Impact of baseline gadoxetic acid-enhanced liver magnetic resonance and diffusion-weighted imaging in resectable colorectal liver metastases: A prospective, monocentric study.

BACKGROUND: Liver magnetic resonance imaging (MRI) utilizing hepatocyte-specific contrast agent and diffusion-weighted imaging (DWI) is currently used to properly stage colorectal liver metastases (CRLM) in patients candidate to liver surgery. However, the added value of liver MRI in choosing the treatment strategy in resectable CRLM over computed tomography (CT)-scan is not clear. PATIENTS AND METHODS: This is a prospective monocentric collection of consecutive cases of patients with CRLM conceived with the aim to assess the added value of liver MRI in changing the initial treatment strategy planned according to CT-scan. Potential changes in the initially planned strategy were defined as: - from upfront surgery to perioperative chemotherapy (fluoropyrimidine and oxaliplatin) - from upfront surgery to first-line systemic therapy (doublet or triplet plus a biological agent) - from perioperative chemotherapy to first-line systemic therapy. Hypothesising that MRI may induce a change in the choice of the treatment strategy in the 20% of cases (alternative hypothesis), against a null hypothesis of 5%, with one-tailed alpha and beta errors of 0.05 and 0.20 respectively, 27 patients were needed. The added value of liver MRI would have been considered clinically meaningful if at least 4 changes in the treatment strategy were observed. RESULTS: Among 27 enrolled patients, upfront surgery and perioperative chemotherapy strategies were chosen in 17 (63%) and 10 (37%) cases, respectively, based on CT-scan. After liver MRI, additional liver lesions were found in 8 patients (30%) and the initial strategy was changed in 7 patients (26%) (4 initially deemed candidate to upfront surgery and 3 initially sent to perioperative chemotherapy) that were treated with first-line systemic therapy. CONCLUSIONS: Our results support the indication of the current guidelines on the routine use of liver MRI in the initial workup of patients with resectable CRLM with an MRI-driven changes of initial treatment plan in a relevant percentage of cases.

The Influence of Gd-EOB-DTPA on T2 Signal Behavior: An Example from Clinical Routine.

In the literature, it has repeatedly been stated that the introduction of hepatospecific contrast agents in Magnetic Resonance Imaging prolongs the acquisition time due to the hepatobiliary phase, normally acquired 15-20 min after injection. Many efforts have been made to shorten the time-consuming protocols, and it was demonstrated that T2-Weighted Images (T2WI) and Diffusion-Weighted Images (DWI) acquired after Gd-EOB-DTPA show a comparable diagnostic capability to pre-contrast T2WI and DWI in the detection and characterization of hepatic tumors. Therefore, T2WI and DWI are usually acquired after the acquisition of vascular phases, in the dead time until the acquisition of the hepatobiliary phase. Unfortunately, contrast agents, especially Gd-EOB-DTPA, reduce the hydrogen nuclei's relaxation time and modify signal intensity. We report a case in which, due to these limitations of the acquisition protocol, two hemangiomas showed an inhomogeneous, low signal on T2WI and DWI that was not visible in a follow-up scan a few days later. In conclusion, when liver lesions of unknown nature must be characterized, and there is a lack of previous radiological investigations, it could be useful to acquire pre-contrast T2WI and DWI to avoid diagnostic confusion, especially in non-tertiary centers.

MRI characterization of focal liver lesions in non-cirrhotic patients: assessment of added value of gadoxetic acid-enhanced hepatobiliary phase imaging.

