BACKGROUND:Juvenile polyps (JPs) are the most common gastrointestinal polyps diagnosed in children. There is paucity of evidence differentiating polyp burden groups and the presence and significance ...of neoplastic changes.
METHODS:A retrospective chart review of patients, ages birth through 18 years with nonsyndromic JPs was performed from 2003 to 2017. Abstracted data included basic demographics, age, clinical presentation, colonoscopy findings, and pathology report. Slides of polyps with neoplasia were reviewed by a pathologist.
RESULTS:A total of 213 subjects underwent 326 procedures and 435 polypectomies. Subjects with positive family history, positive gene mutations, or numerous (>10) polyps were excluded. Groups were defined by polyp number (1, 2–4, 5–10). Polyp recurrence on repeat colonoscopy was significantly related to polyp burden (1 polyp1.5%/2–4 polyps 19.2%/5–10 polyps 82.6%P < 0.001). Polyp distribution was significantly different amongst different groups with isolated polyps favoring a distal distribution. JPs harboring adenomatous foci were reported in 26 (12%) patients. JPs harboring adenomatous foci were significantly more likely to be proximally distributed but the presence of adenomatous transformation within the polyps did not correlate with polyp number or the likelihood of polyp recurrence on repeat colonoscopy.
CONCLUSIONS:JP recurrence is positively and significantly related to polyp burden. JP harbored adenomatous changes independent of polyp number, underscoring a possible malignant potential in JPs. In the absence of a consistent genotype or pedigree, the presence of adenomatous transformation within JPs cannot be construed as a biomarker for syndromic juvenile polyposis.
Inflammatory Bowel Disease (IBD) is a multifactorial disorder that conceptually occurs as a result of altered immune responses to commensal and/or pathogenic gut microbes in individuals most ...susceptible to the disease. During Crohn's Disease (CD) or Ulcerative Colitis (UC), two components of the human IBD, distinct stages define the disease onset, severity, progression and remission. Epigenetic, environmental (microbiome, metabolome) and nutritional factors are important in IBD pathogenesis. While the dysbiotic microbiota has been proposed to play a role in disease pathogenesis, the data on IBD and diet are still less convincing. Nonetheless, studies are ongoing to examine the effect of pre/probiotics and/or FODMAP reduced diets on both the gut microbiome and its metabolome in an effort to define the healthy diet in patients with IBD. Knowledge of a unique metabolomic fingerprint in IBD could be useful for diagnosis, treatment and detection of disease pathogenesis.
Alternative promoter usage generates long and short isoforms (DCLK1-L and DCLK1-S) of doublecortin-like kinase-1 (DCLK1). Tight control of Notch signaling is important to prevent and restitute ...inflammation in the intestine. Our aim was to investigate whether Notch1–DCLK1 axis regulates the mucosal immune responses to infection and whether this is phenocopied in human models of colitis. In the FFPE (formalin-fixed paraffin-embedded) sections prepared from the colons of ulcerative colitis (UC) and immune-mediated colitis (IRAEC) patients, expression of DCLK1 isoforms correlated positively with Notch1 and negatively with a transcriptional repressor, FoxD3 (Forkhead Box D3). DCLK1 protein staining in these sections was predominantly sub-epithelial (stromal) wherein DCLK1 co-localized with NICD, CD68, CD11c, and neutrophil elastase (NE). NE also co-stained with Citrullinated-H3 indicating the presence of neutrophil extracellular traps. In human neutrophils, elevated levels of DCLK1-S, CXCL-10, Ly6G, MPO, NE, and Notch1/2 in LPS-treated cells were inhibited when LPS was added in conjunction with Notch blocker dibenzazepine (DBZ; LPS + DBZ group). In CR-infected Rag1−/− mice, higher levels of DCLK1 in the colonic crypts were inhibited when mice received DBZ for 10 days coincident with significant dysbiosis, barrier disruption, and colitis. Concurrently, DCLK1 immunoreactivity shifted toward the stroma in CR + DBZ mice with predominance of DCLK1-S that coincided with higher Notch1 levels. Upon antibiotic treatment, partial restoration of crypt DCLK1, reduction in MPO activity, and increased survival followed. When intestinal epithelial cell-specific Dclk1-knockout (Dclk1ΔIEC) or Dclk1ΔIEC;Rag1−/− double knockout (DKO) mice were infected with CR and given a single dose of DBZ, they developed barrier defect and severe colitis with higher levels of stromal DCLK1-S, Ly6G, NE, and Notch1. We therefore propose that, by regulating the mucosal immune responses, the Notch–DCLK1 axis may be integral to the development of murine or human colitis.
Individuals with familial adenomatous polyposis (FAP) harbor numerous polyps with inevitable early progression to colon cancer. Complex microbiotic-tumor microenvironment perturbations suggest a ...dysbiotic relationship between polyp and microbiome. In this study, we performed comprehensive analyses of stool and tissue microbiome of pediatric FAP subjects and compared with unaffected cohabiting relatives through 16S V4 region amplicon sequencing and machine learning platforms.
Within our FAP and control patient population, Firmicutes and Bacteroidetes were the predominant phyla in the tissue and stool samples, while Proteobacteria dominated the polyp/non-polyp mucosa. A decline in Faecalibacterium in polyps contrasted with a decline in Bacteroides in the FAP stool. The alpha- and beta-diversity indices differed significantly within the polyp/non-polyp groups, with a concurrent shift towards lower diversity in polyps. In a limited 3-year longitudinal study, the relative abundance of Proteobacteria and Fusobacteria was higher in polyps compared to non-polyp and stool specimens over time. Through machine learning, we discovered that Archaeon_enrichment_culture_clone_A13, Micrococcus_luteus, and Eubacterium_hallii in stool and PL-11B10, S1-80, and Blastocatellaceae in tissues were significantly different between patients with and without polyps.
