|
1
|
Verma J, Gupta N, Jaiswal S, Jaiswal AK. Pediatric Atypical Teratoid Rhabdoid Tumor of Central Nervous System: A Case Series with Review of Literature. Indian J Surg Oncol 2025; 16:611-620. [PMID: 40337040 PMCID: PMC12052647 DOI: 10.1007/s13193-024-02115-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2023] [Accepted: 10/14/2024] [Indexed: 05/09/2025] Open
Abstract
Atypical teratoid rhabdoid tumor (AT/RT) of the central nervous system (CNS) is the rare, aggressive malignant neoplasm of infancy and early childhood and relatively rare in adults. Patients with ATRT typically follow a dismal course. Because of its rarity and rapid course and poor prognosis, there has been no consensus as to the optimal treatment of this tumor. We herein report a series of nine cases collected from the year 2015 to 2021 in a regional tertiary care center in North India. We retrospectively collected histologically diagnosed ATRT cases and obtained demographic and clinical data from the databases. We retrieved the archived slides and tissue blocks for analysis and found nine diagnosed cases of ATRT. The median age of presentation was 3 years (ranging from 0.9 to 13 years) and showed male preponderance (male to female ratio of 2:1). The mean duration of symptoms was 3.5 months with headache and vomiting being the commonest symptoms. The tumors showed heterogenous immunohistochemical expression. Patients with AT/RT underwent multimodal treatment comprising surgical resection, radiotherapy, and chemotherapy based on the patient's age and tumor site and its resectability. The mean overall survival was 15.1 months (range, 1.5-30 months). ATRT is a rare neoplasm with a highly variable clinical course and poor prognosis. It portends poor outcomes in spite of a multimodal approach to treatment; hence, there is a dire need to help combat this enigmatic tumor.
Collapse
Affiliation(s)
- Jyoti Verma
- Department of Pathology, AIIMS, Mangalagiri, Guntur, Andhra Pradesh 522503 India
| | - Neelima Gupta
- Department of Pathology, SGPGIMS, Lucknow, Uttar Pradesh 226014 India
| | - Sushila Jaiswal
- Department of Pathology, SGPGIMS, Lucknow, Uttar Pradesh 226014 India
| | | |
Collapse
|
|
2
|
Griffith-Linsley J, Bell WR, Cohen-Gadol A, Donegan D, Richardson A, Robertson M, Shiue K, Nevel K. Autologous stem cell transplantation in adults with atypical teratoid rhabdoid tumor: a case report and review. CNS Oncol 2024; 13:2375960. [PMID: 39039959 PMCID: PMC11285279 DOI: 10.1080/20450907.2024.2375960] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2023] [Accepted: 06/12/2024] [Indexed: 07/24/2024] Open
Abstract
Aim: Atypical teratoid rhabdoid tumor (ATRT) is a rare and highly aggressive primary CNS neoplasm, predominantly observed in children. The use of autologous stem cell transplantation (ASCT) in pediatric ATRT has shown promise; however, its utility in adult ATRT remains unclear. Patients & methods: This study presents the case of an adult patient with ATRT who is in remission after ASCT and reviews the literature on ASCT in adults with ATRT. Four cases of ATRT in adults who underwent ASCT were identified, with pertinent data summarized. Results: All five patients survived longer than the historical average survival rate, four of whom had no clinical or radiographic evidence of disease at the final follow-up. Conclusion: Based on limited data, there may be a role for ASCT in the treatment of adults with ATRT.
Collapse
Affiliation(s)
| | - William Robert Bell
- Indiana University School of Medicine, Department of Pathology, Indianapolis, Indiana, USA, 46202
| | - Aaron Cohen-Gadol
- Indiana University School of Medicine, Department of Neurological Surgery, Indianapolis, Indiana, USA, 46202
| | - Diane Donegan
- Indiana University School of Medicine, Department of Medicine, Indianapolis, Indiana, USA, 46202
| | - Angela Richardson
- Indiana University School of Medicine, Department of Neurological Surgery, Indianapolis, Indiana, USA, 46202
| | - Michael Robertson
- Indiana University School of Medicine, Department of Medicine, Indianapolis, Indiana, USA, 46202
| | - Kevin Shiue
- Indiana University School of Medicine, Department of Radiation Oncology, Indianapolis, Indiana, USA, 46202
| | - Kathryn Nevel
- Indiana University School of Medicine, Department of Neurology, Indianapolis, Indiana, USA, 46202
| |
Collapse
|
|
3
|
Atypical teratoid rhabdoid tumours (ATRTs)-a 21-year institutional experience. Childs Nerv Syst 2023; 39:1509-1518. [PMID: 36790496 DOI: 10.1007/s00381-023-05828-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 01/05/2023] [Indexed: 02/16/2023]
Abstract
PURPOSE Atypical teratoid/rhabdoid tumours (ATRTs) are malignant embryonal tumours of childhood that affect the central nervous system (CNS). We aim to determine which factors, including patient age, extent of resection (EOR), presence of distal metastasis and use of adjuvant therapies, affect overall survival in children with atypical teratoid/rhabdoid tumours (ATRTs) treated at this single centre. METHODS Retrospective cohort review of patients with histological diagnosis of ATRT treated over 21 years (1999-2020) was conducted. Data on demographics, tumour location, presence of metastasis, use of adjuvant therapy, extent of resection (EOR), complications, neurological outcome post-surgery, and overall survival were collected. Kaplan-Meier survival analysis was performed. RESULTS A total of 45 children (mean age 2 years) underwent 64 operations. 25 patients were <1 year of age. Gross-total resection (GTR) pre-adjuvant therapy was achieved in 15, near-total resection (NTR) in 15, subtotal resection (STR) in 9, and biopsy in 6 children. Most children had good neurological outcomes post-operatively (28/45 with GOS 5). Fourteen patients survived longer than 4 years. Survival analysis showed a significant difference in median survival in favour of GTR and localised disease. There was no significant difference in median survival between patients <1 year vs >1 year of age (p=0.84). CONCLUSION We find that presence of metastasis was an important factor in poor survival in patients with ATRT. GTR, where possible, may confer significant survival benefit in ATRT. Children aged <1 year appear to have performed as well as those >1 year and therefore should still be considered for radical surgery.
Collapse
|
|
4
|
The impact of surgical resection and adjuvant therapy on survival in paediatric patients with Atypical Teratoid Rhabdoid Tumour: Systematic review and pooled survival analysis. World Neurosurg 2022; 164:216-227. [DOI: 10.1016/j.wneu.2022.04.073] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2022] [Revised: 04/17/2022] [Accepted: 04/18/2022] [Indexed: 11/17/2022]
|
|
5
|
Rao R, Koehler A, Rothman Y, Turner B, Denlinger J, Erickson M, Hagen M, Braverman TS, Mahammedi A, Golnik K, Zuccarello M, Gozal YM, Broun ER, Chi SN, Sengupta S. Pearls & Oy-sters: Pivoting Treatment Regimens of Pediatric Atypical Teratoid Rhabdoid Tumors to Optimize Care in Adult ATRT: A Case Report. Neurology 2022; 98:726-730. [PMID: 35256482 DOI: 10.1212/wnl.0000000000200196] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Accepted: 01/27/2022] [Indexed: 11/15/2022] Open
Affiliation(s)
- Rohan Rao
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267 USA
| | - Abigail Koehler
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267 USA
| | - Yehudit Rothman
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267 USA
| | - Brandi Turner
- Barrett Cancer Center, University of Cincinnati, Cincinnati, OH 45219 USA
| | - Jamie Denlinger
- Barrett Cancer Center, University of Cincinnati, Cincinnati, OH 45219 USA
| | - Melissa Erickson
- Department of Family and Community Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267 USA
| | - Matthew Hagen
- Department of Pathology & Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267 USA
| | - Timothy S Braverman
- Department of Anatomy & Clinical Pathology, Jewish Hospital, Cincinnati, OH 45236 USA
| | - Abdelkader Mahammedi
- Department of Radiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267 USA
| | - Karl Golnik
- Department of Ophthalmology, University of Cincinnati College of Medicine, Cincinnati, OH 45267 USA
| | - Mario Zuccarello
- Department of Neurosurgery, University of Cincinnati College of Medicine, Cincinnati, OH 45267 USA
| | | | - E Randolph Broun
- Department of Hematology Oncology, Jewish Hospital, Cincinnati, OH 45236 USA
| | - Susan N Chi
- Department of Pediatric Neuro-Oncology, Dana Farber/Boston Children's Cancer and Blood Disorder Center, Boston, MA 02215 USA
| | - Soma Sengupta
- Department of Neurology and Rehabilitation Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267 USA
| |
Collapse
|
|
6
|
Patterson JD, Henson JC, Breese RO, Bielamowicz KJ, Rodriguez A. CAR T Cell Therapy for Pediatric Brain Tumors. Front Oncol 2020; 10:1582. [PMID: 32903405 PMCID: PMC7435009 DOI: 10.3389/fonc.2020.01582] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 07/22/2020] [Indexed: 12/31/2022] Open
Abstract
Chimeric Antigen Receptor (CAR) T cell therapy has recently begun to be used for solid tumors such as glioblastoma multiforme. Many children with pediatric malignant brain tumors develop extensive long-term morbidity of intensive multimodal curative treatment. Others with certain diagnoses and relapsed disease continue to have limited therapies and a dismal prognosis. Novel treatments such as CAR T cells could potentially improve outcomes and ameliorate the toxicity of current treatment. In this review, we discuss the potential of using CAR therapy for pediatric brain tumors. The emerging insights on the molecular subtypes and tumor microenvironment of these tumors provide avenues to devise strategies for CAR T cell therapy. Unique characteristics of these brain tumors, such as location and associated morbid treatment induced neuro-inflammation, are novel challenges not commonly encountered in adult brain tumors. Despite these considerations, CAR T cell therapy has the potential to be integrated into treatment schema for aggressive pediatric malignant brain tumors in the future.
