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[Background] The 5-aminolevulinic acid (ALA)-based photodynamic diagnosis is based on the accumulation of photosensitizing protoporphyrin IX in the tumor after ALA administration. However, the mechanisms connecting exogenous ALA and tumor fluorescence in pancreatic cancer remain unclear. We aimed to elucidate the mechanism underlying the ALA-induced fluorescent. [Methods] Human pancreatic duct epithelial cells (hPDECs) and pancreatic cancer cell lines were used. The expressions of ALA-associated enzymes and membrane transporters in these cell lines were investigated. ALA-induced fluorescence was also investigated. [Results] The expression of oligopeptide transporter-1 (PEPT-1), through which ALA is absorbed, was significantly higher in AsPC-1 cells and lower in MIA PaCa-2 cells than in hPDECs. AsPC-1 cells showed rapid and intense fluorescence after ALA administration, and that was attenuated by PEPT-1 inhibition. ALA-induced fluorescence was not sufficiently strong in MIA PaCa-2 cells to distinguish the cells from hPDECs. [Conclusion] We revealed the association of PEPT-1 with ALA-induced fluorescence. Cancers expressing PEPT-1 could be easily distinguished by this technique from normal cells. These findings help develop novel diagnostic modalities for pancreatic cancer.

[Background] Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease related to metabolic syndrome, which can progress to liver cirrhosis. Standard medication has not been established. Pemafibrate is a selective peroxisome proliferatoractivated receptor (PPAR) α modulator. We retrospectively evaluated the efficacy of pemafibrate in patients with NAFLD. [Methods] We retrospectively enrolled 17 patients (ten men, seven women; median age, 63 years; range, 27?81 years). They were all proven to have fatty liver through imaging and had little or no history of drinking (ethanol consumption of < 20 g/day for women and < 30 g/day for men). They were administered pemafibrate from October 2018 to June 2020. [Results] After administration, serum triglyceride (TG) tended to be decreased (300.5 ± 22.5 to 239.5 ± 34.3 mg/dL, P = 0.06). Serum high-density lipoprotein (HDL) cholesterol and low density lipoprotein (LDL) cholesterol levels did not change. ALT was significantly decreased (-47.4%) for six months (57.5 ± 8.8 to 30.3 ± 5.8 U/L, P < 0.01). The values of serum GGT significantly decreased (-48.7%) for sixth months (63.9 ± 10.3 to 32.8 ± 6.6 U/L, P < 0.01). Aspartate aminotransferase (AST) to platelet ratio (APRI), a fibrosis marker, also was significantly decreased in the sixth month (0.7 ± 0.1 to 0.4 ± 0.1, P < 0.05). Body mass index (BMI) and hemoglobin A1c (HbA1c) showed no significant change. [Conclusion] Pemafibrate dramatically ameliorated the values of liver function tests and APRI in patients with NAFLD.

[Background] The options for the treatment of nonalcoholic steatohepatitis (NASH) are limited. We examined the effects of ipragliflozin, a sodium-glucose cotransporter 2 inhibitor, on the fatty liver Shionogi (FLS)-ob/ob mice, a non-alcoholic steatohepatitis mouse model. [Methods] FLS-ob/ob male mice were treated with vehicle (n = 10) and ipragliflozin (n = 8). Serum metabolic markers, histopathology of the liver, hepatic cholesterol and triglyceride levels and hepatic mRNA levels related to fibrosis, lipid metabolism and endoplasmic reticulum (ER) stress were compared between the two groups. [Results] The body weight and hepatic cholesterol and triglyceride levels were significantly decreased in the ipragliflozin group compared with the control group. Hepatic steatosis and fibrosis were significantly ameliorated by the treatment with ipragliflozin. Hepatic infiltration of macrophage, expression levels of 8-hydroxy-2-deoxyguanosine (8-OHdG) and hepatic mRNA levels of ER stress markers were not significantly modulated by the treatment with ipragliflozin. [Conclusion] Ipragliflozin can be a therapeutic option for patients with NASH. The precise mechanisms of action need to be clarified in future studies.

