Haruo Miwa

Contrast-enhanced ultrasonography findings using a perflubutane-based contrast agent in patients with early hepatocellular carcinoma

OBJECTIVE We evaluated the contrast-enhanced ultrasonography (US) imaging features of early hepatocellular carcinomas (HCCs) and compared these findings with those obtained using contrast-enhanced computed tomography (CT). SUBJECTS AND METHODS Forty-three patients with 52 early HCCs with a mean maximal diameter of 15.6mm were enrolled in this retrospective study. After confirming the location of the target lesion using fusion imaging combining conventional US and hepatobiliary phase of contrast-enhanced magnetic resonance (MR) imaging with gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid, we evaluated findings of contrast-enhanced US using a perflubutane-based contrast agent. The contrast-enhanced US detection rates for hyper-vascularity in early HCCs were compared with those obtained for contrast-enhanced CT. RESULTS Transient hypo-vascularity subsequent to iso-vascularity during arterial phase and iso-vascularity during portal and post-vascular phases were the predominant contrast-enhanced US findings seen for 25 (48.1%) of the 52 early HCCs. Nine (17.3%) showed iso-vascularity during all three phases, while 1 (1.9%) showed hypo-vascularity during all three phases. The remaining 17 (32.7%) showed partial or whole hyper-vascularity during arterial phase, iso-vascularity during portal phase, and iso- or hypo-vascularity during post-vascular phase. The detection rate for the hyper-vascularity of early HCCs using contrast-enhanced US (32.7%, 17/52) was significantly higher than that obtained using contrast-enhanced CT (21.2%, 11/52) (P<0.05 by McNemar test). CONCLUSION Hypo-vascularity, iso-vascularity, and hyper-vascularity were observed during the arterial phase of contrast-enhanced US in 50.0%, 17.3%, and 32.7% of the early HCCs, respectively. Contrast-enhanced US was more sensitive than contrast-enhanced CT for the detection of hyper-vascularity in early HCCs. Of note, early HCCs might not exhibit the early arterial enhancement that is generally considered to be a typical finding for HCCs.

The Superiority of Vonoprazan-based First-line Triple Therapy with Clarithromycin: A Prospective Multi-center Cohort Study on Helicobacter pylori Eradication

Objective We evaluated the safety and efficacy of vonoprazan-based amoxicillin and clarithromycin 7-day triple therapy (VAC) in comparison to proton pump inhibitor (PPI)-based (PAC) as a first-line treatment and vonoprazan-based amoxicillin and metronidazole 7-day triple therapy (VAM) in comparison to PPI-based (PAM) as a second-line treatment for the eradication of Helicobacter pylori in Japan. Methods We performed a non-randomized, multi-center, parallel-group study to compare first-line VAC to PAC and second-line VAM to PAM. A pre-planned subgroup analysis on CAM resistance was also performed. Safety was evaluated with an adverse effects questionnaire (AEQ), which was completed by patients during therapy. Results The first-line eradication rates (ER) in the intention-to-treat (ITT) and per protocol (PP) analyses were 84.9% (95% CI: 81.9-87.6%, n=623) and 86.4% (83.5-89.1%, n=612), respectively, for VAC and 78.8% (75.3-82.0%, n=608) and 79.4% (76.0-82.6%, n=603), respectively, for PAC. The ER of VAC was higher than that of PAC in the ITT (p=0.0061) and PP analyses (p=0.0013). The ERs for VAC in patients with CAM-resistant and CAM-susceptible bacteria were 73.2% (59.7-84.2%, n=56) and 88.9% (83.4-93.1%, n=180), respectively. PAC was associated with higher AEQ scores for diarrhea, nausea, headache, and general malaise. In the second-line ITT and PP analyses VAM achieved ERs of 80.5% (74.6-85.6%, n=216) and 82.4% (76.6-87.3%, n=211), respectively, while PAM achieved ERs of 81.5% (74.2-87.4%, n=146) and 82.1% (74.8-87.9%, n=145), respectively. No significant differences were observed in the ITT (p=0.89) or PP (p=1.0) analyses. Conclusion The ER of first-line VAC was higher than that of PAC, but still <90%. No difference was observed between second-line VAM and PAM. Vonoprazan-based triple therapy was safe and well tolerated.

Intestine-specific homeobox (ISX) induces intestinal metaplasia and cell proliferation to contribute to gastric carcinogenesis.

