundant cell type and are known to give rise to a subset of medulloblastoma, a histologically similar embryonal brain tumor. METHODS: In order to test how Smarcb1 proteins influence the development of granule neurons and whether this population may serve as cellular origin for AT/RTs, we specifically deleted Smarcb1 in cerebellar granule neuron precursors (GNPs) in vitro and in vivo. Cultured granule cells were analyzed using proliferation assays and gene expression analyses. Behavioral tests and morphological analyses were performed on Math1-cre::Smarcb1Fl/FL and hGFAP-cre::Smarcb1Fl/FL animals. RESULTS: Deletion of Smarcb1 in cultured GNPs resulted in significantly enhanced Wnt signaling and decreased proliferation. Respective mutant mice displayed severe ataxia and motor coordination deficits, but did not develop any tumors. In fact, they suffered from a severely hypoplastic cerebellum due to a significant inhibition of granule neuron precursor proliferation, a phenotype that is strongly reminiscent of mice with constitutively active Wnt signaling in cerebellar granule cells. CONCLUSION: Our results emphasize cell-type dependent roles of Smarcb1 protein and argue against cerebellar granule cells as the cellular origin for AT/RTs. This work was supported by the German Cancer Aid (Max-Eder-Programm), the Else-Kröner-Fresenius-Stiftung and the Wilhelm Sander Stiftung (all to U.S.); the IMF Münster, the IZKF Münster and the Sonja Wasowicz Fundation (all to KK).

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.22

AT-022. THE EPIDEMIOLOGY AND TREATMENT OUTCOME OF ATYPICAL TERATOID RHABDOID TUMOR (ATRT) IN HONG KONG: REPORT FROM THE HONG KONG PEDIATRIC HEMATOLOGY ONCOLOGY STUDY GROUP

GCF Chan 1, MMK Shing 2, HL Yuen 3, RCH Li 4, SL Ling 5

Abstract

OBJECTIVE: There are very few population based study on ATRT and the incidence remains undetermined. MATERIALS AND METHODS: Prospective collection of local childhood pediatric brain tumors data has been performed since early 90′s. Because ATRT was recognized only in recent decade, data from Jan 1999 to Dec 2012 were retrieved. Patients were from 5 public hospitals which handled almost all paediatric cancers in our locality. Data was further crosschecked with the Hong Kong Cancer Registry database which collected all the pathology reports of cancer. RESULTS: Within the 14 yrs, 10 cases of childhood (≤18yrs) ATRT were diagnosed. Excluding 2 non-local residents, the incidence of ATRT was 0.5/million ≤ 15yrs children/year. The median age at diagnosis was 2.6yrs (range 0.2 to 9.5yrs, 7 < 3yrs) and M:F = 1:1. For the 10 patients, tumors was at posterior fossa (5/10) or various locations supratentorially. The commonest presenting symptom were vomiting (8/10) followed by ataxia with unsteady gait (3/10). Only 2 had focal neurological deficit and 1 had convulsion. All had surgical resection; but only 6/10 & 4/10 were treated with chemotherapy and radiation therapy (RT) respectively. Chemotherapy regimens varied with age at presentation and era of diagnosis. They included Baby-POG(n = 3), CCV(n = 1) and Peters' protocol with intraventricular chemotherapy(n = 2). Only one 9.7yrs patient with frontal ATRT treated with total resection + RT + CCV protocol survived at 7.7yrs post-diagnosed. All other patients died with a median survival of 1.1yrs (range 0.2 to 2.3yrs). The 1-&2-year overall survival rate was 40 + /-16% & 30 + /-15% respectively. CONCLUSION: ATRT is a rare disease with extremely poor prognosis. The epidemiology of ATRT among Chinese is similar to that of the West. Patients' young age hinder the application of RT and the efficacy of intraventricular chemotherapy or intensive chemotherapy remains to be confirmed.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.23

AT-023. EXPERIENCE WITH A METRONOMIC ANTIANGIOGENIC THERAPY IN CHILDREN WITH RECURRENT ATRT AND VARIOUS MALIGNANT CNS TUMORS OTHER THAN MEDULLOBLASTOMA

