ANGPTL3 Deficiency and Risk of Hepatic Steatosis.

BACKGROUND: ANGPTL3 (angiopoietin-like 3) is a therapeutic target for reducing plasma levels of triglycerides and low-density lipoprotein cholesterol. A recent trial with vupanorsen, an antisense oligonucleotide targeting hepatic production of ANGPTL3, reported a dose-dependent increase in hepatic fat. It is unclear whether this adverse effect is due to an on-target effect of inhibiting hepatic ANGPTL3. METHODS: We recruited participants with ANGPTL3 deficiency related to ANGPTL3 loss-of-function (LoF) mutations, along with wild-type (WT) participants from 2 previously characterized cohorts located in Campodimele, Italy, and St. Louis, MO. Magnetic resonance spectroscopy and magnetic resonance proton density fat fraction were performed to measure hepatic fat fraction and the distribution of extrahepatic fat. To estimate the causal relationship between ANGPTL3 and hepatic fat, we generated a genetic instrument of plasma ANGPTL3 levels as a surrogate for hepatic protein synthesis and performed Mendelian randomization analyses with hepatic fat in the UK Biobank study. RESULTS: We recruited participants with complete (n=6) or partial (n=32) ANGPTL3 deficiency related to ANGPTL3 LoF mutations, as well as WT participants (n=92) without LoF mutations. Participants with ANGPTL3 deficiency exhibited significantly lower total cholesterol (complete deficiency, 78.5 mg/dL; partial deficiency, 172 mg/dL; WT, 188 mg/dL; P<0.05 for both deficiency groups compared with WT), along with plasma triglycerides (complete deficiency, 26 mg/dL; partial deficiency, 79 mg/dL; WT, 88 mg/dL; P<0.05 for both deficiency groups compared with WT) without any significant difference in hepatic fat (complete deficiency, 9.8%; partial deficiency, 10.1%; WT, 9.9%; P>0.05 for both deficiency groups compared with WT) or severity of hepatic steatosis as assessed by magnetic resonance imaging. In addition, ANGPTL3 deficiency did not alter the distribution of extrahepatic fat. Results from Mendelian randomization analyses in 36 703 participants from the UK Biobank demonstrated that genetically determined ANGPTL3 plasma protein levels were causally associated with low-density lipoprotein cholesterol (P=1.7×10-17) and triglycerides (P=3.2×10-18) but not with hepatic fat (P=0.22). CONCLUSIONS: ANGPTL3 deficiency related to LoF mutations in ANGPTL3, as well as genetically determined reduction of plasma ANGPTL3 levels, is not associated with hepatic steatosis. Therapeutic approaches to inhibit ANGPTL3 production in hepatocytes are not necessarily expected to result in the increased risk for hepatic steatosis that was observed with vupanorsen.

Severe Streptococcus equi Subspecies zooepidemicus Outbreak from Unpasteurized Dairy Product Consumption, Italy.

During November 2021-May 2022, we identified 37 clinical cases of Streptococcus equi subspecies zooepidemicus infections in central Italy. Epidemiologic investigations and whole-genome sequencing showed unpasteurized fresh dairy products were the outbreak source. Early diagnosis by using sequencing technology prevented the spread of life-threatening S. equi subsp. zooepidemicus infections.

Quantitative ultrasound fatty liver evaluation in a pediatric population: comparison with magnetic resonance imaging of liver proton density fat fraction.

