Baseline neutrophil-lymphocyte ratio and platelet-lymphocyte ratio appear predictive of immune treatment related toxicity in hepatocellular carcinoma

BACKGROUND A well-recognized class effect of immune checkpoint inhibitors(ICI)is immune-related adverse events(IrAEs)ranging from low grade toxicities to life-threatening end organ damage requiring permanent discontinuation of ICI.Deaths are reported in<5%of patients treated with ICI.There are,however,no reliable markers to predict the onset and severity of IrAEs.We tested the association between neutrophil-lymphocyte ratio(NLR)and platelet-lymphocyte ratio(PLR)at baseline with development of clinically significant IrAEs(grade≥2)in hepatocellular carcinoma(HCC)patients treated with ICI.AIM To test the association between NLR and PLR at baseline with development of clinically significant IrAEs(grade≥2)in HCC patients treated with ICI.METHODS Data was extracted from an international database from a consortium of 11 tertiary-care referral centers.NLR=absolute neutrophil count/absolute lymphocyte count(ALC)and PLR=platelet count/ALC.Cutoff of 5 was used for NLR and 300 for PLR based on literature.We also tested the association between RESULTS Data was collected from 361 patients treated between 2016-2020 across the United States(67%),Asia(14%)and Europe(19%).Most patients received Nivolumab(n=255,71%).One hundred sixty-seven(46%)patients developed at least one IrAE,highest grade 1 in 80(48%),grade≥2 in 87(52%)patients.In a univariable regression model PLR>300 was significantly associated with a lower incidence of grade≥2 IrAEs(OR=0.40;P=0.044).Similarly,a trend was observed between NLR>5 and lower incidence of grade≥2 IrAEs(OR=0.58;P=0.097).Multivariate analyses confirmed PLR>300 as an independent predictive marker of grade≥2 IrAEs(OR=0.26;P=0.011),in addition to treatment with programmed cell death ligand 1(PD-1)/cytotoxic T lymphocyte-associated protein-4(OR=2.57;P=0.037)and PD-1/tyrosine kinase inhibitor(OR=3.39;P=0.01)combinations.Antibiotic use was not associated with IrAE incidence(OR=1.02;P=0.954).Patients treated with steroids had a>2-fold higher incidence of grade≥2 IrAEs(OR=2.74;P<0.001),although 74%were prescribed steroids for the treatment of IrAEs.CONCLUSION Given that high baseline NLR and PLR are associated with a decreased incidence of IrAEs,lower baseline NLR and PLR may be predictive biomarkers for the appearance of IrAEs in HCC treated with ICI.This finding is in keeping with several studies in solid tumors that have shown that baseline NLR and PLR appear predictive of IrAEs.

Targeted and immune therapies for hepatocellular carcinoma:Predictions for 2019 and beyond

Systemic therapy for hepatocellular carcinoma(HCC) has markedly advanced since the survival benefit of a molecular targeted agent, sorafenib, were demonstrated in the SHARP and Asia Pacific trials in 2007. Treatment options for patients with advanced HCC increased by sorafenib, and long-term survival for patients with advanced stage HCC has become possible to some extent. However,development of a more potent first-line novel molecular targeted agent replacing sorafenib and a potent second-line agent after disease progression on or intolerant to sorafenib has been warranted because sorafenib lacks tumor shrinking/necrotizing effects and induces relatively severe adverse events such as hand foot skin reaction. Many agents in the 1 st line and 2 nd line setting were attempted to develop between 2007 and 2016, but all of these clinical trials failed.On the other hand, clinical trials of 4 agents(regorafenib, lenvatinib,cabozantinib, and ramucirumab) succeeded in succession in 2017 and 2018, and their use in clinical practice is possible(regorafenib and lenvatinib) or underway(cabozantinib and ramucirumab). Furthermore, all of 5 clinical trials of combination therapy with transcatheter chemoembolization(TACE) plus a molecular targeted agent failed to date, however, the combination of TACE and sorafenib(TACTICS trials) was reported to be successful and presented at ASCO in 2018. Phase 3 clinical trials of immune checkpoint inhibitors and a combination therapy of immune checkpoint inhibitors and molecular targeted agents are also ongoing, which suggests treatment paradigm of HCC in all stages from early,intermediate and advanced stage, is expected to be changed drastically in the very near future.