BACKGROUND: To evaluate the added value of the hepatobiliary (HPB) phase in gadoxetic acid-enhanced magnetic resonance imaging (MRI) in characterizing newly discovered indeterminate focal liver lesions in non-cirrhotic patients. RESULTS: One-hundred and twenty-five non-cirrhotic patients (median age, 46 years; range, 20-85 years; 100 females) underwent gadoxetic acid-enhanced MRI, including the 20-min delayed HPB phase, for characterization of newly discovered focal liver lesions. Images were independently evaluated by two blinded, board-certified abdominal radiologists (R1 and R2) who characterized liver lesions without and with assessment of the HPB phase images in two separate readout sessions. Confidence in diagnosis was scored on a scale from 0 to 3. Inter-observer agreement was assessed using Cohen κ statistics. Change in diagnosis and confidence in diagnosis were evaluated by Wilcoxon signed rank test. There was no significant change in diagnosis before and after evaluation of the HPB phase for both readers (p = 1.0 for R1; p = 0.34 for R2). Confidence in diagnosis decreased from average 2.8 ± 0.45 to 2.6 ± 0.59 for R1 and increased from 2.6 ± 0.83 to 2.8 ± 0.46 for R2. Change in confidence was only statistically significant for R1 (p = 0.003) but not significant for R2 (p = 0.49). Inter-reader agreement in diagnosis was good without (k = 0.66) and with (k = 0.75) inclusion of the HPB phase images. CONCLUSIONS: The added information obtained from the HPB phase of gadoxetic acid-enhanced MRI does not change the diagnosis or increase confidence in diagnosis when evaluating new indeterminate focal liver lesions in non-cirrhotic patients.

Understanding the Role of Gadoxetic Acid in MRI.

BACKGROUND: Radiological imaging methods used at a large scale in the assessment of hepatic lesions include: Ultrasound, computed tomography and magnetic resonance. To further characterize these lesions, specific contrast agents may be added, thus revealing the vascularity of the lesions. DISCUSSION: This review focuses on gadoxetic acid, which is a hepatospecific contrast agent used in MRI. The aim of the review is to briefly explain the mechanism of GA enhancement, describe the enhancement patterns of some benign and malignant hepatic lesions and discuss possible advantages of GA over standard contrast agents. CONCLUSION: The role of GA in functional MR cholangiography and the idea of accessing liver function by measuring parenchymal enhancement will also be explained.

Hepatocellular adenoma: An unsolved diagnostic enigma.

Hepatocellular adenoma (HCA) is a rare benign liver tumour associated with the use of oral contraceptives or other steroid medications which occurs predominantly in young and middle-aged women. Unlike other benign liver tumours, an HCA may be complicated by bleeding and malignant transformation. HCAs have been divided into four subtypes based on molecular and pathological features: hepatocyte nuclear factor 1α-mutated HCA, inflammatory HCA, ß-catenin-mutated HCA, and unclassified HCA. ß-catenin-mutated HCA has the highest risk of haemorrhage or malignant transformation. In the latest upgrade of the guidelines regarding the management of benign liver tumours published in 2016 by the European Association for the Study of the Liver, magnetic resonance imaging (MRI) was recognized to be superior to all other imaging modalities in detecting HCAs and in being able to subtype HCAs up to 80%, with positive identification of 1α-mutated HCA or inflammatory HCA achievable with > 90% specificity. This review analyzed the imaging features of HCA using MRI with hepato-specific contrast agents, focusing on the limitations in the HCA characterization.

OATPB1/B3 and MRP3 expression in hepatocellular adenoma predicts Gd-EOB-DTPA uptake and correlates with risk of malignancy.

