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.

Comparative Safety of Biologic Agents in Patients With Inflammatory Bowel Disease With Active or Recent Malignancy: A Multi-Center Cohort Study.

BACKGROUND & AIMS: Safety of biologic agents is a key consideration in patients with inflammatory bowel disease (IBD) and active or recent cancer. We compared the safety of tumor necrosis factor (TNF)-α antagonists vs non-TNF biologics in patients with IBD with active or recent cancer. METHODS: We conducted a multicenter retrospective cohort study of patients with IBD and either active cancer (cohort A) or recent prior cancer (within ≤5 years; cohort B) who were treated with TNFα antagonists or non-TNF biologics after their cancer diagnosis. Primary outcomes were progression-free survival (cohort A) or recurrence-free survival (cohort B). Safety was compared using inverse probability of treatment weighting with propensity scores. RESULTS: In cohort A, of 125 patients (483.8 person-years of follow-up evaluation) with active cancer (age, 54 ± 15 y, 75% solid-organ malignancy), 10 of 55 (incidence rate [IR] per 100 py, 4.4) and 9 of 40 (IR, 10.4) patients treated with TNFα antagonists and non-TNF biologics had cancer progression, respectively. There was no difference in the risk of progression-free survival between TNFα antagonists vs non-TNF biologics (hazard ratio, 0.76; 95% CI, 0.25-2.30). In cohort B, of 170 patients (513 person-years of follow-up evaluation) with recent prior cancer (age, 53 ± 15 y, 84% solid-organ malignancy; duration of remission, 19 ± 19 mo), 8 of 78 (IR, 3.4) and 5 of 66 (IR 3.7) patients treated with TNFα antagonists and non-TNF biologics had cancer recurrence, respectively. The risk of recurrence-free survival was similar between both groups (hazard ratio, 0.94; 95% CI, 0.24-3.77). CONCLUSIONS: In patients with IBD with active or recent cancer, TNFα antagonists and non-TNF biologics have comparable safety. The choice of biologic should be dictated by IBD disease severity in collaboration with an oncologist.

Acetylation of CCAR2 Establishes a BET/BRD9 Acetyl Switch in Response to Combined Deacetylase and Bromodomain Inhibition.

There continues to be interest in targeting epigenetic "readers, writers, and erasers" for the treatment of cancer and other pathologies. However, a mechanistic understanding is frequently lacking for the synergy observed when combining deacetylase and bromodomain inhibitors. Here we identify cell cycle and apoptosis regulator 2 (CCAR2) as an early target for acetylation in colon cancer cells treated with sulforaphane. N-terminal acetylation of CCAR2 diminished its interactions with histone deacetylase 3 and ß-catenin, interfering with Wnt coactivator functions of CCAR2, including in cells harboring genetically encoded CCAR2 acetylation. Protein domain arrays and pull-down assays identified acetyl "reader" proteins that recognized CCAR2 acetylation sites, including BRD9 and members of the bromodomain and extraterminal domain (BET) family. Treatment with the BET inhibitor JQ1 synergized with sulforaphane in colon cancer cells and suppressed tumor development effectively in a preclinical model of colorectal cancer. Studies with sulforaphane+JQ1 in combination implicated a BET/BRD9 acetyl switch and a shift in the pool of acetyl "reader" proteins in favor of BRD9-regulated target genes. SIGNIFICANCE: These results highlight the competition that exists among the "readers" of acetylated histone and nonhistone proteins and provide a mechanistic basis for potential new therapeutic avenues involving epigenetic combination treatments.

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.

Hepatocyte transplantation: Consider infusion before incision.

Human hepatocyte transplantation is undergoing study as a bridge, or even alternative, to orthotopic liver transplantation (OLT). This technique has undergone multiple developments over the past thirty years in terms of mode of delivery, source and preparation of cell cultures, monitoring of graft function, and use of immunosuppression. Further refinements and improvements in these techniques will likely allow improved graft survival and function, granting patients higher yield from this technique and potentially significantly delaying need for OLT.

Evaluation of Chest X-ray and Thoracic Computed Tomography in Patients with Suspected Tuberculosis.

OBJECTIVE: To investigate if there is any correlation between positive findings detected by posterior-anterior (PA) chest radiograph and thoracic computerized tomography (CT) in cases with suspected lung tuberculosis (TB) due to positive tuberculin skin test (TST) results. METHODS: This is a retrospective evaluation of the medical files of patients who visited the Department of Pediatrics, Istanbul University, Istanbul Faculty of Medicine from 2006, through 2011 as outpatients and had positive TST (>15 mm) results. RESULTS: A total of 326 patients were included in the study; 45.7 % (n = 149) were girls, and the mean age was 9.0 ± 4.1 y (range: 1-17 y). In total, 14.4 % (n = 47) had TB findings, all of which were in the form of hilar lymphadenopathy. Among the 47 cases with TB findings in PA chest X-ray, 45 (95.7 %) also had findings in thoracic CT. Only 2 (4.3 %) patients had normal thoracic CT results although their PA chest X-ray results were positive. CONCLUSIONS: Evaluation for pulmonary TB in children with positive isolated TSTs should be made primarily with PA chest X-ray. A routine thoracic CT scan is not necessary for asymptomatic patients with only hilar lymphadenopathy findings in PA chest radiographs.

Development of a murine colonoscopic polypectomy model (with videos).

BACKGROUND AND AIMS: Colonoscopy provides a means for screening and removal of colon adenomas, preventing such lesions from progressing to late-stage carcinoma. No preclinical model currently exists that closely parallels the clinical scenario with respect to polyp resection and recovery after endoscopy. METHODS: When we used the polyposis in rat colon (Pirc) model, a new polypectomy methodology was developed. A novel PLC classification system (polyp number/location/clockwise orientation) also was devised in order to accurately and reproducibly specify the location of each lesion within the colon. RESULTS: One week after surgery, injuries to the polypectomy site were confined to the submucosa, indicating that little or no damage occurred to the inner muscle layer of the colon. Polypectomy sites occasionally continued to show ulcer formation, whereas others exhibited tissue regeneration. A pilot study (n = 6 animals), involving a total of 37 polypectomies, confirmed that the new methodology could be applied by using either air insufflation or water-assisted techniques, with either hot or cold snare. As a general observation, polyps tended to be more fully distended and less flattened against the colon mucosa by using the water-assisted protocol, increasing the technical ease of ensnaring and resecting lesions. The PLC system proved to be straightforward and facilitated longitudinal studies by allowing the investigator to track each polypectomy site on repeated examination. CONCLUSIONS: The Pirc model was ideally suited to colonoscopy with polypectomy. Because the main cause of morbidity in the Pirc model is blockage of the colon, polypectomy can be used as a preventive strategy and will likely facilitate long-term investigations of single agent and combination therapies with potential direct clinical relevance.

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.