Review of dynamic contrast-enhanced ultrasound guidance in ablation therapy for hepatocellular carcinoma

Local ablative techniques-percutaneous ethanol injection, microwave coagulation therapy and radiofrequency ablation (RFA)-have been developed to treat unresectable hepatocellular carcinoma (HCC). The success rate of percutaneous ablation therapy for HCC depends on correct targeting of the tumor via an imaging technique. However, probe insertion often is not completely accurate for small HCC nodules, which are poorly def ined on conventional B-mode ultrasound (US) alone. Thus, multiple sessions of ablation therapy are frequently required in diffi cult cases. By means of two breakthroughs in US technology, harmonic imaging and the development of second-generation contrast agents, dynamic contrast-enhanced harmonic US imaging with an intravenous contrast agent can depict tumor vascularity sensitively and accurately, and is able to evaluate small hypervascular HCCs even when B-mode US cannot adequately characterize the tumors. Therefore, dynamic contrast-enhanced US can facilitate RFA electrode placement in hypervascular HCC, which is poorly depicted by B-mode US. The use of dynamic contrast-enhanced US guidance in ablation therapy for liver cancer is an effi cient approach. Here, we present an overview of the current status of dynamic contrast-enhanced US-guided ablation therapy, and summarize the current indications and outcomes of reported clinical use in comparison with that of other modalities.

Urgent endoscopic ultrasound-guided choledochoduodenostomy for acute obstructive suppurative cholangitis-induced sepsis

Acute obstructive suppurative cholangitis(AOSC) due to biliary lithiasis is a life-threatening condition that requires urgent biliary decompression. Although endoscopic retrograde cholangiopancreatography(ERCP) with stent placement is the current gold standard for biliary decompression, it can sometimes be difficult because of failed biliary cannulation. In this retrospective case series, we describe three cases of successful biliary drainage with recovery from septic shock after urgent endoscopic ultrasound-guided choledochoduodenostomy(EUS-CDS) was performed for AOSC due to biliary lithiasis. In all three cases, technical success in inserting the stents was achieved and the patients completely recovered from AOSC with sepsis in a few days after EUS-CDS. There were no procedure-related complications. When initial ERCP fails, EUS-CDS can be an effective life-saving endoscopic biliary decompression procedure that shortens the procedure time and prevents post-ERCP pancreatitis, particularly in patients with AOSC-induced sepsis.

Efficacy of treatment with rebamipide for endoscopic submucosal dissection-induced ulcers

AIM:To prospectively compare the healing rates of endoscopic submucosal dissection(ESD)-induced ulcers treated with either a proton-pump inhibitor(PPI)or rebamipide.METHODS:We examined 90 patients with early gastric cancer who had undergone ESD.All patients were administered an intravenous infusion of the PPI lansoprazole(20 mg)every 12 h for 2 d,followed by oral administration of lansoprazole(30 mg/d,5 d).After7-d treatment,the patients were randomly assigned to 2 groups and received either lansoprazole(30 mg/d orally,n=45;PPI group)or rebamipide(300 mg orally,three times a day;n=45;rebamipide group).At 4and 8 wk after ESD,the ulcer outcomes in the 2 groups were compared.RESULTS:No significant differences were noted in patient age,underlying disease,tumor location,Helicobacter pylori infection rate,or ESD-induced ulcersize between the 2 groups.At both 4 and 8 wk,the healing rates of ESD-induced ulcers were similar in the PPI-treated and the rebamipide-treated patients(4 wk:PPI,27.2%;rebamipide,33.3%;P=0.5341;8 wk:PPI,90.9%;rebamipide,93.3%;P=0.6710).At 8 wk,the rates of granulation lesions following ulcer healing were significantly higher in the PPI-treated group(13.6%)than in the rebamipide-treated group(0.0%;P=0.0103).Ulcer-related symptoms were similar in the2 treatment groups at 8 wk.The medication cost of 8-wk treatment with the PPI was 10945 yen vs 4889 yen for rebamipide.No ulcer bleeding or complications due to the drugs were observed in either treatment group.CONCLUSION:The healing rate of ESD-induced ulcers was similar with rebamipide or PPI treatment;however,rebamipide treatment is more cost-effective and prevents granulation lesions following ulcer healing.