[Background] Nonalcoholic fatty liver disease/steatohepatitis (NAFLD/NASH) is a chronic liver disease related to metabolic syndrome that can progress to liver cirrhosis. The involvement of the endoplasmic reticulum (ER) stress response in NAFLD progression and the roles played by activating factor 3 (ATF3) and the downstream nuclear protein 1 (NUPR1) are poorly understood. The aim of this study was to determine the gene expression profiles around the ATF3/NUPR1 axis in relation to the development of NAFLD using novel mouse models. [Methods] Fatty liver Shionogi (FLS) mice (n = 12) as a NAFLD model and FLS-ob/ob mice (n = 28) as a NASH model were fed a standard diet. The FLS mice were sacrificed at 24 weeks of age as a control, whereas the FLS-ob/ob mice were sacrificed at 24, 36, and 48 weeks of age. Hepatic steatosis, inflammation, and fibrosis were evaluated by biochemical, histological, and gene expression analyses. The expression levels of the ER-stress related genes Jun proto-oncogene (C-jun), Atf3, Nupr1, and C/EBP homologous protein (Chop) were measured in liver tissue. Apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining. [Results] Control mice demonstrated hepatic steatosis alone without apparent fibrosis. On the other hand, FLS-ob/ob mice showed severe steatohepatitis at both 24 and 36 weeks of age and severe fibrosis at both 36 and 48 weeks of age. The expression levels of Atf3, Nupr-1, and C-jun significantly increased from 24 to 48 weeks of age in FLS-ob/ob mice compared with control mice. The expression level of Chop was already high in FLS mice and maintained similar levels in FLS-ob/ob mice; the expression level was consistent with the percentage of TUNEL-positive cells. [Conclusion] The ATF3/NUPR1 axis plays a pivotal role in NASH progression in association with C-jun and Chop and appears to induce apoptosis from early steatosis in the NASH model mice.

BACKGROUND: Patient-derived xenografts (PDX) provide histologically accurate cancer models that recapitulate patient malignant phenotype and allow for highly correlative oncologic in-vivo downstream translational studies. Primary PDX engraftment failure has significant negative consequences on programmatic efficiency and resource utilization and is due to either no tumor growth or development of lymphoproliferative tumors. We aimed to determine if secondary engraftment of previously cryopreserved patient tumor tissues would allow salvage of PDX models that failed previous primary engraftment and increase overall engraftment efficiency. METHODS: Patient hepatobiliary and pancreatic cancers that failed primary engraftment were identified. Previously cryopreserved primary patient cancerous tissues were implanted into immunodeficient mice (NOD/SCID). Mice were monitored, growth metrics calculated, and secondary engraftment outcomes were recorded. Established PDX were verified and compared to original patient tissue through multiple generations by a GI pathologist. RESULTS: We identified 55 patient tumors that previously failed primary engraftment: no tumor growth (n = 46, 84%) or lymphoproliferative tumor (LT) (n = 9, 16%). After secondary implantation using cryopreserved patient tissues, 29 new histologically validated PDX models were generated with an overall secondary engraftment rate of 53% for all tumor types with greatest yield in pancreatic and biliary tract cancers. Of the secondary engraftment failures (n = 26), 21 (38%) were due to no growth and 5 (9%) developed LT. CONCLUSION: Secondary PDX engraftment using cryopreserved primary cancerous is feasible after previous failed engraftment attempts and can result in a 50% increase in overall engraftment efficiency with decreases in LT formation. This technique allows for salvage of critical patient PDX models that would otherwise not exist. SYNOPSIS: Patient-derived xenografts have many important translational applications however can be limited by engraftment failure. We demonstrate optimized methodology utilizing cryopreservation of primary tumor tissue that allows for subsequent successful secondary engraftment and creation of PDX models that failed previous primary engraftment and allowed salvage of patient PDX models that would otherwise not exist.

Background & aims Glycogenic hepatopathy (GH) in type 1 diabetes-mellitus (T1DM) is characterized by hepatomegaly and perturbations of liver chemistries (LC) that have not been well studied. Furthermore, misdiagnosis with other hepatic complications of T1DM, such as nonalcoholic fatty liver disease, has been described. We perform a systematic review of biopsy-proven GH reports in T1DM patients to identify LC patterns. Methods A systematic review identified reports of biopsy-proven GH in patients with T1DM. We excluded GH with other liver diseases, Mauriac syndrome, or GH without T1DM. Two reviewers screened and extracted studies and assessed their methodological quality. LC elevation magnitude, AST-to-ALT ratio, R-ratio to designate hepatocellular, cholestatic or mixed pattern of hepatic injury, and evolution of transaminases after glycemic control were analyzed. Results A total of 192 patients were included, with median age of 20 years, 73% adults, 66% females, median duration of T1DM before diagnosis 10 years, median adult body mass index 21 kg/m2 , median HbA1c 12%, at least one episode of diabetic ketoacidosis 70%, and hepatomegaly 92%. ALT and AST showed moderate-to-severe elevation in 78% and 76%, respectively, AST/ALT >1 in 71% and hepatocellular to mixed pattern of hepatic injury in 81%. Transaminase improvement with glycemic control was the rule, regardless of other factors in multilinear regression analysis. Conclusion GH tends to have AST-predominant elevation with a median of 13 times the upper normal limit and R-ratio >2, which may distinguish it from other etiologies of AST-predominant LC elevation, and in the appropriate clinical context, may obviate invasive tests.

