ABSTRACT
BACKGROUND: The optimal timing of colonoscopy in acute lower gastrointestinal bleeding (LGIB) remains controversial. AIM: To characterise the utility of early colonoscopy (within 24 hours) in managing acute LGIB. METHODS: A systematic literature search to October 2019 identified fully published articles and abstracts of randomised controlled trials (RCTs) and observational studies with control groups assessing early colonoscopy in acute LGIB. The primary outcome was rebleeding. Secondary outcomes included mortality, surgery, length of stay (LOS), definite cause of bleeding and adverse events. Odds ratios (ORs) and mean differences (MD) were calculated. RESULTS: Of 1116 citations, 4 RCTs (466 patients) and 13 observational studies with elective colonoscopy (>24 hours) as control group (1 061 281 patients) were included. No differences in rebleeding were noted between early and elective colonoscopy groups among RCTs alone (OR = 1.70; 0.79; 3.64), or observational studies alone (OR = 1.20; 0.69; 2.09). No other significant between-group differences in outcomes were found when restricting the analysis to RCTs. Among observational studies only, early colonoscopy was associated with lower rates of all-cause mortality (OR = 0.86; 0.75; 0.98), surgery (OR = 0.52; 0.42; 0.64), blood transfusion (OR = 0.81; 0.75; 0.87), units of blood transfusion (MD = -4.30; -6.24; -2.36) and shorter LOS (MD = -1.70; -1.70; -1.70 days). CONCLUSION: In contradistinction to observational studies, data from RCTs do not support a role for early colonoscopy in the routine management of acute LGIB with regards to the most important clinical outcomes. Further research is needed to better identify patients with high-risk LGIB who may benefit from early colonoscopy.
Subject(s)
Colonoscopy , Gastrointestinal Hemorrhage/diagnosis , Acute Disease , Colonoscopy/adverse effects , Colonoscopy/methods , Colonoscopy/statistics & numerical data , Early Diagnosis , Elective Surgical Procedures/adverse effects , Elective Surgical Procedures/methods , Elective Surgical Procedures/statistics & numerical data , Gastrointestinal Hemorrhage/epidemiology , Humans , Length of Stay , Predictive Value of Tests , Prognosis , Risk AssessmentABSTRACT
We recently demonstrated that lack of Furin-processing of the N-cadherin precursor (proNCAD) in highly invasive melanoma and brain tumor cells results in the cell-surface expression of a nonadhesive protein favoring cell migration and invasion in vitro. Quantitative polymerase chain reaction analysis of malignant human brain tumor cells revealed that of all proprotein convertases (PCs) only the levels of Furin and PC5A are modulated, being inversely (Furin) or directly (PC5A) correlated with brain tumor invasive capacity. Intriguingly, the N-terminal sequence following the Furin-activated NCAD site (RQKR↓DW(161), mouse nomenclature) reveals a second putative PC-processing site (RIRSDR↓DK(189)) located in the first extracellular domain. Cleavage at this site would abolish the adhesive functions of NCAD because of the loss of the critical Trp(161). This was confirmed upon analysis of the fate of the endogenous prosegment of proNCAD in human malignant glioma cells expressing high levels of Furin and low levels of PC5A (U343) or high levels of PC5A and negligible Furin levels (U251). Cellular analyses revealed that Furin is the best activating convertase releasing an ~17-kDa prosegment, whereas PC5A is the major inactivating enzyme resulting in the secretion of an ~20-kDa product. Like expression of proNCAD at the cell surface, cleavage of the NCAD molecule at RIRSDR↓DK(189) renders the U251 cancer cells less adhesive to one another and more migratory. Our work modifies the present view on posttranslational processing and surface expression of classic cadherins and clarifies how NCAD possesses a range of adhesive potentials and plays a critical role in tumor progression.
Subject(s)
Antigens, CD/metabolism , Brain Neoplasms/metabolism , Cadherins/metabolism , Cell Movement , Furin/metabolism , Glioma/metabolism , Proprotein Convertase 5/metabolism , Antigens, CD/genetics , Blotting, Western , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Cadherins/genetics , Furin/antagonists & inhibitors , Furin/genetics , Glioma/genetics , Glioma/pathology , HeLa Cells , Humans , Immunoenzyme Techniques , Proprotein Convertase 5/antagonists & inhibitors , Proprotein Convertase 5/genetics , RNA, Messenger/genetics , RNA, Small Interfering/genetics , Real-Time Polymerase Chain Reaction , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured , Wound HealingABSTRACT
The expression of N-cadherin (NCAD) has been shown to correlate with increased tumor cell motility and metastasis. However, NCAD-mediated adhesion is a robust phenomenon and therefore seems to be inconsistent with the "release" from intercellular adhesion required for invasion. We show that in the most invasive melanoma and brain tumor cells, altered posttranslational processing results in abundant nonadhesive precursor N-cadherin (proNCAD) at the cell surface, although total NCAD levels remain constant. We demonstrate that aberrantly processed proNCAD promotes cell migration and invasion in vitro. Furthermore, in human tumor specimens, we find high levels of proNCAD as well, supporting an overall conclusion that proNCAD and mature NCAD coexist on these tumor cell surfaces and that it is the ratio between these functionally antagonistic moieties that directly correlates with invasion potential. Our work provides insight into what may be a widespread mechanism for invasion and metastasis and challenges the current dogma of the functional roles played by classic cadherins in tumor progression.
