Navigating the landscape of liver cancer management: Study designs in clinical trials and clinical practice.

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer death worldwide and its prognosis is highly heterogeneous, being related not only to tumour burden but also to the severity of underlying chronic liver disease. Moreover, advances in systemic therapies for HCC have increased the complexity of patient management. Randomised-controlled trials represent the gold standard for evidence generation across all areas of medicine and especially in the oncology field, as they allow for unbiased estimates of treatment effect without confounders. Observational studies have many problems that could reduce their internal and external validity. However, large prospective (well-conducted) observational real-world studies can detect rare adverse events or monitor the occurrence of long-term adverse events. How best to harness real world data, which refers to data generated from the routine care of patients, and real-world 'evidence', which is the evidence generated from real-world data, represents an open challenge. In this review article, we aim to provide an overview of the benefits and limitations of different study designs, particularly focusing on randomised-controlled trials and observational studies, to address important and not fully resolved questions in HCC research.

Screening of liver cancer with abbreviated MRI.

Current recommendations for the surveillance of HCC are based on the semiannual liver ultrasound (with or without serum alpha-fetoprotein) in patients with cirrhosis and in subgroups with chronic hepatitis B infection. However, the sensitivity of this strategy is suboptimal for the detection of early-stage tumors, especially in obese patients, due to interoperator variability and poor adherence. The detection rate of focal liver lesions is excellent with MRI, making it the best alternative candidate for surveillance. However, performing a full contrast-enhanced MRI is unrealistic because of limited availability and health economics. Abbreviated MRI (AMRI) corresponds to the acquisition of a limited number of sequences with a high detection rate. The theoretical benefits of AMRI are a reduced acquisition time (≤10 min) with improved time-effectiveness and cost-effectiveness compared with conventional MRI, and greater accuracy than ultrasound. Numerous protocols may be performed, including T1-weighted, T2-weighted, and DWI sequences, with or without contrast administration. Although published studies report promising per-patient results, they should be interpreted with caution. Indeed, most studies were simulated, retrospectively reviewing a subset of sequences in relatively small populations who underwent a full MRI. They also included groups that were not representative of screening populations. In addition, most were published by Asian groups, with at-risk populations that were different from Western populations. There are no existing longitudinal studies that directly compare the different AMRI approaches or AMRI to ultrasound. Finally, it is possible that 1 approach will not fit all patients and that strategies should be tailored to the risk of HCC, in particular in relation to the cost and availability of AMRI. Several trials are ongoing to evaluate these questions.

Contemporary Imaging Assessment of Strictures and Fibrosis in Crohn Disease, With Focus on Quantitative Biomarkers: From the AJR Special Series on Imaging of Fibrosis.

Patients with Crohn disease commonly have bowel strictures develop, which exhibit varying degrees of inflammation and fibrosis. Differentiation of the distinct inflammatory and fibrotic components of strictures is key for the optimization of therapeutic management and for the development of antifibrotic drugs. Cross-sectional imaging techniques, including ultrasound, CT, and MRI, allow evaluation of the full thickness of the bowel wall as well as extramural complications and associated mesenteric abnormalities. Although promising data have been reported for a range of novel imaging biomarkers for detection of fibrosis and quantification of the degree of fibrosis, these biomarkers lack sufficient validation and standardization for clinical use. Additional methods, including PET with emerging radiotracers, artificial intelligence, and radiomics, are also under investigation for stricture characterization. In this review, we highlight the clinical relevance of identifying fibrosis in Crohn disease, review the histopathologic aspects of strictures in Crohn disease, summarize the morphologic imaging findings of strictures, and explore contemporary developments in the use of cross-sectional imaging techniques for detecting and characterizing intestinal strictures, with attention given to emerging quantitative biomarkers.

ADC Values for Detecting Bowel Inflammation and Biologic Therapy Response in Patients With Crohn Disease: A Post Hoc Prospective Trial Analysis.