To assess the agreement between ablative margin (AM) predicted by preablation three-dimensional ultrasonography (3D-US) and AM measured on postablation computed tomography (CT)/magnetic resonance (MR) images.Sixty patients with 73 hepatocellular carcinoma nodules were enrolled. 3D-US data were collected immediately after puncture by the electrode before ablation. The maximum distance from the electrode to the edge of the tumor in the plane perpendicular to the electrode (C-plane) was defined as "a" and the diameter of the ablation zone as "b". We classified predicted AM into "0.5b - a" ≥0 mm as AM(+) or0 mm as AM(-), and "0.5b - a" ≥3 mm or3 mm.Forty-eight nodules (66 %) were visualized in the C-plane. There was an agreement between the predicted and measured AMs for 39 (81 %) of the 48 nodules. Local tumor progression was observed in 3 (7%) of 43 nodules with predicted AM(+) and in 2 (40 %) of 5 nodules with predicted AM(-) but was not observed in any of 21 nodules with predicted AM ≥ 3 mm. The local tumor progression rate was significantly lower for nodules with predicted AM(+) compared with predicted AM(-)(p = 0.03), and for nodules with predicted AM ≥ 3 mm compared with predicted AM 3 mm (p = 0.04). Local progression was detected in 2 (4.7 %) of 42 nodules with a sufficient AM (≥0 mm) on postablation CT/MR images and in 5 (83.3 %) of 6 nodules with an insufficient AM (0 mm); the difference in progression rate was significant (p = 0.0008).3D-US allows prediction of the AM before radiofrequency ablation.

Gamma-glutamyl hydroxymethyl rhodamine green (gGlu-HMRG) is an activatable fluorescent probe that can be activated by γ-glutamyltranspeptidase (GGT). The expression of GGT in the kidney, which is one of the major organs exhibiting enhanced GGT expression, is exclusively localised to the cortex. Here, we aimed to investigate the feasibility of gGlu-HMRG as a probe for the on-site assessment of renal biopsy specimens. gGlu-HMRG fluorescent probe was applied to the renal proximal tubular epithelial cells and cortical collecting duct cells in vitro, mouse kidneys ex vivo, and human biopsy specimens. In addition, the fluorescence intensities in the cortex and the medulla were comparatively evaluated in the biopsy specimens. The fluorescence signal was rapidly detected in the renal proximal tubular epithelial cells, whereas that in the cortical collecting duct cells was not detected. The fluorescence signal was detected in the mouse kidneys ex vivo without markedly affecting the tissue morphology. In the human biopsy specimens, the fluorescence signal in the cortex was significantly distinct from that in the medulla (p

The Hippo pathway effector, Yes-associated protein (YAP), is a transcriptional coactivator implicated in cholangiocarcinoma (CCA) pathogenesis. YAP is known to be regulated by a serine/threonine kinase relay module (MST1/2–LATS1/2) culminating in phosphorylation of YAP at Serine 127 and cytoplasmic sequestration. However, YAP also undergoes tyrosine phosphorylation, and the role of tyrosine phosphorylation in YAP regulation remains unclear. Herein, YAP regulation by tyrosine phosphorylation was examined in human and mouse CCA cells, as well as patient-derived xenograft (PDX) models. YAP was phosphorylated on tyrosine 357 (Y357) in CCA cell lines and PDX models. SRC family kinase (SFK) inhibition with dasatinib resulted in loss of YAPY357 phosphorylation, promoted its translocation from the nucleus to the cytoplasm, and reduced YAP target gene expression, including cell lines expressing a LATS1/2-resistant YAP mutant in which all serine residues were mutated to alanine. Consistent with these observations, precluding YAPY357 phosphorylation by site-directed mutagenesis (YAPY357F) excluded YAP from the nucleus. Targeted siRNA experiments identified LCK as the SFK that most potently mediated YAPY357 phosphorylation. Likewise, inducible CRISPR/Cas9-targeted LCK deletion decreased YAPY357 phosphorylation and its nuclear localization. The importance of LCK in CCA biology was demonstrated by clinical observations suggesting LCK expression levels were associated with early tumor recurrence following resection of CCA. Finally, dasatinib displayed therapeutic efficacy in PDX models. Mol Cancer Res; 16(10); 1556–67. ©2018 AACR.