Collapse
Affiliation(s)
- John D Patterson
- Department of Neurosurgery, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Jeffrey C Henson
- Department of Neurosurgery, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| | - Rebecca O Breese
- Department of General Surgery, Wake Forest Baptist Medical Center, Winston-Salem, NC, United States
| | - Kevin J Bielamowicz
- Division of Hematology/Oncology, Department of Pediatrics, Arkansas Children's Research Institute, Little Rock, AR, United States
| | - Analiz Rodriguez
- Department of Neurosurgery, University of Arkansas for Medical Sciences, Little Rock, AR, United States
| |
Collapse
|
|
7
|
Underiner RM, Eltobgy M, Stanek JR, Finlay JL, AbdelBaki MS. Meta-Analysis of Treatment Modalities in Metastatic Atypical Teratoid/Rhabdoid Tumors in Children. Pediatr Neurol 2020; 108:106-112. [PMID: 32402552 DOI: 10.1016/j.pediatrneurol.2020.03.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Revised: 02/11/2020] [Accepted: 03/01/2020] [Indexed: 12/30/2022]
Abstract
BACKGROUND Metastatic atypical teratoid/rhabdoid tumors (AT/RTs) 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 patients. METHODS We performed a meta-analysis of 1578 articles published through September 2018, including 44 studies with a total of 123 subjects. In addition, seven patients were included 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 effect on survival (P = 0.0355); 3-year OS for infants less than 18 months was 21%, 18 to 36 months was 26%, and greater than 36 months was 36%. Location of the primary tumor, metastatic stage, and extent of surgical resection did not have a significant impact on OS. On univariate analysis, XRT (P < 0.0001), IT (P = 0.01), and AuHCR (P < 0.0001) were found to significantly improve survival. The most substantial effect was noted in patients who received AuHCR (3-year OS of 60% vs 9% in those who did not). On multivariable analysis, XRT (P = 0.0006), IT (P = 0.0124), and AuHCR (P < 0.0001) were independently associated with reduced risk of death. CONCLUSIONS Although more research is warranted to make generalizable conclusions, these results suggest that treatment regimens for patients with metastatic AT/RTs should include AuHCR, XRT, and IT.
Collapse
Affiliation(s)
| | - Mostafa Eltobgy
- Department of Microbial Infection and Immunity, The Ohio State University Wexner Medical Center, Columbus, Ohio
| | - Joseph R Stanek
- Division of Hematology, Oncology and Bone Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio
| | - Jonathan L Finlay
- The Ohio State University College of Medicine, Columbus, Ohio; Division of Hematology, Oncology and Bone Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio
| | - Mohamed S AbdelBaki
- The Ohio State University College of Medicine, Columbus, Ohio; Division of Hematology, Oncology and Bone Marrow Transplant, Nationwide Children's Hospital, Columbus, Ohio.
| |
Collapse
|
|
8
|
Yang WC, Yen HJ, Liang ML, Chen HH, Lee YY, Chang FC, Lin SC, Wong TT, Hu YW, Chen YW. Effect of early radiotherapy initiation and high-dose chemotherapy on the prognosis of pediatric atypical teratoid rhabdoid tumors in different age groups. J Neurooncol 2020; 147:619-631. [PMID: 32222933 DOI: 10.1007/s11060-020-03456-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 03/09/2020] [Indexed: 01/05/2023]
Abstract
PURPOSE The optimal treatment strategy for pediatric atypical teratoid rhabdoid tumor (ATRT) is inconclusive. This study evaluated the prognostic value of early radiotherapy (RT) and high-dose chemotherapy with autologous stem cell rescue (HDC/ASCR) in pediatric ATRT. METHODS This pooled analysis included ATRT patients treated at our institution and from other studies who were identified by a search of the PubMed electronic database. The effect of patient demographics and treatment profiles on progression-free survival (PFS) and overall survival (OS) were analyzed using Cox regression. RESULTS Overall, 34 patients from our institution and 436 patients from 35 published studies were included. In multivariable analysis, patients with gross total resection (GTR), early RT (time to RT interval < 2 months), and HDC/ASCR had both better PFS [hazard ratio (HR) 0.46, p[Formula: see text] 0.001; HR 0.64, p = 0.011; and HR 0.51, p = 0.005, respectively] and OS (HR 0.55, p = 0.002; HR 0.48, p = 0.004; and HR 0.42, p < 0.001, respectively). For patients aged < 3 years, both RT and HDC/ASCR were significant favorable factors for PFS (HR 0.32 and 0.46, respectively) and OS (HR 0.40 and 0.36, respectively), while early RT was not prognostic. For patients aged ≥ 3 years, early RT was significantly associated with better PFS (HR 0.51) and HDC/ASCR did not affect PFS, and neither was related to OS. CONCLUSION Both early RT initiation and HDC/ASCR were important components in the treatment of pediatric ATRT. However, the optimal treatment strategies might differ by age.
Collapse
Affiliation(s)
- Wan-Chin Yang
- Division of Radiation Oncology, Department of Oncology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Beitou District, Taipei, 112, Taiwan (ROC)
- School of Medicine, National Yang-Ming University No, 155, Sec.2, Linong Street, Taipei, 112, Taiwan (ROC)
| | - Hsiu-Ju Yen
- School of Medicine, National Yang-Ming University No, 155, Sec.2, Linong Street, Taipei, 112, Taiwan (ROC)
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Beitou District, Taipei, 112, Taiwan (ROC)
| | - Muh-Lii Liang
- School of Medicine, National Yang-Ming University No, 155, Sec.2, Linong Street, Taipei, 112, Taiwan (ROC)
- Division of Pediatric Neurosurgery, The Neurological Institute, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Beitou District, Taipei, 112, Taiwan (ROC)
| | - Hsin-Hung Chen
- School of Medicine, National Yang-Ming University No, 155, Sec.2, Linong Street, Taipei, 112, Taiwan (ROC)
- Division of Pediatric Neurosurgery, The Neurological Institute, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Beitou District, Taipei, 112, Taiwan (ROC)
| | - Yi-Yen Lee
- School of Medicine, National Yang-Ming University No, 155, Sec.2, Linong Street, Taipei, 112, Taiwan (ROC)
- Division of Pediatric Neurosurgery, The Neurological Institute, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Beitou District, Taipei, 112, Taiwan (ROC)
| | - Feng-Chi Chang
- School of Medicine, National Yang-Ming University No, 155, Sec.2, Linong Street, Taipei, 112, Taiwan (ROC)
- Department of Radiology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Beitou District, Taipei, 112, Taiwan (ROC)
| | - Shih-Chieh Lin
- School of Medicine, National Yang-Ming University No, 155, Sec.2, Linong Street, Taipei, 112, Taiwan (ROC)
- Department of Pathology and Laboratory Medicine, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Beitou District, Taipei, Taiwan (ROC)
| | - Tai-Tong Wong
- Department of Neurosurgery, Taipei Medical University Hospital, No.252, Wuxing St, Xinyi District, Taipei, Taiwan (ROC)
| | - Yu-Wen Hu
- Division of Radiation Oncology, Department of Oncology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Beitou District, Taipei, 112, Taiwan (ROC).
- School of Medicine, National Yang-Ming University No, 155, Sec.2, Linong Street, Taipei, 112, Taiwan (ROC).
- Institute of Public Health, National Yang-Ming University, No.155, Sec.2, Linong Street, Taipei, 112, Taiwan (ROC).
| | - Yi-Wei Chen
- Division of Radiation Oncology, Department of Oncology, Taipei Veterans General Hospital, No. 201, Sec. 2, Shipai Road, Beitou District, Taipei, 112, Taiwan (ROC).
- School of Medicine, National Yang-Ming University No, 155, Sec.2, Linong Street, Taipei, 112, Taiwan (ROC).
| |
Collapse
|
|
9
|
Meena RK, Doddamani RS, Chipde H, Mahajan S, Chandra SP, Sawarkar DP. Primary spinal atypical teratoid/rhabdoid tumour presenting with hematomyelia and subarachnoid haemorrhage-a case report. Childs Nerv Syst 2020; 36:655-659. [PMID: 31664561 DOI: 10.1007/s00381-019-04412-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2019] [Accepted: 10/10/2019] [Indexed: 11/25/2022]
Abstract
Atypical teratoid/rhabdoid tumours (AT/RTs) are highly aggressive and uncommon malignant tumours of the central nervous system (CNS) affecting children younger than 3 years of age. Primary spinal cord involvement is an extremely rare presentation. AT/RTs show necrosis and haemorrhages on histopathology frequently. However, spinal atypical teratoid/rhabdoid tumour (AT/RT) with hematomyelia and spinal subarachnoid haemorrhage (SAH), as seen in our case, has never been reported in the literature in the paediatric age group. We report a case of primary spinal AT/RT in a 3-year-old male child presenting acutely with hematomyelia and spinal SAH and try to elucidate its pathophysiological basis.
