scholarly journals ATRT-18. SHH-SUBTYPE ATYPICAL TERATOID/RHABDOID TUMORS ARE SELECTIVELY SENSITIVE TO GEMCITABINE TREATMENT

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii279-iii279
Author(s):  
Dennis Metselaar ◽  
Michaël Hananja Meel ◽  
Joshua Goulding ◽  
Piotr Waranecki ◽  
Mark de Gooijer ◽  
...  
Keyword(s):  
Large Scale ◽  
Expression Profiles ◽  
Sirtuin 1 ◽  
Rank Test ◽  
Specific Cell ◽  
Dismal Prognosis ◽  
Atypical Teratoid ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors ◽  
Gemcitabine Treatment

Abstract Atypical Teratoid Rhabdoid Tumors (ATRT) are highly malignant embryonal tumors of the central nervous system with a dismal prognosis. ATRT can be divided into three molecular subgroups of which the Sonic Hedgehog (SHH) subgroup is most prevalent. In this study, we developed and validated a novel patient-derived ATRT model, which we used along a panel of other primary ATRT models for large scale drug discovery assays. We found that ATRTs are selectively sensitive to the nucleoside analogue gemcitabine, with SHH-subtype ATRTs being the most sensitive subgroup. Gene expression profiles and protein analysis indicated that gemcitabine treatment causes degradation of Sirtuin 1 (SIRT1), which causes ATRT specific cell-death through NF-kB and p53 activation. Furthermore, we found that this gemcitabine induced loss of SIRT1 results in a nucleus-to-cytoplasm shift of the SHH signaling activator Gli, explaining the additional gemcitabine sensitivity in SHH-subtype ATRT. Treatment of SHH-subgroup ATRT xenograft-bearing mice resulted in a >40% increase in median survival (p<0.01, log-rank test) and long-term survivors in two independent models. To prepare translation of our findings to the clinic, we investigated potential gemcitabine induced resistance mechanisms by conducting kinome-wide CRISPR/Cas9 knockout screens in primary ATRT cells. Through these experiments we found that low-dose gemcitabine treatment combined with inhibition of protein kinase C zeta (PKCζ) prevents regrowth of resistant ATRT subclones. Together, these findings show that ATRT are highly sensitive to gemcitabine treatment; and as such we suggest that gemcitabine may be rapidly incorporated into future treatment regimens for SHH-ATRT.

Infantile Atypical Teratoid Rhabdoid Tumor of the Spine Presenting with Acute Hydrocephalus

2020 ◽  
Vol 55 (5) ◽  
pp. 313-318
Author(s):  
Parmenion P. Tsitsopoulos ◽  
Konstantinos Marinos ◽  
Elpis Chochliourou ◽  
Marios Theologou ◽  
Christina Nikolaidou ◽  
...  
Keyword(s):  
Multimodality Treatment ◽  
Ventilator Weaning ◽  
Massive Bleeding ◽  
Acute Hydrocephalus ◽  
Subaxial Cervical Spine ◽  
Dismal Prognosis ◽  
Atypical Teratoid ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors ◽  
Whole Spine

<b><i>Introduction:</i></b> Central nervous system atypical teratoid rhabdoid tumors (ATRTs) are aggressive lesions usually presenting during the first 3 years of life. These tumors have a dismal prognosis with most patients dying within 1 year from presentation. Primary spinal location in infants is very rare. <b><i>Case Presentation:</i></b> We report a case of a 4-month-old boy who presented with a history of hypotonia, poor head control, and gradually reduced level of consciousness, over the past week. Computed tomography (CT) showed acute hydrocephalus with no underlying intracranial pathology. A ventriculoperitoneal shunt was inserted acutely. Postoperatively, ventilator weaning was unsuccessful. MRI of the brain and whole spine revealed an intraspinal extradural contrast-enhancing heterogenous mass in the subaxial cervical spine extending to the thoracic cavity. A biopsy was taken through a transthoracic approach, and histopathology confirmed the diagnosis of ATRT. Several cycles of radiation therapy and chemotherapy were given but the tumor progressed both locally and intracranially. Eventually, pupils became dilated and fixed. Brain CT scan showed widespread ischemic lesions and an extensive intracranial tumor extension with massive bleeding. The child eventually died 110 days after admission. <b><i>Conclusions:</i></b> In infants presenting with acute hydrocephalus where an obvious intracranial cause is not detected, the whole neuraxis should be screened. However, despite aggressive measures and advances in multimodality treatment, prognosis of ATRT remains dismal.

