Central Nervous System Atypical Teratoid Research Articles

In Vitro Investigation Demonstrates IGFR/VEGFR Receptor Cross Talk and Potential of Combined Inhibition in Pediatric Central Nervous System Atypical Teratoid Rhabdoid Tumors.

Atypical teratoid rhabdoid tumor of the central nervous system (CNS ATRT) is a malignancy that commonly affects young children. The biological mechanisms contributing to tumor aggressiveness and resistance to conventional therapies in ATRT are unknown. Previous studies have shown the activity of insulin like growth factor-I receptor (IGF-1R) in ATRT tumor specimens and cell lines. IGF-1R has been shown to cross-talk with other receptor tyrosine kinases (RTKs) in a number of cancer types, leading to enhanced cell proliferation. This study aims to evaluate the role of IGF-1 receptor cross-talk in ATRT biology and the potential for therapeutic targeting. Cell lines derived from CNS ATRT specimens were analyzed for IGF-1 mediated cell proliferation. A comprehensive receptor tyrosine kinase (RTK) screen was conducted following IGF-1 stimulation. Bioinformatic analysis of publicly available cancer growth inhibition data to identify correlation between IC50 of a VEGFR inhibitor and IGF-1R expression. Comprehensive RTK screen identified VEGFR-2 cross-activation following IGF-1 stimulation. Bioinformatics analysis demonstrated a positive correlation between IC50 values of VEGFR inhibitor Axitinib and IGF-1R expression, supporting the critical influence of IGF-1R in modulating response to anti-angiogenic therapies. Overall, our data present a novel experimental framework to evaluate and utilize receptor cross-talk mechanisms to select effective drugs and combinations for future therapeutic trials in ATRT.

Overall Survival of Primary Intracranial Atypical Teratoid Rhabdoid Tumor Following Multimodal Treatment: A Pooled Analysis of Individual Patient Data.

No standard treatment protocol to guide the management of the primary central nervous system atypical teratoid rhabdoid tumors (ATRTs). To evaluate the efficacy of GTR (gross total resection), RT (radiotherapy), CCMT (conventional chemotherapy), or intensified chemotherapy (ICMT) and verify the optimal treatment strategy. A total of 501 cases (18 cases from our center and 483 cases from published literature) were eligible for analysis. Clinical characteristics were reviewed, and overall survival (OS) of each combined treatment modality was compared. These prior publication data were processed according to PRISMA guidelines. This study included 265 (52.9%) males and 216 (43.1%) females. The median age of the cohort was 2.2years with 295 (58.9%) cases younger than 3years. GTR was achieved in 217 (43.3%) patients. Initial adjuvant CCMT, CCMT plus intrathecal chemotherapy (ITCMT), CCMT plus high-dose chemotherapy (HDCMT), and CCMT plus ITCMT and HDCMT were administered in 228 (45.5%), 78 (15.6%), 55 (11.0%), and 24 (4.8%) patients, respectively. Radiotherapy (RT) was prescribed in 266 (53.1%) patients. Fewer patients younger than 3years old received RT (21.9% vs 33.0%, p < 0.001, chi-square test). The OS of the entire cohort at 1, 3, and 5years were 56.6, 35.9, and 30.8%, respectively. After adjusting for age and sex, GTR (HR 0.630; p < 0.001), RT (HR = 0.295; p < 0.001), CCMT (HR = 0.382; p < 0.001), and ICMT (HR = 0.209; p < 0.001) were independent prognostic factors. The 3-year OS of surgery alone, surgery plus CCMT, surgery plus RT, surgery plus ICMT, surgery plus CCMT and RT, and surgery plus ICMT and RT were 8.9, 13.4, 23.7, 37.4, 48.3, and 68.5%, respectively. When taking into consideration the extent of tumor resection (n = 462), GTR followed by RT, CCMT, intrathecal chemotherapy, and high-dose chemotherapy provided the best OS (5-year OS 88.2%). In younger children, adjuvant ICMT had a greater 3-year OS than adjuvant RT alone (34.0% vs 0%, p = .001). This study identified independent favorable predictors for OS of ATRTs and distinguished significantly different OS following various treatment modalities. If tolerable, intensive treatment with GTR followed by adjuvant RT and ICMT is recommended. Intensified CCMT could be an alternative to avoid radiological radiotoxicity for younger children CRD42018098841.

