Histologic Activity From Neoterminal Ileal Biopsies in Patients With Crohn's Disease in Endoscopic Remission is Associated With Postoperative Recurrence.

INTRODUCTION: Following ileocolic resection (ICR), the clinical importance and prognostic implications of histologic activity on biopsies in Crohn's disease (CD) patients with endoscopic remission are not well defined. The aim of this study was to determine if histologic activity in patients with endoscopic remission is associated with future risk of endoscopic and/or radiologic postoperative recurrence (POR). METHODS: In this multicenter retrospective cohort study, adult patients with CD who underwent ICR between 2009 and 2020 with endoscopic biopsies of ileal mucosa from Rutgeerts i0 on index colonoscopy were included. The composite rate of endoscopic (Rutgeerts score ≥i2b) and radiologic (active inflammation on imaging) recurrence was compared in patients with and without histologic activity using a Kaplan-Meier survival analysis. A multivariable Cox proportional hazard regression model including clinically relevant risk factors of POR, postoperative biologic prophylaxis, and histology activity was designed. RESULTS: A total of 113 patients with i0 disease on index colonoscopy after ICR were included. Of these, 42% had histologic activity. Time to POR was significantly earlier in the histologically active versus normal group ( P = 0.04). After adjusting for clinical risk factors of POR, histologic activity (HR 2.37, 95% CI 1.17-4.79; P = 0.02) and active smoking (HR 2.54, 95% CI 1.02-6.33; P = 0.05) were independently associated with subsequent composite POR risk. DISCUSSION: In patients with postoperative CD, histologic activity despite complete endoscopic remission is associated with composite, endoscopic, and radiographic recurrence. Further understanding of the role of histologic activity in patients with Rutgeerts i0 disease may provide a novel target to reduce disease recurrence in this population.

American Gastroenterological Association-Proposed Fecal Calprotectin Cutoff of 50 ug/g is Associated With Endoscopic Recurrence in a Real-World Cohort of Patients With Crohn's Disease Post-ileocolic Resection.

Background: Fecal calprotectin (FC) is a reliable predictor of active bowel inflammation in postoperative Crohn's disease (CD), but cutoffs vary between studies. Recent guidelines recommend a cutoff of <50 ug/g to avoid routine endoscopy in patients at low pretest probability for CD recurrence. We evaluated the performance of this threshold in a real-world CD cohort after ileocolic resection (ICR). Methods: In this retrospective study, patients with CD post-ICR between 2009 to 2020 with FC > 60 days but < 1 year of surgery were included from a multicenter database. Established risk factors and/or biologic prophylaxis (biologic within 90 days of surgery) defined pretest probability. Those without postoperative colonoscopy were excluded. Rates of endoscopic recurrence, defined as Rutgeerts score ≥ i2b at any time after surgery, were compared between FC < 50 versus  ≥ 50 ug/g. Student's t-test and Fisher's exact test were utilized for statistical analysis. All postoperative FCs were matched to closest colonoscopy within 1 year to calculate sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Results: Thirty-seven patients categorized as either low-risk or high-risk and received biologic prophylaxis and had postoperative colonoscopy were included. Median time to first FC was 217 days (IQR 131-288). 15 (41%) patients had initial FC < 50 ug/g versus 22 (59%) ≥50 ug/g. Median time to first colonoscopy was 234 days (IQR 189-369). Compared to initial FC ≥ 50 ug/g, FC < 50ug/g experienced less endoscopic recurrence (0% vs. 36%, P = .005). Median time to first endoscopic recurrence in FC ≥ 50 ug/g was 145 days. There were 39 matched pairs of FC and colonoscopy. At an FC cutoff of 50 ug/g, calculated sensitivity was 90% and NPV was 93%, whereas specificity and PPV were 48% and 38%, respectively. Conclusions: In this real-world cohort, FC < 50 ug/g is a useful cutoff to exclude endoscopic recurrence in a post-ICR CD population that is at low pretest probability of recurrence.

Real-World Surgical and Endoscopic Recurrence Based on Risk Profiles and Prophylaxis Utilization in Postoperative Crohn's Disease.