BACKGROUND: Biopsy remains the gold standard for the diagnosis of hepatic steatosis, the leading cause of pediatric chronic liver disease; however, its costs call for less invasive methods. OBJECTIVE: This study examined the diagnostic accuracy and reliability of quantitative ultrasound (QUS) for the assessment of liver fat content in a pediatric population, using magnetic resonance imaging proton density fat fraction (MRI-PDFF) as the reference standard. MATERIALS AND METHODS: We enrolled 36 patients. MRI-PDFF involved a 3-dimensional T2*-weighted with Dixon pulse multiple-echo sequence using iterative decomposition of water and fat with echo asymmetry and least squares estimation (IDEAL IQ). QUS imaging relied on the ultrasound system "RS85 A" (Samsung Medison, Seoul, South Korea) and the following software: Hepato-Renal Index with automated region of interest recommendation (EzHRI), Tissue Attenuation Imaging (TAI), and Tissue Scatter Distribution Imaging (TSI). For each QUS index, receiver operating characteristic (ROC) curve analysis against MRI-PDFF was used to identify the associated cut-off value and the area under the ROC curve (AUROC). Concordance between two radiologists was assessed by intraclass correlation coefficients (ICCs) and Bland-Altman analysis. RESULTS: A total of 61.1% of the sample (n=22) displayed a MRI-PDFF ≥ 5.6%; QUS cut-off values were TAI=0.625 (AUROC 0.90, confidence interval [CI] 0.77-1.00), TSI=91.95 (AUROC 0.99, CI 0.98-1.00) and EzHRI=1.215 (AUROC 0.98, CI 0.94-1.00). Inter-rater reliability was good-to-excellent for EzHRI (ICC 0.91, 95% C.I. 0.82-0.95) and TAI (ICC 0.94, 95% C.I. 0.88-0.97) and moderate to good for TSI (ICC 0.73; 95% C.I. 0.53-0.85). CONCLUSION: Our results suggest that QUS can be used to reliably assess the presence and degree of pediatric hepatic steatosis.

Pyrrolizidine Alkaloids in Food on the Italian Market.

Pyrrolizidine alkaloids (PAs) are secondary metabolites produced by over 6000 plant species worldwide. PAs enter the food chain through accidental co-harvesting of PA-containing weeds and through soil transfer from the living plant to surrounding acceptor plants. In animal studies, 1,2-unsaturated PAs have proven to be genotoxic carcinogens. According to the scientific opinion expressed by the 2017 EFSA, the foods with the highest levels of PA contamination were honey, tea, herbal infusions, and food supplements. Following the EFSA's recommendations, data on the presence of PAs in relevant food were monitored and collected. On 1 July 2022, the Commission Regulation (EU) 2020/2040 came into force, repealed by Commission Regulation (EU) 2023/915, setting maximum levels for the sum of pyrrolizidine alkaloids in certain food. A total of 602 food samples were collected from the Italian market between 2019 and 2022 and were classified as honey, pollen, dried tea, dried herbal infusions, dried herbs, and fresh borage leaves. The food samples were analyzed for their PA content via an in-house LC-MS/MS method that can detect PAs according to Regulation 2023/915. Overall, 42% of the analyzed samples were PA-contaminated, 14% exceeded the EU limits, and the items most frequently contaminated included dried herbs and tea. In conclusion, the number of food items containing considerable amounts of PAs may cause concern because they may contribute to human exposure, especially considering vulnerable populations-most importantly, children and pregnant women.

Relevance of Spontaneous Portosystemic Shunts Detected with CT in Patients with Cirrhosis.

Background Cirrhosis leads to portal hypertension and to the consequent formation of spontaneous portosystemic shunts (SPSSs), leading to complications related to the diversion of portal blood into the systemic circulation, which is called portosystemic shunt syndrome. Purpose To investigate the characteristics of patients with cirrhosis and an SPSS and secondarily to assess the prognostic impact of SPSSs on portal hypertension-related complications and transplant-free survival. Materials and Methods A retrospective database review of patients with cirrhosis (observed from March 2015 to July 2019) was performed to identify patients with CT imaging and outcomes data. For each patient, clinical and biochemical data were collected, and the presence, types, and sizes of SPSSs were investigated with CT. Patients were followed for a mean of 27.5 months ± 22.8. Multivariable logistic analysis was used to identify the clinical characteristics associated with the presence of SPSSs (any size) and presence of SPSSs 1 cm or larger. Competitive risk analysis (Fine and Gray model) was used to identify the association between SPSSs and complications and mortality. Results Two hundred twenty-two patients with cirrhosis (157 male, 65 female; mean age, 62 years ± 12 [standard deviation]) were evaluated. An SPSS was found in 141 of 222 patients (63.5%), and 40 of 222 (18%) had a shunt diameter of at least 1 cm. At presentation, variables independently associated with the presence of SPSSs (any size) were portal vein thrombosis (odds ratio, 5.5; P = .008) and Child-Pugh class C (odds ratio, 3.0; P = .03). Previous hepatic encephalopathy (odds ratio, 4.4; P = .001) and portal vein thrombosis (odds ratio, 5.3; P = .001) were the only variables associated with SPSSs larger than 1 cm. Patients with SPSSs of any size had higher mortality (subdistribution hazard ratio, 1.9; P < .001) and higher frequency of hepatic encephalopathy (subdistribution hazard ratio, 2.3; P = .023), gastrointestinal bleeding (subdistribution hazard ratio, 2.9; P = .039), and portal vein thrombosis (subdistribution hazard ratio, 7.6; P = .005). Conclusion The presence of spontaneous portosystemic shunts on CT images in patients with cirrhosis was associated with higher mortality and complications, including portal vein thrombosis, hepatic encephalopathy, and gastrointestinal bleeding. © RSNA, 2021 See also the editorial by Reeder in this issue.