Atypical Teratoid/Rhabdoid Tumors (ATRT): Improved Survival in Children 3 Years of Age and Older With Radiation Therapy and High-Dose Alkylator-Based Chemotherapy

2005 ◽  
Vol 23 (7) ◽  
pp. 1491-1499 ◽  
Author(s):  
Tanya M. Tekautz ◽  
Christine E. Fuller ◽  
Susan Blaney ◽  
Maryam Fouladi ◽  
Alberto Broniscer ◽  
...  
Keyword(s):  
Older Patients ◽  
Immunohistochemical Analysis ◽  
High Dose ◽  
Younger Patients ◽  
Clinical Criteria ◽  
Dismal Prognosis ◽  
Atypical Teratoid ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors ◽  
Clinical Records

PurposeTo describe clinical features, therapeutic approaches, and prognostic factors in pediatric patients with atypical teratoid/rhabdoid tumors (ATRT) treated at St Jude Children's Research Hospital (SJCRH).Patients and MethodsPrimary tumor samples from patients diagnosed with ATRT at SJCRH between July 1984 and June 2003 were identified. Pathology review included histologic, immunohistochemical analysis, and fluorescence in situ hybridization for SMARCB1 (also known as hSNF5/INI1) deletion. Clinical records of patients with pathologic confirmation of ATRT were reviewed.ResultsThirty-seven patients were diagnosed with ATRT at SJCRH during the 19-year study interval. Six patients were excluded from this clinical review based on pathologic or clinical criteria. Of the remaining 31 patients, 22 were younger than 3 years. Posterior fossa primary lesions and metastatic disease at diagnosis were more common in younger patients with ATRT. All patients underwent surgical resection; 30 received subsequent chemotherapy. The majority of patients aged 3 years or older received postoperative craniospinal radiation. Two-year event-free (EFS) and overall survival (OS) of children aged 3 years or older (EFS, 78% + 14%; OS, 89% ± 11%) were significantly better than those for younger patients (EFS, 11% ± 6%; OS, 17% ± 8%); EFS, P = .009 and OS, P = .0001. No other clinical characteristics were predictive of survival. Three of four patients 3 years or older with progressive disease were successfully rescued with ifosfamide, carboplatin, and etoposide therapy.ConclusionChildren presenting with ATRT before the age of 3 years have a dismal prognosis. ATRT presenting in older patients can be cured using a combination of radiation and high-dose alkylating therapy. Older patients with relapsed ATRT can have salvage treatment using ICE chemotherapy.

scholarly journals ATRT-05. RESULTS OF MULTICENTER TRIAL CONCERNING THE TREATMENT OF CHILDREN WITH ATYPICAL TERATOID/RHABDOID TUMORS (ATRT) OF THE CENTRAL NERVOUS SYSTEM

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii276-iii276
Author(s):  
Olga Zheludkova ◽  
Lyudmila Olkhova ◽  
Yuri Kushel’ ◽  
Armen Melikyan ◽  
Marina Ryzhova ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Progression Free Survival ◽  
Multicenter Trial ◽  
Intrathecal Methotrexate ◽  
Subtotal Resection ◽  
Tumor Biopsy ◽  
Atypical Teratoid ◽  
The Central Nervous System ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors

