Real-World Outcomes of Dual Advanced Therapy in Children and Young Adults with Inflammatory Bowel Disease.

BACKGROUND: Data are limited on the safety and efficacy of combining advanced therapies for refractory patients with IBD. AIM: To evaluate the real-world efficacy and safety of dual advanced therapy (DAT), combining 2 biologics or a biologic with a small molecule, in children and young adults with refractory IBD. METHODS: Primary outcome of this single IBD center cohort was DAT remission (clinical and biomarker remission) at first assessment (T1). Secondary outcomes included remission at T2, if DAT de-intensification (De-I) occurred and T3, if T2 DAT re-intensification (Re-I) occurred. Efficacy and safety outcomes were described. RESULTS: Of the 30 patients [43% female, 30% CD, median age of 18.3 [15.1-19.8] years], all 11 UST + TOFA achieved T1 remission; 6/10 De-I failed at T2; and 4/4 Re-I achieved T3 remission. Of 9 VDZ + TOFA, 6 achieved T1 remission; 5/6 De-I failed at T2; and 1/1 failed T3 Re-I. Of 4 UST + VDZ, 3 achieved T1 remission; 2/3 De-I failed at T2; and 0 had Re-I. Of 5 UST + UPA, 4 achieved T1 remission; 1/5 De-I failed at T2 but recaptured T3 remission post-Re-I. One VDZ + OZA achieved T1 remission and maintained T2 remission post-De-I to OZA monotherapy. At last follow-up, 43% were on original DAT, 17% on one of original DAT, and 40% neither. One UST + TOFA patient developed mild leukopenia and another developed septic arthritis and venous thromboembolism on VDZ + TOFA and prednisone. CONCLUSION: Most children and young adults treated with DAT achieved remission with minimal safety events; however, de-intensification had limited success.

Clinical Application of Intestinal Ultrasound in Inflammatory Bowel Disease.

PURPOSE OF REVIEW: Intestinal ultrasound (IUS) is a non-invasive, accurate, and well-tolerated tool that provides real-time assessment of inflammatory bowel disease (IBD) activity and is therefore an ideal monitoring tool. This review describes the evolving role of IUS in each phase of clinical management of IBD. RECENT FINDINGS: Accumulating evidence has demonstrated that IUS is an excellent tool for the assessment of suspected IBD, with a very high negative predictive value. It accurately assesses disease activity, disease complications, and in the pre-treatment phase, provides a benchmark for subsequent follow-up. IUS can detect early therapeutic response and correlates well with other established monitoring modalities with arguably superior predictive capabilities and ability to assess a deeper degree of remission, transmural healing (TH). IUS has a crucial role in the management of IBD and has ushered in a new era of monitoring with more rapid evaluation and the opportunity for early optimization, deeper therapeutic targets, and improved outcomes.

Determining the Accuracy of Intestinal Ultrasound Scores as a Prescreening Tool in Crohn's Disease Clinical Trials.

INTRODUCTION: High rates of screen failure for the minimum Simple Endoscopic Score for Crohn's Disease (SES-CD) plague Crohn's disease (CD) clinical trials. We aimed to determine the accuracy of segmental intestinal ultrasound (IUS) parameters and scores to detect segmental SES-CD activity. METHODS: A single-center, blinded, cross-sectional cohort study of children and young adult patients with CD undergoing IUS and ileocolonoscopy, comparing segmental IUS bowel wall thickness (BWT), hyperemia (modified Limberg score [MLS]), and scores to detect segmental SES-CD activity: (i) SES-CD ≤2, (ii) SES-CD ≥6, and (iii) SES-CD ≥4 in the terminal ileum (TI) only. Primary outcome was accuracy of BWT, MLS, and IUS scores to detect SES-CD ≤2 and SES-CD ≥6. Secondary outcomes were accuracy of TI BWT, MLS, and IUS scores to detect SES-CD ≥4 and correlation with the SES-CD. RESULTS: Eighty-two patients (median [interquartile range] age 16.5 [12.9-20.0] years) underwent IUS and ileocolonoscopy of 323 bowel segments. Segmental BWT ≤3.1 mm had a similar high accuracy to detect SES-CD ≤2 as IUS scores (area under the receiver operating curve [AUROC] 0.833 [95% confidence interval 0.76-0.91], 94% sensitivity, and 73% specificity). Segmental BWT ≥3.6 mm and ≥4.3 mm had similar high accuracy to detect SES-CD ≥6 (AUROC 0.950 [95% confidence interval 0.92-0.98], 89% sensitivity, 93% specificity) in the colon and an SES-CD ≥4 in the TI (AUROC 0.874 [0.79-0.96], 80% sensitivity, and 91% specificity) as IUS scores. Segmental IUS scores strongly correlated with the SES-CD. DISCUSSION: Segmental IUS BWT is highly accurate to detect moderate-to-severe endoscopic inflammation. IUS may be the ideal prescreening tool to reduce unnecessary trial screen failures.

