Efficacy of Ustekinumab and Vedolizumab Among Postoperative Crohn's Disease Patients as Postoperative Prophylaxis and Rescue Therapy: Real-world Data.

BACKGROUND: Almost half of patients with Crohn's disease (CD) require bowel surgeries in their lifetime. Due to the high risk of postoperative disease recurrence and high rate of previous antitumor necrosis factor (anti-TNF) failure, often alternative therapy options such as ustekinumab (UST) and vedolizumab (VDZ) are used. We aimed to evaluate the efficacy of UST and VDZ among postoperative CD patients as postoperative prophylaxis and rescue therapy. METHODS: Consented CD patients who underwent initial ileocecal resection and were treated with UST and VDZ were included in this study. Demographics, clinical characteristics, health care utilization, endoscopy scores, and surgery outcomes were collected. Postoperative early CD recurrence was defined as a Rutgeerts endoscopic score ≥i2 within the first 2 years. The rescue therapy group was defined as patients who received either UST or VDZ after having Rutgeerts endoscopic score ≥i2 postoperatively. RESULTS: During 2009 to 2019, 98 CD patients were treated with UST or VDZ postoperatively. Postoperative early recurrence rates were 5% (n = 1 out of 20) and 6% (1 out of 15) for the UST and VDZ groups, respectively. Two patients from the UST group and 1 patient from the VDZ group required bowel surgery during follow-up with median drug exposure of 51 (95% confidence interval [CI], 29-61) and 30 (95% CI, 14-63) months, respectively; 55% and 69% of patients had at least 1 point of improvement on postoperative endoscopic Rutgeerts score, respectively, for UST and VDZ. Only 3 out of 40 and 1 out of 23 patients required bowel surgery during follow-up while receiving UST and VDZ as rescue therapy. CONCLUSIONS: Both UST and VDZ were effective as postoperative therapies either as prophylaxis or rescue therapy.

This retrospective 11-year data examines the efficacy of ustekinumab and vedolizumab among postoperative Crohn's disease patients. When utilizing postoperative Rutgeerts score, this study confirms that both ustekinumab and vedolizumab were effective as postoperative therapies either as prophylaxis or rescue therapy.

Granuloma Presence at Initial Surgery Predicts Need for Repeat Surgery Independent of Rutgeerts Score in Crohn's Disease.

BACKGROUND: Approximately half of Crohn's disease (CD) patients experience recurrence and need for repeat resections, highlighting need for prognostic biomarkers. Presence of epithelioid granuloma on surgical tissue and high Rutgeerts endoscopic score are associated with postoperative CD clinical recurrence. We sought to evaluate presence of epithelioid granuloma at first surgery and Rutgeerts score as a combined risk assessment for CD surgical recurrence. METHODS: Our study included consented CD patients who underwent initial ileocecal resection and were prospectively followed postoperatively. From 2009 to 2019, 418 CD patients underwent initial ileocecal resection with >4 years of follow-up, including postoperative endoscopic assessment (Rutgeerts score). RESULTS: Postoperative CD patients were grouped based on granuloma presence (30.6%; n = 128) or absence (69.4%; n = 290). Endoscopic recurrence (defined as Rutgeerts score ≥i2) was similar between the granuloma (26%) and no granuloma (25%) groups, respectively (P = .82). Patients with granuloma and CD endoscopic recurrence at first postoperative endoscopy had higher number of bowel surgeries compared with all other groups (no granuloma or CD endoscopic recurrence, P = .007; no granuloma but CD endoscopic recurrence present, P = .04; granuloma present and no CD endoscopic recurrence, P = .04). Epithelioid granuloma presence was associated with 1.65 times higher risk of subsequent surgery independently from first postoperative endoscopic recurrence Rutgeerts score. CONCLUSIONS: Granuloma presence on initial surgical histology is immediately available and identifies high-risk CD patients who may benefit from early postoperative treatment, and these precision intervention trials are warranted.

This study shows the presence of epithelioid granuloma as a risk factor for repeat Crohn's disease­related surgery, which is independent of first postoperative Rugteerts score. These 11-year observational data provide a risk factor that is immediately available after surgery and identifies high-risk CD patients who may benefit from early postoperative treatment.

Incidence of interval colorectal cancer attributable to an endoscopist in clinical practice.