BACKGROUND & AIMS: Preoperative risk stratification may help guide prophylactic biologic utilization for the prevention of postoperative Crohn's disease (CD) recurrence; however, there are limited data exploring and validating proposed clinical risk factors. We aimed to explore the preoperative clinical risk profiles, quantify individual risk factors, and assess the impact of biologic prophylaxis on postoperative recurrence risk in a real-world cohort. METHODS: In this multicenter retrospective analysis, patients with CD who underwent ileocolonic resection (ICR) from 2009 to 2020 were identified. High-risk (active smoking, ≥2 prior surgeries, penetrating disease, and/or perianal disease) and low-risk (nonsmokers and age >50 y) features were used to stratify patients. We assessed the risk of endoscopic (Rutgeert score, ≥i2b) and surgical recurrence by risk strata and biologic prophylaxis (≤90 days postoperatively) with logistic and time-to-event analyses. RESULTS: A total of 1404 adult CD patients who underwent ICR were included. Of the high-risk factors, 2 or more ICRs (odds ratio [OR], 1.71; 95% CI, 1.13-2.57), active smoking (OR, 1.73; 95% CI, 1.17-2.53), penetrating disease (OR, 1.41; 95% CI, 1.02-1.94), and history of perianal disease alone (OR, 1.99; 95% CI, 1.42-2.79) were associated with surgical but not endoscopic recurrence. Surgical recurrence was lower in high-risk patients receiving prophylaxis vs not (10.2% vs 16.7%; P = .02), and endoscopic recurrence was lower in those receiving prophylaxis irrespective of risk strata (high-risk, 28.1% vs 37.4%; P = .03; and low-risk, 21.1% vs 38.3%; P = .002). CONCLUSIONS: Clinical risk factors accurately illustrate patients at risk for surgical recurrence, but have limited utility in predicting endoscopic recurrence. Biologic prophylaxis may be of benefit irrespective of risk stratification and future studies should assess this.

Suboptimal Guideline Adherence and Biomarker Underutilization in Monitoring of Post-operative Crohn's Disease.

BACKGROUND: Crohn's disease recurrence after ileocecal resection is common. Guidelines suggest colonoscopy within 6-12 months of surgery to assess for post-operative recurrence, but use of adjunctive monitoring is not protocolized. We aimed to describe the state of monitoring in post-operative Crohn's. METHODS: We conducted a retrospective study of patients with Crohn's after ileocolic resection with ≥ 1-year follow-up. Patients were stratified into high and low risk based on guidelines. Post-operative biomarker (C-reactive protein, fecal calprotectin), cross-sectional imaging, and colonoscopy use were assessed. Biomarker, radiographic, and endoscopic post-operative recurrence were defined as elevated CRP/calprotectin, active inflammation on imaging, and Rutgeerts ≥ i2b, respectively. Data were stratified by surgery year to assess changes in practice patterns over time. P-values were calculated using Wilcoxon test and Fisher exact test. RESULTS: Of 901 patients, 53% were female and 78% high risk. Median follow-up time was 60 m for LR and 50 m for high risk. Postoperatively, 18% low and 38% high risk had CRPs, 5% low and 10% high risk had calprotectins, and half of low and high risk had cross-sectional imaging. 29% low and 38% high risk had colonoscopy by 1 year. Compared to pre-2015, time to first radiography (584 days vs. 398 days) and colonoscopy (421 days vs. 296 days) were significantly shorter for high-risk post-2015 (P < 0.001). Probability of colonoscopy within 1 year increased over time (0.48, 2011 vs. 0.92, 2019). CONCLUSION: Post-operative colonoscopy completion by 1 year is low. The use of CRP and imaging are common, whereas calprotectin is infrequently utilized. Practice patterns are shifting toward earlier monitoring.

Early Initiation of Antitumor Necrosis Factor Therapy Reduces Postoperative Recurrence of Crohn's Disease Following Ileocecal Resection.

BACKGROUND: Postoperative recurrence (POR) of Crohn's disease (CD) is common after surgical resection. We aimed to compare biologic type and timing for preventing POR in adult CD patients after ileocecal resection (ICR). METHODS: We performed a retrospective cohort study of CD patients who underwent an ICR at 2 medical centers. Recurrence was defined by endoscopy (≥ i2b Rutgeerts score) or radiography (active inflammation in neoterminal ileum) and stratified by type and timing of postoperative prophylactic biologic within 12 weeks following an ICR (none, tumor necrosis factor antagonists [anti-TNF], vedolizumab, and ustekinumab). RESULTS: We identified 1037 patients with CD who underwent an ICR. Of 278 (26%) who received postoperative prophylaxis, 80% were placed on an anti-TNF agent (n = 223) followed by ustekinumab (n = 28, 10%) and vedolizumab (n = 27, 10%). Prophylaxis was initiated in 35% within 4 weeks following an ICR and in 65% within 4 to 12 weeks. After adjusting for factors associated with POR, compared with no biologic prophylaxis, the initiation of an anti-TNF agent within 4 weeks following an ICR was associated with a reduction in POR (adjusted hazard ratio, 0.61; 95% CI, 0.40-0.93). Prophylaxis after 4 weeks following an ICR or with vedolizumab or ustekinumab was not associated with a reduction in POR compared with those who did not receive prophylaxis. CONCLUSION: Early initiation of an anti-TNF agent within 4 weeks following an ICR was associated with a reduction in POR. Vedolizumab or ustekinumab, at any time following surgery, was not associated with a reduction in POR, although sample size was limited.

