Post on 24-Sep-2020
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The Children’s Brain Tumor Tissue Consortium
Annual Report 2015 CBTTC Operations Center
The Children’s Brain
Tumor Tissue Consortium
Annual Report
Acknowledgments
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
Enrollment
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
Accelerating
Pediatric
Brain Tumor
Research
‘The CBTTC is a
collaborative
research program
dedicated to
improving prognostic
testing, treatments
and outcomes for
children diagnosed
with these
devastating
diseases’
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.
Table1. Enrollment by Site To Date*
CBTTC Subject
Site Totals
CHOP 881
Seattle 288
PITT 105
Lurie 328
Meyer 95
East Tennessee** 1
Total 1698
*Clinical Database Subject Numbers as of January 2016
**One time specimen transfer
Specimens
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)
CBTTC Blood Blood Blood CSF Tissue Tissue
Site Child Maternal Paternal Child Flash Frozen Freezing Media
CHOP 83 0 0 12 78 45
Seattle 80 0 0 6 53 3
PITT 5 0 0 0 13 0
Lurie 52 0 0 12 89 8
Meyer 53 0 0 0 54 32
Total 273 0 0 30 287 88
Histological Subtypes
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.
0 100 200 300 400 500 600 700
Gliomatosis Cerebri
Langerhans Cell histiocytosis
Neurocytoma
Chordoma
Malignant peripheral nerve sheath tumor (MPNST)
Pineoblastoma
Non-germinomatous germ cell tumor
Teratoma
Adenoma
Germinoma
Dysplasia/Gliosis
Oligodendroglioma
Choroid plexus carcinoma
Choroid plexus papilloma
Schwannoma
Neurofibroma/Plexiform
Metastatic secondary tumors
Dysembryoplastic neuroepithelial tumor (DNET)
Brainstem glioma- Diffuse intrinsic pontine glioma
Meningioma
Atypical Teratoid Rhabdoid Tumor (ATRT)
Craniopharyngioma
Supratentorial or Spinal Cord
Ganglioglioma
Medulloblastoma
High-grade glioma/astrocytoma (WHO grade III/IV)
Ependymoma
Low-grade glioma/astrocytoma (WHO grade I/II)
Histological Subtypes
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.
Scientific Projects
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.
Informatics
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.
Operations
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.
The Ann and Robert Lurie
Children’s Hospital of Chicago
CBTTC Core Member
Seattle Children’s Hospital
CBTTC Core Member
The Children's Hospital of
Philadelphia
CBTTC Operations Center
Children’s Hospital of Pittsburgh
CBTTC Core Member
UCSF Benioff Children’s Hospital
Funding
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
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
Naya Foundation
Pearce Q. Foundation, Inc.
PLGA Foundation
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
Smiles for Jake Foundation
Stanley’s Dream
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.