Prognostic Role of Mismatch Repair Status, Histotype and High-Risk Pathologic Features in Stage II Small Bowel Adenocarcinomas.

BACKGROUND: Small bowel adenocarcinoma is a relatively rare cancer, often diagnosed in an advanced stage. In localized and resectable disease, surgery alone or in combination with adjuvant chemotherapy is the mainstay of treatment. In the recently published National Comprehensive Cancer Network Clinical Practice guidelines, criteria for selecting patients with stage II small bowel adenocarcinoma to receive adjuvant chemotherapy are provided, and they are mainly extrapolated from studies on colorectal cancer. PATIENTS AND METHODS: In the present study, we aimed to verify whether mismatch repair deficiency phenotype, high-risk pathologic features (including T4, positive resection margins and a low number of lymph nodes harvested), as well as tumor histologic subtype, were associated with cancer-specific survival in 66 stage II non-ampullary small bowel adenocarcinoma patients, collected through the Small Bowel Cancer Italian Consortium. A central histopathology review was performed. Mismatch repair deficiency was tested by immunohistochemistry for MLH1, MSH2, MSH6 and PMS2, and confirmed by polymerase chain reaction for microsatellite instability. RESULTS: We identified mismatch repair deficiency, glandular/medullary histologic subtype, and celiac disease as significant predictors of favorable cancer-specific survival using univariable analysis with retained significance in bivariable models adjusted for pT stage. Among the high-risk features, only T4 showed a significant association with an increased risk of death; however, its prognostic value was not independent of mismatch repair status. CONCLUSIONS: Mismatch repair protein expression, histologic subtype, association with celiac disease, and, in the mismatch repair proficient subset only, T stage, may help identify patients who may benefit from adjuvant chemotherapy.

Sarco-Model: A score to predict the dropout risk in the perspective of organ allocation in patients awaiting liver transplantation.

BACKGROUND & AIMS: Sarcopenia in liver transplantation (LT) cirrhotic candidates has been connected with higher dropouts and graft losses after transplant. The study aims to create an 'urgency' model combining sarcopenia and Model for End-stage Liver Disease Sodium (MELDNa) to predict the risk of dropout and identify an appropriate threshold of post-LT futility. METHODS: A total of 1087 adult cirrhotic patients were listed for a first LT during January 2012 to December 2018. The study population was split into a training (n = 855) and a validation set (n = 232). RESULTS: Using a competing-risk analysis of cause-specific hazards, we created the Sarco-Model2 . According to the model, one extra point of MELDNa was added for each 0.5 cm2 /m2 reduction of total psoas area (TPA) < 6.0 cm2 /m2 . At external validation, the Sarco-Model2 showed the best diagnostic ability for predicting the risk of 3-month dropout in patients with MELDNa < 20 (area under the curve [AUC] = 0.93; P = .003). Using the net reclassification improvement, 14.3% of dropped-out patients were correctly reclassified using the Sarco-Model2 . As for the futility threshold, transplanted patients with TPA < 6.0 cm2 /m2 and MELDNa 35-40 (n = 16/833, 1.9%) had the worse results (6-month graft loss = 25.5%). CONCLUSIONS: In sarcopenic patients with MELDNa < 20, the 'urgency' Sarco-Model2 should be used to prioritize the list, while MELDNa value should be preferred in patients with MELDNa ≥ 20. The Sarco-Model2 played a role in more than 30% of the cases in the investigated allocation scenario. In sarcopenic patients with a MELDNa value of 35-40, 'futile' transplantation should be considered.