BACKGROUND. New biologic agents for Crohn disease (CD) create a need for noninvasive disease markers. DWI may assess bowel inflammation without contrast agents. OBJECTIVE. The purpose of this study was to evaluate ADC values for identifying bowel inflammation and therapeutic response in patients with CD treated with biologic therapy. METHODS. This study entailed post hoc analysis of prospective trial data. Analysis included 89 patients (median age, 37 years; 49 women, 40 men) with CD treated by biologic therapy who underwent MR enterography (MRE) at baseline and 46 weeks after therapy, from March 2013 to April 2021; 43 patients underwent ileocolonoscopy at both time points. Analysis was conducted at the level of small-bowel and colorectal segments (586 segments analyzed). MR index of activity (MaRIA) score and presence of endoscopic ulcers were determined at both time points. One observer measured bowel wall ADC. Diagnostic performance was evaluated. Dichotomous ADC assessments used a threshold of 1301 × 10-6 mm2/s based on initial ROC analysis; dichotomous MaRIA score assessments used a threshold of 11 (moderate to severe inflammation). A second observer repeated ADC measurements in 15 patients. RESULTS. At baseline, ADC had AUC of 0.92, sensitivity of 78.6%, specificity of 91.4%, and accuracy of 88.2% for detecting segments with MaRIA score 11 or greater. At baseline, AUC for detecting endoscopic ulcers was 0.96 for MaRIA score versus 0.87 for ADC (p < .001); sensitivity, specificity, and accuracy were 70.8%, 90.2%, and 85.1% for ADC and 86.2%, 96.2%, and 93.6% for MaRIA score. At follow-up, ADC had AUC of 0.87, sensitivity of 75.4%, specificity of 83.6%, and accuracy of 80.0% for detecting improvement in MaRIA score to less than 11. At follow-up, AUC for detecting endoscopic ulcer healing was 0.94 for MaRIA score versus 0.84 for ADC (p = .01); sensitivity, specificity, and accuracy were 70.7%, 95.8%, and 84.4% for ADC and 90.2%, 100.0%, and 95.6% for MaRIA score. Interobserver agreement for ADC, based on intraclass correlation coefficient, was 0.70 at baseline and 0.65 at follow-up. CONCLUSION. The findings do not support use of ADC rather than MaRIA scores for detecting biologic therapy response. CLINICAL IMPACT. ADC may have an adjunct role in assessing bowel inflammation in CD, but showed limited performance for detecting biologic therapy response.

Reliability of extracellular contrast versus gadoxetic acid in assessing small liver lesions using liver imaging reporting and data system v.2018 and European association for the study of the liver criteria.

BACKGROUND & AIMS: The diagnostic accuracy of Liver Imaging Reporting and Data System (LI-RADS) v.2018 and European Association for the Study of the Liver (EASL) criteria for the diagnosis of HCC have been widely evaluated, but their reliability should be investigated. We aimed to assess and compare the reliability of LI-RADS v.2018 and EASL criteria for the diagnosis of HCC using MRI with extracellular contrast agents (ECAs) and gadoxetic acid (GA) and determine the effect of ancillary features on LI-RADS reliability. APPROACH & RESULTS: Ten readers reviewed MRI studies of 92 focal liver lesions measuring <3 cm acquired with ECAs and GA <1 month apart from two prospective trials, assessing EASL criteria, LI-RADS major and ancillary features, and LI-RADS categorization with and without including ancillary features. Inter-reader agreement for definite HCC diagnosis was substantial and similar for the two contrasts for both EASL and LI-RADS criteria. For ECA-MRI and GA-MRI, respectively, inter-reader agreement was k = 0.72 (95% CI, 0.63-0.81) and k = 0.72 (95% CI, 0.63-0.80); for nonrim hyperenhancement, k = 0.63 (95% CI, 0.54-0.72) and k = 0.57 (95% CI, 0.48-0.66); and for nonperipheral washout, k = 0.49 (95% CI, 0.40-0.59) and k = 0.48 (95% CI, 0.37-0.58) for enhancing capsule. The inter-reader agreement for LI-RADS after applying ancillary features remained in the same range of agreement. CONCLUSIONS: Agreement for definite HCC was substantial and similar for both scoring systems and the two contrast agents in small focal liver lesions. Agreement for LI-RADS categorization was lower for both contrast agents, and including LI-RADS ancillary features did not improve agreement.

Recent advances in clinical practice: advances in cross-sectional imaging in inflammatory bowel disease.

Endoscopy remains the reference standard for the diagnosis and assessment of patients with inflammatory bowel disease (IBD), but it has several important limitations. Cross-sectional imaging techniques such as magnetic resonance enterography (MRE) and intestinal ultrasound (IUS) are better tolerated and safer. Moreover, they can examine the entire bowel, even in patients with stenoses and/or severe inflammation. A variety of cross-sectional imaging activity scores strongly correlate with endoscopic measures of mucosal inflammation in the colon and terminal ileum. Unlike endoscopy, cross-sectional techniques allow complete visualisation of the small-bowel and assess for extraintestinal disease, which occurs in nearly half of patients with IBD. Extramural findings may predict outcomes better than endoscopic mucosal assessment, so cross-sectional techniques might help identify more relevant therapeutic targets. Coupled with their high sensitivity, these advantages have made MRE and IUS the primary non-invasive options for diagnosing and monitoring Crohn's disease; they are appropriate first-line investigations, and have become viable alternatives to colonoscopy. This review discusses cross-sectional imaging in IBD in current clinical practice as well as research lines that will define the future role of these techniques.