Radiofrequency ablation of hepatocellular carcinoma:Current status

Ablation therapy is one of the best curative treatment options for malignant liver tumors,and can be an alternative to resection.Radiofrequency ablation(RFA) of primary and secondary liver cancers can be performed safely using percutaneous,laparoscopic,or open surgical techniques,and RFA has markedly changed the treatment strategy for small hepatocellular carcinoma(HCC).Percutaneous RFA can achieve the same overall and disease-free survival as surgical resection for patients with small HCC.The use of a laparoscopic or open approach allows repeated placements of RFA electrodes at multiple sites to ablate larger tumors.RFA combined with transcatheter arterial chemoembolization will make the treatment of larger tumors a clinically viable treatment alternative.However,an accurate evaluation of treatment response is very important to secure successful RFA therapy.Since a sufficient safety margin(at least 0.5 cm) can prevent local tumor recurrences,an accurate evaluation of treatment response is very important to secure successful RFA therapy.To minimize complications of RFA,clinicians should be familiar with the imaging features of each type of complication.Appropriate management of complications is essential for successful RFA treatment.

Therapeutic response assessment of RFA for HCC:Contrast-enhanced US,CT and MRI

Radiofrequency ablation(RFA)is commonly applied for the treatment of hepatocellular carcinoma(HCC)because of the facile procedure,and the safety and effectiveness for the treatment of this type of tumor.On the other hand,it is believed that HCC cells should spread predominantly through the blood flow of the portal vein,which could lead to the formation of intrahepatic micrometastases.Therefore,monitoring tumor response after the treatment is quite important and accurate assessment of treatment response is critical to obtain the most favorable outcome after the RFA.Indeed,several reports suggested that even small HCCs of≤3 cm in diameter might carry intrahepatic micrometastases and/or microvascular invasion.From this point of view,for preventing local recurrences,RFA should be performed ablating a main tumor as well as its surrounding non-tumorous liver tissue where micrometastases and microvascular invasion might exist.Recent advancement of imaging modalities such as contrast-enhanced ultrasonic,computed tomography,and magnetic resonance imaging are playing an important role on assessing the therapeutic effects of RFA.The local recurrence rate tends to be low in HCC patients who were proven to have adequate ablation margin after RFA;namely,not only disappearance of vascular enhancement of main tumor,but also an adequate ablation margin.Therefore,contrast enhancement gives important findings for the diagnosis of recurrent HCCs on each imaging.However,hyperemia of non-tumorous liver surrounding the ablated lesion,which could be attributed to an inflammation after RFA,may well obscure the findings of local recurrence of HCCs after RFA.Therefore,we need to carefully address to these imaging findings given the fact that diagnostic difficulties of local recurrence of HCC.Here,we give an overview of the current status of the imaging assessment of HCC response to RFA.

Signaling pathway/molecular targets and new targeted agents under development in hepatocellular carcinoma

Advances in molecular cell biology over the last decade have clarified the mechanisms involved in cancer growth,invasion,and metastasis,and enabled the development of molecular-targeted agents.To date,sorafenib is the only molecular-targeted agent whose survival benefit has been demonstrated in two global phase Ⅲ randomized controlled trials,and has been approved worldwide.Phase Ⅲ clinical trials of other molecular targeted agents comparing them with sorafenib as first-line treatment agents are ongoing.Those agents target the vascular endothelial growth factor,platelet-derived growth factor receptors,as well as target the epidermal growth factor receptor,insulinlike growth factor receptor and mammalian target of rapamycin,in addition to other molecules targeting other components of the signal transduction pathways.In addition,the combination of sorafenib with standard treatment,such as resection,ablation,transarterial embolization,and hepatic arterial infusion chemotherapy are ongoing.This review outlines the main pathways involved in the development and progression of hepatocellular carcinoma and the new agents that target these pathways.Finally,the current statuses of clinical trials of new agents or combination therapy with sorafenib and standard treatment will also be discussed.