Abstract We analyzed 105 patients under 18 years. The median age was 21 months. There were 54 boys and 51 girls. The supratentorial tumors were in 53 patients, infratentorial in 48, and in spinal cord in 4. 60 had stage M0,29-М+and 16-Mx. All the patients got surgical treatment:total tumor removal in 34,subtotal in 37,partial in 30,and biopsy in 4;75 patients got chemoradiotherapy to ATRT-2006;6-CWS;13-EU-RHAB;5-HIT-SKK;individual schemes in 6. RESULTS: 47 are alive,1 was LFU, and 57 died. PFS was 32%±0.05; the five-year OS 40%±0.05. The median survival-30 months, the median progression-free survival-12 months, and the median of follow-up-23 months. PFS was significantly better in patients more than 12 months compared to patients younger than 12 months:40 and 12%;p=0.00161.After total resection PFS was higher compared to subtotal resection, partial resection, and tumor biopsy:48,38,0,and 0%(p=0.025). After chemoradiotherapy, PFS was higher compared to patients without radiotherapy: 49and 0%(р=0.0000000).PFS for stage M0 was higher compared to stage M+and stage Mx:41,15,and 27%,respectively(р=0.00032).PFS was better for the tumors in the spinal cord and infratentorial location compared to the supratentorial location:67,37,and 25%(p=0.0876).The survival rate was higher among the patients who got treatment according to the ATRT-2006 protocol compared to EU-RHAB, individual regimens, CWS, and HIT-SKK:39,19,17,17,and 0% respectively;p=0.00159.The survival was higher among the patients who got intraventricular/intrathecal Methotrexate,Cytarabine, Prednisolone than among the patients who got only Methotrexate or none at all:40,0,and 5%, respectively; p=0.00015. CONCLUSIONS: Survival was significantly better in patients more than 12month, without metastases, with total removal tumor, chemotheradiotherapy by ATRT-2006 protocol with i/t, i/v Methotrexate/Cytarabine/Prednisolone.

scholarly journals Histomorphology Evolution of Recurrent Atypical Teratoid/Rhabdoid Tumors

2015 ◽  
Vol 144 (suppl 2) ◽  
pp. A023-A023
Author(s):  
Esther Yoon ◽  
Taliya Farooq ◽  
Lawrence Sann ◽  
Eric Vail ◽  
George Kleinman
Keyword(s):  
Atypical Teratoid ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors

scholarly journals ATRT-26. META-ANALYSIS OF TREATMENT MODALITIES IN METASTATIC ATYPICAL TERATOID/RHABDOID TUMORS IN CHILDREN

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii281-iii281
Author(s):  
Reena M Underiner ◽  
Mostafa Eltobgy ◽  
Joseph R Stanek ◽  
Jonathan L Finlay ◽  
Mohamed S AbdelBaki
Keyword(s):  
Surgical Resection ◽  
Meta Analysis ◽  
Univariate Analysis ◽  
Multivariable Analysis ◽  
Substantial Effect ◽  
Treatment Modalities ◽  
Risk Of Death ◽  
Atypical Teratoid ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors

Abstract BACKGROUND Metastatic atypical teratoid/rhabdoid tumors (AT/RT) are aggressive central nervous system tumors that present during infancy and are associated with dismal outcomes. Patients receive multimodal treatment including surgical resection, systemic chemotherapy and one or more of intrathecal chemotherapy (IT), marrow-ablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and radiation therapy (XRT). While data regarding treatment modalities for AT/RT patients exist, no comprehensive data have been published regarding the metastatic patient population. METHODS We performed a meta-analysis of 1,578 articles published through September 2018, including 44 studies with a total of 123 subjects. Additionally, seven patients were incorporated through chart review of patients treated at Nationwide Children’s Hospital. RESULTS Analysis of 130 patients revealed a 3-year overall survival (OS) of 25%. Age at diagnosis had a significant impact on survival (p=0.0355); 3-year OS for infants &lt; 18 months was 21%; 18–36 months was 26%; and &gt; 36 months was 36%. Location of the primary tumor, metastatic stage and extent of surgical resection did not have significant impact on OS. On univariate analysis, XRT (p&lt;0.0001), IT (p=0.01) and AuHCR (p&lt;0.0001) were found to significantly improve survival. The most substantial effect was noted in patients who received AuHCR (3-year OS of 60% versus 9% in those who did not). On multivariable analysis XRT (p=0.0006), IT (p=0.0124) and AuHCR (p&lt;0.0001) were independently associated with reduced risk of death.

scholarly journals AT-18INVESTIGATING THE BIOLOGY OF ATYPICAL TERATOID/RHABDOID TUMORS BY WHOLE GENOME CRISPR/CAS9 SCREENING

2016 ◽  
Vol 18 (suppl 3) ◽  
pp. iii5.2-iii5
Author(s):  
Matthew P. Selby ◽  
Martina A. Finetti ◽  
Matthew Bashton ◽  
Ruth E. Cranston ◽  
Alicia Del-Carpio-Pons ◽  
...  
Keyword(s):  
Whole Genome ◽  
Atypical Teratoid ◽  
Atypical Teratoid Rhabdoid Tumors ◽  
Rhabdoid Tumors
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