Spontaneous rupture is a life-threatening complication of hepatocellular carcinoma (HCC). Detecting active bleeding is critical. Color Doppler and contrast-enhanced ultrasonography (CEUS) with Levovist® are reported to be useful for detecting active bleeding. A few reports have described using Sonazoid® to detect bleeding in ruptured HCC. This report describes two distinctive patterns of bleeding from ruptured HCC observed in CEUS with Sonazoid®. Four patients with suspected HCC rupture were examined by gray-scale ultrasonography (US) and then CEUS with Sonazoid®. Two patterns of bleeding were observed with CEUS: jet-like extravasation (n = 2) and bubble leakage (n = 2). While contrast-enhanced computed tomography and angiography revealed active bleeding in only one patient, CEUS detected active bleeding and enabled the bleeding site to be estimated in all patients. Transcatheter arterial embolization was performed based on the findings of CEUS, and hemostasis was achieved in all patients. CEUS using Sonazoid® could demonstrate active bleeding as two patterns, and these findings enabled us to detect the rupture site of HCC more confidently than with other modalities.

BACKGROUND Diuretics are essential for treating acute decompensated heart failure (ADHF), but the response is inconsistent. This study aimed to clarify whether kidney volume as assessed by ultrasound (US) predicts diuretic resistance in patients with ADHF. METHODS We enrolled 29 patients with ADHF and 32 controls. Height-adjusted kidney volume was assessed by US. We divided patients into two groups based on the median value of total daily use of furosemide (intravenous dose plus 0.5 × oral dose of furosemide equivalents) during 3 days from admission. RESULTS Patients with ADHF had a significantly smaller left kidney volume than did control subjects (27.7 ± 10.0 vs. 32.8 ± 8.8 mL/m, P < 0.05). Patients in the high-dose furosemide group (≥ 51.7 mg/d) had a significantly lower estimated glomerular filtration rate (eGFR) and a significantly smaller kidney volume than did those in the low-dose furosemide group (eGFR: 43.9 ± 20.4 vs. 60.8 ± 21.6 mL/min/1.73 m2, left kidney volume: 23.2 ± 5.2 vs. 32.6 ± 11.0 mL/m, right kidney volume: 26.5 ± 7.5 vs. 32.6 ± 7.9 mL/m, all P < 0.05). Multivariate logistic analysis showed that left kidney volume, but not eGFR, was independently associated with the requirement of high-dose furosemide (odds ratio: 0.856, 95% confidence interval: 0.735-0.997, P < 0.05). CONCLUSION Kidney volume as assessed by US is a useful predictor of diuretic resistance in patients with ADHF.

Background Hepatocellular carcinoma (HCC) in patients without hepatitis B (HBV) and -C virus (HCV) infection are increasing in Japan. Method for detecting high-risk liver diseases of HCC in general population has still not been established. Liver stiffness measurement (LSM) and Controlled Attenuation Parameter (CAP) using transient elastography (TE; FibroScan System) are useful for detecting liver fibrosis and steatosis. The aim of this study is to clarify TE for risk assessment of HCC in general population. Methods This cross-sectional study was performed for residents aged ≥ 40 years in an intermountain town in Japan with a population of 3,493. Blood laboratory testing included tumor markers, abdominal ultrasound (AUS), and TE was performed. Results Among 175 subjects (64 men, 111 women), TE was evaluated and three patients with HCC were detected by AUS. For detecting HCC, the cut-off value of LSM was 5.3 kPa sensitivity 100%, specificity 75%, AUROC 0.88). The combination of LSM and CAP (LSM > 5.3 kPa with any CAP and CAP > 248 dB/m with any LSM) could detect the high-risk liver diseases of HCC (HCC, nonalcoholic fatty liver/steatohepatitis, HBV or HCV related chronic viral hepatitis with alanine transaminase (ALT) > 30 IU/L for men or > 19 IU/L for women or cirrhosis of any cause) with high sensitivity (sensitivity 90%, specificity 55%, positive predictive value 10%, negative predictive value 99%, P = 0.006). Conclusion The combination of LSM and CAP can be useful in detecting high-risk liver diseases of HCC out of general population.