BCLC strategy for prognosis prediction and treatment recommendation: The 2022 update.

There have been major advances in the armamentarium for hepatocellular carcinoma (HCC) since the last official update of the Barcelona Clinic Liver Cancer prognosis and treatment strategy published in 2018. Whilst there have been advances in all areas, we will focus on those that have led to a change in strategy and we will discuss why, despite being encouraging, data for select interventions are still too immature for them to be incorporated into an evidence-based model for clinicians and researchers. Finally, we describe the critical insight and expert knowledge that are required to make clinical decisions for individual patients, considering all of the parameters that must be considered to deliver personalised clinical management.

Liver cancer risk after HCV cure in patients with advanced liver disease without non-characterized nodules.

BACKGROUND & AIMS: Recognition of non-characterized liver nodules (NCLN) prior to direct-acting antivirals (DAAs) is associated with increased hepatocellular carcinoma (HCC) risk in patients with HCV. The risk of HCC has not been defined in F3/F4 patients in whom NCLN have been ruled-out before starting DAAs and at sustained virological response (SVR). This study aimed to estimate HCC incidence in this population. METHODS: We performed a prospective study including HCV-infected patients with F3/F4 fibrosis, without a history of HCC, and who achieved SVR after DAAs. Patients were only included if they had undergone ultrasound imaging that excluded the presence of HCC/NCLN within 30 days after SVR. All patients were evaluated every 6 months until developing primary liver cancer, death or withdrawal of informed consent. HCC incidence was expressed per 100 patient-years (/100PY). Adherence to screening program was calculated every 6 months for the first 48 months. RESULTS: A total of 185 patients (63/122, F3/F4) were included. Among those with cirrhosis, 92% were Child-Pugh A and 42.7% had clinically significant portal hypertension (CSPH). Albumin-bilirubin score was 1 in 84.9% and 2 in 15.1% of patients, respectively. The median clinical and radiologic follow-up was 52.4 months and 48 months, respectively. Ten patients developed HCC: HCC incidence was 1.46/100PY (95% CI 0.79-2.71) in the whole cohort, 2.24/100PY (95% CI 1.21-4.17) in F4 only and 3.63/100PY (95% CI 1.95-6.74) in patients with CSPH. No HCC was registered in patients with F3. Median time between SVR and HCC occurrence was 28.1 months; 12 non-primary liver cancers were also identified. CONCLUSIONS: Patients with cirrhosis without NCLN at SVR remain at risk of HCC development. The absence of HCC in patients with F3 reinforces their marginal cancer risk, but prospective studies are needed to exclude them from screening programs. LAY SUMMARY: Patients with HCV-related cirrhosis, without non-characterized liver nodules at sustained virologic response, remain at risk of hepatocellular carcinoma despite viral cure. However, the cancer risk after successful direct-acting antiviral treatment is marginal in patients with F3 fibrosis without non-characterized liver nodules. If confirmed in larger prospective studies, current screening recommendations may need to be revisited in this group of patients.

Responsiveness of Magnetic Resonance Enterography Indices for Evaluation of Luminal Disease Activity in Crohn's Disease.

BACKGROUND & AIMS: Magnetic resonance enterography (MRE) is having an increasing role in Crohn's disease; however, fully validated indices are needed. We evaluated the responsiveness of 4 MRE indices in luminal Crohn's disease. METHODS: Paired MRE images (pretreatment and post-treatment at weeks 12 or 14) from 41 patients were scored by 3 blinded radiologists. Disease activity was scored for 4 MRE indices (magnetic resonance index of activity [MaRIA], simplified MaRIA, London index, and London extended index) and a 100-mm visual analog scale (VAS) of overall disease activity. The criterion for change was an improvement by at least one half of an SD in the VAS after treatment. Responsiveness was evaluated using the standardized effect size (SES). Longitudinal validity was evaluated using correlations between changes in MRE index scores and disease activity measures including endoscopy and the VAS. RESULTS: The SES was 1.17 (95% CI, 0.56-1.77) for the simplified MaRIA, 0.98 (95% CI, 0.42-1.55) for the MaRIA, 0.95 (95% CI, 0.38-1.51) for the London extended index, and 0.85 (95% CI, 0.31-1.39) for the London index. The simplified MaRIA was significantly more responsive than the London index (ΔSES, 0.32; 95% CI, 0.05-0.58) but not the MaRIA (ΔSES, 0.18; 95% CI, -0.01 to 0.38) or the London extended index (ΔSES, 0.22; 95% CI, -0.05 to 0.50). Correlations with endoscopy (simplified MaRIA: r = 0.72) were not different from correlations with the VAS (London extended index: r = 0.70). CONCLUSIONS: Evaluated MRE indices showed moderate-to-large responsiveness and are suitable for use in clinical trials. The simplified MaRIA may be preferred because of its responsiveness and nonreliance on gadolinium administration.