Postoperative recurrence of Crohn's disease is common after ileocecal resection. In this dual-center study, early initiation of an anti-TNF agent within 4 weeks following an ileocecal resection was associated with a reduction in postoperative recurrence of Crohn's disease.

Test Characteristics of Cross-sectional Imaging and Concordance With Endoscopy in Postoperative Crohn's Disease.

BACKGROUND & AIMS: Postoperative Crohn's disease (CD) surveillance relies on endoscopic monitoring. The role of cross-sectional imaging is less clear. We evaluated the concordance of cross-sectional enterography with endoscopic recurrence and the predictive ability of radiography for future CD postoperative recurrence. METHODS: We performed a multi-institution retrospective cohort study of postoperative adult patients with CD who underwent ileocolonoscopy and cross-sectional enterography within 90 days of each other following ileocecal resection. Imaging studies were interpreted by blinded, expert CD radiologists. Patients were categorized by presence of endoscopic postoperative recurrence (E+) (modified Rutgeerts' score ≥i2b) or radiographic disease activity (R+) and grouped by concordance status. RESULTS: A total of 216 patients with CD with paired ileocolonoscopy and imaging were included. A majority (54.2%) exhibited concordance (34.7% E+/R+; 19.4% E-/R-) between studies. The plurality (41.7%; n = 90) were E-/R+ discordant. Imaging was highly sensitive (89.3%), with low specificity (31.8%), in detecting endoscopic postoperative recurrence. Intestinal wall thickening, luminal narrowing, mural hyper-enhancement, and length of disease on imaging were associated with endoscopic recurrence (all P < .01). Radiographic disease severity was associated with increasing Rutgeerts' score (P < .001). E-/R+ patients experienced more rapid subsequent endoscopic recurrence (hazard ratio, 4.16; P = .033) and increased rates of subsequent endoscopic (43.8% vs 22.7%) and surgical recurrence (20% vs 9.5%) than E-/R- patients (median follow-up, 4.5 years). CONCLUSIONS: Cross-sectional imaging is highly sensitive, but poorly specific, in detecting endoscopic disease activity and postoperative recurrence. Advanced radiographic disease correlates with endoscopic severity. Patients with radiographic activity in the absence of endoscopic recurrence may be at increased risk for future recurrence, and closer monitoring should be considered.

Management of adult tuberous sclerosis complex-related angiomyolipoma: A single-center experience.

INTRODUCTION: Tuberous sclerosis complex (TSC) is a rare, multi-system, genetic disease. A significant cause of TSC-related morbidity is potential bleeding from renal angiomyolipoma (AML). To pre-emptively decrease AML bleeding, mTOR inhibitors can be used; however, thresholds for initiating and maintaining everolimus therapy remain uncertain. Recent literature suggests not triggering active treatment of AMLs based on size thresholds alone. We evaluated the appropriateness of initiating everolimus therapy in asymptomatic patients after considering AML size, rate of growth, and other factors. METHODS: Diagnostic criteria developed by the 2012 International TSC Consensus Group and presence of AML were used as inclusion criteria. Medical and imaging reports of 11/20 TSC patients from a single center were reviewed. RESULTS: Mean age was 40.55 (±16.27) and 11 patients were female. Eight asymptomatic patients at high risk for complications underwent everolimus therapy, of which seven (88%) demonstrated decreased AML size, but multiple side effects were reported. Four high-risk asymptomatic patients did not undergo therapy due to side effect concerns, while four low-risk asymptomatic patients had stable AMLs under active surveillance. Four patients had reduced AMLs through local therapy. CONCLUSIONS: Everolimus treatment was effective for managing AML size in most high-risk, asymptomatic patients with tolerable side effects. AML size can remain relatively stable for asymptomatic, low-risk patients despite not receiving intervention(s). Patients with TSC-related AML can be safely managed with mTOR inhibitors like everolimus with shared decision-making, including factors such as bleeding risk, AML growth rate, and number and absolute size of AMLs.

