No abstract

Sporadic colorectal cancer initiates with mutations in APC or its degradation target β-catenin, producing TCF-dependent nuclear transcription driving tumorigenesis. The intestinal epithelial receptor, GUCY2C, with its canonical paracrine hormone guanylin, regulates homeostatic signaling along the crypt-surface axis opposing tumorigenesis. Here, we reveal that expression of the guanylin hormone, but not the GUCY2C receptor, is lost at the earliest stages of transformation in APC-dependent tumors in humans and mice. Hormone loss, which silences GUCY2C signaling, reflects transcriptional repression mediated by mutant APC-β-catenin-TCF programs in the nucleus. These studies support a pathophysiological model of intestinal tumorigenesis in which mutant APC-β-catenin-TCF transcriptional regulation eliminates guanylin expression at tumor initiation, silencing GUCY2C signaling which, in turn, dysregulates intestinal homeostatic mechanisms contributing to tumor progression. They expand the mechanistic paradigm for colorectal cancer from a disease of irreversible mutations in APC and β-catenin to one of guanylin hormone loss whose replacement, and reconstitution of GUCY2C signaling, could prevent tumorigenesis ARTICLE HISTORY

The importance of preventing venous thromboembolism (VTE) in hospitalized adults is well recognized. We recently developed and published our institutional guidelines for the prevention of VTE in high-risk hospitalized patients in a pediatric hospital. The objective of this prospective observational study was to evaluate the safety of anticoagulation after these guidelines were instituted. The primary outcome was major bleeding and secondary outcomes included minor bleeding and VTE. Eighty-nine patients were enrolled, with a mean age of 16.6 years. The most common risk factors for VTE were impaired mobility, lower extremity orthopedic surgery, and obesity. The majority of patients (63%) had 3 or more risk factors. There were 2 major bleeding events, and minor bleeding occurred in 5 patients, all in patients who had undergone major orthopedic surgery. Therefore the risk of major bleeding in orthopedic surgery patients was 4% (2/51), and 0% (0/38) in the remaining patients. No patient developed a non-catheter-related VTE, which was the primary intent of our guidelines. Although there remains much work to be done to optimize VTE strategies in pediatric patients, this study provides information regarding the risks of VTE prophylaxis using a pragmatic approach in hospitalized patients with multiple risk factors for VTE. More studies are needed to better define the risk:benefit ratio in this population.

Background Small intestinal ischemia is a challenging diagnosis to make, even with the combination of imaging, laboratory analysis, and physical exam. This pilot study investigated the role of CEUS in evaluating small bowel wall vascularity in participants with suspected ischemia. Methods In this IRB‐approved pilot study, CEUS using perflutren lipid microspheres (DEFINITY®; Lantheus Medical Imaging Inc., N. Billerica, MA) was performed on participants determined by the clinical surgical team to have concerns for small intestinal ischemia. CEUS interpretations were performed at both the bedside and later by a blinded radiologist and compared to clinical imaging, surgical findings, or long‐term clinical outcomes. Results Fifteen CEUS examinations were performed on 14 participants. Five of the participants underwent exploratory laparotomy. Of these, one had small intestinal ischemia (without necrosis). Point of care CEUS demonstrated no evidence of bowel necrosis in any case, and delayed enhancement (indicative of intestinal ischemia) in three cases, resulting in a sensitivity of 100% (95% CI 2.5–100%) and specificity of 85.7% (95% CI 57.2–98.2%). CEUS correctly ruled out ischemia in 91.7% of cases with CT suspicion of small bowel obstruction and 60% of cases that underwent surgical intervention. Additionally, the rate of agreement between bedside interpretation and later radiologist read was high (93%). Conclusions CEUS is uniquely positioned for evaluating the small intestine, because of its high temporal resolution and immediacy of results. Combined with multi‐sectional imaging for focal areas of ischemia and/or clinical suspicion for pan ischemia, CEUS may be a useful rule out test for small intestinal ischemia.

Gastrointestinal cancers remain a tremendous burden on society. Despite advances in therapy options, including chemotherapy and radiation, cancer mortality from recurrences and metastases occur frequently. Cancer stem cells (CSCs) drive disease recurrence and metastasis, as these cells are uniquely equipped to self-renew and evade therapy. Therefore, cancer eradication requires treatment strategies that target CSCs in addition to differentiated cancer cells. This review highlights current literature on therapies targeting CSCs in gastrointestinal cancer.