The Children’s Brain Tumor Tissue Consortium Annual Report 2015
The Consortium enrolled its 1500th subject in 2015 and is expected to reach 3000 unique tissue specimens during the 2nd quarter of 2016. These achievements are the result of the hard work and dedication of the CBTTC Institutional Members at The Children’s Hospital of Philadelphia (CHOP), The University of Pittsburgh Children’s Hospital, Seattle Children’s Hospital, Lurie Children’s Hospital in Chicago, Meyer Children’s Hospital in Florence, Italy and the dedication and support of the Children’s Brain Tumor Foundation, the Licensing Industry Merchandisers’ Association, countless volunteers and dedicated donors. The commitments of these partnerships and others being forged will only further ensure the shared vision to identify better testing, treatments, and outcomes for children diagnosed with these devastating diseases.
Growth of the Repository
In 2015, three additional institutions were approved by the CBTTC Executive Committee to join the consortium. Two as primary members, The UCSF Benioff Children’s Hospital led by Sabine Mueller M.D., Ph.D. and Joanna Phillips M.D. and The Lucile Packard Children’s Hospital at Stanford led by Michelle Monje M.D., Ph.D. Gerald Grant M.D., FACS, and one new satellite member, The Bristol-Myers Squibb Children’s Hospital at Robert Wood Johnson University Hospital led by Dr. Wilbur Pan. We are extremely excited to welcome these institutional leaders in the field of pediatric brain tumor community research.
The 2015 calendar year has seen substantial advances in the CBTTC clinical database, specimen numbers, and histological diversity within the repository. 2015 also represented our focus on prospectively enrolling subjects within the CBTTC.
Current enrollment numbers are represented in Table 1 below.
Table 1. Enrollment by Site to Date*
** One-time specimen transfer
The CBTTC Operations Center (OC) at CHOP received over 600 specimens from CBTTC member institutions’ subjects during this reporting period including frozen tissue, cerebral spinal fluid, and blood from the children and their parents as detailed in Table 2 below. All sites will continue prospective enrollment and, per the CBTTC Constitution, our goal is to submit 75% of all brain tumor cases to the CBTTC OC. In 2016, our efforts to obtain parent samples for genomic analysis will be facilitated by the use of saliva samples. The method is less invasive and logistically more convenient for parents to contribute to the research process. The saliva kits will be readily available in each clinic at each consortium site and can be taken home and returned via mail as well.
Table 2. Specimen Inventory Submitted by Site and Specimen Type in 2015(Specimens are totaled by aliquot – multiple aliquots for one collected date equal 1; all received in 2015)
There are over 28 different histological subtypes within the CBTTC repository. As we receive more specimens and subtypes, the clinical data is regularly reviewed to update the repository status. The objective of the CBTTC is collect all pediatric brain tumor subtypes to provide the largest and most comprehensive repository of specimens. The volume of available specimens along with the clinical annotations are provided in real time on the CBTTC Clinical Data and Specimen Repository Portal. The portal can be accessed via this link https://eig.research.chop.edu
New users must register for access which is received by the CBTTC Operations center for approval.
The graph below identifies the type and number of diagnoses within the database and provides an up-do-date snap shot with the real time specimen counts available on the CBTTC Clinical Data and Specimen Repository Portal. The count represents numbers of individual diagnoses per subject. For example, if a subject has an initial diagnosis of Medulloblastoma and a recurrent diagnosis of Medulloblastoma, this is counted twice.
Focused Working Groups
Due to the CBTTC’s unprecedented growth, we identified a need for focused working groups within the consortium. The first to launch was the Clinical Working Group, developed and led by Dr. Angela Waanders. The group is composed of clinicians, within and outside of the consortium as well as CBTTC clinical research coordinators and is tasked with evaluating the clinical data that will be collected by the CBTTC and providing these recommendations to the Executive Board and Scientific Committee for review. The Clinical Working Group meets monthly by conference calls to determine recommendations. The initial set of changes included, but wasn’t limited to, updates to the list of tests performed in pathology and clarifications to treatment data, such as radiation sites and dates of radiation and/or chemotherapy. Those recommendations have since been approved and implemented. Moving forward, the group will continue its efforts to ensure standardization and evaluation of the CBTTC clinical data models. This will position the CBTTC to continually support robust longitudinal clinical data annotation of the repository.