Removal of diminutive colorectal polyps: A prospective randomized clinical trial between cold snare polypectomy and hot forceps biopsy

AIM To compare the efficacy and safety of cold snare polypectomy(CSP) and hot forceps biopsy(HFB) for diminutive colorectal polyps.METHODS This prospective, randomized single-center clinical trial included consecutive patients ≥ 20 years of age with diminutive colorectal polyps 3-5 mm from December 2014 to October 2015. The primary outcome measures were en-bloc resection(endoscopic evaluation) and complete resection rates(pathological evaluation). The secondary outcome measures were the immediate bleeding or immediate perforation rate after polypectomy, delayed bleeding or delayed perforation rate after polypectomy, use of clipping for bleeding or perforation, and polyp retrieval rate. Prophylactic clipping after polyp removal wasn't routinely performed.RESULTS Two hundred eight patients were randomized into the CSP(102), HFB(106) and 283 polyps were evaluated(CSP: 148, HFB: 135). The en-bloc resection rate was significantly higher with CSP than with HFB [99.3%(147/148) vs 80.0%(108/135), P < 0.0001]. The complete resection rate was significantly higher with CSP than with HFB [80.4%(119/148) vs 47.4%(64/135), P < 0.0001]. The immediate bleeding rate was similar between the groups [8.6%(13/148) vs 8.1%(11/135), P = 1.000], and endoscopic hemostasis with hemoclips was successful in all cases. No cases of perforation or delayed bleeding occurred. The rate of severe tissue injury to the pathological specimen was higher HFB than CSP [52.6%(71/135) vs 1.3%(2/148), P < 0.0001]. Polyp retrieval failure was encountered CSP(7), HFB(2).CONCLUSION CSP is more effective than HFB for resecting diminutive polyps. Further long-term follow-up study is required.

Diagnosis of subepithelial tumors in the upper gastrointestinal tract by endoscopic ultrasonography

Endoscopic ultrasonography(EUS) is the most accurate procedure for detecting and diagnosing subepithelial tumors,due to its higher sensitivity and specificity than other imaging modalities.EUS can characterize lesions by providing information on echogenic origin,size,borders,homogeneity,and the presence of echogenic or anechoic foci.Linear echoendoscopes,and recently also electronic radial echoendoscopes,can be used with color Doppler or power Doppler to assess the vascular signals from subepithelial masses,and thus permit the differentiation of vascular structures from cysts,as well as the assessment of the tumor blood supply.However,the diagnostic accuracy of EUS imaging alone has been shown to be low in subepithelial lesions with 3rd and 4th layers.It is also difficult to differentiate exactly between benign and malignant tumors and to gain an accurate picture of histology using EUS.On the other hands,EUS guided fine needle aspiration(EUS-FNA) can provide samples for cytologic or histologic analysis.Hypoechoic lesions of the 3rd and the 4th EUS layers,more than in 1 cm diameter are recommended,and histologic confirmation using endoscopic submucosal resection or EUSFNA should be obtained when possible.Therefore,EUSFNA plays an important role in the clinical management of subepithelial tumors.Furthermore improvements in endoscopic technology are expected to be more useful modalities in differential diagnosis and discrimination between benign and malignant subepithelial

Autoimmune hepatitis and IgG4-related disease

IgG4-related disease(IgG4-RD) is a chronic-fibroinflammatory disorder affecting a wide range of organs. Elevation of serum IgG4 concentrations and abundant infiltration of IgG4-expressing plasma cells are key diagnostic features of this autoimmune disease. Although common organ involvement of IgG4-RD includes the salivary glands, pancreas, and bile duct, hepatic involvement is less well established. Recently, five studies identified a subtype of autoimmune hepatitis(AIH), called IgG4-associated AIH(IgG4-AIH). IgG4-AIH is diagnosed based on significant accumulation of IgG4-expressing plasmacytes in the liver in patients who met the diagnostic criteria for classical AIH. Although four of the five reports regarded IgG4-AIH based on hepatic accumulation of IgG4-positive cells alone, one report diagnosed IgG4-AIH based on both hepatic accumulation of IgG4-positive cells and elevated serum concentrations of IgG4. IgG4-AIH diagnosed based on the latter criteria may be a hepatic manifestation of IgG4-RD whereas IgG4-AIH diagnosed based on the former criteria may be a subtype of AIH. In this review article, we summarize and discuss clinicopathological features of IgG4-AIH.