BackgroundHelicobacter pylori induces chronic inflammation and intestinal metaplasia (IM) through genetic and epigenetic changes and activation of intracellular signaling pathways that contribute to gastric carcinogenesis. However, the precise mechanism of IM in gastric carcinogenesis has not been fully elucidated. We previously found that intestine-specific homeobox (ISX) mRNA expression increased in organoids cultured from Helicobacter-infected mouse mucosa. In this study, we elucidate the role of ISX in the development of IM and gastric carcinogenesis.MethodsISX expression was assessed in Helicobacter-infected mouse and human gastric mucosa. MKN45 gastric cancer cells were co-cultured with H. pylori to determine whether Helicobacter infection induced ISX expression. We established stable MKN45 transfected cells expressing ISX (Stable-ISX MKN45) and performed a spheroid colony formation assay and a xenograft model. We performed ISX immunohistochemistry in cancer and adjacent gastric tissues.ResultsISX expression was increased in mouse and human gastric mucosa infected with Helicobacter. The presence of IM and H. pylori infection in human stomach was correlated with ISX expression. H. pylori induced ISX mRNA and protein expression. CDX1/2, cyclinD1, and MUC2 were upregulated in Stable-ISX MKN45, whereas MUC5AC was downregulated. Stable-ISXMKN45 cells formed more spheroid colonies, and had high tumorigenic ability. ISX expression in gastric cancer and adjacent mucosa were correlated.ConclusionsISX expression induced by H. pylori infection may lead to IM and hyperproliferation of gastric mucosa through CDX1/2 and cyclinD1 expression, contributing to gastric carcinogenesis.

Efficacy of plastic stent placement inside bile ducts for the treatment of unresectable malignant hilar obstruction (with videos)

Recent reports have addressed the utility of plastic stent (PS) placement inside bile ducts for treating biliary obstructions. Here, we evaluated the utility and safety of PS placement inside bile ducts for treating unresectable malignant hilar biliary obstruction.

Diagnosis of pancreatic lesions collected by endoscopic ultrasound-guided fine-needle aspiration using next-generation sequencing

Endoscopic ultrasound-guided fine-needle aspiration (EUF-FNA) has improved the diagnosis of pancreatic lesions. Next-generation sequencing (NGS) facilitates the production of millions of sequences concurrently. Therefore, in the current study, to improve the detectability of oncogenic mutations in pancreatic lesions, an NGS system was used to diagnose EUS-FNA samples. A total of 38 patients with clinically diagnosed EUS-FNA specimens were analyzed; 27 patients had pancreatic ductal adenocarcinoma (PDAC) and 11 had non-PDAC lesions. DNA samples were isolated and sequenced by NGS using an Ion Personal Genome Machine system. The Cancer Hotspot Panel v2, which includes 50 cancer-related genes and 2,790 COSMIC mutations, was used. A >2% mutation frequency was defined as positive. KRAS mutations were detected in 26 of 27 PDAC aspirates (96%) and 0 of 11 non-PDAC lesions (0%). The G12, G13, and Q61 KRAS mutations were found in 25, 0, and 1 of the 27 PDAC samples, respectively. Mutations were confirmed by TaqMan® polymerase chain reaction analysis. TP53 mutations were detected in 12 of 27 PDAC aspirates (44%). SMAD4 was observed in 3 PDAC lesions and cyclin-dependent kinase inhibitor 2A in 4 PDAC lesions. Therefore, the current study was successfully able to develop an NGS assay with high clinical sensitivity for EUS-FNA samples.

Differential diagnosis of solid pancreatic lesions using contrast-enhanced three-dimensional ultrasonography

PurposeTo investigate the usefulness of contrast-enhanced three-dimensional ultrasonography (CE 3D US) for differential diagnosis of solid pancreatic lesions.MethodsEighty-five patients with solid pancreatic lesions who underwent CE 3D US were retrospectively analyzed. Sixty-four patients had pancreatic ductal adenocarcinoma (PDAC), 10 had mass-forming pancreatitis (MFP), and 11 had neuroendocrine tumor (NET). Two blinded readers evaluated the enhancement patterns using four features: vascularity in the arterial phase, vascularity in the venous phase, vessel location, and vessel form. Vascularity in both phases was classified as hypervascular, isovascular, or hypovascular. Vessel location was classified into peritumoral or intratumoral. Vessel form was classified into fine or irregular. Kappa values were used to assess inter-reader agreement. The institutional review board approved this study, and informed consent was obtained.ResultsKappa values of the four features were 0.75, 0.72, 0.85, and 0.65, which were graded as good or excellent. The most typical combined enhancement pattern in PDAC was hypovascularity in both phases with peritumoral and irregular vessels; MFP was isovascular in both phases with intratumoral and fine vessels; and NETs were hypervascular in both phases with intratumoral and irregular vessels. The sensitivity and positive predictive value of the three patterns were 93.8% and 96.7% for the PDAC pattern, 80.0% and 100% for the MFP pattern, and 81.8%, and 69.2% for the NET pattern, respectively. The accuracy of these diagnostic criteria was 90.5%.ConclusionCE 3D US allows detailed visualization of the enhancement patterns of various pancreatic lesions and can be used for the differential diagnosis.