Collapse
Affiliation(s)
- Rajesh Kumar Meena
- Department of Neurosurgery, All India Institute of Medical Sciences (AIIMS), New Delhi, 110049, India
| | - Ramesh S Doddamani
- Department of Neurosurgery, All India Institute of Medical Sciences (AIIMS), New Delhi, 110049, India.
| | - Harshad Chipde
- Department of Neurosurgery, All India Institute of Medical Sciences (AIIMS), New Delhi, 110049, India
| | - Swati Mahajan
- Department of Pathology, All India Institute of Medical Sciences (AIIMS), New Delhi, 110049, India
| | - Sarat P Chandra
- Department of Neurosurgery, All India Institute of Medical Sciences (AIIMS), New Delhi, 110049, India
| | - Dattaraj P Sawarkar
- Department of Neurosurgery, All India Institute of Medical Sciences (AIIMS), New Delhi, 110049, India
| |
Collapse
|
|
10
|
Bernstock JD, Alva E, Cohen JL, Lobbous M, Chagoya G, Elsayed GA, Orr BA, Rozzelle C, Rocque B, Blount J, Johnston JM, Li R, Fiveash JB, Dhall G, Reddy AT, Friedman GK. Treatment of pediatric high-grade central nervous system tumors with high-dose methotrexate in combination with multiagent chemotherapy: A single-institution experience. Pediatr Blood Cancer 2020; 67:e28119. [PMID: 31850678 DOI: 10.1002/pbc.28119] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2019] [Revised: 11/18/2019] [Accepted: 11/19/2019] [Indexed: 11/06/2022]
Abstract
BACKGROUND Effective treatment for pediatric embryonal brain tumors includes dose-intensive multiagent chemotherapy (DIMAC) followed by high-dose chemotherapy with stem cell rescue (HDCSCR). Use of repeated cycles of DIMAC including high-dose methotrexate (HDMTX) without HDCSCR has not been described. PROCEDURE We retrospectively reviewed the responses/toxicities in 13 patients (aged 2-155 months, median 22 months) with central nervous system (CNS) tumors (atypical teratoid rhabdoid tumors, CNS embryonal tumors not otherwise specified, pineoblastoma, embryonal tumor with multilayered rosettes, and CNS sarcoma) treated over a 12-year period with repeated cycles of HDMTX followed by etoposide, cisplatin, cyclophosphamide, and vincristine. RESULTS Six patients (46.2%) had disseminated disease at presentation and five (38.5%) had gross total resection. A total of 64 courses of therapy were administered with a median of five courses per patient. Eight patients (61.5%) received radiation therapy (one at relapse). By completion of therapy, 11 patients (84.6%) achieved a response (six complete, five partial). Six of the 13 patients (46.2%) remain alive with a median follow-up of 48 months (6-146). Acute toxicities included fever/neutropenia (70.3%), bacteremia (15.6%), and grade 3 mucositis (18.8%). Long-term complications included learning disability, seizure disorder, and brain necrosis, without treatment-related deaths. CONCLUSIONS DIMAC with HDMTX without HDCSCR may be an effective treatment option for selected patients with embryonal or high-grade CNS tumors.
Collapse
Affiliation(s)
- Joshua D Bernstock
- Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, Alabama.,Department of Neurosurgery, Brigham and Women's, Harvard Medical School, Boston, Massachusetts
| | - Elizabeth Alva
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama
| | - Joshua L Cohen
- Medical Scientist Training Program, University of Alabama at Birmingham, Birmingham, Alabama
| | - Mina Lobbous
- Department of Neurology, University of Alabama at Birmingham, Birmingham, Alabama.,Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Gustavo Chagoya
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Galal A Elsayed
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Brent A Orr
- Pathology Department, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Curtis Rozzelle
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Brandon Rocque
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Jeffrey Blount
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - James M Johnston
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama
| | - Rong Li
- Department of Pathology, Children's of Alabama, Birmingham, Alabama
| | - John B Fiveash
- Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, Alabama
| | - Girish Dhall
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama
| | - Alyssa T Reddy
- Department of Neurology, University of California at San Francisco, San Francisco, California
| | - Gregory K Friedman
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama.,Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama
| |
Collapse
|
|
11
|
Reddy AT, Strother DR, Judkins AR, Burger PC, Pollack IF, Krailo MD, Buxton AB, Williams-Hughes C, Fouladi M, Mahajan A, Merchant TE, Ho B, Mazewski CM, Lewis VA, Gajjar A, Vezina LG, Booth TN, Parsons KW, Poss VL, Zhou T, Biegel JA, Huang A. Efficacy of High-Dose Chemotherapy and Three-Dimensional Conformal Radiation for Atypical Teratoid/Rhabdoid Tumor: A Report From the Children's Oncology Group Trial ACNS0333. J Clin Oncol 2020; 38:1175-1185. [PMID: 32105509 DOI: 10.1200/jco.19.01776] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
PURPOSE Atypical teratoid/rhabdoid tumor (AT/RT) is an aggressive, early-childhood brain tumor without standard effective treatment. To our knowledge, we conducted the first AT/RT-specific cooperative group trial, ACNS0333, to examine the efficacy and safety of intensive postoperative chemotherapy and focal radiation to treat AT/RT. PATIENTS AND METHODS Patients from birth to 22 years of age with AT/RT were eligible. After surgery, they received 2 courses of multiagent chemotherapy, followed by 3 courses of high-dose chemotherapy with peripheral blood stem cell rescue and involved-field radiation therapy. Timing of radiation was based on patient age and disease location and extent. Central testing of tumor and blood for SMARCB1 status was mandated. Tumor molecular subclassification was performed retrospectively. The primary analysis was event-free survival (EFS) for patients < 36 months of age compared with a cooperative groups' historical cohort. Although accrual was based on the therapeutic question, potential prognostic factors, including age, tumor location, M stage, surgical resection, order of therapy, germline status, and molecular subtype, were explored. RESULTS Of 65 evaluable patients, 54 were < 36 months of age. ACNS0333 therapy significantly reduced the risk of EFS events in patients < 36 months of age compared with the historical cohort (P < .0005; hazard rate, 0.43; 95% CI, 0.28 to 0.66). Four-year EFS and overall survival for the entire cohort were 37% (95% CI, 25% to 49%) and 43% (95% CI, 31% to 55%), respectively. Timing of radiation did not affect survival, and 91% of relapses occurred by 2 years from enrollment. Treatment-related deaths occurred in 4 patients. CONCLUSION The ACNS0333 regimen dramatically improved survival compared with historical therapies for patients with AT/RT. Clinical characteristics and molecular subgrouping suggest prognostic differences. ACNS0333 results lay a foundation on which to build future studies and incorporate testing of new therapeutic agents.
Collapse
Affiliation(s)
- Alyssa T Reddy
- Departments of Neurology and Pediatrics, University of California San Francisco, San Francisco, CA
| | - Douglas R Strother
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Alexander R Judkins
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles; Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Peter C Burger
- Department of Pathology, Johns Hopkins University, Baltimore, MD
| | - Ian F Pollack
- Department Neurosurgery, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA
| | - Mark D Krailo
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | | | | | - Maryam Fouladi
- Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH
| | - Anita Mahajan
- Department of Radiation Oncology, Mayo Clinic, Rochester, MN
| | - Thomas E Merchant
- Department of Radiation Oncology, St Jude Children's Research Hospital, Memphis, TN
| | - Ben Ho
- Department of Cell Biology, Hospital for Sick Children, Toronto, Ontario, Canada
| | - Claire M Mazewski
- Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA
| | - Victor A Lewis
- Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Amar Gajjar
- Department of Oncology, St Jude Children's Research Hospital, Memphis, TN
| | - Louis-Gilbert Vezina
- Department of Radiology, The George Washington University School Medicine and Health Sciences, Washington, DC
| | - Timothy N Booth
- Department of Radiology, University of Texas Southwestern, Dallas, TX
| | | | - Vicky L Poss
- Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL
| | - Tianni Zhou
- Department of Mathematics and Statistics, California State University at Long Beach, Long Beach, CA
| | - Jaclyn A Biegel
- Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles; Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Annie Huang
- Department of Pediatrics, Hospital for Sick Children, Arthur and Sonia Labatt Brain Tumour Research Centre, Toronto, Ontario, Canada
| |
Collapse
|
|
12
|
Ma XJ, Li D, Wang L, Hao SY, Zhang LW, Zhang JT, Wu Z. Overall Survival of Primary Intracranial Atypical Teratoid Rhabdoid Tumor Following Multimodal Treatment: A Pooled Analysis of Individual Patient Data. Neurosurg Rev 2018; 43:281-292. [PMID: 30535934 DOI: 10.1007/s10143-018-1055-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2018] [Accepted: 11/13/2018] [Indexed: 11/27/2022]
Abstract
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 2.2 years with 295 (58.9%) cases younger than 3 years. 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 3 years old received RT (21.9% vs 33.0%, p < 0.001, chi-square test). The OS of the entire cohort at 1, 3, and 5 years 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.