Long-term outcome of percutaneous ethanol injection therapy for minimum-sized hepatocellular carcinoma

AIM: To evaluate long-term follow-up of minimum-sized hepatocellular carcinoma (HCC) treated with percutaneous ethanol injection (PEI). METHODS: PEI was applied to 42 lesions in 31 patients (23 male and eight female) with HCC < 15 mm in diameter, over the past 15 years. RESULTS: Overall survival rate was 74.1% at 3 years, 49.9% at 5 years, 27.2% at 7 years and 14.5% at 10 years. These results are superior to, or at least the same as those for hepatic resection and radiofrequency ablation. Survival was affected only by liver function, but not by sex, age, etiology of Hepatitis B virus or Hepatitis C virus, α-fetoprotein levels, arterial and portal blood flow, histological characteristics, and tumor multiplicity or size. Patients in Child-Pugh class A and B had 5-, 7- and 10-years survival rates of 76.0%, 42.2% and 15.8%, and 17.1%, 8.6% and 0%, respectively (P = 0.025). CONCLUSION: Treatment with PEI is best indicated for patients with HCC < 15 mm in Child-Pugh class A.

Contrast-enhanced harmonic endoscopic ultrasonography for assessment of lymph node metastases in pancreatobiliary carcinoma

AIM: To assess the usefulness of contrast-enhanced harmonic endoscopic ultrasonography(CH-EUS) for lymph node metastasis in pancreatobiliary carcinoma.METHODS: All patients suspected of pancreatobiliary carcinoma with visible lymph nodes after standard EUS between June, 2009 and January, 2012 were enrolled.In the primary analysis, patients with successful EUSfine needle aspiration(FNA) were included. The lymph nodes were assessed by several standard EUS variables(short and long axis lengths, shape, edge characteristic and echogenicity), color Doppler EUS variable [central intranodal blood vessel(CIV) presence] and CH-EUS variable(heterogeneous/homogeneous enhancement patterns). The diagnostic accuracy relative to EUSFNA was calculated. In the second analysis, N-stage diagnostic accuracy of CH-EUS was compared with EUS-FNA in patients who underwent surgical resection.RESULTS: One hundred and nine patients(143 lymph nodes) fulfilled the criteria. The short axis cutoff ≥ 13 mm predicted malignancy with a sensitivity and specificity of 72% and 85%, respectively. These values were 72% and 63% for the long axis cut-off ≥ 20 mm, 62% and 75% for the round shape variable, 81% and 30% for the sharp edge variable, 66% and 61% for the hypoechogenicity variable, 70% and 72% for the CIV-absent variable, and 83% and 91% for the heterogeneous CH-EUS-enhancement variable, respectively. CH-EUS was more accurate than standard and color Doppler EUS, except the short axis cut-off. Notably, three patients excluded because of EUS-FNA failure were correctly N-staged by CH-EUS.CONCLUSION: CH-EUS complements standard and color Doppler EUS and EUS-FNA for assessment of lymph node metastases.

Can the biliary enhancement of Gd-EOB-DTPA predict the degree of liver function?