Early Intestinal Ultrasound Response to Biologic Therapy Predicts Endoscopic Remission in Children with Ileal Crohn's Disease: Results from the Prospective Super Sonic Study.

BACKGROUND AND AIMS: STRIDE-II recommends early biomarker targets for treatment optimization to achieve treat-to-target (T2T) endoscopic remission (ER) in Crohn's disease (CD). Predictive capabilities of intestinal ultrasound (IUS) for T2T ER remains unknown. We aimed to evaluate IUS response to predict ER in children with CD. METHODS: Prospective longitudinal cohort study of children with ileal (TI) CD initiating biologic therapy undergoing IUS, clinical disease activity, and C-reactive protein (CRP) assessments at baseline, week 8, 6 months, and T2T within 1 year. Primary outcome was the accuracy of optimal cut-points to predict TI ER (SES-CD < 2) for change in bowel wall thickness (BWT) on IUS from baseline to week 8, and BWT at week 8. Area under the receiver operating curve analysis was performed and univariate analysis tested associations. RESULTS: 44 children (median age 13 [IQR 12-17] years, 29 (66%) biologic naïve) were included, 29 (66%) achieved ER. A > 18% decrease in TI BWT at week 8 predicted ER with an AUROC of 0.99 [95% CI 0.98-1.00], 100% sensitivity, 93% specificity, 97% PPV, and 100% NPV, superior to a > 46% decrease in PCDAI (AUROC 0.67 [95% CI 0.49-0.84]) and > 84% decrease in CRP (AUROC 0.49 [95% CI 0.31-0.67]) at week 8. CONCLUSIONS: Early change in TI BWT on IUS is highly predictive of ER in children with CD and superior to symptoms and CRP. Our findings suggest that IUS could be used for treatment optimization and tight control to guide T2T strategy.

Single-center Experience With Upadacitinib for Adolescents With Refractory Inflammatory Bowel Disease.

BACKGROUND: Upadacitinib (UPA) is a novel selective JAK inhibitor approved for adults with ulcerative colitis (UC) and with positive phase 3 data for Crohn's disease (CD). Pediatric off-label use is common due to delays in pediatric approvals; real-world data on UPA are needed to understand the safety and effectiveness in pediatric IBD. METHODS: This is a single-center retrospective case series study of adolescents (12-17 years) with inflammatory bowel disease IBD on UPA. The primary outcome was postinduction steroid-free clinical remission (SF-CR) defined as Pediatric UC Activity Index (PUCAI) or Pediatric CD Activity Index (PCDAI) ≤10. Secondary outcomes include postinduction clinical response (decrease ≥12.5 in PUCAI/PCDAI), postinduction C-reactive protein (CRP) normalization, 6-month SF-CR, and intestinal ultrasound response and remission. Adverse events were recorded through last follow-up. RESULTS: Twenty patients (9 CD, 10 UC, 1 IBD-U; 55% female; median age 15 years, 90% ≥2 biologics) were treated with UPA for ≥12 weeks (median 51 [43-63] weeks). Upadacitinib was used as monotherapy in 55% and as combination with ustekinumab and vedolizumab in 35% and 10%, respectively. Week 12 SF-CR was achieved in 75% (15/20) and 80% (16/20) with CRP normalization. About 3/4 (14/19) achieved SF-CR at 6 months. Adverse event occurred in 2 patients (10%): Cytomegalovirus colitis requiring hospitalization and hyperlipidemia requiring no treatment. In the 75% with ultrasound monitoring, response and remission were achieved in 77% and 60%, respectively. CONCLUSION: While awaiting pediatric registration trials, our data suggest that UPA is effective in inducing and maintaining SF-CR in adolescents with highly-refractory IBD with an acceptable safety profile.