The Coordinator Working Group was also initiated in 2015 to address the workflow complexities we are encountering in this multi-institutional effort. The Coordinator Working Group is led by Emily Golbeck, Clinical Research Coordinator at the Ann and Robert Lurie Children’s Hospital of Chicago. Early initiatives partnered Emily directly with the CBTTC Operations Center informatics teams to improve the clinical data collection informatics portal. This group meets monthly to address issues around standard operating procedures, best practices, guidelines feasibility, efficiency, and quality control. The Coordinating Working Group’s finding are communicated as recommendations to the CBTTC Executive Board. We look forward to the additional finding from this group to ensure the continued operational success of the CBTTC.
Looking forward, a Pathology Working Group will be created in 2016 to bring together the pathology expertise among the consortium members, create a more robust central pathology review of the specimen received by the repository, continue work on standardization of pathology practices and nomenclature, and provide new platforms for research such as tissue microarrays (TMA). The pathology working group will be led by Dr. Ron Hamilton, Associate Professor of Neuropathology at Pittsburgh Children’s Hospital. This group will work with the BioInformatics group at CHOP and an outside vendor, Blackfynn, to also create a web-based pathology portal space for the CBTTC. We anticipate that this will facilitate the sharing of digital images for pathology central review with real-time collaborative opportunities within the consortium members.
A primary objective of the CBTTC is to provide high-quality biospecimens annotated with clinical and genomic data to facilitate and advance childhood brain tumor research. Investigators do not have to be part of the CBTTC to submit a scientific proposal to the CBTTC Scientific Committee. If the Scientific Committee approves the proposal, materials are provided without charge to that investigator on the condition that all data generated will be shared with the CBTTC. Scientific proposals can be submitted at any time and are evaluated as soon as they are received. The current time from approved scientific proposal to release of specimens by the CBTTC Operations Center is less than one month and is expected to be faster once a new automated request system is launched in 2016. The process follows a review of the project proposal by the scientific committee along with a detailed report of the specimens being requested. In this way, the committee can evaluate the use of the very limited specimens to maximize their use. Additionally, a rigorous quality control check is done on the clinical data and the specimens before scientific committee review and release of the materials. To maximize specimen use, the CBTTC will provide the DNA and/or RNA extractions from the requested tissue rather than releasing the primary tissue specimen itself. This approach maximizes and conserves valuable specimens for future studies. DNA and RNA extractions are done by the Biorepository Core at the Children’s Hospital of Philadelphia to ensure standardization unless there is an overriding scientific rationale that mandates processing by a outside facility. Genomic sequencing may be performed at CHOP by the Sequencing Core Facility (BGI@CHOP) or at a facility identified by the investigator. To date, 56 whole genomes and 50 RNA profiles have been sequenced.
Currently, the CBTTC is supporting five pediatric brain tumor research projects.
Project 1. Genomic Investigation of Gangliogliomas. This study, funded by the Voices Against Brain Cancers Foundation, characterizes the genomic landscape of gangliogliomas by whole genome sequence analysis of 8 matched tissue/blood samples. Principal Investigator: Adam Resnick Ph.D. Assistant Professor of Neurosurgery at The Children’s Hospital of Philadelphia
Project 2. Genomic Investigation of Craniopharyngiomas. This project, a joint effort between investigators at CHOP, The University of Pennsylvania, and the Dana Farber Foundation. Seeks to identify the genomic characteristics of craniopharyngiomas by means of whole genome sequencing of 5 matched pairs of tumor/blood, whole exome sequencing of 7 tumor/blood, and targeted sequencing of 30 additional formalin fixed paraffin embedded craniopharyngioma samples. Principal Investigator: Adam Resnick Ph.D. Assistant Professor of Neurosurgery at The Children’s Hospital of Philadelphia
Project 3. Genomic Evaluation of Malignant Pediatric Cortical Tumors. This is the first research project launched by a CBTTC member site that uses CBTTC specimens and clinical data. Dr. Sarah Leary, Associate Professor of Pediatrics at Seattle Children’s Hospital aims to describe genomic alterations and tumor subtypes within a large cohort of well-characterized supratentorial malignant pediatric brain tumors. The goal of this project is to evaluate the association between genetically determined subtypes and standard clinical factors such as histology, location, metastatic status, and survival. In collaboration with Dr. Angela Waanders, Assistant Professor of Pediatric Oncology at Children’s Hospital of Philadelphia and Dr. Annie Huang, Associate Professor of Pediatrics from Toronto Hospital for Sick Children.