Correction: PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

PD-L1 in small bowel adenocarcinoma is associated with etiology and tumor-infiltrating lymphocytes, in addition to microsatellite instability.

Small bowel adenocarcinomas (SBAs) are often associated with poor prognosis and have limited therapeutic options. Programmed cell death protein-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway blockade is an effective treatment in many microsatellite instability-high (MSI-H) solid tumors. We aimed at investigating PD-L1 and PD-1 expression in non-hereditary, non-ampullary SBAs, associated with celiac disease (CeD), Crohn's disease (CrD), or sporadic, recruited through the Small Bowel Cancer Italian Consortium. We assessed PD-L1 and PD-1 by immunohistochemistry in a series of 121 surgically resected SBAs, including 34 CeD-SBAs, 49 CrD-SBAs, and 38 sporadic SBAs. PD-L1 and PD-1 expression was correlated with several clinico-pathological features, such as the etiology, microsatellite instability status, and tumor-infiltrating lymphocyte (TIL) density. The prevalence of PD-L1 positivity according to combined positive score (CPS) was 26% in the whole cohort of SBAs, with significantly (p = 0.001) higher percentage (35%) in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs (5%). CPS ≥ 1 SBAs were significantly (p = 0.013) more frequent in MSI-H cases (41%) than in non-MSI-H ones (18%); however, 15 CPS ≥ 1 microsatellite stable SBAs were also identified. CPS ≥ 1 SBAs showed higher TIL and PD-1+ immune cell density, more frequently medullary histotype, as well as a better outcome in comparison with CPS < 1 cases. This study demonstrates an increased proportion of PD-L1+ cases in both CeD-SBAs and CrD-SBAs in comparison with sporadic SBAs. In addition, the identification of a subset of PD-L1+ microsatellite stable SBAs supports the need to ascertain additional biomarkers of response to immune checkpoint inhibitors along with MSI-H.

Genetic and metabolic predictors of hepatic fat content in a cohort of Italian children with obesity.

OBJECTIVES: To comprehensively explore metabolic and genetic contributors to liver fat accumulation in overweight/obese children. METHODS: Two hundred thirty Italian children with obesity were investigated for metabolic parameters and genotyped for PNPLA3, TM6SF2, GCKR, and MBOAT7 gene variants. Percentage hepatic fat content (HFF%) was measured by nuclear magnetic resonance. RESULTS: HFF% was positively related with BMI, HOMAIR, metabolic syndrome, ALT, AST, γGT, and albumin. Carriers of [G] allele in PNPLA3, [T] allele in GCKR and [T] allele in TM6SF2 genes had significantly higher hepatic fat content than wild-type carriers. HFF% was explained for 8.7% by metabolic and for 16.1% by genetic factors and, a model including age, gender, BMI, HOMAIR, PNPLA3, GCKR, and TM6SF2 variants was the best predictor of HFF%, explaining 24.8% of its variation (P < 0.001). A weighted-genetic risk score combining PNPLA3, GCKR, and TM6SF2 risk alleles was associated with almost eightfold higher risk of NAFLD. CONCLUSIONS: Our data highlighted the predominant role of genetic factors in determining the amount of liver fat content in children with obesity.

Nonalcoholic Fatty Liver Disease (NAFLD), But not Its Susceptibility Gene Variants, Influences the Decrease of Kidney Function in Overweight/Obese Children.

: Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of kidney disease in adults and children. However, it is uncertain whether this association is influenced by major NAFLD susceptibility genes. In a sample of 230 overweight/obese children, 105 with NAFLD (hepatic fat fraction ≥5% by magnetic resonance imaging) and 125 without NAFLD, rs738409 in PNPLA3, rs58542926 in TM6SF2, rs1260326 in GCKR, and rs641738 in MBOAT7 were genotyped. Abnormal kidney function was defined as estimated glomerular filtration rate (eGFR) < 90 mL/min/1.73 m2 and/or the presence of microalbuminuria (24 h urinary albumin excretion between 30 and 300 mg). In comparison with children without NAFLD, those with NAFLD showed increased prevalence of reduced eGFR (13.3% vs. 1.6%; p < 0.001) and microalbuminuria (8.6% vs. 3.4%, p = 0.025). TM6SF2, GCKR, and MBOAT7 risk alleles did not show any impact on kidney function, while the PNPLA3 G allele was associated with lower eGFR, but only in children with NAFLD (p = 0.003). After adjustment for confounders, NAFLD (OR, 4.7; 95% CI, 1.5-14.8; padj = 0.007), but not the PNPLA3 gene variant, emerged as the main independent predictor of renal dysfunction. Overall, our findings suggest that NAFLD remains the main determinant of decline in kidney function in overweight/obese children, while the PNPLA3 rs738409 prosteatogenic variant has a small impact, if any.