BACKGROUND AND AIMS: Hepatobiliary phase (HBP) Gd-EOB-DTPA-enhanced magnetic resonance imaging (MRI) has increased the accuracy in differentiating focal nodular hyperplasia (FNH) and hepatocellular adenoma (HCA). However, the ability of this technique to distinguish HCA subtypes remains controversial. The aim of this study was to investigate the expression of hepatocyte transporters (OATPB1/B3, MRP2, MRP3) in HCA subtypes, hence to understand their MRI signal intensity on HBP Gd-EOB-DTPA-enhanced MRI. METHODS: By means of immunohistochemistry (IHC), we scored the expression of OATPB1/B3, MRP2 and MRP3, in resected specimens of FNH (n = 40), subtyped HCA (n = 58) and HCA with focal malignant transformation (HCA-HCC, n = 4). Results were validated on a supplementary set of FNH (n = 6), subtyped HCA (n = 17) and HCA-HCC (n = 1) with Gd-EOB-DTPA MR images. RESULTS: All FNH showed a preserved expression of hepatocytes transporters. Beta-catenin-activated HCA (at highest risk of malignant transformation) and HCA-HCC were characterized by preserved/increased OATPB1/B3 expression (predictor of hyperintensity on HBP), as opposed to other HCA subtypes (P < 0.01) that mostly showed OATPB1/B3 absence (predictor of hypointensity on HBP). HCA-HCC showed an additional MRP3 overexpressed profile (P < 0.01). On HBP Gd-EOB-DTPA-enhanced MRI, FNH and HCA signal intensity reflected the profile predicted by their specific OATPB1/B3 tissue expression. The hyperintense vs hypointense HBP signal criterion was able to distinguish all higher risk HCA and HCA-HCC (100% accuracy). CONCLUSIONS: OATPB1/B3 and MRP3 IHC and signal intensity on HBP Gd-EOB-DTPA-enhanced MRI can help to stratify HCA according to their risk of malignant transformation.

Demonstration of a bronchobiliary fistula using magnetic resonance image with hepatospecific contrast agent. / Demostración de fístula biliobronquial mediante resonancia magnética con contraste hepatoespecífico.

Bronchobiliary fistulas are a rare entity of difficult diagnosis. The utility of magnetic resonance image (MRI) with hepatospecific contrast agents to demonstrate such condition is seldom described in the literature. This case reports a patient with pulmonary infection with a past history of hepatic surgery for hydatid disease in whom the presence of bile in the sputum rose the suspicious of a bronchobiliary fistula. MRI with hepatospecific contrast agents showed the communication between the biliary and bronchial tree and provided anatomic data to allow a therapeutic approach.

Discovery of orally active hepatoselective glucokinase activators for treatment of Type II Diabetes Mellitus.

Systemically acting glucokinase activators (GKA) have been demonstrated in clinical trials to effectively lower blood glucose in patients with type II diabetes. However, mechanism-based hypoglycemia is a major adverse effect that limits the therapeutic potential of these agents. We hypothesized that the predominant mechanism leading to hypoglycemia is GKA-induced excessive insulin secretion from pancreatic ß-cells at (sub-)euglycemic levels. We further hypothesized that restricting GK activation to hepatocytes would maintain glucose-lowering efficacy while significantly reducing hypoglycemic risk. Here we report the discovery of a novel series of carboxylic acid substituted GKAs based on pyridine-2-carboxamide. These GKAs exhibit preferential distribution to the liver versus the pancreas in mice. SAR studies led to the identification of a potent and orally active hepatoselective GKA, compound 6. GKA 6 demonstrated robust glucose lowering efficacy in high fat diet-fed mice at doses ⩾10mpk, with ⩾70-fold liver:pancreas distribution, minimal effects on plasma insulin levels, and significantly reduced risk of hypoglycemia.

Misdiagnosed epigastric mass: Ectopic liver.

We discuss an ectopic liver misdiagnosed as an abdominal mass and the importance of magnetic resonance imaging (MRI) in liver positional anomalies. A solid midline mass midline adjacent to the liver was found in a 45-year-old female at an external center during an ultrasound investigation conducted for occasional abdominal pain of many years. The patient was referred to us for MRI. MRI revealed a solid epigastric lesion adjacent to the liver but unrelated to the liver parenchyma. The mass was of similar intensity as the liver in all sequences and in postcontrast dynamic phases following hepatospecific contrast material administration. We also observed contrast material excretion into the solid lesion from the biliary ducts in the hepatobiliary phase. The lesion was diagnosed as ectopic liver tissue with these findings. LEVEL OF EVIDENCE: 5 J. Magn. Reson. Imaging 2017;45:761-763.