Irene Slavc 1, Andreas Peyrl 1, Monika Chocholous 1, Amedeo Azizi 1, Thomas Czech 2, Karin Dieckmann 3, Christine Haberler 4, Ulrike Leiss 1

Abstract

BACKGROUND: Patients with recurrent malignant CNS tumors have a poor prognosis. We used a metronomic antiangiogenic salvage therapy and report on the response of individual tumor types to this approach. PATIENTS: From 2/2007 to 9/2013, 34 patients with various recurrent brain tumors started treatment with an antiangiogenic multidrug-regime consisting of bevacizumab, thalidomide, celecoxib, fenofibrate, and etoposide, alternating with cyclophosphamide with or without intraventricular therapy (etoposide and liposomal cytarabine). Diagnoses were ATRT (n = 5), ependymoma (n = 4), CNS PNET (n = 3), ETANTR (n = 3), pineoblastoma (n= 2), HGG (n = 2), DIPG (n = 3), NGGCT (n = 2), MPNST (n = 2) and choroid plexus carcinoma, astroblastoma, paraganglioma, meningioma, oncocytoma, epitheloid sarcoma, endolymphatic sac tumor and neuroblastoma in one each. RESULTS: OS for the whole cohort was 39.5. ± 9.1% at three years and 23.7 ± 9.0% at 5 years. 3/5 patients with ATRT survive for 70, 38, and 30 months after their last recurrence and are off therapy for 37, 23, and 18 months. Patients with CNS PNET, ETANTR, HGG, DIPG, oncocytoma and neuroblastoma did not appear to respond to this strategy. The 2 patients with pineoblastoma survived for 38 and 27 months, respectively, despite extensive leptomeningeal disease. The 2 patients with NGGCT showed a dramatic drop of their Alpha-Fetoprotein levels. CONCLUSION: The proposed antiangiogenic regimen that has prior shown activity in medulloblastoma leading to an international phase II protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290) seems to be also efficacious in recurrent ATRTs. In a number of other tumor entities time to progression could be prolonged while maintaining good quality of life.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.24

AT-024. A CASE OF RELAPSING SPINAL ATYPICAL TERATOID/RHABDOID TUMOR (AT/RT) RESPONDING TO VINORELBINE, CYCLOPHOSPHAMIDE AND CELECOXIB

Giacomo Gotti 1, Veronica Biassoni 1, Elisabetta Schiavello 1, Filippo Spreafico 1, Emilia Pecori 2, Lorenza Gandola 2, Maura Massimino 1

Abstract

BACKGROUND: Isolated spinal AT/RT rarely occurs. Despite chemotherapy and radiotherapy rapid progression is often described with mean survival less than 1 year. CASE REPORT: A 19 year-old girl was admitted at our hospital after surgical subtotal resection of a L4-L5 mass. AT/RT was diagnosed, confirmed by central histopathological review. Adjuvant treatment according to the European Rhabdoid registry was delivered: Doxorubicin, Ifosfamide/Carboplatinum/Etoposide and Vincristine/Cyclophosphamide/Actynomicin-D were repeated twice. Intratechal MTX was not administered due to tumour site. High dose Carboplatinum (500 mg/sqm day 1-2) and Thiothepa (300 mg/sqm day 1-2-3) and further lumbar RT (54 Gy with standard fractionation) were delivered. At the end of the treatment, neurological deficits (hypostenia and bladder dysfunction) consistently regressed and MRI showed PR. After 7 months from the end of treatment, she complained worsening lower back pain and gait impairment and MRI documented local tumor progression She underwent new surgical partial resection of the intradural mass. Post-operative flaccid paraparesis and sphincter incontinence required intensive rehabilitation. Histopathological examination confirmed AT/RT. Re-irradiation was excluded because the relapse was within the already irradiated field that received a maximal cumulative dose. Second line chemotherapy with Vinorelbine (60 mg/sqm day 1-8-21), Cyclophosphamide (50 mg/sqm/die) and Celecoxib (800 mg/sqm/die) was started from June 2013. Last MRI (November 2013) revealed cystic evolution of the lesion without significant increase in size. The girl was able to taper morphine off; neurological examination was stable with paraparesis and slightly improved sphincteric incontinence. After 7 months of 2nd-line treatment the patient is still alive with no clinical sign of PD, at 26 months from diagnosis. CONCLUSIONS. The peculiarity of this case report is the clinical-radiological response to a metronomic therapy in a case of early-relapsing spinal AT/RT occurred after maximal surgery, chemotherapy and radiotherapy.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.25