Background: Chronic kidney disease (CKD) and non-alcoholic steatohepatitis (NASH) are major health burdens closely related to metabolic syndrome. A link between CKD and NASH has been assumed, however, the underlying mechanism is still unknown. Ectopic lipid deposition (ELD) in the hepatocyte results in endoplasmic reticulum (ER) stress, which plays an important role in the development of steatohepatitis. ELD is also assumed to play a role in the development of kidney injury. We aimed to investigate the role of ELD and ER stress in the development of CKD, and evaluate the efficacy of a sodium glucose cotransporter-2 inhibitor, ipragliflozin. Methods: Male FLS-ob/ob mice that closely imitate the pathophysiology of NASH were treated with vehicle or ipragliflozin. Metabolic characteristics, histology of the kidney, ER stress, and apoptotic signals were evaluated. Results: The serum triglyceride was significantly lower in mice treated with ipragliflozin. Ipragliflozin reduced ELD in renal tubules. Ipragliflozin also reduced the expression levels of GRP78 and CHOP, apoptotic cells, and interstitial fibrosis. Conclusions: ELD induced kidney injury through ER stress. Ipragliflozin improved the pathogenesis of CKD by reducing ELD and ER stress in NASH-model mice. Our results suggest ipragliflozin has therapeutic effect on CKD in NASH.

IntroductionNon-alcoholic fatty liver disease (NAFLD) has a wide spectrum, eventually leading to cirrhosis and hepatic carcinogenesis. We previously reported that a series of microRNAs (miRNAs) mapped in the 14q32.2 maternally imprinted gene region (Dlk1-Dio3 mat) are related to NAFLD development and progression in a mouse model. We examined the suitability of miR-379, a circulating Dlk1-Dio3 mat miRNA, as a human NAFLD biomarker.MethodsEighty NAFLD patients were recruited for this study. miR-379 was selected from the putative Dlk1-Dio3 mat miRNA cluster because it exhibited the greatest expression difference between NAFLD and non-alcoholic steatohepatitis in our preliminary study. Real-time PCR was used to examine the expression levels of miR-379 and miR-16 as an internal control.ResultsCompared to normal controls, serum miR-379 expression was significantly up-regulated in NAFLD patients. Receiver operating characteristic curve analysis suggested that miR-379 is a suitable marker for discriminating NAFLD patients from controls, with an area under the curve value of 0.72. Serum miR-379 exhibited positive correlations with alkaline phosphatase, total cholesterol, and low-density-lipoprotein cholesterol levels in patients with early stage NAFLD (Brunt fibrosis stage 0 to 1). The correlation between serum miR-379 and cholesterol levels was lost in early stage NAFLD patients treated with statins. Software-based predictions indicated that various energy metabolism–related genes, including insulin-like growth factor-1 (IGF-1) and IGF-1 receptor, are potential targets of miR-379.ConclusionsSerum miR-379 exhibits high potential as a biomarker for NAFLD. miR-379 appears to increase cholesterol lipotoxicity, leading to the development and progression of NAFLD, via interference with the expression of target genes, including those related to the IGF-1 signaling pathway. Our results could facilitate future research into the pathogenesis, diagnosis, and treatment of NAFLD.

Gastrointestinal stromal tumor (GIST) is the most common submucosal tumor of the stomach. GISTs are often detected by esophagogastroduodenal endoscopy. We have previously reported on endoscopically invisible medium-sized exophytic type GISTs. We present here a case of small exophytic GIST detected by transabdominal ultrasonography (TUS) in which the natural history of the tumor could be traced retrospectively through incidental findings obtained during follow-up for intraductal papillary mucinous neoplasm by magnetic resonance of imaging or computed tomography over about 10 years. The tumor appeared 7 years before its detection, and the doubling time was calculated as 6.9 years. In conclusion, low-risk exophytic GIST was estimated to have taken at least about 7 years to reach a size detectable by TUS.

Cholangiocarcinoma (CCA) has an increasing incidence and remains a difficult to treat malignancy. In a search for more effective treatment options, progress has been made in identifying molecular drivers of oncogenic signaling including IDH mutations and FGFR2 fusions. In addition, multiple investigators have identified increased activity of YAP, the effector protein of the Hippo pathway, in CCA. The Hippo pathway regulates organ size, cellular proliferation, and apoptosis via YAP, a transcriptional co-activator. Targeting of the pathway has been difficult due the lack of a dedicated cell-surface receptor. However, more recently, additional cross-regulatory pathways have been identified that are potentially targetable. In this review, we address the current treatment landscape for CCA, the Hippo pathway broadly, animal models of CCA with attention to Hippo-related models, and the current strategies for targeting YAP.