Evaluating bowel enterotomy closures in simulated deep body cavities using the reversing half-hitch alternating post and square knots: a randomized controlled trial.

Background: Square knots can be difficult to construct in deep body cavities. The reversing half-hitch alternating post (RHAP) surgical knot has noninferior tensile strength and performance characteristics in deep body cavities. We compared the enterotomy repairs of novice learners in simulated deep body cavities using RHAP versus square knots after proficiency-based training. Methods: Undergraduate students were randomized to RHAP (n = 10) or square knot (n = 10) groups and trained to defined proficiency. They then performed hand-sewn enterotomy repairs of cadaveric porcine small bowels on flat surfaces and in simulated deep body cavities. We recorded time to knot-tying proficiency and to enterotomy repair, and burst pressures for the repair. Results: Mean time-to-proficiency in knot tying was equivalent between the RHAP and square knot groups (23 [standard deviation (SD) 3] v. 21 [SD 2] min, p = 0.33). Mean time for enterotomy repair in deep cavities was shorter for the RHAP group (16 [SD 2] min v. 21 [SD 1] min, p = 0.02). Mean burst pressures for enterotomy repair were equivalent on flat surfaces (128 [SD 41] v. 101 [SD 36] mm Hg, p = 0.31), and were significantly higher for the RHAP group in simulated deep body cavities (32 [SD 13] v. 105 [SD 37] mm Hg, p = 0.05). Conclusion: The RHAP knots appear to have superior performance versus square knots when tied in a deep body cavity by novice learners. Future work should focus on demonstrating the clinical relevance and broad utility of the RHAP knot in abdominal surgery. Both knot types should be taught to novice learners.

Contexte: L'exécution de noeuds plats peut être difficile dans les cavités corporelles profondes. Les noeuds de type demi-clé inversée alternée (RHAP, pour reversing halfhitch alternating post) ont une résistance à la traction et un rendement semblables à ceux des noeuds plats dans ces cavités. Nous avons comparé l'efficacité des noeuds plats et des noeuds de type RHAP réalisés par de nouveaux apprenants dans des cavités profondes simulées, après leur avoir enseigné les compétences nécessaires. Méthodes: Les étudiants de premier cycle ont été aléatoirement répartis en 2 groupes, soit le groupe RHAP (n = 10) et le groupe noeud plat (n = 10), et ont reçu une formation pour développer des compétences prédéfinies. Ils ont ensuite suturé à la main un intestin grêle provenant d'un cadavre de porc, sur une surface plane et à l'intérieur d'une cavité profonde simulée. Nous avons mesuré le temps nécessaire à l'exécution du noeud et à la suture complète de l'incision, de même que la pression que pouvait subir cette suture sans se rompre. Résultats: Le temps moyen d'exécution du noeud était semblable entre les groupes RHAP et noeud plat (23 min [écart type (E.T.) 3 min] c. 21 min [E.T. 2 min]; p = 0,33). Le temps moyen nécessaire à la suture de l'incision dans la cavité profonde était plus court dans le groupe RHAP (16 min [E.T. 2 min] c. 21 min [E.T. 1 min]; p = 0,02). La pression moyenne que pouvait subir la suture sans se rompre était comparable pour les sutures effectuées sur une surface plane (128 mm Hg [E.T. 41 mm Hg] c. 101 mm Hg [E.T. 36 mm Hg]; p = 0,31), mais était significativement plus élevée dans le groupe RHAP pour les sutures faites dans la cavité profonde (32 mm Hg [E.T. 13 mm Hg] c. 105 mm Hg [E.T. 37 mm Hg], p = 0,05). Conclusion: Les noeuds de type RHAP semblent avoir un rendement supérieur à celui des noeuds plats lorsqu'ils sont réalisés dans une cavité profonde par de nouveaux apprenants. Des études ultérieures devraient se pencher sur la pertinence clinique et l'utilité générale de ces noeuds en chirurgie abdominale. Les 2 types de noeuds devraient être enseignés aux nouveaux apprenants.

Circulating Gas6 is associated with reduced human carotid atherosclerotic plaque burden in high risk cardiac patients.