AT-025. EZH2 REGULATES THE EXPRESSION OF DNMTs IN MALIGNANT RHABDOID TUMORS

Julius Mertins 1, Kornelius Kornelius 1, Natalia Moreno 1, Till Holsten 1, Michael Frühwald 3, Marcel Kool 2, Michael Meisterernst 1

Abstract

PURPOSE: SMARCB1 (INI1) is a well-known tumor suppressor gene that is biallelically inactivated in atypical teratoid/rhabdoid tumors (ATRTs). According to exome sequencing studies no further genes are affected in primary rhabdoid tumors, suggesting that the epigenetic impact of the altered SWI/SNF remodeling complex is sufficient for cancer formation. As one possible effector SMARCB1 controls the expression of the histone methyltransferase EZH2, a member of the Polycomb 2 complex. Additionally multiple genes can be found downregulated by DNA methylation in those tumors. METHODS: In order to test how overexpressed EZH2 affects DNA methylation we repressed it and different DNMTs by genetic and pharmacological approaches. Rhabdoid tumor cell culture and mouse xenograft models were used to study possible synergistic effects of targeting EZH2 in combination with DNMT inhibitors. RESULTS: EZH2, DNMT1 and DNMT3a/3b are overexpressed in primary rhabdoid tumors and in rhabdoid tumor cell lines. Downregulation of overexpressed EZH2 affects the expression of deregulated DNMTs. Inhibition of EZH2 and DNMTs caused a synergistic effect in blocking the proliferation of rhabdoid tumor cells both in vitro and in the in vivo xenograft model. CONCLUSION: Our results support the hypothesis that overexpressed EZH2 regulates the DNA methylation of rhabdoid tumors, which uncovers new therapeutic options for the treatment of rhabdoid tumor patients.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.26

AT-026. A CASE OF ATYPICAL TERATOID/RHABDOID TUMOR FOLLOWED BY RAPID GROWTH OF KIDNEY TUMOR

Hirohito Yano 1, Noriyuki Nakayama 1, Naoyuki Ohe 1, Michio Ozeki 2, Kaori Kanda 2, Takeshi Kimura 2, Tomohiro Hori 2, Toshiyuki Fukao 2, Toru Iwama 1

Abstract

CASE PRESENTATION: An 18-month-old girl suddenly presented generalized seizure. The computed tomography (CT) scan and magnetic resonance imaging (MRI) revealed the lobulated and cystic lesion in her right frontal lobe. Her postnatal development had been normal. The chest and abdominal CT for systemic check showed no abnormalities. She underwent gross total removal of the tumor, and her seizures subsided. The pathological diagnosis was atypical teratoid/rhabdoid tumor (AT/RT), because of the positive immunoreactivity for cytokeratin, epithelial membranous antigen, synaptophisin and vimentin, more than 50% of Ki-67 labeling index and and negative for INI-1. She underwent 4 courses of ICE (ifosfamide, carboplatin and etoposide) therapy followed by 45 grey of the extended local irradiation. After 3 courses of chemotherapy, she presented macro-hematuria, which was considered to be the side effect of ifosfamide because of no abnormal findings on the abdominal CT. However, macro-hematuria continued after withdrawal of ifosfamide. Then she was examined on the abdominal MRI at 3 months after the last CT. It revealed a massive tumor in her left kidney, which was considered as the true cause of the macro-hematuria. She underwent 5th ICE, 2 courses of VDC (vincristine, doxorubicin and cyclophosphamide) and 1 course of irinotecan followed by local irradiation for the kidney tumor (KT). Although the KT slightly diminished, the re-examination of CT revealed the multiple metastases to her lung and liver. She received the palliative care using morphine. DISCUSSION: This is a rare case of AT/RT combined with a KT that was so-called malignant rhabdoid tumor of kidney (MRTK) not pathologically demonstrated in this case. The KT assumed to be too small to be found in the initial CT scan, and to rapidly grew after withdrawal of ICE therapy. Alternatively, AT/RT might develop metastasis to the kidney. We discuss the pathogenesis, diagnosis and therapy of this entity.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.27