Double-deleted vaccinia virus in virotherapy for refractory and metastatic pediatric solid tumors

BackgroundPrevious studies have shown successful antitumor effects of systemically delivered double-deleted vaccinia virus (vvDD) against a number of adult tumor models, including glioma, colon and ovarian cancers. The purpose of this study was to investigate the oncolytic potential of vvDD against a panel of cell lines representative of pediatric solid tumors that are currently difficult to cure. MethodsCell lines derived from central nervous system atypical teratoid rhabdoid tumor (AT/RT) (BT12, BT16 and KCCF1), sarcoma (143B, HOS, RD and RH30), and neuroblastoma (SKNAS, SKNBE2, IMR-5 and IMR-32) were examined for vvDD mediated cytotoxicity defined by virus expansion followed by loss of tumor cell viability. The normal human fibroblast cell line HS68 was used as a control. Next, relevant orthotopic, subcutaneous and lung metastasis xenograft models were treated with intravenous doses of live vvDD or killed virus controls (DV). Tumor growth inhibition and viral replication were quantified and survival outcomes of these animals were assessed. ResultsvvDD was able to infect and kill nine of eleven of the pediatric tumor cells (81.8%) in vitro. In xenograft models, intravenous administration of a single dose of vvDD significantly inhibited the growth of tumors and prolonged the survival of intracranial and metastatic tumors. ConclusionsOncolytic vvDD administered i.v. shows activity in preclinical models of pediatric malignancies that are resistant to many currently available treatments. Our data support further evaluation of vvDD virotherapy for refractory pediatric solid tumors.

Epigenetic modification after inhibition of IGF-1R signaling in human central nervous system atypical teratoid rhabdoid tumor (AT/RT)

This study investigated epigenetic modifications in human central nervous system atypical teratoid rhabdoid tumors (AT/RTs), in response to inhibition of insulin-like growth factor receptor 1 (IGF-1R). Tumor tissue was obtained from two pediatric patients, tissue was dissociated, and primary cultures were established. Cultured cells were treated with picropodophyllin (PPP; 0, 1, and 2 μM for 48 h), a selective IGF-1R inhibitor. Histone acetylation and methylation patterns (H3K9ac, H3K18ac, H3K4me3, H3K27me3) and levels of histone deacetylases (HDACs; HDAC1, HDAC3, and SirT1) and histone acetyl transferases (GCN5 and p300) were examined. H3K9ac and H3K18ac decreased in response to treatment with PPP. HDAC levels showed a biphasic response, increasing with 1 μM PPP, but then decreasing with 2 μM PPP. Inhibition of IGF-1R modified epigenetic status in AT/RT. Determining the mechanisms behind these modifications will guide the development of novel therapeutic targets for this malignant embryonal cancer.

Early Clinical Outcomes Using Proton Radiation for Children With Central Nervous System Atypical Teratoid Rhabdoid Tumors

Atypical teratoid/rhabdoid tumor (AT/RT) is an uncommon and aggressive tumor that often affects infants. Irradiation improves survival but has traditionally been avoided in patients under the age of 3 due to the increasing risk of neurocognitive side effects. We report the first cohort of AT/RT patients treated with proton therapy. All patients with AT/RT treated at Massachusetts General Hospital (MGH) Frances H. Burr Proton Beam Therapy Benter between July 2004 and November 2011 were included in this study. All patients were treated with 3-dimensional conformal proton therapy (3D-CPT). Ten consecutive patients of a median 2.3 years of age and with a median follow-up of 27.3 months (range, 11.3-99.4 months) were identified. Two patients suffered distant relapse; 1 patient was successfully treated with involved field irradiation and chemotherapy, while the second patient died of disease. At last follow-up, 9 patients were alive without evidence of disease. Proton radiation demonstrated increasing sparing of the cerebrum, temporal lobe, cochlea, and hypothalamus. Initial clinical outcomes with proton therapy are favorable. The advantages of proton therapy are particularly suited to the treatment of AT/RT, a tumor that often requires irradiation treatment at an age when avoiding irradiation to healthy tissues is most desirable.

Profiling pathway-specific novel therapeutics in preclinical assessment for central nervous system atypical teratoid rhabdoid tumors (CNS ATRT): Favorable activity of targeting EGFR- ErbB2 signaling with lapatinib