Collapse
Affiliation(s)
- Xiu-Jian Ma
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantan Xili 6, Dongcheng District, Beijing, People's Republic of China
| | - Da Li
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantan Xili 6, Dongcheng District, Beijing, People's Republic of China.
| | - Liang Wang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantan Xili 6, Dongcheng District, Beijing, People's Republic of China
| | - Shu-Yu Hao
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantan Xili 6, Dongcheng District, Beijing, People's Republic of China
| | - Li-Wei Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantan Xili 6, Dongcheng District, Beijing, People's Republic of China
| | - Jun-Ting Zhang
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantan Xili 6, Dongcheng District, Beijing, People's Republic of China
| | - Zhen Wu
- Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Tiantan Xili 6, Dongcheng District, Beijing, People's Republic of China.
| |
Collapse
|
|
13
|
Richardson EA, Ho B, Huang A. Atypical Teratoid Rhabdoid Tumour : From Tumours to Therapies. J Korean Neurosurg Soc 2018; 61:302-311. [PMID: 29742888 PMCID: PMC5957315 DOI: 10.3340/jkns.2018.0061] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Revised: 03/29/2018] [Accepted: 03/29/2018] [Indexed: 12/29/2022] Open
Abstract
Atypical teratoid rhabdoid tumours (ATRTs) are the most common malignant central nervous system tumours in children ≤1 year of age and represent approximately 1–2% of all pediatric brain tumours. ATRT is a primarily monogenic disease characterized by the bi-allelic loss of the SMARCB1 gene, which encodes the hSNF5 subunit of the SWI/SNF chromatin remodeling complex. Though conventional dose chemotherapy is not effective in most ATRT patients, high dose chemotherapy with autologous stem cell transplant, radiotherapy and/or intrathecal chemotherapy all show significant potential to improve patient survival. Recent epigenetic and transcriptional studies highlight three subgroups of ATRT, each with distinct clinical and molecular characteristics with corresponding therapeutic sensitivities, including epigenetic targeting, and inhibition of tyrosine kinases or growth/lineage specific pathways.
Collapse
Affiliation(s)
- Elizabeth Anne Richardson
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada.,Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada.,Department of Cell Biology, Hospital for Sick Children, Toronto, Canada
| | - Ben Ho
- Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada.,Department of Cell Biology, Hospital for Sick Children, Toronto, Canada
| | - Annie Huang
- Department of Laboratory Medicine and Pathobiology, Faculty of Medicine, University of Toronto, Toronto, Canada.,Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, Canada.,Department of Cell Biology, Hospital for Sick Children, Toronto, Canada.,Department of Paediatrics, University of Toronto, Toronto, Canada.,Division of Hematology/Oncology, Hospital for Sick Children, Toronto, Canada
| |
Collapse
|
|
14
|
Babgi M, Samkari A, Al-Mehdar A, Abdullah S. Atypical Teratoid/Rhabdoid Tumor of the Spinal Cord in a Child: Case Report and Comprehensive Review of the Literature. Pediatr Neurosurg 2018; 53:254-262. [PMID: 29788028 DOI: 10.1159/000488459] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2017] [Accepted: 03/13/2018] [Indexed: 01/02/2023]
Abstract
INTRODUCTION Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system is characterized by SMARCB1/INI deletion or mutation in the long arm of chromosome 22 11(22q11.2), also resulting in loss of nuclear expression of INI1 protein immunohistochemically. AT/RT tumors usually occur in children below 3 years. The tumor is usually seen in the cerebellum or the cerebrum, with an extremely rare incidence in the spinal cord. MATERIALS AND METHODS We report a rare case of AT/RT in a 6-year-old boy who had a primary spinal cord lesion in the thoracolumbar junction. Pathology revealed loss of nuclear staining of INI1 immunohistochemically. This is the first case reported with mixed intraspinal lesion (intra- and extramedullary). The patient underwent two surgeries and received radiotherapy and chemotherapy; however, he died 16 months after the initial presentation. RESULTS AND DISCUSSION We reviewed the literature on all children with spinal cord AT/RT. The review showed that the cervical region is the most common location of origin, especially in younger children. Reported cases were treated with a combination of surgery, systemic and intrathecal chemotherapy, and radiation therapy, and a survival time of 18 months represented the best outcome. Overall mean survival time was 10 months.
Collapse
Affiliation(s)
- Mohammed Babgi
- College of Medicine, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia
| | - Alaa Samkari
- College of Medicine, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.,Department of Pathology, National Guard Hospital, King Abdulaziz Medical City, Jeddah, Saudi Arabia
| | - Abeer Al-Mehdar
- College of Medicine, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.,Department of Radiology, National Guard Hospital, King Abdulaziz Medical City, Jeddah, Saudi Arabia
| | - Shaker Abdullah
- College of Medicine, King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, Jeddah, Saudi Arabia.,Department of Pediatric Oncology, National Guard Hospital, King Abdulaziz Medical City, Jeddah, Saudi Arabia
| |
Collapse
|
|
15
|
Thatikunta M, Mutchnick I, Elster J, Thompson MP, Huang MA, Spalding AC, Moriarty T. Neoadjuvant chemotherapy for atypical teratoid rhabdoid tumors: case report. J Neurosurg Pediatr 2017; 19:546-552. [PMID: 28291373 DOI: 10.3171/2016.12.peds16427] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Atypical teratoid rhabdoid tumors (ATRTs) are a rare pediatric brain tumor with high mortality rate. Several large series have reported achieving gross-total resection (GTR) in less than 50% of patients due to the lesions' large size, vascularity, and limited blood volume in young patients. While neoadjuvant chemotherapy for choroid plexus carcinomas in pediatric patients has become widely accepted, it has not been used as widely for other pediatric brain tumors. To the best of the authors' knowledge, there are only 3 published cases of neoadjuvant chemotherapy for ATRTs. In the present report, the authors present a fourth case of neoadjuvant chemotherapy for ATRT and review the available literature on this strategy. A 17-month-old child presented with a left ventricular ATRT for which imaging raised concern for a highly vascularized tumor. The authors undertook neoadjuvant chemotherapy with 2 cycles of Head Start II therapy, which reduced the size of the ventricular tumor by 35% and decreased the vascularity of the lesion on imaging. The estimated blood loss during resection was 425 ml and GTR was achieved. The patient continued with postoperative chemotherapy but suffered an on-therapy recurrence. While higher-quality data are necessary, available evidence suggests that neoadjuvant chemotherapy can reduce the size and vascularity of ATRTs and facilitate a surgical avenue for large or "inoperable" tumors.
Collapse
Affiliation(s)
- Meena Thatikunta
- Department of Neurosurgery, University of Louisville School of Medicine
| | - Ian Mutchnick
- Department of Neurosurgery, University of Louisville School of Medicine.,Pediatric Neurosurgery, Norton Children's Hospital.,Norton Neuroscience Institute, Louisville, Kentucky
| | - Jennifer Elster
- Pediatric Hematology/Oncology, UC San Diego School of Medicine.,Rady Children's Hospital-San Diego, California
| | - Matthew P Thompson
- Pediatric and Perinatal Pathology Associates, Norton Children's Hospital
| | - Michael A Huang
- Pediatric Cancer & Blood Disorders, University of Louisville School of Medicine; and
| | - Aaron C Spalding
- Radiation Oncology, Norton Cancer Institute, Norton Healthcare, Louisville, Kentucky
| | - Thomas Moriarty
- Department of Neurosurgery, University of Louisville School of Medicine.,Pediatric Neurosurgery, Norton Children's Hospital.,Norton Neuroscience Institute, Louisville, Kentucky
| |
Collapse
|
|
16
|
Kramer K. Rare Primary Central Nervous System Tumors Encountered in Pediatrics. J Child Neurol 2016; 31:1394-8. [PMID: 26801774 PMCID: PMC5028308 DOI: 10.1177/0883073815627878] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Accepted: 12/20/2015] [Indexed: 01/03/2023]
Abstract
As part of the special issue on Pediatric Neuro-Oncology, this article will focus on 4 of the rarer tumors in this spectrum, including atypical teratoid rhabdoid tumors, embryonal tumors with multilayered rosettes, choroid plexus tumors, and pleomorphic xanthoastrocytoma. Incidence and current understanding of the molecular pathogenesis of these tumors are discussed, and avenues of therapy both current and prospective are explored.
Collapse
Affiliation(s)
- Kim Kramer
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| |
Collapse
|
|
17
|
Abstract
Rhabdoid tumor is a rare, highly aggressive malignancy that primarily affects infants and young children. These tumors typically arise in the brain and kidney, although extrarenal, non-central nervous system tumors in almost all soft-tissue sites have been described. SMARCB1 is a member of the SWI/SNF chromatin-remodeling complex and functions as a tumor suppressor in the vast majority of rhabdoid tumors. Patients with germline mutations or deletions affecting SMARCB1 are predisposed to the development of rhabdoid tumors, as well as the genetic disorder schwannomatosis. The current hypothesis is that rhabdoid tumors are driven by epigenetic dysregulation, as opposed to the alteration of a specific biologic pathway. The strategies for novel therapeutic approaches based on what is currently known about rhabdoid tumor biology are presented.
Collapse
Affiliation(s)
- James I Geller
- Division of Oncology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Jacquelyn J Roth
- Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Jaclyn A Biegel
- Department of Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles; Keck School of Medicine, University of Southern California, Los Angeles, Ca
| |
Collapse
|
|
18
|
Multimodal therapy in children and adolescents with newly diagnosed atypical teratoid rhabdoid tumor: individual pooled data analysis and review of the literature. J Neurooncol 2015; 126:81-90. [DOI: 10.1007/s11060-015-1904-0] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2015] [Accepted: 08/29/2015] [Indexed: 02/05/2023]
|
|
19
|
Atypical teratoid rhabdoid tumors of the posterior fossa in children. Childs Nerv Syst 2015; 31:1717-28. [PMID: 26351225 DOI: 10.1007/s00381-015-2844-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2015] [Accepted: 07/16/2015] [Indexed: 12/23/2022]
Abstract
PURPOSE Atypical teratoid rhabdoid tumors (AT/RT) are rare, aggressive, central nervous system neoplasms that typically affect children under 3 years of age and have a very poor prognosis. Early case series consistently demonstrated rapid recurrence with progression to death, but more recent experience has shown significant improvements in progression free and overall survival. METHODS A retrospective analysis of the clinical data of children diagnosed with AT/RT at the Ann & Robert H. Lurie Children's Hospital of Chicago (formerly Children's Memorial Hospital) between 2000 and 2014 was performed. Overall survival (OS) was used to describe outcome. Our small sample size and the utilization of different adjuvant regimens over the study period precluded a detailed statistical analysis. RESULTS Eight children with AT/RT of the posterior fossa were included in our report. Gross total resection (GTR) was achieved in five children (63 %), two children underwent subtotal resection (25 %), and there was one who underwent biopsy. Patients were treated with various combinations of chemotherapy with or without conformal radiation therapy (RT). Median overall survival was 5 months (range 1 to 107 months) with two patients achieving sustained responses to 45 and 107 months. CONCLUSIONS Our experience is in line with prior reports that show that children diagnosed with AT/RT of the posterior fossa have a poor prognosis, but that long-term survival is possible. These tumors provide many challenges, but contemporary series are beginning to show improvements in survival.