AT-027. MANAGEMENT OF ATYPICAL/RHABDOID TUMOR OF THE CENTRAL NERVOUS SYSTEM

Alexander G Weil 1, Ana Diaz 1, Joanna Gernsback 1, Sanjiv Bhatia 1, John Ragheb 1, Toba Niazi 1, Ziad Khatib 1

Abstract

Central nervous system (CNS) atypical teratoid/rhabdoid tumors (ATRTs) are highly malignant tumors associated with a very poor prognosis despite aggressive management. Due to the rarity of this tumor, there is no consensus on the optimal therapeutic regimen. We sought to assess the outcome and prognostic factors for patients harboring CNS ATRTs managed in our institution. METHODOLOGY: Retrospective chart study of 11 consecutive patients treated for AT/RT of the CNS at Miami Children's Hospital between November 2000 and January 2013. We assessed overall survival (OS), progression free survival (PFS) and functional outcome using Langsky performance scale (LPS). RESULTS: Eleven patients (8 girls) with a mean age of 20.3 months (range 2-60) of whom 8 were < 3 years old were included. Six were located in posterior fossa and 5 were supratentorial. One patient had metastatic disease at diagnosis. 8 underwent gross total resection (GTR) (3 underwent subtotal resection). All patients received high dose (HD) alkylating chemotherapy (CT), 5 received primary radiation therapy (RT; 3 were < 3 years old). Three patients received delayed RT and salvage CT for disease progression. The mean OS was 80 months +/- 20.2 (40.4-119.5, 95% CI). The mean PFS was 10 months (1.23-18.75, 95% CI). At last follow-up, 6 were dead of disease, 3 were alive with no disease and 2 were alive with disease. Four of the 5 survivors were assessed using LPS and 3 had at least moderate restriction of activities. CONCLUSION: CNS AT/RT is associated with progression despite aggressive management . Long-term survival can be achieved in up to half of patients with aggressive therapy particularly using early primary RT in combination with chemotherapy. Long-term survival comes at the cost of significant neurological morbidity related to radiation-induced damage to the developing brain. Other options can be considered to improve OS and PFS while avoiding cognitive impairment that include delaying radiation therapy from intrathecal CT and HD myelosuppressive CT with autologous stem cell rescue.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.28

AT-028. COMBINATORIAL INHIBITION OF BRD4 AND CDK9 LEADS TO GLOBAL REPRESSION OF RNAPII TRANSCRIPTION ASSOCIATED WITH CELL DEATH IN RHABDOID TUMORS

Kornelius Kerl 1, Till Holsten 1, Natalia Moreno 1, Annabelle Zoghbi 1, amd Michael Meisterernst 1

Abstract

PURPOSE: Malignant rhabdoid tumors of infants are caused by the deletion of the INI1 subunit of the chromatin remodeling complex SWI/SNF, a factor that is involved in global chromatin and gene expression control. We have followed the assumption that these alterations render the tumor especially sensitive to further targeting of global gene expression control. CDK9 is the kinase subunit of the P-TEFb complex and is necessary to continue processive elongation by phosphorylation of serine 2 of the Pol II. P-TEFb exists in two major forms. The catalytic active form consists of CDK9 and cyclin T proteins in association with BRD4. BRD4 recruits CDK9 by binding to acetylated histones. RESULTS: Using very specific BRD4 inhibitors and highly specific CDK9 inhibitors, we could demonstrate that both inhibitors act synergistic on inhibition of proliferation, induction of apoptosis and inhibition of general transcription in rhabdoid tumor cell lines. CONCLUSION: These molecular insights provide a very promising new therapeutical approach for these highly malignant rhabdoid tumors. This work was supported by the IMF Münster, the IZKF Münster and the Sonja Wasowicz Foundation (all to KK).