Avoiding contrast-enhanced sequences does not compromise the precision of the simplified MaRIA for the assessment of non-penetrating Crohn's disease activity.

OBJECTIVES: Patients with Crohn's disease (CD) require multiple assessments with magnetic resonance enterography (MRE) from a young age. Standard MRE protocols for CD include contrast-enhanced sequences. Gadolinium deposits in brain tissue suggest avoiding gadolinium could benefit patients with CD. This study aimed to compare the accuracy of the simplified Magnetic Resonance Index of Activity (sMaRIA) calculated with and without contrast-enhanced sequences in determining the response to biologic drugs in patients with CD. METHODS: This post hoc analysis of a prospective study included patients with CD with endoscopic ulceration in ≥ 1 intestinal segment starting biologic drug therapy. Two blinded radiologists used the sMaRIA to score images obtained at baseline and week 46 of treatment first using only unenhanced sequences (T2-sMaRIA) and 1 month later using both unenhanced and enhanced images (CE-sMaRIA). We calculated the rates of agreement between T2-sMaRIA, CE-sMaRIA, and ileocolonoscopy for different conceptualizations of therapeutic response. RESULTS: A total of 46 patients (median age, 36 years [IQR: 28-47]) were included. Agreement with ileocolonoscopy was similar for CE-sMaRIA and T2-sMaRIA in identifying ulcer healing (kappa = 0.74 [0.55-0.93] and 0.70 [0.5-0.9], respectively), treatment response (kappa = 0.53 [0.28-0.79] and 0.44 [0.17 - 0.71]), and remission (kappa = 0.48 [0.22-0.73] and 0.43 [0.17-0.69]). The standardized effect size was moderate for both CE-sMaRIA = 0.63 [0.41-0.85] p < 0.001 and T2-sMaRIA = 0.58 [0.36-0.80] p < 0.001. CONCLUSIONS: sMaRIA with and without contrast-enhanced images accurately classified the response according to different therapeutic endpoints determined by ileocolonoscopy. KEY POINTS: • The simplified Magnetic Resonance Index of Activity is accurate for the assessment of Crohn's disease activity, severity, and therapeutic response, using four dichotomic components that can be evaluated without the need of using contrast-enhanced sequences, representing a practical and safety advantage, but concerns have been expressed as to whether the lack of contrast sequences may compromise precision. • The simplified Magnetic Resonance Index of Activity can assess the response to biologic therapy in patients with Crohn's disease without the need for intravenous contrast agents obtaining comparable results without and with contrast-enhanced sequences. • Avoiding intravenous contrast agents could reduce the duration of the MRE examination and its cost and would increase the acceptance and safety of MRE in clinical research in patients with Crohn's disease.

Immunotherapy-Based Treatments of Hepatocellular Carcinoma: AJR Expert Panel Narrative Review.

The advent of immunotherapy for patients with hepatocellular carcinoma (HCC) has changed the treatment landscape and conferred a survival benefit on patients with advanced HCC, who typically have a very poor prognosis. The most pronounced improvements in response, as documented by standardized response criteria based on CT or MRI, have been achieved when immunotherapy is combined with other systemic or locoregional therapies. Immune checkpoint inhibitor treatments result in unique patterns on CT and MRI that challenge the application of conventional response criteria such as RECIST, modified RECIST, and European Association for the Study of the Liver criteria. Thus, newer criteria have been developed to gauge therapy response or disease progression for patients receiving immunotherapy, including immune-related RECIST (iRECIST) and immune-modified RECIST (imRECIST), though these remain unvalidated. In this review, we describe the current landscape of immunotherapeutic agents used for HCC, summarize the results of published studies, review the pathobiologic mechanisms that provide a rationale for the use of these agents, and report on the status of response assessment for immunotherapy either alone or in combination with other treatment options. Finally, consensus statements are provided to inform radiologists about essential considerations in the era of a rapidly changing treatment paradigm for patients with HCC.

Infliximab Exposure Associates With Radiologic Evidence of Healing in Patients With Crohn's Disease.