Aim Acoustic radiation force impulse is a noninvasive method for evaluating tissue elasticity on ultrasound. Renal shear wave velocity measured by this technique has not been fully investigated in patients with renal disease. The aim of the present study was to compare renal shear wave velocity in end-stage renal disease patients and that in patients without chronic kidney disease and to investigate influencing factors. Methods Renal shear wave velocities were measured in 59 healthy young subjects (control group), 31 subjects without chronic kidney disease (non-CKD group), and 39 end-stage renal disease patients (ESRD group). Each measurement was performed 10 times at both kidneys, and the mean value of eight of 10 measurements, excluding the maximum and minimum values, was compared. Results Renal shear wave velocity could be measured in all subjects. Renal shear wave velocity in the control group was higher than in the non-CKD group and in the ESRD group, and no difference was found between the non-CKD group and the ESRD group. Age and depth were negatively correlated to the renal shear wave velocity. In multiple regression analysis, age and depth were independent factors for renal shear wave velocity, while renal impairment was not. There was no difference between the non-CKD group and the ESRD group, even when ages were matched and depth was adjusted. Conclusion Renal shear wave velocity was not associated with advanced renal impairment. However, it reflected alteration of renal aging, and this technique may be useful to detect renal impairment in the earlier stages.

Photodynamic therapy (PDT) is a therapeutic method used to destroy tumor tissue via reactive oxygen. Notably, reactive oxygen is induced by a combination of photosensitizers, including talaporfin sodium (TS) and laser light. Gastric cancer cell lines, MKN45 and MKN74, were used to evaluate the effect of TS-PDT in vitro. The antitumor effect of TS-PDT, which was evaluated via cellular viability assay, on MKN74 was weaker than that on MKN45 cells, suggesting that MKN74 cell could be resistant to TS-PDT. However, using a higher TS concentration or setting a longer treatment time (24 h) resulted in effective TS-PDT treatment on MKN74 cells. In addition, when irradiation power of LED was raised up to 5.06 J/cm2, TS-PDT was able to induce an antitumor effect on MKN74 cells. This suggested that the difference in TS-PDT efficacy between MKN45 and MKN74 cells is based on the difference in cellular uptake of TS. As expected, uptake of TS by MKN74 cells was lower than that by MKN45 cells. The expression levels of low-density lipoprotein (LDL) receptor in MKN74 cells were lower than those in MKN45 cells. With GW3965 treatment, an agonist/activator of Liver X Receptor, LDL receptor expression was reduced, weakening the TS-PDT effect. Furthermore, as a hydroxymethylglutaryl-Coenzyme A reductase inhibitor, treatment using simvastatin increased LDL receptor expression, leading to enhancement of the TS-PDT effect on MKN74 cells. In conclusion, the difference in LDL receptor expression between the two gastric cell lines could influence TS-PDT efficacy; simvastatin may enhance the antitumor effect of TS-PDT through upregulating the LDL receptor even on PDT-resistant gastric cancer cells.

Detection of reticuloendothelial system (RES) cells is essential for the differential diagnosis of splenic hamartoma. Among the imaging techniques using contrast agents phagocytosed by RES cells, contrast-enhanced ultrasonography (CEUS) with Sonazoid is less invasive and less costly than (99m)Tc-labeled colloid scintigraphy. We report a case of non-symptomatic splenic hamartoma in a 40-year-old woman detected as an abdominal tumor by screening ultrasonography. The tumor was 4 cm in diameter, round, slightly hypoechoic, and associated with a cystic lesion. The tumor region was stained on enhanced computed tomography with prolonged enhancement, while the cystic lesion was not. The mass appeared as mainly isointense with partial hyperintensity on T1-weighted and as a mixed hypo- and hyperintense region on T2-weighted magnetic resonance images. (99m)Tc-labeled colloid scintigraphy demonstrated uptake in only the tumor region. CEUS with Sonazoid revealed that the tumor was mainly hypervascular with non-enhanced areas in the early vascular phase, but the hypervascular region appeared also as a hyperechoic area (indicating microbubble phagocytosis) in the post-vascular phase. Thus, CEUS with Sonazoid revealed all three cardinal features of splenic hamartoma: hypervascularity, presence of RES cells, and tissue heterogeneity. Splenectomy and histopathology confirmed the presence of a splenic hamartoma with associated hematoma. CEUS with Sonazoid is a promising new diagnostic tool for splenic hamartoma.