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.29

AT-029. KNOCK-DOWN OF YAP1 REDUCES PROLIFERATION AND SURVIVAL OF AT/RT CELLS

Diane Birks 1, Andrea Griesinger 1, Vladimir Amani 1, Andrew Donson 1, Raphaela Posner 1, Christopher Dunham 2, B K Kleinschmidt-DeMasters 1, Michael Handler 1, Rajeev Vibhakar 1, Nicholas Foreman 1

Abstract

INTRODUCTION: Atypical Teratoid/Rhabdoid Tumors (AT/RTs) are highly aggressive central nervous system tumors of children. From gene expression studies, we have observed that multiple Hippo pathway genes are dysregulated in AT/RTs, including YAP1, WWTR1 (TAZ), MST1 and LATS2. Hippo is a recently identified developmental pathway that controls organ growth via regulation of its two pro-proliferative transcriptional co-factors, YAP1 and TAZ. In the current study, we examined the expression and biological role of YAP1 in AT/RTs. METHODS: mRNA expression was measured by microarray and qRT-PCR. Protein expression was assayed using immunohistochemistry and western blots. siRNA oligonucleotides were used for knock-down of YAP1 expression in AT/RT cell lines. Proliferation was measured using Excelligence Real Time Monitoring. Cell cycle and apoptosis were measured with flow cytometry. Anchorage independent growth was measured using methyl-cellulose colony assay. RESULTS: YAP1 gene expression was significantly higher in AT/RTs compared to other pediatric CNS tumors and non-tumor brain (all p < 0.0001). Immunohistochemistry showed nuclear expression of YAP1 in 16/22 (73%) AT/RT patient samples. Short-term knock-down of YAP1 in 3 AT/RT cell lines resulted in significantly slower growth rates compared to non-silencing controls. Knock-down of YAP1 also resulted in inhibition of anchorage-independent growth. Combining YAP1 knock-down with etoposide resulted in higher levels of cleaved caspase-3 and greater numbers of apoptotic cells compared to controls. CONCLUSIONS: YAP1 is over-expressed in both AT/RT tumors and cell lines. The presence of nuclear YAP1 seen in 70% of AT/RT patient samples suggests that YAP1 is affecting transcriptional programs in these tumors. Results from YAP1 knock-down in AT/RT cell lines indicate that YAP1 promotes proliferation and survival in AT/RT cells. Further studies are warranted to determine if drugs that block the transcriptional activity of YAP1, such as the recently reported small molecule verteporfin, may be a useful therapeutic adjunct in AT/RT treatment.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.30

AT-030. EXPRESSION OF HOX GENES AND HOTAIR IN ATRT COMPARED TO OTHER PEDIATRIC BRAIN TUMORS

Ratan Bhardwaj 1, Victor Ozals 1, Christopher Hampton 1, L Zhou 2, D Catchpoole 2, Madhavi Chakravadhanula 1

Abstract

Atypical teratoid rhabdoid tumors (ATRT) are highly malignant brain tumors predominantly occurring in young children. A characteristic feature of these tumors is aberrations of the SMARCB1 (hSNF5/INI1) locus on chromosome band 22q11.2 which result in loss of SMARCB1 protein expression. In most of the cases SMARCB1 aberrations encountered in ATRT are remarkably uniform, unlike most other pediatric brain tumors. HOX genes have been reported to be misexpressed in many tumors including lung carcinoma, neuroblastoma, ovarian carcinoma, cervical carcinoma, prostate carcinoma, breast carcinoma, and leukemia. HOX genes are transcription factors that play a pivotal role in patterning of the anterior-posterior body axis during embryonic development. In mammals such as mouse and human, 39 HOX genes are organized into 4 clusters on 4 different chromosomes. Recent studies have shown that HOXD9 contributes to cell proliferation and/or survival in glioma cells and glioma cancer stem-like cells. HOXB3, HOXB4, and HOXC6 were found to be expressed in pediatric medulloblastomas and PNETs. HOX genes are also known to be associated with long non-coding RNAs (lncRNAs) such as HOTAIR. Studies show that HOTAIR induces transcriptional silencing of the HOXD locus on chromosome 2 by interacting and recruiting the polycomb repressive complex 2 (PRC2) to the HOXD locus. PRC2, comprising of the subunits EZH2, SUZ12, and EED, is involved in developmental gene silencing and cancer progression. In this study, transcriptome sequencing analysis using the nanoString platform was performed. Expression of HOX genes was studied in ATRT and compared to expression of these genes in other pediatric brain tumors including Ependymoma, Medulloblastoma, Glioblastoma (GBM), and cerebellar pilocytic astrocytoma. Along with HOX genes, the transcriptome expression of HOTAIR was also studied in ATRT and compared to HOTAIR expression in the other pediatric brain tumors mentioned.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.31

