Comprehensive evaluation of disulfidptosis in intestinal immunity and biologic therapy response in Ulcerative Colitis.

Objective: Ulcerative Colitis (UC) manifests as a chronic inflammatory condition of the intestines, marked by ongoing immune system dysregulation. Disulfidptosis, a newly identified cell death mechanism, is intimately linked to the onset and advancement of inflammation. However, the role of disulfidptosis in UC remains unclear. Methods: We screened differentially expressed genes (DEGs) associated with disulfidptosis in multiple UC datasets, narrowed down the target gene number using lasso regression, and conducted immune infiltration analysis and constructed a clinical diagnostic model. Additionally, we explored the association between disulfidptosis-related key genes and disease remission in UC patients receiving biologic therapy. Finally, we confirmed the expression of key genes in FHC cells and UC tissue samples. Results: In the differential analysis, we identified 20 DEGs associated with disulfidptosis. Immune infiltration results revealed that five genes (PDLIM1, SLC7A11, MYH10, NUBPL, OXSM) exhibited strong correlations with immune cells and pathways. Using GO, KEGG and WGCNA analyses, we discovered that gene modules highly correlated with disulfidptosis-related gene expression were significantly enriched in inflammation-related pathways. Additionally, we developed a nomogram based on these five immune-related disulfidptosis genes for UC diagnosis, showing robust diagnostic capability and clinical efficacy. Kaplan-Meier survival analysis revealed a significant link between changes in the expression levels of these cell genes and disease remission in UC patients receiving biologic therapy. In line with previous studies, similar expression changes of the target gene were seen in both UC cell models and tissue samples. Conclusions: This study utilized bioinformatic analysis and machine learning to identify and analyze features associated with disulfidptosis in multiple UC datasets. This enhances our comprehension of the role disulfidptosis plays in intestinal immunity and inflammation in UC, providing new perspectives for developing innovative treatments for UC.

Surgical management of duodenal Crohn's disease.

BACKGROUND: The case of Crohn's disease involving the duodenum is rare, and its surgical management requires a thorough understanding. AIM: To investigate the surgical management of duodenal Crohn's disease. METHODS: We systematically reviewed patients diagnosed with duodenal Crohn's disease who underwent surgery in the Department of Geriatrics Surgery of the Second Xiangya Hospital of Central South University from January 1, 2004, to August 31, 2022. The general information, surgical procedures, prognosis, and other information of these patients were collected and summarized. RESULTS: A total of 16 patients were diagnosed with duodenal Crohn's disease, where 6 cases had primary duodenal Crohn's disease, and 10 had secondary duodenal Crohn's disease. Among patients with primary disease, 5 underwent duodenal bypass and gastrojejunostomy, and 1 received pancreaticoduodenectomy. Among those with a secondary disease, 6 underwent closure of duodenal defect and colectomy, 3 received duodenal lesion exclusion and right hemicolectomy, and 1 underwent duodenal lesion exclusion and double-lumen ileostomy. CONCLUSION: Crohn's disease involving the duodenum is a rare condition. Different surgical management should be applied for patients with Crohn's disease presenting with different clinical manifestations.

Quantitative analysis of adipose tissue for predicting Crohn's disease postoperative endoscopic recurrence and anastomotic ulcer.