Background & Aims: Transient elastography (TE) is a noninvasive technique used to measure liver stiffness to estimate the severity of fibrosis. The range of liver stiffness measurements (LSMs) in healthy individuals is unclear. We performed a systematic review to determine the range of LSMs, examined by TE, in healthy individuals and individuals who are susceptible to fibrosis. Methods: We collected data from 16,082 individuals, in 26 cohorts, identified from systematic searches of Embase, Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews for studies of liver stiffness measurements. Studies analyzed included apparently healthy adults (normal levels of liver enzymes, low-risk alcohol use patterns, and negative for markers of viral hepatitis). The presence of diabetes, hypertension, dyslipidemia, or steatosis, based on ultrasound examination, was known for most participants. We performed a meta-analysis of data from individual participants. The cohort was divided into 4 groups; participants with a body mass index

To examine the effects of the endothelin type A receptor antagonist ambrisentan on hepatic steatosis and fibrosis in a steatohepatitis mouse model.Fatty liver shionogi (FLS) FLS-ob/ob mice (male, 12 wk old) received ambrisentan (2.5 mg/kg orally per day; n = 8) or water as a control (n = 5) for 4 wk. Factors were compared between the two groups, including steatosis, fibrosis, inflammation, and endothelin-related gene expression in the liver.In the ambrisentan group, hepatic hydroxyproline content was significantly lower than in the control group (18.0 μg/g ± 6.1 μg/g vs 33.9 μg/g ± 13.5 μg/g liver, respectively, P = 0.014). Hepatic fibrosis estimated by Sirius red staining and areas positive for α-smooth muscle actin, indicative of activated hepatic stellate cells, were also significantly lower in the ambrisentan group (0.46% ± 0.18% vs 1.11% ± 0.28%, respectively, P = 0.0003; and 0.12% ± 0.08% vs 0.25% ± 0.11%, respectively, P = 0.047). Moreover, hepatic RNA expression levels of procollagen-1 and tissue inhibitor of metalloproteinase-1 (TIMP-1) were significantly lower by 60% and 45%, respectively, in the ambrisentan group. Inflammation, steatosis, and endothelin-related mRNA expression in the liver were not significantly different between the groups.Ambrisentan attenuated the progression of hepatic fibrosis by inhibiting hepatic stellate cell activation and reducing procollagen-1 and TIMP-1 gene expression. Ambrisentan did not affect inflammation or steatosis.

Background: Kidney size is associated with renal function, however it is not elucidated whether kidney size is a risk for the progression of chronic kidney disease. The aim of this study was to investigate the predictive value of morphological evaluation of kidney size by ultrasonography for the progression of renal dysfunction. Methods: Morphological parameters including kidney length, volume, cortical thickness, and medullary thickness were measured by ultrasonography in 87 patients with chronic kidney disease, and adjusted by body size. Renal functions at baseline and after 2 years were measured and the associations of morphological parameters to decline in renal function over 2 years were analyzed. Results: Height-adjusted cortical thickness was correlated to decline in renal function (r = 0.426, p &lt, 0.001). Height-adjusted cortical thickness could predict renal dysfunction with the area under the curve of 0.786, and height-adjusted cortical thickness of 4.0 mm/cm was a cut off value with a sensitivity of 72.5% and a specificity of 80.0% for the risk of a more than 30% decline in renal function or initiation of dialysis. Conclusions: We provide new insights into the utility of measuring cortical thickness by ultrasonography for predict future renal impairment.

Objective Peribiliary cysts are usually benign, although severe complications and mortality may occur, and they may be confounded with other diseases. No classification delineating their different characteristics exists. Design We performed a systematic review of the frequency and clinical manifestations of peribiliary cysts. Two reviewers identified studies after searching multiple databases on 2 August 2017. Results These cysts were prevalent in cirrhosis (9%). A total of 135 patients were reported in 72 papers with sufficient clinical data (10 countries, 65% from Japan, median age 63 years (range: 4–88), and 80% were males). Symptoms were present in 70%. Misdiagnosis occurred in 40%, and 33% underwent therapeutic misadventures. Cysts were solitary in 10%. Obstructive features and cholangitis were observed in 36% and 12.5%, respectively. Cysts progression was observed in 37.5% over a median of 18 months. Mortality was 24%, mostly due to cirrhosis. A classification framework is proposed, wherein type I includes hepatic, type II extrahepatic and type III mixed hepatic and extrahepatic cysts, each having distinct features. Specifically, type II was more frequent in females, solitary, without cirrhosis, presenting with obstructive jaundice, more difficult to diagnose and required more surgical interventions (all p Conclusion Although rarely studied in the literature, peribiliary cysts were frequent in studies designed to evaluate their prevalence, and were mostly asymptomatic. Inaccurate diagnosis, therapeutic misadventures, cysts progression and cysts-related complications are frequent. In a novel classification framework based on location, extrahepatic peribiliary cysts have distinct characteristics and require a special approach for diagnosis and management.