Prognostic Evaluations Tailored to Specific Gastric Neuroendocrine Neoplasms: Analysis Of 200 Cases with Extended Follow-Up.

BACKGROUND: Gastric neuroendocrine neoplasms (NENs) are very heterogeneous, ranging from mostly indolent, atrophic gastritis-associated, type I neuroendocrine tumors (NETs), through highly malignant, poorly differentiated neuroendocrine carcinomas (pdNECs), to sporadic type III NETs with intermediate prognosis, and various rare tumor types. Histologic differentiation, proliferative grade, size, level of gastric wall invasion, and local or distant metastases are used as prognostic markers. However, their value remains to be tailored to specific gastric NENs. METHODS: Series of type I NETs (n = 123 cases), type III NETs (n = 34 cases), and pdNECs (n = 43 cases) were retrospectively collected from four pathology centers specializing in endocrine pathology. All cases were characterized clinically and histopathologically. During follow-up (median 93 months) data were recorded to assess disease-specific patient survival. RESULTS: Type I NETs, type III NETs, and pdNECs differed markedly in terms of tumor size, grade, invasive and metastatic power, as well as patient outcome. Size was used to stratify type I NETs into subgroups with significantly different invasive and metastatic behavior. All 70 type I NETs < 0.5 cm (micro-NETs) were uneventful. Ki67-based grading proved efficient for the prognostic stratification of type III NETs; however, grade 2 (G2) was not associated with tumor behavior in type I NETs. Although G3 NETs (2 type I and 9 type III) had a very poor prognosis, it was found that patient survival was longer with type III G3 NETs compared to pdNECs. CONCLUSIONS: Given the marked, tumor type-related behavior differences, evaluation of gastric NEN prognostic parameters should be tailored to the type of neoplastic disease.

Peritoneal and pleural fluids may appear hyperintense on hepatobiliary phase using hepatobiliary MR contrast agents.

AIM: To describe the effect of hepatobiliary-specific MR imaging contrast agent (HBCA) administration on the signal intensity of peritoneal and pleural fluid effusions on T1-weighted MR images. MATERIALS AND METHODS: From October 2015 to May 2016 139 patients (mean 60±10 years old, 69 % males) with peritoneal or pleural effusions without biliary leakage who underwent HBCA-MRI (Gd-BOPTA or Gd-EOB-DTPA) at 1.5T and 3T were included from two centres. The fluid signal intensity was classified as hypo/iso/hyperintense before/after HBCA administration. The relative signal enhancement (RE) was calculated. RESULTS: On hepatobiliary phase (HBP), peritoneal fluids appeared hyper/isointense in 88-100 % and pleural effusions in 100 % of the patients following Gd-BOPTA administration. All fluids remained hypointense following Gd-EOB-DTPA. The signal intensity of fluids increased with both HBCA but RE was significantly higher following Gd-BOPTA (p=0.002 to <0.001). RE was correlated with HBP acquisition time-point (r=0.42, p<0.001 and r=0.50, p=0.033 for peritoneal and pleural fluids). CONCLUSION: The signal intensity of pleural and peritoneal fluids progressively increases following HBCA administration in the absence of biliary leakage. Due to its later hepatobiliary phase, this is more pronounced after Gd-BOPTA injection, leading to fluid hyperintensity that is not observed after Gd-EOB-DTPA injection. KEY POINTS: • Fluids appear hyper/isointense on HBP in most patients after Gd-BOPTA injection. • Fluids remain hypointense on HBP after Gd-EOB-DTPA injection. • RE of fluids increases with time after liver-specific Gd injection. • RE of fluids is higher in patients with chronic liver disease.

Volumetric Distribution of the White Matter Hyper-Intensities in Subject with Mild to Severe Carotid Artery Stenosis: Does the Side Play a Role?