OBJECTIVE: Inflammation and ulcers at the anastomotic site are frequently observed after intestinal resection surgery for Crohn's disease (CD), which often signify postoperative recurrence. Crohn's disease causes abnormalities in whole-body fat metabolism, and alterations in subcutaneous and visceral fat are potential indicators of disease development. This study aimed to quantify the areas of subcutaneous (SFA) and visceral fat (VFA) and investigate the relationship between fat tissue and endoscopic recurrence and anastomotic ulceration after Crohn's disease surgery. METHODS: We conducted a retrospective analysis of clinical data from 279 patients diagnosed with Crohn's disease. Using abdominal CT (Computed Tomography) scans at the level of the umbilicus, we measured the area of subcutaneous and visceral fat, and calculated the Mesenteric Fat Index (MFI), which is defined as the ratio of the area of visceral fat to subcutaneous fat. We compared the changes in fat tissue between surgical Crohn's disease patients and non-surgical patients in remission, as well as changes in fat tissue before and after surgery, and between patients with and without endoscopic recurrence after surgery. RESULTS: The MFI value of the surgical group was higher than that of the non-surgical group(0.88(1.27 ± 1.26) VS 0.39(0.44 ± 0.21), P < 0.001), while the SFA value was lower(70.16(92.97 ± 78.23) VS 157.64(175.96 ± 101.58), P < 0.001). Of the 134 surgical patients who underwent abdominal CT examination after surgery, the SFA value was significantly higher after surgery(143.61 ± 81.86 VS 90.87 ± 71.93, P < 0.001), and the MFI value decreased accordingly(0.57 ± 0.36 VS 1.30 ± 1.35, P < 0.001). Multivariate Cox analysis indicated that high VFA and MFI values, smoking history, and preoperative biologic therapy were all risk factors for postoperative endoscopic recurrence(p < 0.05), while high MFI values and preoperative biologic therapy were also risk factors for anastomotic ulcers(p < 0.05). The Kaplan-Meier analysis showed that these factors increased the risk of reaching the endpoint with time(p < 0.05). The ROC curve results showed that MFI value had high diagnostic value for postoperative endoscopic recurrence [AUC:0.831, 95% CI: 0.75-0.91, p < 0.001] and anastomotic ulcers [AUC:0.801, 95% CI: 0.71-0.89, p < 0.001]. CONCLUSIONS: Surgical CD patients have significantly higher MFI values but the values decline after surgery. When the preoperative MFI value is > 0.82, the risk of postoperative endoscopic recurrence increases significantly, and when the MFI value is ≥ 1.10, the risk of anastomotic ulceration after surgery increases significantly. Meanwhile, biologic therapy preoperatively also is a high-risk factor for early postoperative endoscopic recurrence or anastomotic ulcers after intestinal resection surgery.

Ginsenoside Rg3 Ameliorates DSS-Induced Colitis by Inhibiting NLRP3 Inflammasome Activation and Regulating Microbial Homeostasis.

Ulcerative colitis (UC) is a recurrent inflammatory disease without a specific cure or treatment for improvement. Here, we investigated the potential therapeutic effect and mechanism of ginsenoside Rg3 (Gin Rg3) on UC. We constructed an in vitro cellular inflammatory model and a dextran sulfate sodium (DSS)-induced UC mouse model. We also used Gin Rg3, MCC950 (NLRP3 inhibitor), MSU (NLRP3 activator), and fecal transplantation (FMT) to intervene the model. The results showed that Gin Rg3 inhibited NLRP3 inflammasome activation, pyroptosis, and apoptosis in vitro and in vivo. DSS-induced changes in the abundance of gut microbiota at the phylum or genus level were partially restored by Gin Rg3. Furthermore, gin Rg3 affected intestinal metabolism in mice by inhibiting the activation of NLRP3 inflammasome. The gut microbiota treated with Gin Rg3 was sufficient to alleviate DSS-induced UC. In summary, Gin Rg3 alleviated DSS-induced UC by inhibiting NLRP3 inflammasome activation and regulating gut microbiota homeostasis.

Surgical strategies for intestinal Crohn's disease. / è‚ é“å ‹ç½—æ©ç— çš„å¤–ç§‘æ²»ç–—ç­–ç•¥.