Despite intensifying multimodal treatments, children with central nervous system atypical teratoid/rhabdoid tumor (CNS ATRT) continue to endure unacceptably high mortality rates. At present, concerted efforts are focusing on understanding the characteristic INI1 mutation and its implications for the growth and survival of these tumors. Additionally, pharmaceutical pipeline libraries constitute a significant source of potential agents that can be taken to clinical trials in a timely manner. However, this process requires efficient target validation and relevant preclinical studies. As an initial screening approach, a panel of 129 small molecule inhibitors from multiple pharmaceutical pipeline libraries was tested against three ATRT cell lines by in vitro cytotoxicity assays. Based on these data, agents that have strong activity and corresponding susceptible cellular pathways were identified. Target modulation, antibody array analysis, drug combination and in vivo xenograft studies were performed on one of the pathway inhibitors found in this screening. Approximately 20% of agents in the library showed activity with IC50 values of 1 μM or less and many showed IC50 values less than 0.05 μM. Intra cell line variability was also noted among some of the drugs. However, it was determined that agents capable of affecting pathways constituting ErbB2, mTOR, proteasomes, Hsp90, Polo like kinases and Aurora kinases were universally effective against the three ATRT cell lines. The first target selected for further analysis, the inhibition of ErbB2-EGFR pathway by the small molecule inhibitor lapatinib, indicated inhibition of cell migration properties and the initiation of apoptosis. Synergy between lapatinib and IGF-IR inhibition was also demonstrated by combination index (CI) values. Xenograft studies showed effective antitumor activity of lapatinib in vivo. We present an experimental approach to identifying agents and drug combinations for future clinical trials and provide evidence for the potential of lapatinib as an effective agent in the context of the biology and heterogeneity of its targets in ATRT.

Central nervous system atypical teratoid rhabdoid tumours: The Canadian Paediatric Brain Tumour Consortium experience

BackgroundAtypical teratoid rhabdoid tumours (ATRT) are aggressive brain tumours mostly occurring in early childhood. Largest published series arise from registries and institutional experiences (1–4). The aim of this report is to provide population-based data to further characterise this rare entity and to delineate prognostic factors. Patients and methodsA national retrospective study of children ⩽18years diagnosed with a central nervous system (CNS) ATRT between 1995 and 2007 was undertaken. All cases underwent central pathology review. ResultsThere were 50 patients (31 males; median age at diagnosis of 16.7months). Twelve patients were >36months. Infratentorial location accounted for 52% of all cases. Nineteen patients (38%) had metastatic disease. Fifteen (30%) underwent gross total resection (GTR). Ten patients (20%) underwent palliation. Among the 40 remaining patients, 22 received conventional chemotherapy and 18 received high dose chemotherapy regimens (HDC); nine received intrathecal chemotherapy and 15 received adjuvant radiation.Thirty of the 40 treated patients relapsed/progressed at a median time of 5.5months (0–32). The median survival time of the entire cohort was 13.5months (1–117.5months).Age, tumour location and metastatic status were not prognostic. Patients with GTR had a better survival (2years overall survival (OS): 60%±12.6 versus 21.7%±8.5, p=0.03). HDC conferred better outcome (2years OS 47.9%±12.1 versus 27.3%±9.5, p=0.036). Upfront radiation did not provide survival benefit. Six of the 12 survivors (50%) did not receive radiation. ConclusionThe outcome of CNS ATRT remains poor. However, the use of HDC provides encouraging results. GTR is a significant prognostic factor. The role of adjuvant radiation remains unclear.

SU-E-T-495: Proton Therapy for CNS Atypical Teratoid Rhabdoid Tumor in Children under Three

Purpose: Investigate the possible benefits of treating patients younger than three years of age with central nervous system(CNS) atypical teratoid/rhabdoid tumors (AT/RT) with proton therapy, both double scattering (DS) and intensity modulated proton therapy (IMPT), over intensity modulated photon therapy (IMRT). Method and Materials:CNS AT/RT is a rare, aggressive embryonal tumor with an incidence approaching 20% in children under the age of three with CNSmalignancies. Data from five patients with a mean age of 1.0 years recently treated in our clinic were used for this study. The average time between diagnosis and radiation therapy was three months. DS, IMPT, and IMRTtreatment plans were generated for each patient, ensuring proper coverage of the target (98% of PTV receives 98% dose) for each modality. Special consideration of margin selection for the proton plans was used. Dose heterogeneity in the target, conformality to target, dose to critical structures, dose to normal brain, and integral dose were examined. Results: Preliminary data indicates that given full target coverage, DS has the smallest dose heterogeneity within the target and IMRT the largest. Conformality for IMPT was largest and DS lowest for the most part, however, since larger margins were utilized for proton planning more investigation is required. On average, the dose to critical structures, normal brain, and integral dose was smallest for IMPT, followed by DS, and largest for IMRT. Conclusion: Preliminary data indicates that dose to critical structures, integral dose, and the dose to normal brain is reduced with proton therapy; therefore implying merit in this modality. This dose sparing is crucial because of the high sensitivity of normal tissues for very young patients.

