Pediatric Surgery Research

Pediatric Colorectal and Pelvic Learning Consortium (PCPLC)

Background:

The Pediatric Colorectal and Pelvic Learning Consortium (PCPLC) was organized as an international consortium to identify the areas of most urgent need in colorectal research and conduct prospective studies to solve these problems.

In 2012, ARMs, HD and severe functional constipation combined resulted in 31,000 hospital admissions, 116,000 hospital days and $857,000,000 in charges in the United States (2012 Kids' Inpatient Database [KID]).  Incontinence and other symptoms are frequently under-reported and may have a detrimental long-term effect on educational attainment, quality of life, and family.

Current guidelines for surgical treatment, post-operative care and clinical outcomes for these disorders are based primarily on expert opinion or on retrospective studies performed at single institutions.  Without common definitions and standardized outcome measures applied consistently across multiple centers, the results from these single-center studies may not be generalizable.  Long-term follow-up has also been absent from many studies.  As a result, there is no clear best practice for many aspects of care, and practice varies widely between institutions.   

There has been no comprehensive database for pediatric colorectal disease and its management in North America. The Pediatric Colorectal and Pelvic Learning Consortium (PCPLC) clinical sites will collect information about this patient population and maintain a database. The database will be used by PCPLC to characterize the patient population and to describe treatment practices and functional outcomes. Pilot data from the database will also be used as an aid in hypothesis generation and study design for future PCPLC studies. It is expected that the Core Data Project (CDP) database will provide an infrastructure for the execution of future multi-institutional comparative effectiveness research protocols in this arena.

Specific Aims

Aim 1:  Establish a collaboration group of member institutions and investigators with dedicated research support personnel to create a population dataset, which will characterize the patients and their management in detail.

Aim 2:  Conduct focused studies in specific areas of anorectal malformation, Hirshchsprung’s disease, and severe functional constipation using the dataset

Primary Children's Hospital Colorectal Center Biobank

Background and Introduction:

The Colorectal Center at Primary Children's Hospital has a mission to provide care for children and adolescents with anorectal malformations (ARMS), Hirschsprung’s disease (HD), and other colorectal conditions.  Anorectal malformations (imperforate anus) are defects that occur during the fifth to seventh weeks of fetal development. These defects cause problems in the development of the anus (opening at the end of the large intestine through which stool passes) and the rectum (area of the large intestine just above the anus). Approximately 1 in 5,000 children are born with anorectal malformation and /or other colorectal conditions. The exact etiology or cause of the anorectal malformation is currently unknown but it is thought to be caused in part, from environmental factors, maternal health, gestational diabetes and/or genetic factors. It has long been recognized that colorectal disease recurs in families and possibly from unidentified genetic factors.

Hirschsprung’s disease is a congenital disorder affecting the development of the enteric nervous system.  The abnormal development affects the ganglion cells of the colon and rectum (aganglionosis) resulting in a functional bowel obstruction.  About 1 in 5000 live births is affected, with a variable extent of aganglionic bowel.  HD may be associated with several genetic syndromes including Down syndrome, MEN 2 (RET) and others.  Approximately 50% of cases of HD have been ascribed to mutations of specific genes important for neural crest cell migration into the gastrointestinal tract during early embryonic development but specific mutations in approximately half of patients remain unknown.  Known risk factors affecting recurrence of HD include 1) the occurrence of HD in a genetic syndrome; 2) the presence of HD in 1 or multiple family members; 3) characteristics of the proband, including the length of the involved gastrointestinal segment and the proband’s gender; and 4) the gender of the at-risk baby [6].  A significant challenge in applying our current understanding of HD genetics is the variable penetrance of the disease which is seen even in families with identified genetic mutation/polymorphisms.  This suggests the possibility of environmental influences and genetic modifiers.  Genetic factors may also contribute to HD associated enterocolitis (potentially lethal infection of the intestines) which is an important contributor to morbidity after surgical treatment of HD.

With the help of our patients and their families, we plan to build a repository of biological samples for researchers to study. These samples would allow us to further treat and advance medical diagnostics and therapeutics permitting researchers to study specific types of colorectal disease in future research studies using both a prospective and retrospective study design.

Specific Aims

Aim 1: Create a biospecimen repository of patient’s samples with colorectal diseases including parents and siblings of the patient.

Aim 2: Collect tissue and blood samples of patients with colorectal conditions as part of the standard of care operative management and samples from their immediate family members (blood) to be stored for future testing to assess unknown risk factors.

Aim 3: Use tissue from current patients at the Colorectal Center and already stored post repair of imperforate anus or Hirschsprung’s disease by Pathology at Primary Children’s Hospital, and consent patients to use their previously stored samples which would otherwise be discarded.