This case series presents novel data on the effectiveness and safety of upadacitinib in adolescent patients with IBD.

Point-of-Care Intestinal Ultrasound in Pediatric Inflammatory Bowel Disease.

PURPOSE OF REVIEW: Intestinal ultrasound (IUS) is an emerging non-invasive point-of-care tool utilized by pediatric gastroenterologists for accurately detecting and monitoring inflammatory bowel disease (IBD) activity. In this article, we reviewed the evidence supporting and technique to perform IUS for children with IBD. RECENT FINDINGS: IUS technique can visualize the colon from the distal sigmoid until the cecum and the terminal ileum without the need for bowel preparation, fasting, or sedation in children with IBD. IUS has been shown to be accurate to endoscopy in children with ulcerative colitis and Crohn's disease. IUS may be the most accurate biomarker to follow as a marker of treatment response that is predictive of endoscopic outcomes in children with IBD. Multiple studies have demonstrated that IUS can be performed at the point-of-care for IBD activity assessment in children. Recent studies have demonstrated the accuracy of IUS to endoscopy and magnetic resonance enterography with an ability to be repeated as a monitor of treatment response for tight control monitoring.

Intestinal Ultrasound for the Pediatric Gastroenterologist: A Guide for Inflammatory Bowel Disease Monitoring in Children: Expert Consensus on Behalf of the International Bowel Ultrasound Group (IBUS) Pediatric Committee.

Crohn disease and ulcerative colitis are chronic inflammatory bowel diseases (IBD) often diagnosed in childhood. A strict monitoring strategy can potentially alter the disease course and facilitate early effective treatment before irreversible bowel damage occurs. Serial colonoscopy in children, the gold standard for monitoring, is impractical. Accurate, real-time, noninvasive markers of disease activity are needed. Intestinal ultrasound is an accurate, noninvasive, real-time, point-of-care, cross-sectional imaging tool used to monitor inflammation in pediatric IBD patients in Europe, Canada, and Australia. It is now emerging in a few expert centers in the United States as a safe, non-radiating, inexpensive, bedside tool used by the treating gastroenterologist for real-time decision-making. Unlike the standard biomarkers of pediatric IBD activity, C-reactive protein, and fecal calprotectin, intestinal ultrasound (IUS) facilitates disease localization, characterizes severity, extent, and accurately detects complications. Perhaps most importantly, IUS may enhance shared understanding and ease the burden of treatment decision-making for both the gastroenterologist and the patient. There is a lack of standardization for bedside IUS among pediatric gastroenterologists. The purpose is to outline a standardized approach to pediatric bedside IUS, including basic equipment requirements and technique, patient selection, preparation and positioning, technical considerations and limitations, documentation of mesenteric and luminal features of IBD, characterization of penetrating disease and strictures, and provide a proposed pediatric IUS monitoring algorithm to guide care.

The Simple Pediatric Activity Ultrasound Score (SPAUSS) for the Accurate Detection of Pediatric Inflammatory Bowel Disease.