OBJECTIVES: As a type of inflammatory bowel disease, Crohn's disease (CD) is characterized by jumping lesions and transmural inflammation. The treatment goal is to control the development of inflammation with drugs such as 5-Amino Salicylic Acid, azathioprine and hormones, but most patients still need surgical treatment eventually. The surgical treatment of CD requires exquisite surgical design and solid surgical procedures to minimize the progression of intestinal lesions and preserve the normal bowel segment as much as possible. This study aims to summarize and discuss the surgical treatments for intestinal CD, and to provide references for the surgical treatment of intestinal CD. METHODS: Clinical data of 122 patients with CD were analyzed retrospectively. They all received surgical treatments in the Second Xiangya Hospital of Central South University between Jan. 1, 2015 and Jan. 1, 2021. The data included general information, clinical manifestations, preoperative examination, preoperative preparation, surgical methods, pathological examination, complications, and follow-up data. RESULTS: Except 1 case of emergency surgery, all the other patients met the surgical indications of intestinal CD after multi-disciplinary discussion (MDT) and they were transferred to surgery for elective surgery, and received high-quality intestinal preparation before surgery. Among them, 99 cases underwent one-stage abdominal operation and 23 cases underwent the second abdominal operation. All patients underwent successful surgery with good surgical results, with significantly alleviated clinical symptoms and the BMI significantly increased compared with those before surgery. There were 14 cases (11.5%) of postoperative complications. One case of delayed anastomotic fistula and one case of small intestinal cutaneous fistula which were successfully treated by conservative treatment, the other 12 cases were successfully treated by reoperation, and there were no complications with follow-up operation. The postoperative pathological diagnosis for all patients was clear. All patients received regular follow-up with 5-70 (median 36) months and no clinical recurrence was found. CONCLUSIONS: As the surgical treatment of intestinal CD, surgeons should strictly grasp the surgical indications based on the MDT. During the operation of small intestinal CD, it is advisable to preserve bowel segment as much as possible. For patients with short remaining normal bowel segment, the intestinal canal should be preserved as far as possible, even for the mildly diseased bowel, so as to avoid the occurrence of short bowel syndrome and leave room for possible reoperation. In the treatment of secondary duodenal CD, it is necessary to carefully identify the nature of the local lesions. Different surgical treatments should be performed according to whether there is an internal fistula and the size of this fistula. Meanwhile, duodenectomy or pancreaticoduodenectomy should be considered as the final surgical method in the treatment of primary duodenal CD.

Long non-coding RNA SNHG1/microRNA-195-5p/Yes-associated protein axis affects the proliferation and metastasis of gastric cancer via the Hippo signaling pathway.

Long non-coding RNA (lncRNA) small nucleolar RNA host gene 1 (SNHG1) has been found to be highly expressed in gastric cancer (GC). However, the study for exploring the effects of SNHG1 and microRNA (miR)-195-5p on GC is limited. This research commits to unravel the regulatory effects of SNHG1, miRNA-195-5p, and Yes-associated protein 1 (YAP1) on GC. SNHG1, miR-195-5p and YAP1 levels in GC tissues and GC cells were detected. The GC cells were treated with various constructs altering SNHG1 or miR-195-5p expression to determine the biological activities of GC cell in vitro. The effect of SNHG1 inhibition on subcutaneous tumorigenesis of GC cells in a nude mouse model in vivo was detected. The binding relation among SNHG1, miR-195-5p, and YAP1 was validated. SNHG1 and YAP1 levels were elevated and miR-195-5p level was reduced in GC. Reduction of SNHG1 or elevation of miR-195-5p retarded GC cell biological activity in vitro. Downregulated SNHG1 suppressed tumor growth in vivo. SNHG1 bound to miR-195-5p, and miR-195-5p directly targeted YAP1. The downregulated SNHG1 hinders the biological behaviors of GC cells via the modulation of the miR-195-5p/YAP1 axis.

PPARGC1A affects inflammatory responses in photodynamic therapy (PDT)-treated inflammatory bowel disease (IBD).