PURPOSE: The purpose of this paper was to assess the difference in the distribution of white matter hyperintensities (WMHs) on left and right sides of the brain hemispheres of subjects with mild to severe carotid artery stenosis. MATERIAL AND METHODS: Eighty consecutive patients (mean age 71 ± 6 years, males 66) with carotid artery stenosis were prospectively recruited. FLAIR-WMH lesion volume was performed using a semiautomated segmentation technique (Jim, Xinapse System, Leicester, UK). The Wilcoxon test was applied to verify the differences in the volume of WMHs between the right and left hemispheres. RESULTS: A statistically significant difference was found in the middle cerebral artery (MCA) territory for the volume of the lesions (median volume of WMHs of the left side = 889.5 mm3; median volume of WMHs on the right side = 580.5 mm3; P = .0416); no statistically significant difference was found on the other territories by taking into considerations the lesions. By analyzing the degree of stenosis, we found a higher degree of stenosis of the left side (67.9%; 95% confidence interval [CI], 64.8%-70.9%) compared with the right side (65.7%; 95% CI, 62.4%-68.9%), but the Mann-Whitney test did not show a statistically significant difference (P = .3235). CONCLUSIONS: Results of our study suggest that there is a difference in the distribution of WMHs in the brain hemispheres according to the left/right side on the MCA territories and for the periventricular white matter in subjects with mild to severe carotid artery stenosis.

Radiation dose and image quality of computed tomography of the supra-aortic arteries: A comparison between single-source and dual-source CT Scanners.

PURPOSE: The purpose of this work was to compare the image quality and radiation dose delivered to patients during computed tomography (CT) angiography (CTA) of the supra-aortic arteries using two single-source (SS) and two dual-energy (DE) CT scanners. MATERIAL AND METHODS: In this retrospective study, 120 patients who underwent CTA of supra-aortic arteries were studied using four different types of CT scanners: a sixteen and forty-detector-row SS and two DE CT scanners. Seventy milliters of contrast medium were injected at a flow rate of 4mL/s using a power injector. For each patient the dose-length product (DLP), the volume computed tomography dose index (CDTIvol), the length of the scan and the effective dose (ED) were calculated. Qualitative and quantitative [image noise, signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR)] image quality assessment was performed. RESULTS: A statistically significant lower value of the DE compared to the SS technology (P<0.0001) for the CDTI, DLP and ED was found, whereas we did not find any statistically significant difference between the four scanners for the measurements of the image noise, SNR and CNR. CONCLUSION: DS CT scanners allow performing CTAs with a reduced dose compared to SS CT scanner with comparable image quality.

Small bowel carcinomas in celiac or Crohn's disease: distinctive histophenotypic, molecular and histogenetic patterns.

Non-familial small bowel carcinomas are relatively rare and have a poor prognosis. Two small bowel carcinoma subsets may arise in distinct immune-inflammatory diseases (celiac disease and Crohn's disease) and have been recently suggested to differ in prognosis, celiac disease-associated carcinoma cases showing a better outcome, possibly due to their higher DNA microsatellite instability and tumor-infiltrating T lymphocytes. In this study, we investigated the histological structure (glandular vs diffuse/poorly cohesive, mixed or solid), cell phenotype (intestinal vs gastric/pancreatobiliary duct type) and Wnt signaling activation (ß-catenin and/or SOX-9 nuclear expression) in a series of 26 celiac disease-associated small bowel carcinoma, 25 Crohn's disease-associated small bowel carcinoma and 25 sporadic small bowel carcinoma cases, searching for new prognostic parameters. In addition, non-tumor mucosa of celiac and Crohn's disease patients was investigated for epithelial precursor changes (hyperplastic, metaplastic or dysplastic) to help clarify carcinoma histogenesis. When compared with non-glandular structure and non-intestinal phenotype, both glandular structure and intestinal phenotype were associated with a more favorable outcome at univariable or stage- and microsatellite instability/tumor-infiltrating lymphocyte-inclusive multivariable analysis. The prognostic power of histological structure was independent of the clinical groups while the non-intestinal phenotype, associated with poor outcome, was dominant among Crohn's disease-associated carcinoma. Both nuclear ß-catenin and SOX-9 were preferably expressed among celiac disease-associated carcinomas; however, they were devoid, per se, of prognostic value. We obtained findings supporting an origin of celiac disease-associated carcinoma in SOX-9-positive immature hyperplastic crypts, partly through flat ß-catenin-positive dysplasia, and of Crohn's disease-associated carcinoma in a metaplastic (gastric and/or pancreatobiliary-type) mucosa, often through dysplastic polypoid growths of metaplastic phenotype. In conclusion, despite their common origin in a chronically inflamed mucosa, celiac disease-associated and Crohn's disease-associated small bowel carcinomas differ substantially in histological structure, phenotype, microsatellite instability/tumor-infiltrating lymphocyte status, Wnt pathway activation, mucosal precursor lesions and prognosis.