BACKGROUND AND AIMS: Endoscopists who encounter an interval colorectal cancer (I-CRC) may be concerned about the implications because I-CRCs may represent a lapse in colonoscopy quality and a missed opportunity for prevention. We wanted to determine the I-CRC rate per colonoscopy examination and to examine the effect of colonoscopy volume and adenoma detection rate (ADR) on the number of I-CRCs attributable to an endoscopist. METHODS: We determined the rate of I-CRC diagnosis per outpatient colonoscopy examination by measuring the incidence of CRC diagnosis in practice and by assessing, via literature review, the percentage of cancers that are interval. We also estimated the number of attributable I-CRCs as a function of ADR and colonoscopy volume. RESULTS: Among 93,562 colonoscopies performed in 2013 to 2015 by 120 physicians in 4 diverse U.S. medical centers, 526 CRCs were diagnosed (.6%). Of 149,556 CRCs in the published literature, 7958 were I-CRCs (5.25% ± .94%). With rates of .6% (CRC per colonoscopy) and 5.25% (I-CRC per CRC), the rate of I-CRC is 1 per 3174 colonoscopies (95% confidence interval, 1 per 2710 to 1 per 3875). An endoscopist at the median of outpatient colonoscopy volume (316/year) in the lowest ADR quintile of detection (7%-19%) would have an I-CRC attributed every 8.2 years, or 4.2 I-CRCs in a 35-year career, versus every 16.7 years, or 2.0 I-CRCs in a 35-year career, for an endoscopist in the highest ADR quintile (33%-52%). CONCLUSIONS: An average-volume endoscopist will have 2 to 4 attributable I-CRCs in a 35-year career, but the frequency will vary depending on colonoscopy volume and ADR.

Oncogenic targets Mmp7, S100a9, Nppb and Aldh1a3 from transcriptome profiling of FAP and Pirc adenomas are downregulated in response to tumor suppression by Clotam.

Intervention strategies in familial adenomatous polyposis (FAP) patients and other high-risk colorectal cancer (CRC) populations have highlighted a critical need for endoscopy combined with safe and effective preventive agents. We performed transcriptome profiling of colorectal adenomas from FAP patients and the polyposis in rat colon (Pirc) preclinical model, and prioritized molecular targets for prevention studies in vivo. At clinically relevant doses in the Pirc model, the drug Clotam (tolfenamic acid, TA) was highly effective at suppressing tumorigenesis both in the colon and in the small intestine, when administered alone or in combination with Sulindac. Cell proliferation in the colonic crypts was reduced significantly by TA, coincident with increased cleaved caspase-3 and decreased Survivin, ß-catenin, cyclin D1 and matrix metalloproteinase 7. From the list of differentially expressed genes prioritized by transcriptome profiling, Mmp7, S100a9, Nppb and Aldh1a3 were defined as key oncogene candidates downregulated in colon tumors after TA treatment. Monthly colonoscopies revealed the rapid onset of tumor suppression by TA in the Pirc model, and the temporal changes in Mmp7, S100a9, Nppb and Aldh1a3, highlighting their value as potential early biomarkers for prevention in the clinical setting. We conclude that TA, an "old drug" repurposed from migraine, offers an exciting new therapeutic avenue in FAP and other high-risk CRC patient populations.

Novel fibro-inflammation markers in assessing left atrial remodeling in non-valvular atrial fibrillation.

BACKGROUND: Structural remodeling is associated with the fibroinflammatory process in the atrial extracellular matrix. In the present study we aimed to investigate whether serum levels of new circulating remodeling markers differ in patients with atrial fibrillation (AF) compared to patients with sinus rhythm. MATERIAL AND METHODS: The study population included 52 patients diagnosed with non-valvular AF and 33 age-matched patients with sinus rhythm. Serum levels of Galectin-3, matrix metalloproteinase-9 (MMP-9), lipocalin-2 (Lcn2/NGAL), N-terminal propeptide of type III procollagen (PIIINP), Hs-Crp, and neutrophil-to-lymphocyte ratio (NLR) were measured. The left atrial volume (LAV) was calculated by echocardiographic method and LAV index was calculated. RESULTS: Galectin-3, MMP-9, and PIIINP levels were significantly higher in AF patients except NGAL levels (1166 pg/ml (1126-1204) and 1204 pg/ml (1166-1362) p=0.001, 104 (81-179) pg/ml and 404 (162-564) pg/ml p<0.0001, and 1101 (500-1960) pg/ml and 6710 (2370-9950) pg/ml p<0.0001, respectively). The NLR and Hs-CRP levels were also higher in AF (2.1 ± 1.0 and 2.7 ± 1.1 p=0.02 and 4.2 ± 1.9 mg/L and 6.0 ± 4.7 mg/L p=0.04, respectively). In correlation analyses, NLR showed a strongly significant correlation with LAVi, but Hs-CRP did not (p=0.007 r=0.247, Pearson test and p=0.808 r=0.025, Pearson test, respectively). Moreover, Galectin-3, MMP-9, and PIIINP had a strong positive correlation with LAVi (p=0.021 r=640, Spearman test and p=0.004 r=0.319 Pearson test, and p=0.004 r=0.325 Pearson test, respectively). CONCLUSIONS: Novel fibrosis and inflammation markers in AF are correlated with atrial remodeling. Several unexplained mechanisms of atrial remodeling remain, but the present study has taken the first step in elucidating the mechanisms involving fibrosis and inflammation markers.