BACKGROUND: Chronic inflammation of the gastrointestinal tract is a feature of inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC). Targeting inflammatory signaling represents promising strategy for IBD treatment regimens. METHODS: Dextran sulfate sodium (DSS)-induced colitis model was established in mice. Histopathological examinations were conducted by H&E staining and IHC staining. IL-1ß, IL-10, and TNF-α were tested by ELISA kits. TargetScan was used to predict miRNAs that target PPARGC1A and luciferase activity assay was performed to validate the predicted binding. RESULTS: DSS-induced acute colitis model was successfully established in mice; photodynamic therapy (PDT) treatment partially improved DSS-induced colonic damages and cell inflammation. Microarray assays and integrative bioinformatics analysis identified PPARG coactivator 1 alpha (PPARGC1A) as a significantly differentially-expressed gene in PDT-treated IBD compared with non-treated IBD. PPARGC1A expression was downregulated in IBD clinical samples, DSS-induced colitis mice colons, and DSS-stimulated colonic epithelial cells, whereas partially upregulated by PDT treatment in DSS-stimulated cells. Single DSS stimulation significantly promoted cellular inflammation; PDT partially attenuated, whereas sh-PPARGC1A transduction further enhanced DSS effects on cancer cell inflammation. In colitis mice, DSS decreased PPRA-α and PPRA-γ proteins in mice colons; the in vivo effects of DSS were partially attenuated by PDT treatment, whereas amplified by sh-PPARGC1A transduction. Upstream miR-301a-3p targeted and inhibited PPARGC1A expression. CONCLUSIONS: Collectively, PPARGC1A, which is downregulated in DSS-induced acute colitis and DSS-stimulated colonic epithelial cells, could be upregulated by PDT treatment. PPARGC1A knockdown could attenuate PDT therapeutic effects on DSS-induced acute colitis and DSS-stimulated colonic epithelial cells.

Characteristics of mesenteric adipose tissue attached to different intestinal segments and their roles in immune regulation.

Mesenteric adipose tissue (MAT) plays a critical role in the intestinal physiological ecosystems. Small and large intestines have evidently intrinsic and distinct characteristics. However, whether there exist any mesenteric differences adjacent to the small and large intestines (SMAT and LMAT) has not been properly characterized. We studied the important facets of these differences, such as morphology, gene expression, cell components, and immune regulation of MATs, to characterize the mesenteric differences. The SMAT and LMAT of mice were used for comparison of tissue morphology. Paired mesenteric samples were analyzed by RNA-seq to clarify gene expression profiles. MAT partial excision models were constructed to illustrate the immune regulation roles of MATs, and 16S-seq was applied to detect the subsequent effect on microbiota. Our data show that different segments of mesenteries have different morphological structures. SMAT not only has smaller adipocytes but also contains more fat-associated lymphoid clusters than LMAT. The gene expression profile is also discrepant between these two MATs in mice. B-cell markers were abundantly expressed in SMAT, whereas development-related genes were highly expressed in LMAT. Adipose-derived stem cells of LMAT exhibited higher adipogenic potential and lower proliferation rates than those of SMAT. In addition, SMAT and LMAT play different roles in immune regulation and subsequently affect microbiota components. Finally, our data clarified the described differences between SMAT and LMAT in humans. There were significant differences in cell morphology, gene expression profiles, cell components, biological characteristics, and immune and microbiota regulation roles between regional MATs.NEW & NOTEWORTHY Our results change the paradigm of how we regard MAT as a contiguous and homogeneous tissue to an intensely heterogeneous tissue. Appreciation of the differences between regional MATs will guide future research to investigate the specialized roles of different MATs in intestinal health and disease.

Exosomal MicroRNA-181a Derived From Mesenchymal Stem Cells Improves Gut Microbiota Composition, Barrier Function, and Inflammatory Status in an Experimental Colitis Model.