Impact of hepatobiliary phase liver MRI versus Contrast-Enhanced Ultrasound after an inconclusive extracellular gadolinium-based contrast-enhanced MRI for the diagnosis of benign hepatocellular tumors.

PURPOSE: To compare the added values of hepatobiliary phase (HBP) MRI and contrast-enhanced ultrasound (CEUS) in addition to inconclusive extracellular gadolinium-based contrast-enhanced MRI (CE-MRI) to characterize benign hepatocellular tumors (BHT). METHODS: Eighty-three BHT-46 focal nodular hyperplasia (FNH) and 37 hepatocellular adenomas (HCA)-with inconclusive CE-MRI in 54 patients (43 women and 11 men, mean age 42 years old ± 14.8) were retrospectively analyzed. All patients underwent both HBP-MRI and CEUS. Two radiologists independently reviewed 2 sets of images, SET-1: CE-MRI and HBP-MRI; SET-2: CE-MRI and CEUS, and classified lesions as "definite FNH," "possible FNH," or "definitely not FNH." Sensitivity (Se) and specificity (Spe) were compared between the two sets; subgroup analyses according to the lesion's size were performed. RESULTS: Regardless of lesion size, the respective Se and Spe of both datasets were not statistically different (95.7 and 100% vs. 76.1 and 94.6% for set-1 and -2 respectively; p = 0.18). For lesions larger than 35 mm, although both sets had similar specificity (100%), sensitivity was higher for SET-1 (100% vs. 40%); p = 0.04. Tumor classifications using SET-1 and SET-2 could have changed patient management in 35/54 (64.8%) and 33/54 (61.1%) of all patients, respectively. CONCLUSIONS: HBP-MRI or CEUS should be performed after an inconclusive CE-MRI. Both can change patient management by avoiding unnecessary biopsy or surveillance. The use of HBP-MRI should be advocated over CEUS in larger (>35 mm) lesions.

Proposal of a new diagnostic algorithm for hepatocellular carcinoma based on the Japanese guidelines but adapted to the Western world for patients under surveillance for chronic liver disease.

To date, despite many scientific evidences, the guidelines of the principal hepatological societies, such as the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, and the Asian Pacific Association for the Study of the Liver, do not recognize the diagnostic superiority of magnetic resonance imaging (MRI) over computed tomography in the diagnosis of hepatocellular carcinoma (HCC) and, for the most part, do not contemplate the use of hepatospecific contrast media, such as gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (EOB). The aim of this paper was to analyze the recent results of EOB-MRI in the study of chronic liver disease and the differences between the American Association for the Study of Liver Diseases and the Japan Society of Hepatology guidelines, of which the latter represents the most consolidated experience on EOB-MRI use for HCC diagnosis. Finally, a new diagnostic algorithm for HCC in patients under surveillance for chronic liver disease was formulated, which contemplates the use of EOB. This new diagnostic algorithm is based on the Japan Society of Hepatology algorithm but goes beyond it by adapting it to the Western world, taking into account both the difference between the two and the latest results concerning the diagnosis of HCC. This new diagnostic algorithm for HCC is proposed in order to provide useful diagnostic tools to all those Western countries where the use of EOB (more expensive than extracellular contrast media) is widespread but in which common strategies to manage the nodules that this new contrast agent allows identifying have not been available to date.

TCM matrine inducescell arrest and apoptosis with recovery expression of the hepato-specific miR122a in human hepatocellular carcinomaHep G2cell line.