BACKGROUND & AIMS: Higher infliximab trough levels are associated with clinical and endoscopic remission in patients with Crohn's disease (CD). We investigated pharmacodynamic features of infliximab and radiological healing. METHODS: We performed a substudy of the TAILORIX trial (patients with active luminal CD in Europe, treated with infliximab), analyzing baseline and week 54 magnetic resonance enterography (MRE) data. MREs were scored using the MaRIA score by blinded central readers. Radiologic response and remission were defined, based on MaRIA criteria in all segments, as scores below 11 and 7, respectively. We collected data on infliximab trough levels, biomarkers, and endoscopic findings. Our primary aim was to evaluate pharmacodynamic features associated with radiologic response and remission, based on MRE assessments at baseline and at 54 weeks after initiation of infliximab therapy. RESULTS: We analyzed data from 36 patients (50% female; median age 35.7 years; interquartile age range, 25.6-48.6 years; median disease duration, 1.5 months; interquartile duration range, 0.6-22.4 months). At week 54 of treatment, 36.4% of patients had a radiologic response, 30.3% of patients were in remission, and 71% had endoscopic features of remission. At baseline, there was a correlation between the CD endoscopic index of severity and MaRIA scores (κ = 0.46; P = .008), but we found no correlation at week 54 (κ = 0.06; P = .75). Radiologic remission correlated with infliximab trough level at week 14 (P = .049) when the infliximab trough level cut-off value was set at 7.8 µg/mL (area under the curve, 0.74; 75% sensitivity; 86% specificity; 90% negative predictive value; 57% positive predictive value). Radiologic response correlated with infliximab trough levels at week 14 (P = .048) when the infliximab trough level cut-off value was set at 7.8 µg/mL (area under the curve, 0.73; 70% sensitivity; 90% specificity; 86% negative predictive value; 78% positive predictive value) and with continuous pharmacologic evidence of response (infliximab trough levels above 5.0 µg/mL at all time points) (P = .034). CONCLUSIONS: In a substudy of data from the TAILORIX trial of patients with active luminal CD, we identified a relationship between exposure to infliximab and radiologic evidence of outcomes.

Evaluation of LI-RADS 3 category by magnetic resonance in US-detected nodules ≤ 2 cm in cirrhotic patients.

OBJECTIVES: Liver Imaging Reporting and Data System (LI-RADS) for hepatocellular carcinoma (HCC) diagnosis in high-risk patients is a dynamic system, which was lastly updated in 2018. We aimed to evaluate the accuracy for HCC diagnosis of LI-RADS v2018 with magnetic resonance imaging (MRI) with extracellular contrast for solitary nodules ≤ 20 mm detected during ultrasound (US) surveillance in cirrhotic patients, with particular interest in those observations categorized as LI-RADS 3. METHODS: Between November 2003 and February 2017, we included 262 consecutive cirrhotic patients with a newly US-detected solitary ≤ 20-mm nodule. A LI-RADS (LR) v2018 category was retrospectively assigned. The diagnostic accuracy for each LR category was described, and the main MRI findings associated with HCC diagnosis were analyzed. RESULTS: Final diagnoses were as follows: 197 HCC (75.2%), 5 cholangiocarcinoma (1.9%), 2 metastasis (0.8%), and 58 benign lesions (22.1%); 0/15 (0%) LR-1, 6/26 (23.1%) LR-2, 51/74 (68.9%) LR-3, 11/12 (91.7%) LR-4, 126/127 (99.2%) LR-5, and 3/8 (37.5%) LR-M were HCC. LR-5 category displayed a sensitivity and specificity of 64% (95% CI, 56.8-70.7) and 98.5% (95% CI, 91.7-100), respectively. Considering also LR-4 as diagnostic for HCC, the sensitivity slightly increased to 69.5% (95% CI, 62.6-75.9) with minor impact on specificity (96.2%; 95% CI, 89.3-99.6). Regarding LR-3 observations, 51 out of 74 were HCC, 2 were non-HCC malignancies, and 20 out of 21 LR-3 nodules > 15 mm (95.2%) were finally categorized as HCC. CONCLUSIONS: The high probability of HCC in US-detected LR-3 observations (68.9%) justifies triggering an active diagnostic work-up if intended to diagnose HCC at a very early stage. KEY POINTS: • In cirrhotic patients with nodules ≤ 20 mm detected during US surveillance, 51 out of 74 (68.9%) of LR-3 nodules by MRI corresponded to an HCC. • In LR-3 nodules, HCC diagnosis was closely related to baseline tumor size. All 5 nodules smaller than 1 cm were diagnosed as benign. Oppositely, 20 out of 21 LR-3 observations > 15 mm (95.2%) were diagnosed as HCC. • The high probability of HCC in US-detected LR-3 observations justifies triggering an active diagnostic work-up if intended to diagnose HCC at a very early stage.