Background: Mesenchymal stem cell (MSC)-derived exosomes (Exos) are recently proved to be a promising candidate for ulcerative colitis (UC), but the mechanism remains unclear. We investigated the effects of MSC-derived exosomal microRNA-181a (miR-181a) on gut microbiota, immune responses, and intestinal barrier function in UC. Methods: Human bone marrow MSC-derived Exos were extracted and identified via transmission electron microscopy (TEM), Nanoparticle Tracking Analysis (NTA), and Western blotting. Dextran sodium sulfate (DSS)-induced colitis model and lipopolysaccharide (LPS)-induced human colonic epithelial cell (HCOEPIC) model were established to determine the effect of MSC-Exos on gut microbiota, immune responses, and intestinal barrier function in vivo and in vitro. The relationship between miR-181a and UC was analyzed using the Gene Expression Omnibus (GEO) database. MSC-miR-181-inhibitor was used to reveal the role of exosomal miR-181a in DSS-induced colitis. Results: TEM and NTA results showed that Exos of a diameter of about 100 nm with the round and oval vesicle-like structure were successfully extracted. The expressions of the CD63, CD81, and TSG101 proteins were positive in these Exos. After MSC-Exo treatment, the colon length in colitis mice increased; colon inflammatory injury decreased; TNF-α, IL-6, IL-1ß, IL-17, and IL-18 levels decreased; and Claudin-1, ZO-1, and IκB levels increased. In addition, the structure of the gut microbiota in DSS-induced colitis mice was changed by MSC-Exos. MSC-Exos showed antiapoptotic effects on LPS-induced HCOEPIC. The protective effects decreased significantly by treatment with MSC-Exos interfered with miR-181a inhibitor in vivo and in vitro. Conclusion: MSC-derived exosomal miR-181a could alleviate experimental colitis by promoting intestinal barrier function. It exerted anti-inflammatory function and affected the gut microbiota. This indicated that MSC exosomal miR-181a may exhibit potential as a disease-modifying drug for UC.

NEK7: a potential therapy target for NLRP3-related diseases.

NLRP3 inflammasome plays an essential role in innate immunity, yet the activation mechanism of NLRP3 inflammasome is not clear. In human or animal models, inappropriate NLRP3 inflammasome activation is implicated in many NLRP3-related diseases, such as tumors, inflammatory diseases and autoimmune diseases. Until now, a great number of inhibitors have been used to disturb the related signaling pathways, such as IL-1ß blockade, IL-18 blockade and caspase-1 inhibitors. Unfortunately, most of these inhibitors just disturb the signaling pathways after the activation of NLRP3 inflammasome. Inhibitors that directly regulate NLRP3 to abolish the inflammation response may be more effective. NEK7 is a multifunctional kinase affecting centrosome duplication, mitochondrial regulation, intracellular protein transport, DNA repair and mitotic spindle assembly. Researchers have made significant observations on the regulation of gene transcription or protein expression of the NLRP3 inflammasome signaling pathway by NEK7. Those signaling pathways include ROS signaling, potassium efflux, lysosomal destabilization, and NF-κB signaling. Furthermore, NEK7 has been proved to be involved in many NLRP3-related diseases in humans or in animal models. Inhibitors focused on NEK7 may regulate NLRP3 to abolish the inflammation response and NEK7 may be a potential therapeutic target for NLRP3-related diseases.

NEK7 interacts with NLRP3 to modulate the pyroptosis in inflammatory bowel disease via NF-κB signaling.

Inflammatory bowel disease (IBD) is one of the most common diseases in the gastrointestinal tract related to aberrant inflammation. Pyroptosis, which is characterized by inflammasome formation, the activation of caspase-1, and the separation of the N- and C-terminals of GSDMD, might be related to IBD pathogenesis. NEK7 is an important component of the NLRP3 inflammasome in macrophages. We attempted to investigate the mechanism of NEK7 interacting with NLRP3 to modulate the pyroptosis in IBD. NEK7 mRNA and protein expression and pyroptosis-associated factors, including Caspase-1 (p45, p20), NLRP3, and GSDMD, were upregulated in IBD tissues. NEK7 knockdown abolish ATP + LPS-induced pyroptosis in vitro and improved DSS-induced chronic colitis in vivo. NEK7 interacted with NLRP3, as revealed by Co-IP and GST pull-down assays, to exert its effects. Moreover, short-term LPS treatment alone induced no significant changes in NEK7 protein level. TLR4/NF-κB signaling in MODE-K cells could be activated by LPS treatment. LPS-induced NEK7 upregulation could be significantly reversed by JSH-23, an inhibitor of p65. Furthermore, LUC and ChIP assays revealed that RELA might activate the transcription of NEK7 via targeting its promoter region. LPS-induced TLR4/NF-κB activation causes an increase in NEK7 expression by RELA binding NEK7 promoter region. In conclusion, NEK7 interacts with NLRP3 to modulate NLRP3 inflammasome activation, therefore modulating the pyroptosis in MODE-K cells and DSS-induced chronic colitis in mice. We provide a novel mechanism of NEK7-NLRP3 interaction affecting IBD via pyroptosis.