OBJECTIVE: Pre-clinical studies suggest that growth arrest-specific protein 6 (Gas6), a member of the vitamin K dependent family of proteins, is implicated in atherosclerosis. A role for Gas6 in stabilizing atherosclerotic plaque has been suggested. Our aim was to determine the association between Gas6 and measures of carotid artery atherosclerosis in humans undergoing elective coronary angiography. Secondary aims were to determine the association between Gas6 and sex, diabetes, and obesity. METHODS: In 204 outpatients referred for coronary angiography, EDTA plasma was collected and a focused carotid ultrasound performed. Degree of angiographic coronary artery disease was scored. Carotid intima media thickness as well as maximum plaque height, plaque area, and grayscale median were measured by vascular sonography. Gas6 was assessed by enzyme-linked immunosorbent assay. RESULTS: We found that Gas6 concentrations were lower in males and were associated with diabetes, obesity, and lower kidney function. After adjustment for age, sex, kidney function, BMI and traditional cardiac risk factors; diabetes was associated with higher levels of Gas6, whilst there was a significant inverse relationship between Gas6 and total plaque area. Gas6 was inversely associated with maximum plaque height and total plaque area in adjusted multi-variable models. CONCLUSIONS: We observed higher levels of Gas6 in participantswith adverse cardiovascular risk profiles (e.g. diabetes, obesity) yet Gas6 was independently associated with reduced plaque height and total plaque area. These findings suggest that Gas6 may play a role in human atherosclerotic plaque remodeling.

Speckle tracking carotid artery circumferential strain is a marker of arterial sclerosis but not coronary atherosis.

PURPOSE: Circumferential speckle tracking carotid artery strain is a novel method of quantifying vessel wall stiffness. We hypothesized that carotid wall stiffness would be associated with carotid intimal medial thickening (a medial process associated with risk factors), but not coronary artery disease (an intimal process). METHODS: Bilateral carotid artery ultrasound was conducted on outpatients who had previously undergone elective coronary angiography. Mean carotid artery far wall circumferential strain (FWCS) was assessed for correlations with coronary angiographic stenosis, cardiac risk factors, carotid intima-media thickness (CIMT), and carotid plaque. RESULTS: One hundred and sixty five (165) patients were studied. No significant association was found between the presence of coronary artery disease on angiography and mean FWCS. FWCS was higher in current tobacco smokers. In addition, carotid strain was found to decrease with increased age (r = -0.33, P < 0.001). When adjusted for pulse pressure (PP), FWCS/PP was negatively correlated with mean CIMT (r = -0.29, P = 0.002) and bulb maximum plaque height (r = -0.27, P = 0.004). Hypertension and diabetes were associated with decreased FWCS/PP (increased wall stiffness). CONCLUSIONS: While no clear relationship between carotid strain and coronary artery disease was observed, increased CIMT, carotid plaque, and cardiac risk factors were associated with decreased carotid strain. Further work is required to explore the relationship between carotid strain and cardiovascular events.

c-Jun NH2-terminal kinase activating kinase 1/mitogen-activated protein kinase kinase 4-mediated inhibition of SKOV3ip.1 ovarian cancer metastasis involves growth arrest and p21 up-regulation.

In many patients without clinical metastases, cancer cells have already escaped from the primary tumor and entered a distant organ. A long-standing question in metastasis research is why some disseminated cancer cells fail to complete steps of metastatic colonization for extended periods of time. Our laboratory identified c-Jun NH(2)-terminal kinase activating kinase 1/mitogen-activated protein kinase kinase 4 (JNKK1/MKK4) as a metastasis suppressor protein in a mouse xenograft model of experimental i.p. ovarian cancer metastasis. In this model, expression of JNKK1/MKK4 via activation of p38 delays formation of >or=1-mm implants and prolongs animal survival. Here, we elucidate the time course of this delay as well as the biological mechanisms underpinning it. Using the Gompertz function to model the net accumulation of experimental omental metastases, we show that MKK4-expressing implants arise, on average, 30 days later than controls. Quantitative real-time PCR shows that MKK4 expression does not have a substantial effect on the number of cancer cells initially adhering to the omentum, and terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling analysis shows that there is no increase in apoptosis in these cells. Instead, immunohistochemical quantitation of cell cycle proteins reveals that MKK4-expressing cells fail to proliferate once they reach the omentum and up-regulate p21, a cell cycle inhibitor. Consistent with the time course data, in vitro kinase assays and in vivo passaging of cell lines derived from macroscopic metastases show that the eventual outgrowth of MKK4-expressing cells is not due to a discrete selection event. Rather, the population of MKK4-expressing cells eventually uniformly adapts to the consequences of up-regulated MKK4 signaling.