BACKGROUND: Excretion of gadolinium-ethoxybenzyl-diethyl- enetriamine pentaacetic acid (Gd-EOB-DTPA) in the bile may be related to liver function, because of elimination from the liver after preferential uptake by hepatocytes. The purpose of this study was to investigate the relation between liver and biliary enhancement in patients with or without liver dysfunction, and to compare the tumor-to-liver contrast in these patients. METHODS: Forty patients [group 1: normal liver and Child Pugh class A in 20 patients, group 2: Child-Pugh class B in 18 patients and Child-Pugh C in 2] were evaluated. All patients underwent MR imaging of the liver using a 1.5-Tesla system. T1 weighted 3D images were obtained at 5, 10, 15 and 20 minutes after Gd-EOB-DTPA injection. The relation between group 3 (total bilirubin <1.8 mg/dL) and group 4 (total bilirubin ≥1.8 mg/dL) was investigated at 20 minutes. Liver and biliary signals were measured, and compared between groups 1 and 2 or groups 3 and 4. Tumor-to-liver ratio was also evaluated between groups 1 and 2. Scheffé’s post-hoc test after two-way repeated measures ANOVA and Pearson’s correlation test were used for statistical analysis. RESULTS: Liver enhancement showed significant difference at all time points between groups 1 and 2. Biliary enhancement did not show a significant difference between groups 1 and 2 at 5 minutes, but did at 10, 15 and 20 minutes. At 20 minutes significant differences between groups 3 and 4 were seen for liver and biliary enhancement. At all time points, liver enhancement correlated with biliary enhancement in both groups. At 5 minutes and 20 minutes, statistical differences between groups 1 and 2 were seen for tumor-to-liver ratio.CONCLUSIONS: The degree of biliary enhancement has a close correlation to that of liver enhancement. It is especially important that insufficient liver enhancement causes lower tumor-to-liver contrast in the hepatobiliary phase of Gd-EOB- DTPA.

Antiviral therapy for chronic hepatitis B: Combination of nucleoside analogs and interferon

The ideal goal of chronic hepatitis B(CHB) treatment should be suppression of emergence of hepatocellular carcinoma through the disappearance of hepatitis B s antigen(HBs Ag) rather than the control of serum hepatitis B virus-DNA level. For this purpose, various types of combination therapies using nucleoside analogs(NAs) and interferon(IFN) have been conducted. The therapeutic effects of combination of two different kinds of agents are better than those of the monotherapy using NAs or IFN alone, probably because different pharmaceutical properties might act in a coordinated manner. Recently, combination therapies with NAs and IFN and sequential therapies with NAs administration followed by IFN therapy have been routinely employed. We previously reported that combination therapy using entecavir(ETV) and pegylated(PEG)-IFN showed antiviral effects in 71% of CHB patients; the effect of this combination was better than that using lamivudine(LAM) and PEG-IFN. This is partially explained by the better antiviral effects of ETV than those of LAM. In our analysis, the cohort of CHB consisted of the patients who showed a flare-up of hepatitis before antiviral therapy, and their baseline HBs Ag levels were relatively low. Therefore, in addition to the combination of the agents, the appropriate selection of patients is critical to achieve a good viral response.

Hemodynamic and morphologic changes of peripheral hepatic vasculature in cirrhotic liver disease: A preliminary study using contrast-enhanced coded phase inversion harmonic ultrasonography

AIM: To provide the useful information for the diagnosis of liver cirrhosis by observing the morphology of peripheral hepatic vessels and the hemodynamics of microbubble arrival time in these vessels.METHODS: Twenty-one subjects including 5 normal volunteers and 16 patients (liver cirrhosis, n=10;chronic hepatitis, n=6) were studied by contrast-enhanced coded phase inversion harmonic sonography (GE LOGIQ9 series) using a 6-8 MHz convex-arrayed wide-band transducer. The images of peripheral hepatic artery,portal and hepatic vein were observed in real-time for about 2 min after intravenous injection of Levovist. The time when microbubbles appeared in the peripheral vessels (microbubble arrival time) was also recorded. The morphologic changes of peripheral hepatic vasculature were classified as marked, slight, and no changes based on the regularity in caliber, course, ramification, and the delineation of vessels compared to normal subjects.RESULTS: The microbubble arrival time at peripheral artery, portal, and hepatic vein was shorter in cirrhotic patients than in chronic hepatitis patients and normal subjects. The marked, slight and no morphologic changes of peripheral hepatic vasculature found in 5 (5/6,83.3%), 1 (1/6, 16.7% ), and 0 (0/6, 0%) liver cirrhosis patients, respectively, and in 1 (1/10, 10%), 6 (6/10,60%), and 3 (3/10, 30%) chronic hepatitis patients,respectively. There was a significant difference between the two groups (P＜0.001).CONCLUSION: Evaluation of the hemodynamics and morphology of peripheral hepatic vasculature by contrast-enhanced coded pulse inversion harmonic sonography can provide useful information for the diagnosis of liver cirrhosis.