Mo1190 Differential Diagnosis of Solid Pancreatic Lesions by Using Three-Dimensional Contrast Enhanced Ultrasonography With High Mechanical Index Mode

Background: We have shown that pancreas cells undergo an epithelial-to-mesenchymal transition (EMT), invade the stroma, and enter the blood circulation before tumor formation in epithelial lineage-labeled genetic mouse models of PanIN (Rhim et al., DDW 2011). Because EMT and invasion were most prevalent within areas of dense inflammation, we hypothesized that inflammation was required for early acquisition of a malignant phenotype. Methods: We bred Pdx-Cre; LSL-KrasG12D; p53fl/+; Rosa26LSL-YFPmice in which pancreatic epithelial cells were permanently labeled with yellow fluorescent protein (YFP) and aged 22.5 mo (deemed PanIN mice as only precancerous PanIN lesions and no cancer are found on HE Rosa26LSL-YFPmice (CY) were used as controls. Acute cerulein pancreatitis (AC) or main pancreatic duct ligation (PDL) was performed in PanIN and control animals as previously described (Siveke et al, 2008; Scoggins et al, 2000). Animals were analyzed 3 and 7d after AC and PDL, respectively. 2.5mo old control and PanIN mice were also treated with the potent anti-inflammatory agent dexamethasone (Dex, 10mg/kg daily) for 7d and analyzed 24h after the last dose. Results: Using the YFP label, we found that PanIN mice contained pancreas cells that sustained an EMT, invaded the stroma and seeded the blood, as we previously described. However, we found a significant increase in EMT and invasion in PanIN animals with ACand PDL-induced pancreatitis compared to vehicleand sham laparotomy-treated control PanIN mice (p<0.05 for AC v. vehicle and PDL v. Sham (n=12 & 8)). AC in control CY mice led to the emergence of EMT+ cells lining the pancreas capsule. There was a significant 3-fold increase in circulating YFP+ pancreatic cells (CPCs) in the blood of PDL-treated PanIN mice v. Sham-treated PanIN mice by FACS (p<0.04). Surprisingly, after only one week of PDL, 3/4 pancreases were found to have histologic (HE DK060694 to AKR), AGA/FDHN (Fellow to Faculty Transition Award to ADR), and NPF (MR, ADR).

Case of a tumor comprising gastric cancer and duodenal neuroendocrine tumor

The present report describes a rare case of a tumor composed of early gastric cancer and a duodenal neuroendocrine tumor (NET). A 78-year-old woman underwent esophagogastroduodenoscopy at a local institution for screening of the upper gastrointestinal tract which revealed a protruded tumor through the pyloric ring from the pyloric antrum. The tumor was too large to treat at the facility; consequently, she was referred to our hospital for further management. Esophagogastroduodenoscopy with tumor biopsy of the lesion revealed the diagnosis of early gastric cancer. Endoscopic submucosal dissection was performed with sufficient free margins in both vertical and horizontal directions. Histopathological findings showed NET confined to the submucosal layer and covered by well-differentiated adenocarcinoma. Immunohistochemical stainings showed that the two lesions existed continuously. While the possibility of a collision cancer was considered, it was suggested that the two lesions existed continuously. Finally, the tumor was diagnosed as gastric cancer composed of duodenal NET G1, with a lymphatic invasion of NET component.

Randomized phase II study of gemcitabine monotherapy versus gemcitabine with an EPA-enriched oral supplement in advanced pancreatic cancer (YCOG001).

e14552 Background: Gemcitabine is still standard chemotherapy in pancreatic cancer. Pancreatic cancer patients often have cachexia with body weight loss. It had been reported that eicosapentaenoic acid (EPA) reduced proinflammatory cytokines, leading to improve inflammatory status of cachexia and attenuation of body weight loss in patients with advanced pancreatic cancer (Barber, et al, 1999).We hypothesized that EPA-enriched oral supplement may prevent cancer cachexia and prolong survival in advanced pancreatic cancer with chemotherapy. The aim of this randomized study is to evaluate the efficacy and safety of gemcitabine with an EPA enriched oral supplement compared with gemcitabine monotherapy in patients with unresectable advanced pancreatic cancer. METHODS This is a multicenter randomized phase II study. Patients will be randomized in a 2:1 ratio to Arm A or Arm B. In Arm A, 1,000mg/m2 of gemcitabine will be administered in a 30 minute intravenous infusion on days 1, 8, and 15. This cycle will be repeated every 4 weeks until disease progression. In addition, a maximum of 2 packs of an EPA-enriched oral supplement (Prosure, Abbott) will be administered every day. Arm B patients will receive gemcitabine monotherapy. Major inclusion criteria include patients over 20 years old with recurrent or unresectable pancreatic cancer that is histologically verified, an ECOG PS of 0,1 or 2, sufficient oral intake. The primary endpoint is the evaluation of 1-year survival. The secondary endpoints are progression-free survival, response rate, adverse events, QOL evaluation, body weight and performance status. A sample size of 66 patients was chosen on the basis of the randomized phase II selection design by Simon et al (1985). The design has a 78% correct selection probability if 1-year survival probabilities are 35% and 25% for two treatment arms. To date, 34 patients have been enrolled.