Reply to comments by Dr. de León-Bojorge et al. on our article “Atypical teratoid/rhabdoid tumor of the central nervous system: clinicopathologic and immunohistochemical features of four cases”

Dear Editor: Dr. de Leon-Bojorge et al. have recently made some comments about our article published in Child's Nervous System, entitled “Atypical teratoid/rhabdoid tumor of the central nervous system: clinicopathologic and immunohistochemical features of four cases” [1]. They have mentioned that in the paper, the authors did not find any figure related with the immunohistochemical features, as stated in the title. As the immunohistochemical features were variable among the cases, we preferred to present only the histological figures of the cases. Additionally, all of our cases were immunohistochemically INI-1 negative, the characteristic feature of atypical teratoid/rhabdoid tumors (AT/RT). We have thought that it was not valuable to print the figures of negative cases. However, we had mentioned the details of our immunohistochemical results in the text. In addition, the reviewers were confident with the results, and they did not ask for figures of the immunohistochemical study. As the authors mentioned, we did not include the article by Dr. de Leon-Bojorge et al., entitled “Central nervous system atypical teratoid rhabdoid tumor: experience at the National Institute of Pediatrics, Mexico City” in the references of our paper [2]. Since it was not aimed to be a review article, we are sorry because we have not included all the published papers on AT/RTs.

Intensive induction chemotherapy followed by high dose chemotherapy with autologous hematopoietic progenitor cell rescue in young children newly diagnosed with central nervous system atypical teratoid rhabdoid tumors

Central nervous system (CNS) atypical teratoid rhabdoid tumors (AT/RT) are rare tumors of childhood with a dismal prognosis. Historically, surgery and standard dose chemotherapy have resulted in a median survival of 8.5 months from diagnosis. Thirteen children newly diagnosed with CNS AT/RT were treated with either the "Head Start I" (HS I) or "Head Start II" (HS II) regimens. Therapy included resection followed by five cycles of cisplatin, vincristine, cyclophosphamide, and etoposide. High dose methotrexate was added to each of the five induction courses in HS II. Consolidation for both regimens included carboplatin, thiotepa, and etoposide with autologous hematopoietic progenitor cell rescue (AHPCR). Six children, median age of 36 months, were treated on HS I between 1992 and 1997. Seven children, median age of 28 months, were treated on HS II between 1997 and 2002. One patient received craniospinal irradiation following AHPCR but prior to recurrence. There are presently three event-free survivors 42+, 54+, and 67+ months following diagnosis; none received RT. All three survivors were enrolled on HS II. Eight patients died of disease (six on HS I); one patient died from infection; one patient died from secondary malignancy following treatment for recurrent AT/RT. Three of seven children with CNS AT/RT treated on HS II have experienced long term remissions. Long term survival can be achieved in a subset of young children with CNS AT/RT following resection with the use of multi-drug chemotherapy including high dose methotrexate and myeloablative chemotherapy without radiation therapy (RT).

Central nervous system atypical teratoid rhabdoid tumor: experience at the National Institute of Pediatrics, Mexico City

The purpose of this study is to present our experience with ten cases of Central nervous system atypical teratoid rhabdoid tumor (CNS/ATRT). A series of ten patients with CNS/ATRT, were diagnosed and treated between 1990 and 2005, at the National Institute of Pediatrics, in Mexico City. The gender, age of presentation, clinical features, tumor localization, imaging studies, grade of tumor resection, complications, adjuvant therapy, and survival are presented. The mean age at diagnosis was 37.8 months, seven cases were male, and their average clinical course was 1.3 months. The more common clinical presentation was intracranial hypertension with cranial nerve deficits; location was infratentorial in four patients and supratentorial in six. Hydrocephalus was present as the most common complication (seven cases). In nine patients, the grade of resection was total or subtotal. In one case, it was only possible to perform a biopsy. There were two cases with longer survival (9 and 16 months), and their tumors were resected in total or subtotal manner and received adjuvant therapy (radiotherapy and chemotherapy). Preliminary results, show that in older children, we can improve their survival with the subtotal or total resection of the tumor and the addition of chemotherapy and radiotherapy.

A case of central nervous system atypical teratoid / rhabdoid tumor

The atypical teratoid / rhabdoid tumour is a rare type of tumours of central nervous system appearing usually under 2 years of age, bearing a rather bad prognosis and it may cause serious differential diagnostic problem. The tumour is characterized histologically by the presence of the rhabdoid cells, immunohistochemically by vimentin, SMA, EMA positivity, the frequent presence of cytokeratin, GFAP positivity, but germ cell markers: AFP, hCG negativity, cytogenetically by aberrations of chromosome 22. The case of a one and half month old female infant is presented, who died 8 months after the appearance of the first symptoms. The diagnostic possibilities and the unsolved problem of the therapy are discussed.