AT-031. EXPRESSION OF EZH2, CYCLIN D1 AND VEGF IN ATYPICAL TERATOID/RHABDOID TUMORS OF CNS: POSSIBLE ROLE IN TARGETED THERAPY

Aanchal Kakkar 1, Ahitagni Biswas 1, Vaishali Suri 1, Mehar Sharma 1, Shashank Kale 1, Ashok Mahapatra 1, Chitra Sarkar 1

Abstract

INTRODUCTION: Atypical teratoid/rhabdoid tumor (AT/RT) is an uncommon malignancy with dismal outcome. No definite chemotherapy protocols are defined and these tumors respond poorly to multimodality therapies. Loss of INI1/SMARCB1 in AT/RTs leads to derepression of Cyclin D1 expression, and animal studies have revealed Cyclin D1to be a possible therapeutic target. Addition of vascular endothelial growth factor (VEGF) inhibitors to conventional chemotherapeutic regimens has also shown promising results in pediatric CNS tumors. Enhancer of Zeste 2 (EZH2) is the catalytic subunit of the polycomb repressive complex; its over-expression has been implicated in various cancers, including medulloblastomas, identifying it as a novel therapeutic target. We therefore conducted this study to assess immunohistochemical expression of EZH2, Cyclin D1 and VEGF in AT/RTs. METHODS: Cases of AT/RT diagnosed between 2006 and 2013 were retrieved. Clinical data and histopathological features were reviewed. Immunohistochemistry for EZH2, Cyclin D1 and VEGF was performed. Follow-up was noted where available. RESULTS: Thirteen cases of AT/RT, confirmed by INI1, were identified. Mean age of patients was 3.1 years (range 0.8–8 years). All cases examined showed EZH2 overexpression. Cyclin D1 immunopositivity was also noted in all cases (labelling index: 5 - 90%; mean-46%). VEGF positivity was seen in 80% cases. Follow-up was available in eight cases. (Range: 9-839 days). Two patients died of post-operative complications; one achieved clinical remission after cranio-spinal irradiation and chemotherapy, while five developed progressive disease. CONCLUSIONS: Varying degree of immunoreactivity to EZH2, Cyclin D1 and VEGF is noted in majority of AT/RTs, and detection of these markers may be of value in development of novel therapeutic agents and in determining which patients can benefit from anti-EZH2 and anti-angiogenic agents. Multicentre studies with follow-up of larger number of patients are, however, required to ascertain value of EZH2, cyclin D1 and VEGF expression in outcome-based patient stratification.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.32

AT-032. INTEGRATIVE GENOMIC ANALYSES IDENTIFY RECURRENT STRUCTURAL ALTERATIONS IN ATYPICAL TERATOID RHABDOID TUMOURS (ATRTs)

Jonathon Torchia 1, Daniel Picard 2, King Ching Ho 2, Dong-Anh Khuong-Quang 3, Louis Louterneau 4, Mathieu Bourgey 4, Tiffany Chan 1, Brian Golbourn 1, Lucie-Lafay Cousin 5, Michael D Taylor 6, Peter Dirks 6, James T Rutka 6, Eric Bouffet 7, Cynthia Hawkins 8, Jacek Majewski 4, Seung-Ki Kim 9, Nada Jabado 3, Annie Huang 7