Molecular Classification of Gastric Adenocarcinoma.

As one of the leading causes of cancer-related deaths, gastric cancer (GC) has gained more and more attention. Although most GCs are adenocarcinomas, they have considerable heterogeneity among patients. Thus, appropriate classification and individualized treatment of GCs is essential. The traditional morphology-based classification systems including the World Health Organization (WHO) classification and the Lauren's classification have a limited utility in guiding clinical treatment due to the molecular heterogeneity of GC. Classifications based on molecular features become important. Recent years, molecular methods such as next-generation sequencing (NGS) including deoxyribonucleic acid (DNA) sequencing, ribonucleic acid (RNA) sequencing, whole-exome sequencing, copy number variation analysis and DNA methylation arrays have been used to classify the GC into molecular subtypes which can convey more detailed information of tumor than histopathological characteristics. In this review, we described the current molecular classifications of GC including the intrinsic subtypes, Lei subtypes, The Cancer Genome Atlas (TCGA) subtypes, Asian Cancer Research Group (ACRG) subtypes, and some other additional classifications.

Postoperative excessive gain in visceral adipose tissue as well as body mass index are associated with adverse outcomes of an ileal pouch.

BACKGROUND: There are no published studies on the impact of visceral adipose tissue (VAT) change on outcomes of restorative proctocolectomy and ileal pouch-anal anastomosis (IPAA). The aim of this historic cohort study was to evaluate the impact of excessive VAT gain on the outcomes of inflammatory bowel disease (IBD) patients with IPAA. METHODS: We evaluated all eligible patients with at least two sequential CT scans after pouch construction from our prospectively maintained Pouchitis Registry between 2002 and 2014. The visceral fat area (VFA) was measured on CT images. The study group comprised patients with a significant VAT gain (> 15%), and the control group was those without. The adverse outcomes of the pouch were defined as the new development of chronic pouch inflammation (chronic pouchitis, chronic cuffitis or Crohn's disease of the pouch), anastomotic sinus and the combination of above (the composite adverse outcome) or pouch failure, after the inception CT. RESULTS: Of 1564 patients in the Registry, 59 (3.8%) with at least 2 CT scans after pouch surgery were included. Twenty-nine patients (49.2%) were in the study group, and 30 (50.8%) were in the control group. The median duration from the inception to the latest CT was 552 (range: 31-2598) days for the entire cohort. We compared the frequency of new chronic pouch inflammation (13.8% vs 3.3%, P = 0.195), new pouch sinus (10.3% vs 0%, P = 0.112), composite adverse pouch outcome (24.1% vs 3.3%, P = 0.026) or pouch failure (10.3% vs 6.7%, P = 0.671) between the two groups. Kaplan-Meier plot for time-to-pouch failure between the pouch patients with or without excessive body mass index (BMI) gain (> 10%) showed statistical difference (P = 0.011). Limited stepwise multivariate analysis showed that excessive VAT gain (odds ratio = 12.608, 95% confidence interval: 1.190-133.538, P = 0.035) was an independent risk factor for the adverse pouch comes. CONCLUSIONS: In this cohort of ileal pouch patients, excessive VAT gain as well as gain in BMI after pouch construction was found to be associated with poor long-term outcomes.

Perioperative Blood Transfusion and Postoperative Outcome in Patients with Crohn's Disease Undergoing Primary Ileocolonic Resection in the "Biological Era".