Diagnosis of pancreatic tumors by endoscopic ultrasonography

Pancreatic tumors are highly diverse, as they can be solid or cystic, and benign or malignant. Since their imaging features overlap considerably, it is often difficult to characterize these tumors. In addition, small pancreatic tumors, especially those less than 2 cm in diameter, are difficult to detect and diagnose. For characterizing pancreatic tumors and detecting small pancreatic tumors, endoscopic ultrasonography (EUS) is the most sensitive of the imaging procedures currently available. This technique also provides good results in terms of the preoperative staging of pancreatic tumors. EUS-guided fine needle aspiration (EUS-FNA) has also proved to be a safe and useful method for tissue sampling of pancreatic tumors. Despite these advantages, however, it is still difficult to differentiate between be-nign and malignant, solid or cystic pancreatic tumors, malignant neoplasms, and chronic pancreatitis using EUS, even when EUS-FNA is performed. Recently, contrast-enhanced EUS with Doppler mode (CE-EUS) employing ultrasound contrast agents, which indicate vascularization in pancreatic lesions, has been found to be useful in the differential diagnosis of pancreatic tumors, especially small pancreatic tumors. However, Doppler ultrasonography with contrast-enhancement has several limitations, including blooming artifacts, poor spatial resolution, and low sensitivity to slow flow. Consequently, an echoendoscope was developed recently that has a broad-band transducer and an imaging mode that was designed specifically for contrastenhanced harmonic EUS (CEH-EUS) with a secondgeneration ultrasound contrast agent. The CEH-EUS technique is expected to improve the differential diagnosis of pancreatic disease in the future. This review describes the EUS appearances of common solid and cystic pancreatic masses, the diagnostic accuracy of EUS-FNA, and the relative efficacies and advantages of CE-EUS and CEH-EUS along with their relative advantages and their complementary roles in clinical practice.

Biomarkers in autoimmune pancreatitis and immunoglobulin G4-related disease

Solitary organ autoimmune disorders,formerly known as autoimmune pancreatitis(AIP),autoimmune sialadenitis,and autoimmune sclerosing cholangitis,are now considered organ-specific manifestations of systemic immunoglobulin G4-related disease(IgG4-RD).AIP and IgG4-RD are characterized by elevated serum concentration of IgG4 antibody(Ab),accumulation of IgG4-expressing plasmacytes in the affected organs,and involvement of multiple organs.It is well established that enhanced IgG4 Ab responses are a hallmark of AIP and IgG4-RD for diagnosis and monitoring disease activity.However,a significant fraction of patients with AIP and IgG4-RD who develop chronic fibroinflammatory responses have normal serum concentrations of this IgG subtype.In addition,disease flare-up is sometimes seen even in the presence of normalized serum concentrations of IgG4 Ab after successful induction of remission by prednisolone.Therefore,it is necessary to identify new biomarkers based on the understanding of the pathophysiology of AIP and IgG4-RD.Recently,we found that activation of plasmacytoid dendritic cells producing both interferon-α(IFN-α)and interleukin-33(IL-33)mediate murine AIP and human IgG4-RD.More importantly,we provided evidence that serum concentrations of IFN-αand IL-33 could be useful biomarkers for the diagnosis and monitoring of AIP and IgG4-RD activity after induction of remission in these autoimmune disorders.In this Frontier article,we have summarized and discussed biomarkers of AIP and IgG4-RD,including Igs,autoAbs,and cytokines to provide useful information not only for clinicians but also for researchers.