Hepatocellular carcinoma (HCC) accounts for 80% to 90% of liver cancers and it is one of the most prevalent carcinomas throughout the world. Traditional chemotherapy is often developed chemoresistance HCC patients.Matrine is an active component oftraditional Chinese medicine (TCM) and is a promising alternative HCC drug. In this study, the therapeutic effects and the underlying molecular mechanisms of matrine on the human HCC cell lineHep G2 were investigated. High dosage of matrine (1.0 mg/mL) could significantly (P < 0.05) inhibit cell proliferation by 48.39 ± 3.32%, under which cell shrinkage and disruption were observed. Flow cytometry assay showed that the proportion of G1/G0 cells significantly increased, while that of S and G2/M cells significantly decreased after treatment of matrinefor 48 h. These results indicated that cell arrest by matrine appeared. Up-regulation of the hepato-specific miR122a followed by down expression of its targetcyclin G1 (CG1) gene by low concentration of matrine (0.2 mg/mL) was detected using was observed using quantitative real-time PCR, immunohistochemistry (IHC) and western blot assays. In conclusion, matrineinducescell arrest and apoptosis with recovery expression of the hepato-specific miR122a in human hepatocellular carcinoma Hep G2 cell line.

MRI for characterization of primary tumors in the non-cirrhotic liver: added value of Gd-EOB-DTPA enhanced hepatospecific phase.

PURPOSE: To evaluate the added value of hepatospecific phase in Gd-EOB-DTPA enhanced magnetic resonance imaging (MRI) in patients with primary tumors in non-cirrhotic liver. METHODS: Twenty-nine patients (median, 39 years; range, 18-81 years; 11 male) underwent preoperative Gd-EOB-DTPA enhanced MRI including hepatospecific phase after 10 and 20 min of contrast injection at four institutions in Europe, North America and New Zealand. Images were evaluated by three different readers (R1-R3) who characterized liver tumors with and without consultation of the hepatospecific phase images. Confidence in diagnosis was scored on a visual analog scale from 1 to 10. Histopathology (adenoma, n=5; focal nodular hyperplasia, n=11 and hepatocellular carcinoma, n=13) in all patients served as the standard of reference. Differences were evaluated using the McNemar and Wilcoxon signed rank test. RESULTS: Without hepatospecific phase images available, 22 (76%), 19 (66%) and 19 (66%) of 29 tumors were characterized correctly by the three readers respectively. Mean confidence in diagnosis was 6.1, 5.7 and 5.8. With the hepatospecific phase included, characterization of liver tumors did not change significantly with 21 (72%), 23 (79%) and 19 (66%) of 29 tumors diagnosed correctly (p>0.05). According confidence ratings increased to 6.3, 6.5 and 7.7, respectively. Increase in diagnostic confidence was significant for R2 and R3 (p<0.05) and independent of reader's experience. CONCLUSION: The additional hepatospecific phase in Gd-EOB-DTPA enhanced MRI did not significantly increase diagnostic accuracy in characterization of primary tumors in the non-cirrhotic liver. However, 2/3 readers showed a significant increase in diagnostic confidence after consultation of the hepatospecific phase.

Malignant focal liver lesions at contrast-enhanced ultrasonography and magnetic resonance with hepatospecific contrast agent.