Collapse
|
|
20
|
Torchia J, Picard D, Lafay-Cousin L, Hawkins CE, Kim SK, Letourneau L, Ra YS, Ho KC, Chan TSY, Sin-Chan P, Dunham CP, Yip S, Ng HK, Lu JQ, Albrecht S, Pimentel J, Chan JA, Somers GR, Zielenska M, Faria CC, Roque L, Baskin B, Birks D, Foreman N, Strother D, Klekner A, Garami M, Hauser P, Hortobágyi T, Bognár L, Wilson B, Hukin J, Carret AS, Van Meter TE, Nakamura H, Toledano H, Fried I, Fults D, Wataya T, Fryer C, Eisenstat DD, Scheineman K, Johnston D, Michaud J, Zelcer S, Hammond R, Ramsay DA, Fleming AJ, Lulla RR, Fangusaro JR, Sirachainan N, Larbcharoensub N, Hongeng S, Barakzai MA, Montpetit A, Stephens D, Grundy RG, Schüller U, Nicolaides T, Tihan T, Phillips J, Taylor MD, Rutka JT, Dirks P, Bader GD, Warmuth-Metz M, Rutkowski S, Pietsch T, Judkins AR, Jabado N, Bouffet E, Huang A. Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis. Lancet Oncol 2015; 16:569-82. [PMID: 25882982 DOI: 10.1016/s1470-2045(15)70114-2] [Citation(s) in RCA: 110] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours. METHODS We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling. FINDINGS Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes. INTERPRETATION An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours. FUNDING C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.
Collapse
Affiliation(s)
- Jonathon Torchia
- Division of Hematology-Oncology, University of Toronto, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - Daniel Picard
- Division of Hematology-Oncology, University of Toronto, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - Lucie Lafay-Cousin
- Alberta Children's Hospital, and Departments of Oncology and Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Cynthia E Hawkins
- Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pathology, Hospital for Sick Children, Toronto, ON, Canada
| | - Seung-Ki Kim
- Department of Neurosurgery, Seoul National University Children's Hospital, Seoul, South Korea
| | - Louis Letourneau
- Genome Quebec Innovation Centre, McGill University, Montreal, QC, Canada
| | - Young-Shin Ra
- Department of Neurosurgery, Asan Medical Center, Songpa-gu, Seoul, South Korea
| | - King Ching Ho
- Division of Hematology-Oncology, University of Toronto, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Tiffany Sin Yu Chan
- Division of Hematology-Oncology, University of Toronto, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - Patrick Sin-Chan
- Division of Hematology-Oncology, University of Toronto, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - Christopher P Dunham
- Division of Anatomic Pathology, Children's and Women's Health Centre of British Columbia, Vancouver, BC, Canada
| | - Stephen Yip
- Department of Neuropathology, Vancouver General Hospital, Vancouver, BC, Canada
| | - Ho-Keung Ng
- Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, China
| | - Jian-Qiang Lu
- Department of Laboratory Medicine and Pathology, University of Alberta Hospital, Edmonton, AB, Canada
| | - Steffen Albrecht
- Department of Pathology, Montreal Children's Hospital, McGill University Health Center Research Institute, Montreal, QC, Canada
| | - José Pimentel
- Department of Neurology, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal
| | - Jennifer A Chan
- Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada
| | - Gino R Somers
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON, Canada
| | - Maria Zielenska
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON, Canada
| | - Claudia C Faria
- Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal
| | - Lucia Roque
- Cytogenetic Laboratory, Centro de Investigação em Patobiologia Molecular, Portuguese Cancer Institute, Lisbon, Portugal
| | - Berivan Baskin
- Department of Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden
| | - Diane Birks
- Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA
| | - Nick Foreman
- Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA
| | - Douglas Strother
- Alberta Children's Hospital, and Departments of Oncology and Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Almos Klekner
- Department of Neurosurgery, University of Debrecen, Debrecen, Hungary
| | - Miklos Garami
- Second Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Peter Hauser
- Second Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - Tibor Hortobágyi
- Department of Histopathology, Faculty of Medicine, University of Szeged, Hungary
| | - Laszló Bognár
- Department of Neurosurgery, University of Debrecen, Debrecen, Hungary
| | - Beverly Wilson
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada
| | - Juliette Hukin
- Division of Neurology and Oncology, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
| | - Anne-Sophie Carret
- Division of Hematology-Oncology, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, QC, Canada
| | - Timothy E Van Meter
- Pediatric Hematology-Oncology, Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA
| | - Hideo Nakamura
- Department of Neurosurgery, Kumamoto University, Kumamoto, Japan
| | - Helen Toledano
- Oncology Department, Schneider Hospital, Petach Tikva, Israel
| | - Iris Fried
- Pediatric Hematology Oncology Department, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Daniel Fults
- Department of Neurosurgery, University of Utah, School of Medicine, Salt Lake City, UT, USA
| | - Takafumi Wataya
- Department of Neurosurgery, Shizuoka Children's Hospital, Aoi-ku, Shizuoka, Japan
| | - Chris Fryer
- Division of Hematology and Oncology, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
| | - David D Eisenstat
- Departments of Pediatrics and Medical Genetics, University of Alberta, Edmonton, AB, Canada
| | | | - Donna Johnston
- Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
| | - Jean Michaud
- Department of Pathology and Laboratory Medicine, Ottawa Hospital and Children's Hospital of Eastern Ontario, Ottawa, ON, Canada
| | - Shayna Zelcer
- Division of Children's Health and Therapeutics, Children's Health Research Institute, London, ON, Canada
| | - Robert Hammond
- Department of Pathology, University of Western Ontario, London, ON, Canada
| | - David A Ramsay
- Department of Pathology, London Health Sciences Centre, London, ON, Canada
| | - Adam J Fleming
- Division of Pediatric Hematology/Oncology, McMaster University, Hamilton, ON, Canada
| | - Rishi R Lulla
- Division of Pediatrics-Hematology, Oncology and Stem Cell Transplantation, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA
| | - Jason R Fangusaro
- Division of Pediatrics-Hematology, Oncology and Stem Cell Transplantation, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA
| | - Nongnuch Sirachainan
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Noppadol Larbcharoensub
- Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | - Suradej Hongeng
- Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand
| | | | | | - Derek Stephens
- Department of Clinical Research Services, Hospital for Sick Children, Toronto, ON, Canada
| | - Richard G Grundy
- Children's Brain Tumour Research Centre, School of Clinical Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK
| | - Ulrich Schüller
- Center for Neuropathology, Ludwig-Maximilians-University, Munich, Germany
| | - Theodore Nicolaides
- Department of Pediatrics Hematology/Oncology, University of California, San Francisco, CA, USA
| | - Tarik Tihan
- Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA, USA
| | - Joanna Phillips
- Department of Neurological Surgery, University of California, San Francisco, CA, USA
| | - Michael D Taylor
- Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Division of Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada
| | - James T Rutka
- Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Division of Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada
| | - Peter Dirks
- Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Division of Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada
| | - Gary D Bader
- Department of Computer Science, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, ON, Canada
| | | | - Stefan Rutkowski
- Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Torsten Pietsch
- Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany
| | - Alexander R Judkins
- Department of Pathology and Laboratory Medicine at Children's Hospital Los Angeles, Los Angeles, CA, USA
| | - Nada Jabado
- Department of Pediatrics, McGill University, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Eric Bouffet
- Division of Hematology-Oncology, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - Annie Huang
- Division of Hematology-Oncology, University of Toronto, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
| |
Collapse
|
|
21
|
High-dose Chemotherapy With Autologous Stem Cell Rescue in Saudi Children Less Than 3 Years of Age With Embryonal Brain Tumors. J Pediatr Hematol Oncol 2015; 37:204-8. [PMID: 25551668 DOI: 10.1097/mph.0000000000000301] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
High-dose chemotherapy with autologous stem cell rescue (HDC/ASCR) has been used in children under the age of 3 years with embryonal brain tumors to avoid or delay the use of radiation. We reviewed the medical records of 10 Saudi children less than 3 years of age with embryonal brain tumors who underwent HDC/ASCR. All 10 patients underwent surgical resection followed by 3 to 5 cycles of induction chemotherapy and 1 to 3 cycles of HDC/ASCR using carboplatin and thiotepa. Isotretinoin was used as a maintenance therapy in 4 patients. Five patients had medulloblastoma, 3 had atypical teratoid/rhabdoid tumors, 1 had an embryonal tumor with abundant neuropil and true rosettes, and 1 had pineoblastoma. The median age of the patients was 1.9 years. A total of 19 HDC/ASCR procedures were performed. Radiotherapy (RT) was administered to 5 patients after HDC/ASCR and as a salvage therapy in 1 patient. The progression-free survival rate was 50% at 1 year and at 2 years, with a median follow-up of 24 months. All 5 patients with medulloblastoma are still alive without evidence of disease, but the other patients died secondary to tumor progression. This experience suggests that strategies combining myeloablative chemotherapy and autologous stem cell rescue appear to be feasible for children with embryonal brain tumors in the Middle East.