Volumetric Analysis of Carotid Plaque Components and Cerebral Microbleeds: A Correlative Study.

PURPOSE: The purpose of this work was to explore the association between carotid plaque volume (total and the subcomponents) and cerebral microbleeds (CMBs). MATERIALS AND METHODS: Seventy-two consecutive (male 53; median age 64) patients were retrospectively analyzed. Carotid arteries were studied by using a 16-detector-row computed tomography scanner whereas brain was explored with a 1.5 Tesla system. CMBs were studied using a T2*-weighted gradient-recalled echo sequence. CMBs were classified as from absent (grade 1) to severe (grade 4). Component types of the carotid plaque were defined according to the following Hounsfield unit (HU) ranges: lipid less than 60 HU; fibrous tissue from 60 to 130 HU; calcification greater than 130 HU, and plaque volumes of each component were calculated. Each carotid artery was analyzed by 2 observers. RESULTS: The prevalence of CMBs was 35.3%. A statistically significant difference was observed between symptomatic (40%) and asymptomatic (11%) patients (P value = .001; OR = 6.07). Linear regression analysis demonstrated an association between the number of CMBs and the symptoms (P = .0018). Receiver operating characteristics curve analysis found an association between the carotid plaque subcomponents and CMBs (Az = .608, .621, and .615 for calcified, lipid, and mixed components, respectively), and Mann-Whitney test confirmed this association in particular for the lipid components (P value = .0267). CONCLUSIONS: Results of this study confirm the association between CMBs and symptoms and that there is an increased number of CMBs in symptomatic patients. Moreover, we found that an increased volume of the fatty component is associated with the presence and number of CMBs.

No effects of oral vitamin D supplementation on non-alcoholic fatty liver disease in patients with type 2 diabetes: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common hepatic disorder worldwide, reaching prevalence up to 90 % in obese patients with type 2 diabetes (T2D), and representing an independent risk factor for cardiovascular mortality. Furthermore, the coexistence of T2D and NAFLD leads to higher incidence of diabetes' complications and additive detrimental liver outcomes. The existence of a close association between NAFLD and hypovitaminosis D, along with the anti-inflammatory and insulin-sensitizing properties of vitamin D, have been largely described, but vitamin D effects on hepatic fat content have never been tested in a randomized controlled trial. We assessed the efficacy and safety of 24-week oral high-dose vitamin D supplementation in T2D patients with NAFLD. METHODS: This randomized, double-blind, placebo-controlled trial was carried out at the Diabetes Centre of Sapienza University, Rome, Italy, to assess oral treatment with cholecalciferol (2000 IU/day) or placebo in T2D patients with NAFLD. The primary endpoint was reduction of hepatic fat fraction (HFF) measured by magnetic resonance; as hepatic outcomes, we also investigated changes in serum transaminases, CK18-M30, N-terminal Procollagen III Propeptide (P3NP) levels, and Fatty Liver Index (FLI). Secondary endpoints were improvement in metabolic (fasting glycaemia, HbA1c, lipids, HOMA-IR, HOMA-ß, ADIPO-IR, body fat distribution) and cardiovascular (ankle-brachial index, intima-media thickness, flow-mediated dilatation) parameters from baseline to end of treatment. RESULTS: Sixty-five patients were randomized, 26 (cholecalciferol) and 29 (placebo) subjects completed the study. 25(OH) vitamin D significantly increased in the active treated group (48.15 ± 23.7 to 89.80 ± 23.6 nmol/L, P < 0.001); however, no group differences were found in HFF, transaminases, CK18-M30, P3NP levels or FLI after 24 weeks. Vitamin D neither changed the metabolic profile nor the cardiovascular parameters. CONCLUSIONS: Oral high-dose vitamin D supplementation over 24 weeks did not improve hepatic steatosis or metabolic/cardiovascular parameters in T2D patients with NAFLD. Studies with a longer intervention period are warranted for exploring the effect of long time exposure to vitamin D. TRIAL REGISTRATION: This trial was approved on July 2011 by the Ethics Committee of Policlinico Umberto I, Sapienza University of Rome, Italy, and registered at www.clinicaltrialsregister.eu number 2011-003010-17.

