Need for infliximab dose intensification in Crohn's disease and ulcerative colitis

AIM: To compare the need for infliximab dose intensification in two cohorts of patients with Crohn's disease(CD) or ulcerative colitis(UC).METHODS: Single centre, uncontrolled, observational study. Consecutive patients with CD and UC who responded to infliximab induction doses were included. Data collected in a prospectively maintained database were retrospectively analysed. Differences in the rates of dose intensification per patient-month and the intensification-free survival time were compared. We also evaluated the interval between the first infliximab induction dose and the first infliximab escalated dose. The weight-adjusted infliximab administration costs were also calculated.RESULTS: Fifty nine patients with CD and 38 patients with UC were enrolled. The rate of intensification per patient-month was 3.9% for UC and 1.4% for CD(P = 0.005). The median time from baseline to intensification was significantly shorter in UC compared to CD [6.6 mo(IQR: 4.2-9.5 mo) vs 10.7 mo(IQR: 8.9-11.7 mo), P = 0.005]. In the survival analysis, the cumulative probability of avoiding infliximab dose intensification was significantly higher in CD(P = 0.002). In the multivariate analysis, disease(UC vs CD) was the only factor significantly associated with dose intensification. The infiximab administration costs during the first year were significantly higher for UC compared to CD(mean ± SD 234.9 ± 53.3 Euros/kg vs 212.3 ± 15.1 Euros/kg, P = 0.03).CONCLUSION: The rate of infliximab dose intensification per patient-month is significantly higher in UC patients. The infliximab administration costs are also significantly higher in patients with UC.

New genes emerging for colorectal cancer predisposition

Colorectal cancer(CRC)is one of the most frequent neoplasms and an important cause of mortality in the developed world.This cancer is caused by both genetic and environmental factors although 35%of the variation in CRC susceptibility involves inherited genetic differences.Mendelian syndromes account for about5%of the total burden of CRC,with Lynch syndrome and familial adenomatous polyposis the most common forms.Excluding hereditary forms,there is an important fraction of CRC cases that present familial aggregation for the disease with an unknown germline genetic cause.CRC can be also considered as a complex disease taking into account the common diseasecommom variant hypothesis with a polygenic model of inheritance where the genetic components of common complex diseases correspond mostly to variants of low/moderate effect.So far,30 common,low-penetrance susceptibility variants have been identified for CRC.Recently,new sequencing technologies including exomeand whole-genome sequencing have permitted to add a new approach to facilitate the identification of new genes responsible for human disease predisposition.By using whole-genome sequencing,germline mutations in the POLE and POLD1 genes have been found to be responsible for a new form of CRC genetic predisposition called polymerase proofreading-associated polyposis.

Inflammatory bowel disease and celiac disease:Overlaps and differences

Recent findings demonstrate the common genetic basis for many immune-mediated diseases,and consequently,the partially shared pathogenesis.We collected these findings and reviewed the extension of these overlaps to other disease characteristics.Two autoimmune diseases were selected that also share the specific target organ,the bowel.The etiology and immunopathogenesis of both conditions characterized by chronic intestinal inflammation,inflammatory bowel disease(IBD)and celiac disease(CeD),are not completely understood.Both are complex diseases with genetics and environment contributing to dysregulation of innate and adaptive immune responses,leading to chronic inflammation and disease.CeD constitutes a particular disease because the main environmental and genetic triggers are largely known.IBD comprises two main clinical forms,Crohn’s disease and ulcerative colitis,which most likely involve a complex interplay between some components of the commensal microbiota and other environmental factors in their origin.These multifactorial diseases encompass a broad spectrum of clinical phenotypes and ages of onset,although the clinical presentation often differs depending on childhood or adult onset,with greater heterogeneity commonly observed in adults.

C3G contributes to platelet activation and aggregation by regulating major signaling pathways

C3G is a GEF(guanine nucleotide exchange factor)for Rap GTPases,among which the isoform Rap1b is an essential protein in platelet biology.Using transgenic mouse models with platelet-specific overexpression of C3G or mutant C3GΔCat,we have unveiled a new function of C3G in regulating the hemostatic function of platelets through its participation in the thrombin-PKCRap1b pathway.C3G also plays important roles in angiogenesis,tumor growth,and metastasis through its regulation of the platelet secretome.In addition,C3G contributes to megakaryopoiesis and thrombopoiesis.Here,we used a platelet-specific C3G-KO mouse model to further support the role of C3G in hemostasis.C3G-KO platelets showed a significant delay in platelet activation and aggregation as a consequence of the defective activation of Rap1,which resulted in decreased thrombus formation in vivo.Additionally,we explored the contribution of C3G-Rap1b to platelet signaling pathways triggered by thrombin,PMA or ADP,in the referenced transgenic mouse model,through the use of a battery of specific inhibitors.We found that platelet C3G is phosphorylated at Tyr504 by a mechanism involving PKC-Src.This phosphorylation was shown to be positively regulated by ERKs through their inhibition of the tyrosine phosphatase Shp2.Moreover,C3G participates in the ADP-P2Y12-PI3K-Rap1b pathway and is a mediator of thrombin-TXA2 activities.However,it inhibits the synthesis of TXA2 through cPLA2 regulation.Taken together,our data reveal the critical role of C3G in the main pathways leading to platelet activation and aggregation through the regulation of Rap1b.

克罗恩病初次手术与多次手术患者的治疗及结局:基于PRACTICROHN研究数据

背景:克罗恩病(CD)手术往往预后不佳,常需再次手术。本研究旨在比较初次手术与多次手术CD患者的术后治疗及临床结局。方法:本研究为观察性研究,纳入2007年1月至2010年12月间西班牙26家医院收治的行回结肠切除吻合术的成人CD患者。从医疗记录中回顾性收集数据。结果:314例患者纳入分析,其中262例(83%)为初次手术病例,52例(17%)既往有过CD手术史。除狭窄型病变的患者比例再手术组相对较高以外(P=0.03),其余基线资料两组患者的差异均无统计学意义。术后接受预防性药物治疗的患者比例再手术组高于初次手术组(P=0.04)。再手术患者临床复发的时间与是否接受预防性药物治疗无关;但对于初次手术患者,接受预防性药物治疗者无复发生存时间更长(P=0.03)。结论:与初次手术者相比,既往有过CD手术史的患者术后更多接受了预防性药物(免疫调节剂)治疗。尽管预防性药物治疗可以预防初次手术者的临床复发,但并没有降低再次手术患者的复发风险。提示术后预防性药物治疗仍应仅限于初次手术患者。