Collapse
|
|
22
|
Wang X, Liu X, Lin Z, Chen Y, Wang P, Zhang S. Atypical teratoid/rhabdoid tumor (AT/RT) arising from the acoustic nerve in a young adult: a case report and a review of literature. Medicine (Baltimore) 2015; 94:e439. [PMID: 25634176 PMCID: PMC4602954 DOI: 10.1097/md.0000000000000439] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Atypical teratoid/rhabdoid tumors (AT/RTs) are rare, highly malignant central nervous system tumors that predominantly occur in young children. A 22-year-old woman presented with a 4-year history of relapsing tinnitus and gradual hearing loss. Neuroimaging revealed an enhanced intrinsic left internal auditory canal mass. The patient underwent radiotherapy treatment. Three years later, the tumor size continued to increase, as observed by imaging, and ultimately evolved into the left cerebellopontine angle. As a consequence, a total tumor resection was performed, and a pathological diagnosis of AT/RT was made. Aggressive radiotherapy and chemotherapy treatment continued; however, the tumor recurred within 11 months after the total tumor resection. The patient died within 4 months of the second operation. Histopathologically, the tumor contained characteristic rhabdoid cells with areas that resembled a classical primitive neuroectodermal tumor. Immunostaining showed loss of INI1 protein expression in tumor cells, and fluorescence in situ hybridization showed a hemizygous deletion of the hSNF5/INI1 gene region on 22q11.2. This is the first report of an AT/RT that arised from the acoustic nerve in a young adult. Despite manifold diagnostic and therapeutic advances, the prognosis of patients with AT/RT remains poor.
Collapse
Affiliation(s)
- Xingfu Wang
- From the Department of Pathology (XW, XL, YC, PW, SZ); and Department of Neurosurgery (XL), the First Affiliated Hospital of Fujian Medical University, Fuzhou, China
| | | | | | | | | | | |
Collapse
|
|
23
|
Choi SA, Choi JW, Wang KC, Phi JH, Lee JY, Park KD, Eum D, Park SH, Kim IH, Kim SK. Disulfiram modulates stemness and metabolism of brain tumor initiating cells in atypical teratoid/rhabdoid tumors. Neuro Oncol 2014; 17:810-21. [PMID: 25378634 DOI: 10.1093/neuonc/nou305] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Accepted: 10/01/2014] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Atypical teratoid/rhabdoid tumors (AT/RT) are among the most malignant pediatric brain tumors. Cells from brain tumors with high aldehyde dehydrogenase (ALDH) activity have a number of characteristics that are similar to brain tumor initiating cells (BTICs). This study aimed to evaluate the therapeutic potential of ALDH inhibition using disulfiram (DSF) against BTICs from AT/RT. METHODS Primary cultured BTICs from AT/RT were stained with Aldefluor and isolated by fluorescence activated cell sorting. The therapeutic effect of DSF against BTICs from AT/RT was confirmed in vitro and in vivo. RESULTS AT/RT cells displayed a high expression of ALDH. DSF demonstrated a more potent cytotoxic effect on ALDH(+) AT/RT cells compared with standard anticancer agents. Notably, treatment with DSF did not have a considerable effect on normal neural stem cells or fibroblasts. DSF significantly inhibited the ALDH enzyme activity of AT/RT cells. DSF decreased self-renewal ability, cell viability, and proliferation potential and induced apoptosis and cell cycle arrest in ALDH(+) AT/RT cells. Importantly, DSF reduced the metabolism of ALDH(+) AT/RT cells by increasing the nicotinamide adenine dinucleotide ratio of NAD(+)/NADH and regulating Silent mating type Information Regulator 2 homolog 1 (SIRT1), nuclear factor-kappaB, Lin28A/B, and miRNA let-7g. Animals in the DSF-treated group demonstrated a reduction of tumor volume (P < .05) and a significant survival benefit (P = .02). CONCLUSION Our study demonstrated the therapeutic potential of DSF against BTICs from AT/RT and suggested the possibility of ALDH inhibition for clinical application.
Collapse
Affiliation(s)
- Seung Ah Choi
- Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.)
| | - Jung Won Choi
- Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.)
| | - Kyu-Chang Wang
- Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.)
| | - Ji Hoon Phi
- Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.)
| | - Ji Yeoun Lee
- Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.)
| | - Kyung Duk Park
- Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.)
| | - Dayoung Eum
- Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.)
| | - Sung-Hye Park
- Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.)
| | - Il Han Kim
- Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.)
| | - Seung-Ki Kim
- Division of Pediatric Neurosurgery, Pediatric Clinical Neuroscience Center, Seoul National University Children's Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., K.-C.W., J.H.P., J.Y.L., D.E., S.-K.K.); Adolescent Cancer Center, Seoul National University Cancer Hospital, Seoul, Republic of Korea (S.A.C., J.W.C., J.H.P., J.Y.L., K.D.P., D.E., S.-K.K.); Department of Pediatrics, Seoul National University Children's Hospital, Seoul, Republic of Korea (K.D.P.); Department of Pathology, Seoul National University Children's Hospital, Seoul, Republic of Korea (S-H.P.); Department of Radiation Oncology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea (I.H.K.)
| |
Collapse
|
|
24
|
Benesch M, Bartelheim K, Fleischhack G, Gruhn B, Schlegel PG, Witt O, Stachel KD, Hauch H, Urban C, Quehenberger F, Massimino M, Pietsch T, Hasselblatt M, Giangaspero F, Kordes U, Schneppenheim R, Hauser P, Klingebiel T, Frühwald MC. High-dose chemotherapy (HDCT) with auto-SCT in children with atypical teratoid/rhabdoid tumors (AT/RT): a report from the European Rhabdoid Registry (EU-RHAB). Bone Marrow Transplant 2014; 49:370-5. [PMID: 24419520 DOI: 10.1038/bmt.2013.208] [Citation(s) in RCA: 57] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2013] [Revised: 11/12/2013] [Accepted: 11/12/2013] [Indexed: 12/19/2022]
Abstract
A retrospective analysis of data from the European Rhabdoid Registry (EU-RHAB) was performed to describe the outcome of children with atypical teratoid/rhabdoid tumors (AT/RT) who underwent high-dose chemotherapy (HDCT) with auto-SCT. Nineteen patients (male, n=15; median age at diagnosis 21 months) were identified. Nine patients presented with metastatic disease at diagnosis. A partial or subtotal resection was achieved in 11, a total resection in five and a biopsy in three patients. Patients received a median of six chemotherapy cycles prior to HDCT. Additional radiotherapy was performed in 14 patients (first-line, n=9; following progression, n=5). Six patients underwent tandem auto-SCT. Disease status before HDCT was CR in six, PR in eight, stable disease in two and progressive disease (PD) in two patients (data missing, n=1). With a median follow-up of 16 months, 14 patients progressed. Estimated progression-free and OS at 2 years were 29% (±11%) and 50% (±12%), respectively. At last follow-up, eight patients were alive (first CR, n=4; second CR, n=2; PR, n=1; PD, n=1). Eleven patients died of PD. Median time-to-progression was 14 months. Selected patients with AT/RT might benefit from HDCT with radiotherapy. The definitive impact of this treatment modality has to be evaluated prospectively in a randomized trial.