Pancreatic Insufficiency in Patients Under Sorafenib Treatment for Hepatocellular Carcinoma.

GOALS: To describe the occurrence of malabsorption (MA) in hepatocellular carcinoma (HCC) patients under sorafenib, the potential relationship with pancreatic insufficiency (PI), and the role of pancreatic enzymes supplementation. BACKGROUND: With the increasing options of second-line systemic therapies for HCC, the recognition of drug intolerance using practical tools is crucial. It has been proposed that a MA syndrome could be due to sorafenib-induced pancreatic dysfunction. STUDY: All sorafenib-treated patients with suspicion of MA (defined as decreased stool consistency lasting >4 wk or presenting ≥10% body weight loss without HCC progression) were prospectively evaluated by serum markers, endoscopy, and imaging techniques. RESULTS: We evaluated 81 sorafenib-treated patients and 21 developed MA suspicion (85.7% male, 81.5% Child-Pugh A, 52.4% BCLC-B, and 47.6% BCLC-C) within a median 5.9 months after starting sorafenib. The median treatment duration, follow-up, and overall survival after MA suspicion were 5.9, 20.3, and 20.3 months, respectively. Nine of them (42.9%) presented hyperparathyroidism secondary to vitamin D deficiency and 8 with PI. A gradual decrease in pancreatic volume of up to 19% was observed among patients with PI. Six of the 8 patients with PI received pancreatic enzymes, with complete recovery from MA symptoms and stabilization of pancreatic volume. CONCLUSIONS: We validated the association between MA and PI in 10% of sorafenib-treated patients. Pancreatic enzymes supplementation successfully led to symptomatic recovery. Awareness of this adverse event can help in the management of sorafenib irrespective of cancer type and likely, of other tyrosine kinase inhibitors for HCC patients.

A Distinctive NAFLD Signature in Adipose Tissue from Women with Severe Obesity.

Development and severity of nonalcoholic fatty liver disease (NAFLD) have been linked to obesity and white adipose tissue (WAT) dysfunction plays a key role in this relation. We compared the main features of subcutaneous (SAT) and visceral WAT (VAT) tissue dysfunction in 48 obese women without (Ob) and with NAFLD (Ob-NAFLD) undergoing bariatric surgery and matched for age, BMI and T2D status. Fat cell area, adipocyte size distribution, the degree of histological fibrosis and the mRNA expression of adipokines and genes implicated in inflammation, adipogenesis, angiogenesis, metabolism and extracellular matrix remodeling were measured by RT-qPCR in both fat depots. Ob-NAFLD group showed higher TG and lower HDL circulating levels, increased VAT fat cell area and similar WAT fibrosis in comparison with Ob group. A sPLS-DA was performed in order to identify the set of genes that better characterize the presence of NAFLD. Finally, we build a multinomial logistic model including seven genes that explained 100% of the variance in NAFLD and correctly predicted 100% of cases. Our data support the existence of distinctive NAFLD signatures in WAT from women with severe obesity. A better understanding of these pathways may help in future strategies for the prevention and treatment of NAFLD.

Heterogeneity of Hepatocellular Carcinoma on Imaging.

Tumor heterogeneity in hepatocellular carcinomas (HCC) occurs at different levels. On conventional imaging modalities, the spectrum of tumor heterogeneity is evident in the dynamic enhancement pattern, where the characteristic wash-in and wash-out is present in only 60% of small HCCs. In larger HCCs, heterogeneity within the tumor, known as the mosaic pattern, can reflect the presence of different grades of HCC differentiation. The advent of functional imaging techniques has not improved the diagnostic sensitivity of imaging techniques for the diagnosis of HCC. However, the combination of conventional and functional imaging techniques potentially allows the identification of heterogeneity in tumor vascularity, cellularity, and molecular expression.

Endoscopic, Radiologic, and Histologic Healing With Vedolizumab in Patients With Active Crohn's Disease.