The aim of this study was to compare the diagnostic accuracy of the late phase of CEUS and the hepatobiliary phase of CE-MR with Gd-BOPTA in the characterization of focal liver lesions in terms of benignity and malignancy. A total of 147 solid focal liver lesions (38 focal nodular hyperplasias, 1 area of focal steatosis, 3 regenerative nodules, 8 adenomas, 11 cholangiocarcinomas, 36 hepatocellular carcinomas and 49 metastases) were retrospectively evaluated in a multicentre study, both with CEUS, using sulphur hexafluoride microbubbles (SonoVue, Bracco, Milan, Italy) and CE-MR, performed with Gd-BOPTA (Multihance, Bracco, Milan, Italy). All lesions thought to be malignant were cytohistologically proven, while all lesions thought to be benign were followed up. Sensitivity, specificity, positive (PPV) and negative (NPV) predictive values and accuracy were calculated for the late phase of CEUS and the hepatobiliary phase of CE-MRI, respectively, and in combination. Analysis of data revealed 42 benign and 105 malignant focal liver lesions. We postulated that all hypoechoic/hypointense lesions on the two phases were malignant. The diagnostic errors were 13/147 (8.8%) by CEUS and 12/147 (8.2%) by CE-MR. Sensitivity, specificity, PPV, NPV and accuracy of the late phase of CEUS were 90%, 93%, 97%, 80% and 91%, 93%, 97%, 81% and 92% for the hepatobiliary phase of CE-MRI, respectively. If we considered both techniques, the misdiagnosis diminished to 3/147 (2%) and sensitivity, specificity, PPV, NPV and accuracy were 98%, 98%, 99%, 95% and 98%. The combination of the late phase of CEUS and the hepatobiliary phase of CE-MR in the characterization of solid focal liver lesions in terms of benignity and malignancy is more accurate than the two techniques used separately.

Hepatoprotective effect of an aqueous extract of the leaves of Acalypha wilkesiana 'Godseffiana' Muell Arg (Euphorbiaceae) against carbon tetrachloride induced liver injury in rats.

The potential of aqueous extract of the leaves of Acalypha wilkesiana, to protect against carbon tetrachloride induced liver damage was investigated in Wistar albino rats. The carbon tetrachloride was prepared 1:5 (v:v) in olive oil, and administered subcutaneously at 1 mL/kg body weight. The extract was administered to both normal and carbon tetrachloride treated rats at 100, 200 and 300 mg/kg. On fractionation and gas chromatographic analysis of the crude aqueous extract, thirty nine known alkaloids were detected, consisting mainly of akuamidine (69.027 %), voacangine (26.226 %), echitamine (1.974 %), echitamidine (0.599 %), lupanine (0.521 %) and augustamine (0.278 %). Compared to test control, the treatment dose dependently produced significantly lower (P<0.05) alkaline phosphatase, aspartate and alanine transaminase activities. Histopathological studies on the liver sections showed that pre-treatment with the extract protected against carbon tetrachloride induced fatty degeneration of hepatocytes, thus, confirming the results of the biochemical studies. The above results imply that treatment with the plant extract protects the liver against carbon tetrachloride induced hepatotoxicity, therefore, justifying the use of Acalypha wilkesiana in African traditional health care for the management of liver problems.

Protective effect of aqueous extract of the rhizomes of Sansevieria liberica Gérôme and Labroy on carbon tetrachloride induced hepatotoxicity in rats.

The ability of an aqueous extract of the rhizomes of Sansevieria liberica to protect against carbon tetrachloride induced liver injury was investigated in Wistar albino rats. The carbon tetrachloride was prepared 1:5 (v:v) in olive oil, and administered subcutaneously at 1 mL/kg body weight. The extract was administered to both normal and carbon tetrachloride treated rats at 100, 200 and 300 mg/kg. On gas chromatographic analysis of the extract, twenty nine known flavonoids were detected, consisting mainly of 31.94 % apigenin, 20.66 % quercetin, 11.28 % kaempferol, 5.99 % naringenin, 5.83 % (-)-epicatechin, 3.69 % biochanin, 3.58 % (+)-catechin, 2.72 % diadzein, 2.20 % ellagic acid, 2.04 % butein. Compared to test control, the treatment dose dependently produced significantly (P<0.05) lower alkaline phosphatase, aspartate transaminase and alanine transaminase activities. The plasma total bilirubin and total protein levels of the test animals were lower though not significantly. The hepatic histopathological studies showed that carbon tetrachloride caused fatty degeneration of hepatocytes, which was inhibited by pre-treatment with the extract; thus, confirming the results of the biochemical studies. The results of this study indicated that treatment with the plant extracts protects the liver against carbon tetrachloride induced hepatotoxicity. This supports the use of Sansevieria liberica in traditional health care for managing liver problems.