Collapse
Affiliation(s)
- M Benesch
- Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - K Bartelheim
- Swabian Children's Cancer Center, Children's Hospital Augsburg, Augsburg, Germany
| | - G Fleischhack
- Pediatrics III, University Hospital of Essen, Essen, Germany
| | - B Gruhn
- Department of Pediatrics, Jena University Hospital, Jena, Germany
| | - P G Schlegel
- Department of Pediatric Hematology, Oncology and Neurooncology, University Children's Hospital Würzburg, Würzburg, Germany
| | - O Witt
- Department of Pediatric Oncology, Hematology, Immunology and Pneumonology, Children's Hospital, University of Heidelberg, Heidelberg, Germany
| | - K D Stachel
- Children's University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - H Hauch
- Department of Pediatric Hematology and Oncology, Justus Liebig University Gießen, Gießen, Germany
| | - C Urban
- Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - F Quehenberger
- Institute for Medical Statistics, Medical University of Graz, Graz, Austria
| | - M Massimino
- Department of Pediatrics, Fondazione IRCCS, Istituto Nazionale Tumori, Milan, Italy
| | - T Pietsch
- Institute of Neuropathology, University of Bonn, Bonn, Germany
| | - M Hasselblatt
- Institute of Neuropathology, University Hospital Münster, Münster, Germany
| | - F Giangaspero
- 1] Department of Radiological, Oncological and Anatomo-pathological Sciences, University La Sapienza, Rome, Italy [2] IRCCS Neuromed, Pozzilli, Italy
| | - U Kordes
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - R Schneppenheim
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - P Hauser
- Department of Pediatrics, Semmelweis University, Budapest, Hungary
| | - T Klingebiel
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, J. W. Goethe University Children's Hospital of Frankfurt, Frankfurt, Germany
| | - M C Frühwald
- 1] Swabian Children's Cancer Center, Children's Hospital Augsburg, Augsburg, Germany [2] Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, Münster, Germany
| |
Collapse
|
|
25
|
Slavc I, Chocholous M, Leiss U, Haberler C, Peyrl A, Azizi AA, Dieckmann K, Woehrer A, Peters C, Widhalm G, Dorfer C, Czech T. Atypical teratoid rhabdoid tumor: improved long-term survival with an intensive multimodal therapy and delayed radiotherapy. The Medical University of Vienna Experience 1992-2012. Cancer Med 2013; 3:91-100. [PMID: 24402832 PMCID: PMC3930393 DOI: 10.1002/cam4.161] [Citation(s) in RCA: 80] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2013] [Revised: 10/11/2013] [Accepted: 10/15/2013] [Indexed: 01/01/2023] Open
Abstract
Atypical teratoid rhabdoid tumors (ATRTs) are recently defined highly aggressive embryonal central nervous system tumors with a poor prognosis and no definitive guidelines for treatment. We report on the importance of an initial correct diagnosis and disease-specific therapy on outcome in 22 consecutive patients and propose a new treatment strategy. From 1992 to 2012, nine patients initially diagnosed correctly as ATRT (cohort A, median age 24 months) were treated according to an intensive multimodal regimen (MUV-ATRT) consisting of three 9-week courses of a dose-dense regimen including doxorubicin, cyclophosphamide, vincristine, ifosfamide, cisplatin, etoposide, and methotrexate augmented with intrathecal therapy, followed by high-dose chemotherapy (HDCT) and completed with local radiotherapy. Thirteen patients were treated differently (cohort B, median age 30 months) most of whom according to protocols in use for their respective diagnoses. As of July 2013, 5-year overall survival (OS) and event-free survival (EFS) for all 22 consecutive patients was 56.3 ± 11.3% and 52.9 ± 11.0%, respectively. For MUV-ATRT regimen-treated patients (cohort A) 5-year OS was 100% and EFS was 88.9 ± 10.5%. For patients treated differently (cohort B) 5-year OS and EFS were 28.8 ± 13.1%. All nine MUV-ATRT regimen-treated patients are alive for a median of 76 months (range: 16–197), eight in first complete remission. Our results compare favorably to previously published data. The drug combination and sequence used in the proposed MUV-ATRT regimen appear to be efficacious in preventing early relapses also in young children with M1–M3 stage disease allowing postponement of radiotherapy until after HDCT.
Collapse
Affiliation(s)
- Irene Slavc
- Department of Pediatrics, Medical University of Vienna, Vienna, Austria
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
26
|
Heck JE, Lombardi CA, Cockburn M, Meyers TJ, Wilhelm M, Ritz B. Epidemiology of rhabdoid tumors of early childhood. Pediatr Blood Cancer 2013; 60:77-81. [PMID: 22434719 PMCID: PMC3399923 DOI: 10.1002/pbc.24141] [Citation(s) in RCA: 50] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2012] [Accepted: 02/23/2012] [Indexed: 01/29/2023]
Abstract
BACKGROUND Rhabdoid tumors are a rare and aggressive cancer subtype which is usually diagnosed in early childhood. Little is known about their etiology. The purpose of this study was to describe the epidemiology of rhabdoid tumors and examine their relation to perinatal characteristics. METHODS We identified 44 atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system (CNS) and 61 rhabdoid sarcomas (renal and extra-renal non-CNS tumors) from California Cancer Registry records of diagnoses 1988-2007 among children <6 years of age. We randomly selected 208,178 controls from California birthrolls. Multivariable logistic regression was used to examine associations between rhabdoid tumors and perinatal characteristics. RESULTS After adjustment for demographic characteristics, low birthweight (<2,500 g) strongly increased risk for developing both rhabdoid sarcomas (OR = 2.43, 95% CI 1.09, 5.41) and AT/RT (OR = 2.99, 95% CI 1.31, 6.84). Both preterm delivery (<37 weeks gestation, OR = 2.63, 95% CI 1.34, 5.17) and late term delivery (>42 weeks, OR = 3.66, 95% CI 1.54, 8.71) also increased risk of rhabdoid sarcomas. Rhabdoid sarcoma cases (OR = 3.08, 95% CI 1.11, 8.55) and AT/RT cases (OR = 3.16, 95% CI 1.23, 8.13) also were more likely to be multiple births. CONCLUSION The excess of twin pregnancies may suggest an association with infertility treatments. This is the first population-based epidemiologic study to examine these rare tumors.
Collapse
Affiliation(s)
- Julia E Heck
- Department of Epidemiology, School of Public Health, University of California, Los Angeles, CA, USA.
| | - Christina A Lombardi
- Department of Epidemiology, School of Public Health, University of California, Los Angeles, CA, USA
| | - Myles Cockburn
- Department of Preventive Medicine, University of Southern California Keck School of Medicine, Los Angeles, CA, USA
| | - Travis J Meyers
- Department of Epidemiology, School of Public Health, University of California, Los Angeles, CA, USA
| | - Michelle Wilhelm
- Department of Epidemiology, School of Public Health, University of California, Los Angeles, CA, USA
| | - Beate Ritz
- Department of Epidemiology, School of Public Health, University of California, Los Angeles, CA, USA
| |
Collapse
|
|
27
|
Abstract
OBJECTIVE Atypical teratoid/rhabdoid tumor (AT/RT) is a highly malignant tumor of the central nervous system. Its pathogenesis remains unknown. Like glioblastomas, AT/RTs contain brain cancer stem cells (CSCs) that suppress the immunity of patients and are resistant to conventional chemotherapy and radiation therapy. Considerable infiltration of immune cells, including macrophages/microglia, dendritic cells and T-cells, has been noted in glioblastomas, which correlates with poor prognosis. The present study examines the significance of infiltrating immune cells in four cases of AT/RT; including one associated with an autoimmune disease, Henoch-Schonlein purpura. METHODS Tumor tissues from four patients with AT/RT were analyzed and compared with those from four patients with glioblastomas. The frequency of immune cells, including CD68+, CD4+, and CD8+ cells, was assessed by scoring for statistical analysis. RESULTS The infiltration of immune cells was identified in the case of AT/RT associated with HSP and three other cases of infratentorial AT/RTs. Moderate infiltration of CD68+ macrophages/microglia and CD4+ cells was noted in AT/RTs with no significant difference from that in glioblastomas (p > 0.05). However, the infiltration of CD8+ T-cells was significantly higher in AT/RTs than that in glioblastomas (p < 0.05); CD4+/CD8+ ratio was significantly lower in AT/RTs than that in glioblastomas (p < 0.05). In addition, eosinophils were found in all AT/RTs, but not in glioblastomas. CONCLUSIONS These findings suggest an immune microenvironment of AT/RTs with more immune effectors than glioblastomas. Our observation contributes to understanding the growth environment of AT/RTs for which adjuvant immunotherapy may be potentially beneficial.
Collapse
|
|
28
|
Ginn KF, Gajjar A. Atypical teratoid rhabdoid tumor: current therapy and future directions. Front Oncol 2012; 2:114. [PMID: 22988546 PMCID: PMC3439631 DOI: 10.3389/fonc.2012.00114] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Accepted: 08/22/2012] [Indexed: 01/28/2023] Open
Abstract
Atypical teratoid rhabdoid tumors (ATRTs) are rare central nervous system tumors that comprise approximately 1-2% of all pediatric brain tumors; however, in patients less than 3 years of age this tumor accounts for up to 20% of cases. ATRT is characterized by loss of the long arm of chromosome 22 which results in loss of the hSNF5/INI-1 gene. INI1, a member of the SWI/SNF chromatin remodeling complex, is important in maintenance of the mitotic spindle and cell cycle control. Overall survival in ATRT is poor with median survival around 17 months. Radiation is an effective component of therapy but is avoided in patients younger than 3 years of age due to long term neurocognitive sequelae. Most long term survivors undergo radiation therapy as a part of their upfront or salvage therapy, and there is a suggestion that sequencing the radiation earlier in therapy may improve outcome. There is no standard curative chemotherapeutic regimen, but anecdotal reports advocate the use of intensive therapy with alkylating agents, high-dose methotrexate, or therapy that includes high-dose chemotherapy with stem cell rescue. Due to the rarity of this tumor and the lack of randomized controlled trials it has been challenging to define optimal therapy and advance treatment. Recent laboratory investigations have identified aberrant function and/or regulation of cyclin D1, aurora kinase, and insulin-like growth factor pathways in ATRT. There has been significant interest in identifying and testing therapeutic agents that target these pathways.