BACKGROUND & AIMS: Vedolizumab is a gut-selective monoclonal antibody for the treatment of moderately to severely active Crohn's disease (CD). We performed a prospective study of endoscopic, radiologic, and histologic healing in patients with CD who received vedolizumab therapy. METHODS: We performed a phase 3b, open-label, single-group study of 101 patients with at least 3 months of active CD (a CD Activity Index [CDAI] score of 220-450, a simple endoscopic score for CD [SES-CD] of 7 or more, 1 or more mucosal ulcerations [identified by endoscopy], and failure of conventional therapy) from March 2015 through December 2017. Among the patients enrolled, 54.5% had previous failure of 1 or more tumor necrosis factor (TNF) antagonists and 44.6% had severe endoscopic disease activity (SES-CD scores above 15) at baseline. Participants received vedolizumab (300 mg intravenously) at weeks 0, 2, and 6, and then every 8 weeks thereafter, for 26 weeks (primary study) or 52 weeks (substudy, 56 patients). The primary endpoint at week 26 was endoscopic remission (SES-CD score of 4 or less); other endpoints included endoscopic response (50% reduction in SES-CD), radiologic remission (magnetic resonance index of activity score below 7), and histologic response (modified global histologic disease activity score of 4 or less). RESULTS: At week 26, 11.9% of patients were in endoscopic remission (95% confidence interval [CI] 6.3-9.8); at week 52, 17.9% of the patients were in endoscopic remission (95% CI 8.9-30.4). Higher proportions of patients naïve to TNF antagonists achieved endoscopic remission than patients with TNF-antagonist-failure at weeks 26 and 52. Higher proportion of patients with moderate CD (SES-CD scores, 7-15) achieved endoscopic remission at weeks 26 and 52 than patients with severe CD (SES-CD scores above 15). The proportion of patients with complete mucosal healing increased over time, with greater rates of healing in the colon than in the ileum. Remission was detected by magnetic resonance enterography in 21.9% of patients at week 26 (95% CI 9.3-40.0) and in 38.1% at week 52 (95% CI 18.1-61.6). At week 26, 24.4% of patients had a histologic response in the colon (95% CI 15.3-35.4) and 28.3% of patients had a histologic response in the ileum (95% CI 17.5-41.4). At week 52, 20.5% of patients had a histologic response in the colon (95% CI 9.8-35.3) and 34.3% of patients had a histologic response in the ileum (95% CI 19.1-52.2). There were no notable safety issues, including worsening of extraintestinal manifestations. CONCLUSIONS: In a phase 3b trial, we found that 26 and 52 weeks of treatment with vedolizumab (300 mg, at weeks 0, 2, and 6, and then every 8 weeks thereafter) induces endoscopic, radiologic, and histologic healing in patients with moderately to severely active CD. ClinicalTrials.gov no: NCT02425111.

Development and Validation of a Simplified Magnetic Resonance Index of Activity for Crohn's Disease.

BACKGROUND & AIMS: The magnetic resonance index of activity (MARIA) for Crohn's disease (CD) is used to assess the activity of luminal CD. However, it has a number of practical limitations. We aimed to develop and validate a simplified MARIA to more easily and quickly assess CD activity and response to therapy. PATIENTS AND METHODS: We performed a retrospective analysis of magnetic resonance imaging data from 98 participants in 2 studies. We used logistic regression analysis to identify magnetic resonance imaging parameters independently associated with CD endoscopic index of severity (CDEIS) scores (the reference standard). We validated the responsiveness and reliability of the simplified MARIA in an independent cohort of 37 patients who underwent magnetic resonance imaging and endoscopy before and after a therapeutic intervention. RESULTS: Logistic regression analysis showed that dichotomous qualitative assessment of wall thickening (>3 mm), presence of mural edema, perienteric fat stranding, and ulcers were independently associated with CDEIS scores; we used these factors to create a simplified MARIA. Simplified MARIA scores greater than 1 identified segments with active CD with 90% sensitivity and 81% specificity (area under the curve 0.91; 95% confidence interval 0.88-0.94). Simplified MARIA scores of 2 or more detected severe lesions (ulcers) with 85% sensitivity and 92% specificity (area under the curve 0.94; 95% confidence interval 0.91-0.96). For each patient, there was a high level of correlation between simplified MARIA scores and CDEIS scores (r = 0.83) and simplified MARIA scores and original MARIA scores (and r = 0.93) (P < .001). The simplified MARIA score accurately detected changes in lesion severity in response to therapy and was as reliable as endoscopy for the assessment of mucosal healing. CONCLUSION: We developed and validated a simplified MARIA for easier and faster assessment of CD activity and severity. This index identifies patients with a response to therapy with a high level of accuracy. These findings require confirmation in independent, multireader studies.

Development and Validation of a Magnetic Resonance Index for Assessing Fistulas in Patients With Crohn's Disease.