Endoscopic ultrasound-guided gallbladder drainage for acute cholecystitis: Long-term outcomes after removal of a self-expandable metal stent

AIM To assess the long-term outcomes of this procedure after removal of self-expandable metal stent(SEMS). The efficacy and safety of endoscopic ultrasoundguided gallbladder drainage(EUS-GBD) with SEMS were also assessed.METHODS Between January 2010 and April 2015, 12 patients with acute calculous cholecystitis, who were deemed unsuitable for cholecystectomy, underwent EUSGBD with a SEMS. EUS-GBD was performed under the guidance of EUS and fluoroscopy, by puncturing the gallbladder with a needle, inserting a guidewire, dilating the puncture hole, and placing a SEMS. TheSEMS was removed and/or replaced with a 7-Fr plastic pigtail stent after cholecystitis improved. The technical and clinical success rates, adverse event rate, and recurrence rate were all measured.RESULTS The rates of technical success, clinical success, and adverse events were 100%, 100%, and 0%, respectively. After cholecystitis improved, the SEMS was removed without replacement in eight patients, whereas it was replaced with a 7-Fr pigtail stent in four patients. Recurrence was seen in one patient(8.3%) who did not receive a replacement pigtail stent. The median follow-up period after EUS-GBD was 304 d(78-1492).CONCLUSION EUS-GBD with a SEMS is a possible alternative treatment for acute cholecystitis. Long-term outcomes after removal of the SEMS were excellent. Removal of the SEMS at 4-wk after SEMS placement and improvement of symptoms might avoid migration of the stent and recurrence of cholecystitis due to food impaction.

Diagnostic sensitivity of imaging modalities for hepatocellular carcinoma smaller than 2 cm

AIM:To compare the imaging results with histology and to evaluate the diagnostic sensitivity of imaging modalities for hepatocellular carcinoma(HCC)smaller than 2 cm.METHODS:Nodules smaller than 2 cm(n=34)revealed by ultrasonography(US)in 29 patients with liver cirrhosis were analyzed.Histological diagnosis of HCC was performed by ultrasonographic guidance:moderately-differentiated HCC(n=24);well-differentiated HCC(n=10).The patterns disclosed by the four imaging modalities defined the conclusive diagnosis of HCC:(1)contrast-enhanced computed tomography(CECT),hypervascularity in the arterial phase and washout in the equilibrium phase;(2)Sonazoid contrast-enhanced US(CEUS),hypervascularity in the early vascular phase and defect in the Kupffer phase;(3)gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid(Gd-EOBDTPA)-enhanced magnetic resonance imaging(MRI),hypervascularity in the arterial phase and/or defect in the hepatobiliary phase;and(4)CT arterioportal angiography:hypervascularity by CT during arteriography and/ or perfusion defect by CT during arterial portography.RESULTS:Overall,the sensitivity of diagnosing HCC smaller than 2 cm was 52.9%(18/34)(95%CI:35.170.2)by CECT;67.6%(23/34)(95%CI:49.5-82.6)by Sonazoid CEUS;76.5%(26/34)(95%CI:58.8-89.3) by Gd-EOB-DTPA MRI;and 88.2%(30/34)(95%CI: 72.5-96.7)by CT arterioportal angiography.The diagnostic sensitivity of detecting moderately-differentiated HCC by CECT,Sonazoid CEUS,Gd-EOB-DTPA MRI and CT arterioportal angiography was 62.5%(15/24)(95%CI: 40.6-81.2),79.2%(19/24)(95%CI:57.8-92.9),75.0% (18/24)(95%CI:53.3-90.2)and 95.8%(23/24)(95% CI:78.9-99.9),respectively.A significant difference(P< 0.05)was observed between CECT and CT arterioportal angiography in all nodules.There was no difference between Sonazoid CEUS,Gd-EOB-DTPA MRI,and CT arterioportal angiography.The combined sensitivity of Sonazoid CEUS and Gd-EOB-DTPA MRI was 94.1%(32/34).CONCLUSION:Changing the main diagnostic modality for HCC smaller than 2 cm from CT arterioportal angiography to Sonazoid CEUS and Gd-EOB-DTPA MRI is recommended.