Phenotypical heterogeneity linked to adipose tissue dysfunction in patients with Type 2 diabetes.

Adipose tissue (AT) inflammation leads to increased free fatty acid (FFA) efflux and ectopic fat deposition, but whether AT dysfunction drives selective fat accumulation in specific sites remains unknown. The aim of the present study was to investigate the correlation between AT dysfunction, hepatic/pancreatic fat fraction (HFF, PFF) and the associated metabolic phenotype in patients with Type 2 diabetes (T2D). Sixty-five consecutive T2D patients were recruited at the Diabetes Centre of Sapienza University, Rome, Italy. The study population underwent clinical examination and blood sampling for routine biochemistry and calculation of insulin secretion [homoeostasis model assessment of insulin secretion (HOMA-ß%)] and insulin-resistance [homoeostasis model assessment of insulin resistance (HOMA-IR) and adipose tissue insulin resistance (ADIPO-IR)] indexes. Subcutaneous (SAT) and visceral (VAT) AT area, HFF and PFF were determined by magnetic resonance. Some 55.4% of T2D patients had non-alcoholic fatty liver disease (NAFLD); they were significantly younger and more insulin-resistant than non-NAFLD subjects. ADIPO-IR was the main determinant of HFF independently of age, sex, HOMA-IR, VAT, SAT and predicted severe NAFLD with the area under the receiver operating characteristic curve (AUROC)=0.796 (95% confidence interval: 0.65-0.94, P=0.001). PFF was independently associated with increased total adiposity but did not correlate with AT dysfunction, insulin resistance and secretion or NAFLD. The ADIPO-IR index was capable of predicting NAFLD independently of all confounders, whereas it did not seem to be related to intrapancreatic fat deposition; unlike HFF, higher PFF was not associated with relevant alterations in the metabolic profile. In conclusion, the presence and severity of AT dysfunction may drive ectopic fat accumulation towards specific targets, such as VAT and liver, therefore evaluation of AT dysfunction may contribute to the identification of different risk profiles among T2D patients.

Qualitative analysis of small (≤2 cm) regenerative nodules, dysplastic nodules and well-differentiated HCCs with gadoxetic acid MRI.

BACKGROUND: The characterization of small lesions in cirrhotic patients is extremely difficult due to the overlap of imaging features among different entities in the step-way of the hepatocarcinogenesis. The aim of our study was to evaluate the role of gadoxetic-acid MRI in the differentiation of small (≤2 cm) well-differentiated hepatocellular carcinomas from regenerative and dysplastic nodules. METHODS: Seventy-three cirrhotic patients, with 118 focal liver lesions (≤2 cm) were prospectively recruited. MRI examination was performed with a 3T magnet and the study protocol included T1 - and T2-weighted pre-contrast sequences and T1 -weighted gadoxetic-acid enhanced post-contrast sequences obtained during the arterial, venous, late dynamic and hepatobiliary phases. All lesions were pathologically confirmed. Two radiologists blinded to clinical and pathological information evaluated two imaging datasets; another radiologist analysed the signal intensity characteristics of each lesion. Sensitivity, specificity and diagnostic accuracy were considered for statistical analysis. RESULTS: Good agreement was reported between the two readers (κ 0.70). Both readers reported a significantly improved sensitivity (57.7 and 66.2 vs 74.6 and 83.1) and diagnostic accuracy (0.717 and 0.778 vs 0.843 and 0.901) with the adjunction of the hepatobiliary phase 57.7 vs 74.6 and 66.2 vs 83.1 (p ≤ 0.04). CONCLUSIONS: Gadoxetic-acid MRI is a reliable tool for the characterization of HCC and lesions at high risk to further develop.