BACKGROUND & AIMS: There is no validated magnetic resonance imaging (MRI) index for assessment of perianal fistulas in patients with Crohn's disease (CD). We developed and internally validated a new instrument. METHODS: We used paired baseline and week-24 MRI scans from 160 participants in a randomized placebo-controlled trial of stem cell therapy for patients with perianal fistulizing CD. Four radiologists scored disease activity using index items identified during previous studies and exploratory items. Reliability was assessed using intraclass correlation coefficients. We developed an index using backward elimination linear regression analysis, in which potential independent variables were items having intraclass correlation coefficients of at least 0.4 and the dependent variable was perianal fistulizing disease activity, measured on a 100-mm visual analogue scale. The final model was internally validated using the .632 bootstrap method to correct model optimism and quantify calibration accuracy. We evaluated responsiveness of the index by assessing longitudinal validity and estimating standardized effect sizes. RESULTS: We developed the magnetic resonance novel index for fistula imaging in CD (MAGNIFI-CD) using 6 items. The optimism-corrected R2 of the model was 0.71, which was comparable to R2 for the original sample (0.74). The calibration slope for the model was 0.98. Compared with the original and modified versions of the Van Assche Index, the MAGNIFI-CD had improved operating characteristics. Estimates of intraclass correlation coefficients for MAGNIFI-CD, the modified Van Assche Index, and Van Assche Index were 0.85 (95% confidence interval [CI], 0.77-0.90), 0.81 (95% CI, 0.74-0.86), and 0.81 (95% CI, 0.71-0.86) for intra-rater reliability, and 0.74 (95% CI, 0.63-0.80), 0.67 (95% CI, 0.55-0.75) and 0.68 (95% CI, 0.56-0.77) for inter-rater reliability. Corresponding standardized effect size estimates were 1.02 (95% CI, 0.65-1.39), 0.84 (95% CI, 0.48-1.21), and 0.68 (95% CI, 0.33-1.03). CONCLUSIONS: We developed an index called the MAGNIFI-CD, which is based on 6 items. It assesses MRI data and determines perianal fistulizing CD activity with improved operating characteristics compared to previous indices. This index may be used as an outcome measure in clinical trials comparing treatment effects in patients with perianal fistulizing CD. Although the performance of the MAGNIFI-CD indicates its stability and reasonable external validity, external validation is needed.

Does transient arterial-phase respiratory-motion-related artifact impact on diagnostic performance? An intra-patient comparison of extracellular gadolinium versus gadoxetic acid.

OBJECTIVE: To compare the frequency of transient arterial-phase respiratory-motion-related artifacts in liver MRI after extracellular gadolinium and gadoxetic acid injection, and to determine the impact of these artifacts on the detection of focal areas of enhancement on arterial-phase images. MATERIALS AND METHODS: Intra-patient comparison of 82 cirrhotic patients who prospectively underwent liver MR with extracellular gadolinium and with gadoxetic acid within 1 month. Two readers independently assessed the quality of dynamic T1-weighted MR images (pre-contrast, arterial, and portal-venous phases), rating respiratory-motion-related artifacts on four-point scale (0 [none]-3 [non-diagnostic]). We dichotomized these assessments, which were compared using McNemar's test, defining transient arterial-phase respiratory-motion-related artifacts as a study with a pre-contrast score < 2 and arterial-phase score ≥ 2. Readers also recorded whether at least one focal area of enhancement ≥ 10 mm on arterial phase was present. RESULTS: The quality of arterial-phase images was worse when obtained after gadoxetic acid than after extracellular gadolinium (p < 0.01), and transient arterial-phase respiratory-motion-related artifacts were more common after gadoxetic acid than after extracellular gadolinium (p < 0.02). At least one area of arterial-phase enhancement ≥ 10 mm was detected more often after extracellular gadolinium than after gadoxetic acid. We observed significant differences on the comparison of the distributions of the presence of arterial-phase artifacts against the presence of arterial-phase enhancement ≥ 10 mm between the two contrast agents (p < 0.0001). CONCLUSION: In cirrhotic patients, transient arterial-phase respiratory-motion-related artifacts are more common after gadoxetic acid than after extracellular gadolinium. Worse detection of arterial-phase enhancement on gadoxetic acid is only partly due to these artifacts. KEY POINTS: • In a patient-by-patient analysis, the quality of arterial-phase liver MR images was significantly worse with gadoxetic acid than with extracellular gadolinium. • The frequency of transient arterial-phase artifacts was significantly higher after gadoxetic acid injection than after extracellular gadolinium injection. • Differences in the detection of areas of arterial-phase enhancement between MRI studies done with extracellular gadolinium and those done with gadoxetic acid might not be related only to image quality.