Collapse
Affiliation(s)
- Kevin F. Ginn
- Division of Neuro-Oncology, St. Jude Children’s Research HospitalMemphis, TN, USA
| | - Amar Gajjar
- Division of Neuro-Oncology, St. Jude Children’s Research HospitalMemphis, TN, USA
| |
Collapse
|
|
29
|
Buscariollo DL, Park HS, Roberts KB, Yu JB. Survival outcomes in atypical teratoid rhabdoid tumor for patients undergoing radiotherapy in a Surveillance, Epidemiology, and End Results analysis. Cancer 2011; 118:4212-9. [PMID: 22213196 DOI: 10.1002/cncr.27373] [Citation(s) in RCA: 125] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2011] [Revised: 11/06/2011] [Accepted: 11/14/2011] [Indexed: 12/15/2022]
Abstract
BACKGROUND Atypical teratoid rhabdoid tumor (ATRT) is a rare central nervous system malignancy with a poor prognosis that affects mostly young children. Although radiotherapy (RT) historically has been delayed in patients aged <3 years, emerging evidence suggests a role for RT to achieve long-term survivorship. Clinical features and age-dependent trends of RT use were evaluated for patients with ATRT. METHODS The National Cancer Institute's Surveillance, Epidemiology, and End Results database was used to identify 144 patients with ATRT from 1973 to 2008. The primary endpoint was median overall survival (OS). Clinical and treatment variables were assessed for an association with OS using Cox proportional hazards models. Landmark analysis was used to correct for immortal time bias of adjuvant RT. RESULTS The median age at diagnosis was 1 year (range, 0-67 years). Gross total resection of the primary tumor was achieved in 39% of patients, and 33% of patients received RT. From 1992 to 2008, RT use increased 2.4-fold in patients aged ≤3 years. The median OS for was 10 months. In multivariate analyses, metastatic disease (hazard ratio, 2.83; 95% confidence interval, 1.53-5.23; P = .001) and RT (hazard ratio, 0.10; 95% confidence interval, 0.01-0.73; P = .02) were identified as independent predictors of survival. Landmark analysis confirmed a robust association between RT use and survival, which was attenuated in patients ages 4 to 17 years compared with younger patients. CONCLUSIONS The current results indicated that RT may offer a significant survival benefit for patients with ATRT and that patients aged ≤3 years may derive more benefit from initial RT compared with older children. The authors concluded that prospective clinical trials are needed to examine the role of RT in the initial management of ATRT in patients aged <3 years.
Collapse
|
|
30
|
von Hoff K, Hinkes B, Dannenmann-Stern E, von Bueren AO, Warmuth-Metz M, Soerensen N, Emser A, Zwiener I, Schlegel PG, Kuehl J, Frühwald MC, Kortmann RD, Pietsch T, Rutkowski S. Frequency, risk-factors and survival of children with atypical teratoid rhabdoid tumors (AT/RT) of the CNS diagnosed between 1988 and 2004, and registered to the German HIT database. Pediatr Blood Cancer 2011; 57:978-85. [PMID: 21796761 DOI: 10.1002/pbc.23236] [Citation(s) in RCA: 97] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2010] [Accepted: 05/18/2011] [Indexed: 02/01/2023]
Abstract
PURPOSE To analyze the frequency, prognostic factors, and outcome of children with atypical teratoid/rhabdoid tumors (AT/RT), a rare and highly malignant embryonal brain tumor. MATERIALS AND METHODS Clinical data of patients diagnosed between 1988 and 2004 with AT/RT who were registered to the German HIT trial center, were correlated with outcome. Patient numbers for AT/RT were compared to numbers for primitive neuroectodermal tumors and medulloblastomas (PNET/MB) registered to the population-based HIT trials. RESULTS We identified 56 patients with the centrally confirmed histopathological diagnosis of AT/RT with a median age of 1.2 years (range, 0.1-14.0 years). The AT/RT:PNET/MB ratio was 1:12.2 for all children, and 1:1.5 for children younger than 1 year at diagnosis. Three-year overall survival (OS) and event-free survival (EFS) for all patients were 22% and 13%, respectively. Eight patients (14%) are considered long-term event-free survivors (follow-up 1.4-10.6 years). By univariable analyses, younger age, metastatic disease, infratentorial location, and less than complete remission at the end of chemotherapy were identified as negative influencing factors for OS. By multivariable analyses, younger age (OS, EFS) and metastatic disease (OS) were identified as independent risk factors. CONCLUSION The incidence of AT/RT in children below 1 year is higher than previously reported. A subset of patients with favorable clinical risk factors profits from intensive multimodal treatment. Prospective clinical and biological studies are needed to further define prognostic factors and optimize therapy.
Collapse
Affiliation(s)
- Katja von Hoff
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
31
|
Lafay-Cousin L, Hawkins C, Carret AS, Johnston D, Zelcer S, Wilson B, Jabado N, Scheinemann K, Eisenstat D, Fryer C, Fleming A, Mpofu C, Larouche V, Strother D, Bouffet E, Huang A. Central nervous system atypical teratoid rhabdoid tumours: the Canadian Paediatric Brain Tumour Consortium experience. Eur J Cancer 2011; 48:353-9. [PMID: 22023887 DOI: 10.1016/j.ejca.2011.09.005] [Citation(s) in RCA: 145] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2011] [Revised: 08/02/2011] [Accepted: 09/12/2011] [Indexed: 10/16/2022]
Abstract
BACKGROUND Atypical 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 METHODS A 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. RESULTS There 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. CONCLUSION The 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.
Collapse
Affiliation(s)
- L Lafay-Cousin
- Division of Pediatric Hematology Oncology and Bone Marrow Transplantation, Alberta Children's Hospital, Calgary, Alberta, Canada.
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
32
|
Toth G, Zraly CB, Thomson TL, Jones C, Lapetino S, Muraskas J, Zhang J, Dingwall AK. Congenital anomalies and rhabdoid tumor associated with 22q11 germline deletion and somatic inactivation of the SMARCB1 tumor suppressor. Genes Chromosomes Cancer 2011; 50:379-88. [PMID: 21412926 PMCID: PMC3075385 DOI: 10.1002/gcc.20862] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2010] [Accepted: 01/26/2011] [Indexed: 12/31/2022] Open
Abstract
The most common microdeletion in humans involves the 22q11 region. Congenital anomalies associated with 22q11 loss include cardiac and facial defects. Less frequent is the co-presentation of malignant rhabdoid tumors that are highly aggressive childhood malignancies typically found in renal or extra-renal soft tissues and central nervous system. A newborn patient presented with multiple congenital anomalies consistent with 22q11 deletion syndrome including cleft lip and palate, ear tags and ventricular septal defects co-presenting with an axillary rhabdoid tumor. Comparative genomic hybridization revealed a 2.8 Mb germline deletion in the 22q11.2 region containing genes required for normal fetal development and the SMARCB1 tumor suppressor gene. Analysis of tumor DNA revealed a somatic deletion of exon 7 in the second allele of SMARCB1. Expression of SMARCB1 was absent, while tumor markers including MYC, GFAP, and CLAUDIN-6 were upregulated. The presence of tandem oriented BCRL modules located within interspersed low copy repeat elements throughout the 22q11 distal region may predispose this area for microdeletions through nonalleleic homologous recombination.
Collapse
Affiliation(s)
- George Toth
- Stritch School of Medicine, Loyola University of Chicago, Maywood, IL 60153, USA
| | - Claudia B. Zraly
- Stritch School of Medicine, Loyola University of Chicago, Maywood, IL 60153, USA
- Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University of Chicago, Maywood, IL 60153, USA
| | - Tricia L. Thomson
- Stritch School of Medicine, Loyola University of Chicago, Maywood, IL 60153, USA
- Department of Pediatrics, Loyola University of Chicago, Maywood, IL 60153, USA
| | - Carolyn Jones
- Stritch School of Medicine, Loyola University of Chicago, Maywood, IL 60153, USA
- Department of Pediatrics, Loyola University of Chicago, Maywood, IL 60153, USA
- Department of Pathology, Loyola University of Chicago, Maywood, IL 60153, USA
| | - Shawn Lapetino
- Stritch School of Medicine, Loyola University of Chicago, Maywood, IL 60153, USA
- Department of Pathology, Loyola University of Chicago, Maywood, IL 60153, USA
| | - Jonathan Muraskas
- Stritch School of Medicine, Loyola University of Chicago, Maywood, IL 60153, USA
- Department of Pediatrics, Loyola University of Chicago, Maywood, IL 60153, USA
| | - Jiwang Zhang
- Stritch School of Medicine, Loyola University of Chicago, Maywood, IL 60153, USA
- Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University of Chicago, Maywood, IL 60153, USA
- Department of Pathology, Loyola University of Chicago, Maywood, IL 60153, USA
| | - Andrew K. Dingwall
- Stritch School of Medicine, Loyola University of Chicago, Maywood, IL 60153, USA
- Oncology Institute, Cardinal Bernardin Cancer Center, Loyola University of Chicago, Maywood, IL 60153, USA
- Department of Pathology, Loyola University of Chicago, Maywood, IL 60153, USA
| |
Collapse
|
|
33
|
Sarin H. Overcoming the challenges in the effective delivery of chemotherapies to CNS solid tumors. Ther Deliv 2010; 1:289-305. [PMID: 22163071 PMCID: PMC3234205 DOI: 10.4155/tde.10.22] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Locoregional therapies, such as surgery and intratumoral chemotherapy, do not effectively treat infiltrative primary CNS solid tumors and multifocal metastatic solid tumor disease of the CNS. It also remains a challenge to treat such CNS malignant solid tumor disease with systemic chemotherapies, although these lipid-soluble small-molecule drugs demonstrate potent cytotoxicity in vitro. Even in the setting of a 'normalized' tumor microenvironment, small-molecule drugs do not accumulate to effective concentrations in the vast majority of tumor cells, which is due to the fact that small-molecule drugs have short blood half-lives. It has been recently shown that drug-conjugated spherical lipid-insoluble nanoparticles within the 7-10 nm size range can deliver therapeutic concentrations of drug fraction directly into individual tumor cells following systemic administration, since these functionalized particles maintain peak blood concentrations for several hours and are smaller than the physiologic upper limit of pore size in the VEGF-derived blood capillaries of solid tumors, which is approximately 12 nm. In this article, the physiologic and ultrastructural basis of this novel translational approach for the treatment of CNS, as well as non-CNS, solid cancers is reviewed.
Collapse
Affiliation(s)
- Hemant Sarin
- National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, Maryland 20892, USA.
| |
Collapse
|