This study aimed to compare the tissue stiffness of pancreatic ductal adenocarcinoma (PDAC) with that of pancreatic parenchyma using virtual touch quantification (VTQ). SWV was measured in 34 PDAC lesions and in pancreatic parenchyma of both controls and patients. SWVs in PDAC lesions were significantly higher than in pancreatic parenchyma in both healthy controls and in patients with PDAC. The area under the ROC for diagnosis of PDAC was 0.94 for pancreatic parenchyma in healthy controls, and 0.85 for pancreatic parenchyma in patients with PDAC. VTQ can provide a useful and additional information for diagnosis of PDAC.

Aims: The kidney becomes atrophic in advanced chronic kidney disease, and renal size and parenchymal volume correlate with renal function. However, alterations in renal parenchymal volume have not been adequately studied in terms of the renal cortex and medulla. We investigated the relationship between the changes in the renal cortex and medulla and renal function. Methods: Renal ultrasound (US) parameters including renal length, parenchymal thickness, cortical thickness and medullary thickness were assessed in 176 subjects, who were categorized into 4 groups based on the estimated glomerular filtration rate (ml/min/1.73 m2): group 1, ≥90; group 2, ≥60 but Results: We found stepwise associations in renal length, cortical thickness and parenchymal thickness with decreased renal function. Medullary thickness showed no changes among groups 1-3. Multiple linear regression analysis including sex, age and renal US parameters showed that only renal length was an independent predictor of renal function. When analyzed in groups 1-3, cortical thickness was the strongest associated parameter. Lower cortical left/right ratio (left cortical thickness/right cortical thickness) showed a stepwise association with a decrease in renal function. Conclusion: Renal length and cortical thickness measured by US were correlated with renal function. In particular, left cortical thickness could help to detect early changes in renal function.

Gastrointestinal stromal tumors (GISTs) are the most common submucosal tumors of the stomach. GISTs are often detected by esophagogastroduodenal endoscopy (EGD). However, the exophytic GIST type is relatively rare and difficult to detect by EGD. Most exophytic GISTs found are large and symptomatic. We present three cases with exophytic GISTs less than 5 cm in diameter detected by transabdominal ultrasound (TUS). All patients were asymptomatic and TUS revealed hypoechoic solid masses 2–3 cm in diameter between the stomach and left lobe of the liver. In contrast, no tumor in the stomach was detected by esophagogastroduodenal endoscopy. Endoscopic ultrasound and enhanced CT showed gastric tumors protruding outward. All three cases underwent partial gastrectomy, and the excised tumor was diagnosed as low-grade GIST. In conclusion, TUS can be a starting point for diagnosing exophytic GISTs of the stomach.

Background & Aims Simple steatosis (SS) and non-alcoholic steatohepatitis (NASH) are subtypes of non-alcoholic fatty liver disease (NAFLD), and the pathogenic differences between SS and NASH remain unclear. MicroRNAs (miRNAs) are endogenous, non-coding, short RNAs that regulate gene expression. The aim of this study was to use animal models and human samples to examine the relationship between miRNA expression profiles and each type of NAFLD (SS and NASH). Methods DD Shionogi, Fatty Liver Shionogi (FLS) and FLS ob/ob mice were used as models for normal control, SS and NASH, respectively. Microarray analysis and real-time PCR were used to identify candidate NAFLD-related miRNAs. Human serum samples were used to examine the expression profiles of these candidate miRNAs in control subjects and patients with SS or NASH. Results Fourteen miRNAs showed clear expression differences among liver tissues from SS, NASH, and control mice with good reproducibility. Among these NAFLD candidate miRNAs, seven showed similar expression patterns and were upregulated in both SS and NASH tissues; these seven candidate miRNAs mapped to an miRNA cluster in the 14q32.2 maternally imprinted region delineated by delta-like homolog 1 and type III iodothyronine deiodinase (Dlk1-Dio3 mat). Software-based predictions indicated that the transforming growth factor-β pathway, insulin like growth factor-1 and 5' adenosine monophosphate activated protein kinase were potential targets of theses Dlk1-Dio3 mat NAFLD candidate miRNAs. In addition, serum samples from patients with SS or NASH differed markedly with regard to expression of the putative Dlk1-Dio3 mat miRNAs, and these differences accurately corresponded with NAFLD diagnosis. Conclusion The expression profiles of seven miRNAs in 14q32.2 mat have high potential as biomarkers for NAFLD and for improving future research on the pathogenesis and treatment of NASH.