BACKGROUND: Perioperative blood transfusion has been shown to be associated with inflammatory response and immunosuppression. Patients receiving blood transfusion may have an increased risk for developing postoperative morbidities. The impact of blood transfusion on the postoperative recurrence of Crohn's disease (CD) has been controversial. The aim of this study was to assess the effect of blood transfusion on postoperative outcomes in CD in the current biological era. METHODS: This historical cohort study involved data collection and analysis of CD patients who underwent the index ileocolonic resection in our institution between 2000 and 2012. Postoperative complications were compared between the transfused and nontransfused patients. The effects of perioperative blood transfusion on postoperative complications and disease recurrence were analyzed with both univariate and multivariate analyses. RESULTS: A total of 318 patients were included in the study, and 52 of them (16.5 %) received perioperative blood transfusion. Blood transfusion was found to be associated with an increased risk of postoperative infectious and noninfectious complications both in univariate (P < 0.001 for each) and multivariable analyses (infectious complications: odds ratio [OR] = 8.73, 95 % confidence interval [CI] 2.85-26.78, P < 0.001; noninfectious complications: OR = 3.64, 95 % CI 1.30-10.18; P = 0.014). In addition, the Cox regression model indicated that blood transfusion was associated with both surgical (hazard ratio [HR] = 3.43, 95 % CI 1.92-6.13; P < 0.001) and endoscopic (HR = 2.08, 95 % CI 1.38-3.14; P < 0.001) CD recurrence following the index surgery. CONCLUSION: Adverse outcomes after perioperative blood transfusion for the primary ileocolonic resection for CD resemble findings in surgery for other diseases. The presumed immunosuppressive effect of blood transfusion did not confer any protective effect on disease recurrence.

Presence of Granulomas in Mesenteric Lymph Nodes Is Associated with Postoperative Recurrence in Crohn's Disease.

BACKGROUND: The association between the presence of granulomas in the mesenteric lymph node (MLN) and postoperative recurrent Crohn's disease (CD) is unknown. Our aim was to assess the predictive value of the presence of granulomas in MLN as well as in bowel wall for postoperative recurrence of CD. METHODS: Patients with CD who underwent the index ileocolonic resection between 2004 and 2012 were included. Surgical pathology reports were reviewed for the presence and location of granulomas. The status of MLN granulomas was confirmed by re-review of surgical pathology specimen from randomly sampled patients by an expert pathologist. Both univariable and multivariable analyses were performed to assess the risk factors associated with postoperative recurrent CD. RESULTS: A total of 194 patients were included. Granulomas were detected in the MLN in 23 patients (11.9%), and in the intestinal wall in 57 (29.4%). On Kaplan-Meier curve, the presence of granulomas in MLN was found to be a risk factor for postoperative endoscopic recurrence (P = 0.015) as well as surgical recurrence (P = 0.035). In contrast, granulomas in the bowel wall, which was not found to be associated with neither endoscopic recurrence (P = 0.94) or surgical recurrence (P = 0.56). On Cox proportional hazards regression analysis, the presence of MLN granulomas was independently associated with an increased risk for both postoperative endoscopic recurrence (hazard ratio [HR] = 1.91; 95% confidence interval [CI], 1.06-3.45; P = 0.031) and surgical recurrence (HR = 3.43; 95% CI, 1.18-9.99; P = 0.023). CONCLUSIONS: The presence of granulomas in MLN but not in intestine per se was found to be an independent risk factor for recurrence in CD patients undergoing ileocolonic resection.

Clinical Implications of Noncaseating Granulomas on Histology in Patients with Ileal Pouches.