Detection of certain bacterial concentrations within stool or biopsied polyps could serve as adjuncts to current screening modalities to help identify higher-risk patients.
Desmoid tumors are a group of benign, invasive, solid tumors that are relatively rare in the general population, but can occur in up to 21 % of patients with Familial Adenomatous Polyposis (FAP). ...They can be difficult to treat and have high rates of recurrence even after resection. Our goal with this study was to identify the genetic mutations that put certain patients with FAP at high risk for desmoid tumors and could be future targets for research.
We performed a search in Pubmed, Ovid Medline and Embase to identify subjects with desmoid tumors and FAP. As a reference group for APC mutations in the unselected FAP population, we used the UMD-APC database referenced in the Orphanet portal which includes APC mutation data on 2040 individuals with FAP.
Mutations were able to be broken down into 7 regions based on previously published data. Mutations in the APC gene from codons 1310 to 2011 were the most common region encompassing 48 % of published desmoid cases and 40 % of the reference population. It had a slightly elevated odds ratio of 1.4 that was statistically significant along with codon region 543-713 that had an odds ratio of 2.0. Using a combination of p-value and CI, the remaining 5 regions did not meet statistical significance as either the p >0.05 or the CI included 1.0. The most common point mutation found was codon 1309 (13.1 %), but it was also the most commonly found mutation in our reference population (12.9 %) and had an odds ratio of 1.0.
There is an increased risk for desmoid tumors in individuals with APC mutations between codons 543-713 and 1310-2011 when compared to a reference population. These patients may benefit from further study to develop surveillance protocols that could improve outcomes.
Familial adenomatous polyposis (FAP) is a hereditary condition with a near 100 % lifetime risk of colorectal cancer without prophylactic colectomy. Most patients with FAP have a mutation in the ...adenomatous polyposis coli gene on chromosome 5q22. This condition frequently presents in children with polyps developing most frequently in the second decade of life and surveillance colonoscopy is required starting at age ten. Polyps are found not only in the colon, but in the stomach and duodenum. Knowledge of the natural history of FAP is important as there are several extra-colonic sequelae which also require surveillance. In infants and toddlers, there is an increased risk of hepatoblastoma, while in teenagers and adults duodenal carcinomas, desmoid tumors, thyroid cancer and medulloblastoma are more common in FAP than in the general population. Current chemopreventive strategies include several medications and natural products, although to this point there is no consensus on the most efficacious and safe agent. Genetic counseling is an important part of the diagnostic process for FAP. Appropriate use and interpretation of genetic testing is best accomplished with genetic counselor involvement as many families also have concerns regarding future insurability or discrimination when faced with genetic testing.
It is known that the liver undergoes size increase and differentiation simultaneously during the postnatal period. Cells in the liver undergo a period of well-controlled proliferation to achieve the ...adult liver-to-body weight ratio. The postnatal liver growth is also accompanied by simultaneous hepatic differentiation. However, the mechanisms of liver size regulation and differentiation are not completely clear. Herein we report that yes-associated protein (Yap), the downstream effector of the Hippo Kinase signaling pathway, plays a role in liver size regulation and differentiation during the postnatal liver growth period. Postnatal liver growth was studied in C57BL/6 mice over a time course of postnatal days (PND) 0-30. Analysis of nuclear Yap by Western blot indicated peak Yap activation between PND15-20, which coincided with increased cyclin D1 expression and liver cell proliferation. Analysis of postnatal liver development in Yap(+/-) mice revealed a significant decrease in the liver-to-body weight ratio compared with Yap(+/+) mice at PND15 and -30. Yap(+/-) mice exhibited a significant decrease in postnatal liver cell proliferation, but no change in apoptosis was observed. Furthermore, global gene expression analysis of Yap(+/-) livers revealed a role of Yap in regulation of genes involved in bile acid metabolism, retinoic acid metabolism, ion transport, and extracellular matrix proteins. Taken together, these data indicate that Yap plays a role in both cell proliferation and possibly in hepatic differentiation during postnatal liver development.
ABSTRACT
Consensuses on fellowship training in wireless capsule endoscopy (WCE) interpretation have been published for adult gastroenterology (GI) but not in pediatric GI training. A questionnaire ...has been sent to 64 pediatric and 45 adult GI fellowship programs to compare their present training approach. Adult GI programs reported having a formal GI capsule endoscopy module in 38% and required to attend hands‐on course in 27% as compared with 4% and 8% in pediatric programs, respectively. A more formalized approach to WCE training may be required for credentialing pediatric trainees to be aligned with expectations in adult GI programs.
ABSTRACT
Familial adenomatous polyposis (FAP) is a well‐described inherited syndrome, characterized by the development of hundreds to thousands of adenomas in the colorectum, with implications in ...children and adolescents. Almost all adult patients will develop colorectal cancer if they are not identified and treated early enough. Identifying and screening for FAP commences in adolescence. The syndrome is inherited as an autosomal dominant trait and caused by mutations in the adenomatous polyposis (APC) gene. This European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) position paper provides a guide for diagnosis, assessment, and management of FAP in children and adolescents.
This is the first position paper regarding FAP published by ESPGHAN. Literature from PubMed, Medline, and Embase was reviewed and in the absence of evidence, recommendations reflect the opinion of paediatric and adult experts involved in the care of polyposis syndromes. Because many of the studies that form the basis for the recommendations were descriptive and/or retrospective in nature, these of the recommendations are supported on expert opinion. This position paper will instruct on the appropriate management and timing of procedures in children and adolescents with FAP.
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