Project 4. Whole Genome Sequencing of Medulloblastoma. This study, led by Dr. Tom Curran while at the Children’s Hospital of Philadelphia, is designed to genomically characterize a subsets of medulloblastoma tumor specimens tumors either express or do not express Gab1 or Nestin as determined by Tissue Microarray staining. Dr. Curran will continue this work as he takes his new position as the Chief Scientific Officer and Executive Director of the Children’s Mercy Hospital Research Institute at the University of Kansas School of Medicine.
Project 5. Exploration of IDO1 as a Therapeutic Target in pCNS tumors. This project, led by Dr. Rishi Lulla MD, Assistant Professor of Pediatrics at The Ann and Robert Lurie Children’s’ Hospital of Chicago, together with a team of scientists with specific expertise in IDO1, aims to measure the level of IDO1 expression in pediatric CNS tumors, specifically focus on low-grade glioma, high-grade glioma, medulloblastoma, and ependymoma. Published studies suggests that IDO1 is a promising target for immunotherapy in adult gliomas. However, similar data for pediatric brain tumors is not available and may have significant translational implications in children.
The informatics portals that connect the clinical and genomic data to specimens available to request from the bank represent the backbone of the CBTTC repository. These allow any researcher around the world to access the repository in real time and collaborators to deposit data remotely, thereby positioning the CBTTC as a sustainable research resource.
The BioInformatics Group (at CHOP) continues to fine-tune the Harvest Portal, which links the clinical and specimen inventories, allows investigators worldwide the ability to access the CBTTC Biorepository and view the available samples based on queryable fields from the clinical database. In 2016, the harvest portal team will launch a new automated request system for Scientific Projects with real-time analytics. This process will identify specific specimens that are requested for study, compare them to tests already performed, and identify overlap of simultaneous requests. By removing a large portion of manual work, the system will ultimately reduce the amount of time for scientific project review and approval by the Scientific Committee and provide a greater level of transparency. Additionally, a new information analyst has joined the Bioinformatics Group at CHOP team to facilitate data quality assurance assist in ensuring quality data, both within the clinical database and in Nautilus (the specimen management database). Automating quality control and allowing coordinators at each site to quickly identify errors within the data will improve our data quality and data entry procedures.
The informatics team grew in 2015 and added 10 new members, which was funded by CHOP institutional funds. This expanded team supports two new informatics portals designed to extend CBTTC data sharing and advance collaborative research. The first portal, CBIO+, was developed to support genomic data visualization. This portal is a collaboration with Memorial Sloan Kettering and builds upon the success of CBIO+ portal created for genomic data visualization of the adult NIH supported TCGA (define TCGA) data. The CBIO+ portal allows for the deposition of any cancer or normal genomic data set for pediatric or adults. The genomic data visualization tools allow researchers to identify new mutations through pan-cancer analysis, target mutations of interest across cancer types, and provide interface functionality for integration into the CHOP Harvest portal described above.
The second portal, called Cavatica, is a pediatric genomic cloud that began development in 2015 and is expected to launch version 1 in the second quarter of 2016. This platform will interfact with Harvest and CBIO+ to remove obstacles researchers currently face in efforts to analyze, collaborate and store very large raw genomic data. The informatics team partnered with Seven Bridges Genomics (SBG) an NCI Cancer Genomic Cloud grant recipient to develop Cavatica.
The Operations Center at CHOP continues to receive, process, store and perform quality control on specimens and clinical data obtained from the member sites as well as those from CHOP subjects. The group has made tremendous strides in standardization. documenting the processes and procedures within Manual Operating Procedures (MOPS). CHOP continues its commitment to this program with over twenty institutional leaders and personnel contributing to the project. The Operations Center team led by Peter Phillips MD, Director of CHOP’s Pediatric Neuro-Oncology Program, Adam Resnick Ph.D., Assistant Professor of Neurosurgery, Phillip (Jay) Storm MD, Chair, Division of Neurosurgery, and Angela Waanders M.D. MPH, Assistant Professor of Pediatric Oncology.