Abstract

ATRTs (Atypical teratoid rhabdoid tumours) represent one of the most aggressive pediatric brain tumours. Paradoxically, ATRTs are reported to exhibit balanced genomes with alterations of the SMARCB1 locus on chr22, as the sole recurrent somatic genetic event. To better define molecular mechanisms underlying ATRT biology we comprehensively interrogated 63 ATRTs by integrating a combination of ultra-high resolution SNP genotyping whole-genome/exome and RNA sequencing. Copy number and structural alterations were mapped using orthogonal bioinformatics techniques. Structural alterations and mutations were validated by targeted re-sequencing using the Sanger method and/or MiSeq and Ion Torrent analyses. ATRTs exhibited few recurrent deleterious SNVs with exception of loss of function mutations in SMARCB1 (15 SNVs in 63 tumours). As reported previously, we observed a low mutation rate in primary ATRTs. Significantly, we observed structural alterations as predominant genetic mechanisms (∼3.2/tumor) in primary ATRTs. Notably, bi-allelic structural events leading to loss of SMARCB1 function were observed in the majority of primary ATRTs (76% of tumours) and included novel intra-chromosomal translocations of SMARCB1 not detected using conventional diagnostic techniques. We observed novel recurrent structural alterations associated with corresponding copy number driven gene expression changes in novel loci not previously implicated in ATRTs, in nearly 20% of primary ATRTs. These included focal deletions of BCR, MKL1, EP300, LRP1B, CDH13, ODZ2 and ZNF407. Our integrated high resolution genomics approach has uncovered novel loci with predicted functions in cell adhesion, DNA damage response and epigenetic regulation that will inform a better understanding of ATRT tumour biology. The identification of novel structural events in SMARCB1 and other genes indicates that the scope of genetic alterations in ATRTs has to date been underestimated and underscore WGS as an important tool for gene discovery as well as clinical diagnostics in ATRT.

Neuro Oncol. 2014;16(Suppl 1):i1–i9. doi: 10.1093/neuonc/nou065.33

AT-033. PROSPECTIVE STUDY ON PEDIATRIC PATIENTS WITH ATYPICAL TERATOID RHABDOID TUMORS (ATRT) OF THE CENTRAL NERVOUS SYSTEM (CNS)

John Han-Chih Chang 1, Michael Confer 2, Andrew Chang 2, Stewart Goldman 3, Megan Dunn 4, William Hartsell 1

Abstract

PURPOSE: ATRT is a rare and aggressive CNS tumor usually presenting in very young children. Aggressive treatments have improved outcomes. Such strategies have included radiation therapy. However, at such a young age, short and long term radiation toxicities are prevalent. We prospectively enrolled pediatric CNS ATRT patients onto the Proton Collaborative Group registry protocol to evaluate the efficacy and toxicities of proton radiation therapy in this population. MATERIALS AND METHODS: 12 consecutive pediatric ATRT patients were treated with at the Central DuPage Hospital Proton Center and the Oklahoma City Procure Proton Therapy Center between March 2010 – December 2013 utilizing 3D Conformal Proton Therapy. RESULTS: 12 patients were evaluated. They were all under 3 years of age. Six patients had gross total resections, while 4 had subtotal resections along with another 2 not documented. All patients received multiagent intensive chemotherapy while one had stem cell transplant as part of his regimen. Radiation was to local fields for 9 patients, while 3 had craniospinal irradiation. The mean follow up was 11.9 months (range of 1-43 months). At last follow up 10 patients were alive without evidence of disease. Only 4 children had grade 3 toxicities (all acute nausea, vomiting and anorexia during radiation therapy that responded to steroids). Proton therapy was able to reduce the dose to the cochlea, optic chiasm, hippocampus, temporal lobes and integral whole brain. CONCLUSION: The initial results on the largest prospective series of CNS ATRT patients treated with proton therapy seem to be favorable. The aggressive treatment regimens utilizing proton beam therapy yield proven efficacy and improved toxicity profiles, which is critically important in this young patient population with such an aggressive disease.

Articles from Neuro-Oncology are provided here courtesy of Society for Neuro-Oncology and Oxford University Press

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