OBJECTIVE: The aim of the study was to identify the most significant ultrasound (US) parameters that predict inflammatory activity and develop a simple US activity score. METHODS: Patients were identified through retrospective evaluation of an established database of children with inflammatory bowel disease (IBD). Patients with endoscopy and US within 60 days were included (N = 75). US parameters evaluated included: bowel wall thickness (BWT), mesenteric inflammatory fat, lymphadenopathy, and hyperemia. The weighted kappa statistic was calculated to assess agreement between sonographic and endoscopically identified disease location. Using a proportional odds model and ordinal logistic regression, statistically significant (P < 0.05) parameters were used to generate a score. Variables were weighted to classify individuals into severity classes. Receiver operating characteristic curves were plotted to demonstrate the score's discriminative and predictive capacity. RESULTS: There was substantial agreement between US and endoscopy for all disease locations (weighted kappa = 0.85) and substantial agreement for ileocolonic disease (weighted kappa = 0.96). Two sonographic parameters were identified as contributing significantly to disease activity: BWT and mesenteric inflammatory fat (P < 0.05). A predictive score was developed incorporating BWT, hyperemia and inflammatory fat, and receiver operating characteristic curve curves demonstrated good predictive capacity to distinguish between the absence of disease (normal) and active disease with an area under the curve of 82.1%. CONCLUSIONS: The most important sonographic parameters for predicting disease activity were BWT and mesenteric inflammatory fat. When combined with hyperemia into a simple score, there was accurate detection of inflammatory activity in children with inflammatory bowel disease. This score may facilitate noninvasive, bedside detection of inflammation, and standardize the use of US in children.

Subcutaneous Fat Necrosis of the Newborn With Initial Hypocalcemia and Familial Recurrence: A Case Report.

Subcutaneous fat necrosis of the newborn (SFNN) is a rare disorder characterised by indurated plaques or nodules with or without erythema, typically distributed over the cheeks, extremities, posterior trunk, buttocks, and thighs, and appears during the first 2 weeks of life. It is commonly associated with perinatal asphyxia and, while usually self-limited, can lead to severe hypercalcemia. There is no known familial association. The present article describes a neonate with extensive disease, counterintuitive hypocalcemia, and a family history of SFNN and reviews the existing literature on SFNN.

A Simple Ultrasound Score for the Accurate Detection of Inflammatory Activity in Crohn's Disease.

BACKGROUND: Ultrasound is accurate in the detection of Crohn's disease. Our aim was to identify ultrasound parameters contributing to inflammatory disease activity, develop a simple score, and validate this score prospectively. METHODS: This study comprised 2 single-center investigations. The first was a retrospective study on a population that had received colonoscopies (as a gold-standard diagnostic) within 60 days of ultrasound. The second was a prospective study on 2 populations: patients requiring induction with adalimumab and patients on adalimumab maintenance therapy. Ultrasound and endoscopy were preformed within 14 days in both prospective groups. The endoscopy results were graded with the Simple Endoscopic Score and the Rutgeerts score and compared with 5 ultrasound parameters. We used a proportional odds model to determine which ultrasound parameters correlated significantly with the endoscopy results. We then developed a predictive ultrasound score for disease activity, plotted the receiver operating characteristic curves, and undertook prospective validation of the score. RESULTS: We evaluated 160 patients retrospectively to compare ultrasound and colonoscopy. Two of 5 parameters were found to correlate significantly with disease activity: bowel wall thickness (P = <0.0001) and color Doppler signal (P = 0.0292). We developed a score that uses weighted variables. The area under the corresponding receiver operating characteristic curve was 0.8658. CONCLUSIONS: A simple ultrasonographic score that accurately identifies Crohn's disease activity has been developed and validated. Ultrasound may be a surrogate for endoscopy to guide disease management, but future studies should be conducted to establish interrater variability.

Preclinical Murine Models for Lung Cancer: Clinical Trial Applications.

Murine models for the study of lung cancer have historically been the backbone of preliminary preclinical data to support early human clinical trials. However, the availability of multiple experimental systems leads to debate concerning which model, if any, is best suited for a particular therapeutic strategy. It is imperative that these models accurately predict clinical benefit of therapy. This review provides an overview of the current murine models used to study lung cancer and the advantages and limitations of each model, as well as a retrospective evaluation of the uses of each model with respect to accuracy in predicting clinical benefit of therapy. A better understanding of murine models and their uses, as well as their limitations may aid future research concerning the development and implementation of new targeted therapies and chemotherapeutic agents for lung cancer.