The efforts and dedication of our consortium partners is a critical part of the CBTTC’s continued successes. Working with highly commited researchers, clinicians, coordinators, pathologists and support staff at all of our sites ensures a consistency of purpose and focused vision. The Children’s Hospital of Pittsburgh led by Ian Pollack M.D., The Ann and Robert Lurie Children’s Hospital of Chicago is led by Stewart Goldman M.D., Rishi Lulla M.D. and Seattle Children’s Hospital is led by Russ Geyer MD, Sarah Leary MD and the Meyer Children’s’ Hospital in Florence Italy led by Anna Maria Buccoliero M.D. PhD. Joining the consortium and collaboration in 2015 was UCSF Benioff’s Children’s Hospital and is led by Joanna Phillips M.D. Ph.D. and Sabine Mueller M.D. Ph.D.
In 2015 The Children’s Brain Tumor Foundation (CBTF) committed $350,000 to support the CBTTC Operations Center at CHOP. This funding support, defined in the annually executed grant terms agreement, provides partial salaries and laboratory supply support as summarized below:
- Partial salaries for:
- Laboratory technical staff
- Operations Manager
- Clinical Data Coordinator
- Purchase of laboratory supplies and equipment to maintain the CBTTC infrastructure
The CBTF also provides funding for each primary member institution at $75,000 annually. These funds are distributed directly from the CBTF to the member institution. This funding is a key to the success of the CBTTC, and the consortium is continually grateful for the partnership with CBTF and LIMA.
Additional funding, totaling approximately $1.3 million for the CBTTC Operational activities at CHOP, came from philanthropic foundation support and CHOP institutional funding in 2015. These activities include support for the biorepository core, informatics teams, specimen technicians, clinical data coordinators, bioinformaticians, research projects, data generation, equipment, service contracts with commercial partners and one-time pilot grants to support new sites. Leveraging the support of the CBTF the consortium has been able to secure these addition funds to support the growth, new initiatives and sustainability of the CBTTC.
|Alan Stallings Fund
Alex Munoz Foundation
Andrew Noten Hudson Foundation
At Least Kids Foundation
Avery Lubrecht Foundation
BethAnn Telford, TeamBT
Brain Tumor Avengers
Brandles Joy of Hope
Brendan Bovard Fund for Brain Tumor Research
Bryce Hansen Bridge of Hope Fund
Charles and Pat Genuardi
Chester County Community Foundation
Children’s Brain Tumor Foundation and the Licensing and Merchandiser’s Association
David and Deborah Calvaresi
Derrick and Lauren Roamelle
Dragon Master Foundation
Eaise Family Foundation, Inc.
Grayson Saves Foundation
Hanna Duffy Foundation
James and Nancy Minnick
|Joseph T. Lentz Pediatric Brain Cancer Research Fund
Kayla’s Hope for Kids Fund
Kyle Daniel Kerpan Foundation
Lauren’s First and Goal
Miriam’s Kids Research Foundation
Pearce Q. Foundation, Inc.
Smiles for Jake Foundation
Suzanne Gilligan – Luke Forward
The Christopher Court Foundation
The CJR Memorial Foundation
The Kortney Rose Foundation
The Matthew Renk Foundation
The Timothy Pauxtis Foundation
Thea’s Star of Hope
Vs Cancer Foundation
Why Not Me? Foundation
Wylie’s Day Foundation
Looking Forward: CBTTC 2016
The CBTTC will hold its Annual Investigator Meeting in New Orleans in May 2016. The member sites will join with supporting philanthropic foundations to communicate recent achievements, discuss ongoing projects and preview new initiatives. Our 2015 Investigator’s Meeting in Philadelphia set the stage for many of the advances we describe in this report and reconfirmed our commitment to a shared, collaborative vision. In 2016 we anticipate continued growth of the CBTTC by the addition of new consortium institutions, substantially more tumor specimens and types as well as advances in our ability to share data through our new informatics portals (i.e., CBIO+ and the pediatric genomic data cloud, Cavatica). Additionally, the CBTTC will be launching a new website which will better inform researchers and supporters of CBTTC, and the lay public, of CBTTC activities, projects and future initiatives. A portion of the website will also allow [CBTTC]members and external collaborators, to access CBTTC Standard Operating Procedures, process documentation as well as meeting agendas and minutes. We anticipate that this will enhance our shared vision globally and further the collaborative mission of the CBTTC. We gratefully acknowledge the support of The Children’s Brain Tumor Foundation and LIMA and look forward to a strong and productive partnership in 2016.