BACKGROUND: Granulomas are occasionally detected on biopsy specimen of the ileal pouch and their clinical implications are not clear. The aim of this study was to evaluate clinical implications of noncaseating granuloma on histology in patients with ileal pouches. METHODS: All eligible patients with confirmed noncaseating granulomas on histology of the biopsy specimens of the pouch body, afferent limb, or cuff in our prospectively maintained Pouch Registry between 2002 and 2014 were evaluated. Demographic and clinical factors were analyzed. The disease course of those patients was evaluated. RESULTS: Of 1564 patients in the Registry, 42 met the criteria and were included. The median duration from the pouch construction to the last visit was 9 years (range, 2-28 yr). Twenty-eight patients (66.7%) developed clinical Crohn's disease (CD) of the pouch, whereas 14 (33.3%) were classified as having histologic CD of the pouch. Six patients (21.4%) in the clinical CD of the pouch group and 4 (28.6%) in the histologic CD of the pouch group had granulomas on more than 1 endoscopy. Postoperative biological therapy was administered more in the clinical CD group than in the histologic CD group (39.3% versus 0%, P = 0.007). Pouch-related fistulae and presacral sinus were verified more in clinical CD group than the histologic CD group. However, Kaplan-Meier plot showed comparable pouch survival between clinical CD and histologic CD groups. CONCLUSIONS: In our current study, one-third of the patients with noncaseating pouch granulomas did not develop clinical CD of the pouch. With proper medical therapy, long-term pouch outcomes appeared to be similar in those patients with clinical CD or histologic CD of the pouch.

Histomorphological features and prognosis of colitis-associated colorectal cancer in patients with primary sclerosing cholangitis.

BACKGROUND: Histomorphology of colitis-associated colorectal cancer (CAC) in patients with primary sclerosing cholangitis (PSC) remains to be systemically characterized and prognosis in these patient needs to be further defined. AIM: To examine the impact of PSC on histomorphology and to assess prognosis of CAC-PSC patients. METHODS: A cohort of CAC patients were identified from the Pathology Database (1994-2010) at Cleveland Clinic; histomorphological features and other relevant data were collected by retrospective review of pathology slides and medical records. RESULTS: A total of 87 CAC patients were included, with 11 patients having PSC (the study group) and 76 patients without PSC (the control group). The overall median follow up was 6 (range: 0-20) years. The patients in the study group had a longer median duration of inflammatory bowel disease prior to CAC diagnosis (p = 0.046). In study group, seven (63.6%) patients had right-sided CAC (vs. 36.8% in the control group, p = 0.11). Background high-grade dysplasia was noted less (9.1% vs. 44.7%), while low-grade dysplasia was detected more in the study group (72.7% vs. 28.9%) (p = 0.02). All histomorphological features were comparable between groups. The overall survival (OS) and progression-free survival (PFS) showed no statistical difference between CAC patients with or without PSC. After excluding TNM stage IV patients, patients with PSC showed a trend toward shorter OS and PFS (p = 0.07 and p = 0.1). CONCLUSION: In CAC, histomorphology appeared to be independent of PSC. PSC is associated with a trend toward shorter OS and PFS in CAC patients with stage I-III diseases.

Overexpression of p53 predicts colorectal neoplasia risk in patients with inflammatory bowel disease and mucosa changes indefinite for dysplasia.

BACKGROUND AND AIMS: We previously demonstrated a significant colorectal neoplasia risk in inflammatory bowel disease (IBD) patients with mucosal changes indefinite for dysplasia (IND) and the potential diagnostic utility of p53 and cytokeratin 7 immunohistochemistry in IBD-associated neoplasia. The primary aim of this exploratory study was to determine the predictive value of the two markers for neoplasia risk in the IBD-IND population. METHODS: We identified 44 eligible cases with IBD and IND in colon biopsy from our pathology database. We semi-quantified the expression of p53 and cytokeratin 7 in the colon biopsies by immunohistochemistry and correlated their expression, demographic information, and clinical features with colorectal neoplasia outcome. RESULTS: The mean age of the cohort was 46.6 ± 15.1 years, with 25 (56.8%) being male. The median follow-up was 101 months (range: 6-247) after IND diagnosis. Among these 44 patients, 11 (25%) progressed to neoplasia (low-grade dysplasia = 6; high-grade dysplasia = 2; cancer 3) at a median follow-up of 66 months (range: 19-145). Univariate analysis demonstrated that age and p53 overexpression were associated with progression to neoplasia. CONCLUSIONS: Twenty-five percent of patients with IBD and IND developed colorectal dysplasia or cancer. Overexpression of p53 and age are associated with neoplastic progression.