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OBJECTIVES We evaluated the detection rates for perfusion defects in hypervascular hepatocellular carcinomas comparing the low mechanical index (MI) and high MI contrast modes during the post-vascular phase (PVP) of contrast-enhanced ultrasonography. METHODS Seventy-eight patients with 84 hypervascular hepatocellular carcinomas (mean diameter, 23.4 ± 11.2 mm) were selected for this retrospective study. All the patients underwent whole-liver scanning using conventional ultrasonography before injection of a perflubutane-based contrast agent (Sonazoid), and all the detected nodules were classified as either hypoechoic or hyperechoic nodules. Next, hypoechoic and hyperechoic nodules were evaluated using contrast-enhanced ultrasonography, and the presence of a perfusion defect was assessed for each nodule using both the low MI (0.2-0.3) and the high MI (0.7-1.2) contrast modes during the PVP (10 minutes after injection). The data were analyzed using the McNemar test. RESULTS Forty-four nodules were classified as hypoechoic nodules, and the remaining 40 nodules were classified as hyperechoic nodules using conventional ultrasonography. The detection rate for perfusion defects determined using the high MI contrast mode was higher than that determined using the low MI contrast mode in hyperechoic nodules during the PVP (low MI, 58% [23 of 40]; high MI, 90% [36 of 40]; P

A 74-year-old woman with a cyst in her pancreatic tail was referred to our hospital. Computed tomography confirmed a large cystic lesion with irregular wall thickening, abdominal lymph node swelling, and ascites. We diagnosed her with an unresectable mucinous cystic neoplasm, since ascites cytology revealed adenocarcinoma. The patient received chemotherapy up to the fifth line for 55.2 months. Gemcitabine plus nab-paclitaxel and modified FOLFORINOX achieved a partial response with a progression-free survival time of 12.1 and 20.4 months, respectively. The overall survival time from the beginning of first-line chemotherapy was 69.4 months.

Radiotherapy is one of the available curative therapies for hepatocellular carcinoma (HCC). We investigate the use of contrast-enhanced ultrasound using Sonazoid (SCEUS) in evaluating the efficacy of radiotherapy for HCC. We enrolled 59 patients with 59 HCCs in this retrospective study. Tumor size and tumor vascularity were evaluated using SCEUS before and 1, 3, 7, 10, and 13 months after radiotherapy. The median follow-up period was 44.5 months (range: 16–82 months). Of the HCCs, 95% (56/59) had no local recurrence, while 5% (3/59) did. At 13 months after radiotherapy, in cases with no local recurrence, SCEUS showed a reduction in tumor vascularity in all cases, while tumor size reduction (>30% reduction, compared with pre-radiotherapy) was observed in 82.1% (46/56). In all three cases of local recurrence, vascularity and tumor size reduction were not observed during the follow-up period and residual HCCs were demonstrated pathologically. Compared with cases with local recurrence, tumor size reduction and reduction in tumor vascularity (p < 0.001) were significantly greater in cases with no local recurrence at 13 months after radiotherapy. SCEUS may be useful in evaluating radiotherapy efficacy for HCC.

Background Many health care workers around the world tackled with COVID-19, however sadly, the infection of many medical care workers were reported. To reduce the risk of infection, we launched selected team (Team COVID) of non-specialists and brought in active telemedicine method and computed tomography (CT)-first protocol. We describe our actual practice and the health status of medical doctors dealing with COVID-19 patients. Methods Between April 17, 2020 and May 24, 2020, 10 doctors worked with COVID-19 patients as part of Team COVID. The Team COVID doctors used a CT-first triage protocol for outpatients and telemedicine for inpatients and outpatients. We evaluated paired serum-specific antibodies for SARS-CoV-2 at the initial and end of the study duration and PCR results for SARS-CoV-2 at the end of the study duration. Furthermore, 36-item short-form of the Medical Outcome Study Questionnaire (SF-36) at the beginning and end of the study period were evaluated. Results Ten doctors worked as Team COVID: seven internal medicine doctors and three surgeons. During the study period, Team COVID treated 165 individuals in the outpatient clinic and isolated hospitalized patients for 315 person-days. There were no positive results of serum-specific antibody testing and PCR testing for SARS-CoV-2 in Team COVID doctors. Furthermore, the SF-36 showed no deterioration in physical and mental QOL status. No in-hospital infection occurred during the study period. Conclusions The Team COVID fulfilled the treatment using the active telemedicine and CT-first triage protocol without in hospital infection and excess stress. The combination strategy seems acceptable for both the protection and stress relief among the medical staff.

Nonalcoholic fatty liver disease (NAFLD) is an increasingly common condition, affecting up to 25% of the population worldwide. NAFLD has been linked to several conditions, including hepatic inflammation, fibrosis, and hepatocellular carcinoma (HCC), however the role of NAFLD in cholangitis and the development of cholangiocellular carcinoma (CCC) remains poorly understood. This study investigated whether a high‐fat diet (HFD) promotes cholangitis and the development of CCC in mice. We used liver‐specific E‐cadherin gene (CDH1) knockout mice, CDH1∆Liv, which develop spontaneous inflammation in the portal areas along with periductal onion skin‐like fibrosis, similar to that of primary sclerosing cholangitis (PSC). An HFD or normal diet (ND) was fed to CDH1∆Liv mice for 7 mo. In addition, CDH1∆Liv mice were crossed with LSL‐KrasG12D mice, fed an HFD, and assessed in terms of liver tumor development. The extent of cholangitis and number of bile ductules significantly increased in mice fed an HFD compared with ND‐administered CDH1∆Liv mice. The numbers of Sox9 and CD44‐positive stem cell‐like cells were significantly increased in HFD mice. LSL‐KrasG12D /CDH1∆Liv HFD mice exhibited increased aggressiveness along with the development of numerous HCC and CCC, whereas LSL‐KrasG12D/CDH1∆Liv ND mice showed several macroscopic tumors with both HCC and CCC components. In conclusion, NAFLD exacerbates cholangitis and promotes the development of both HCC and CCC in mice., Cdh1 deletion in cholangiocytes develops spontaneous cholangitis and ductular reaction. The extent of cholangitis and ductular reaction is increased in mice with NAFLD. Additional Kras mutation develops cholangiocellular tumors in mice with Cdh1 deleted cholangiocytes and NAFLD promotes development of cholangiocellular tumors.

Background Endoscopic submucosal dissection (ESD) is the treatment of choice for colorectal superficial neoplasia, but certain anatomical locations are challenging even for skilled endoscopists. Ileocecal valve (ICV) is considered a technically challenging site for ESD. Objective Aim of this study was to analyze efficacy and safety of Endoscopic Submucosal Dissection in the treatment of colorectal neoplasia involving the ileocecal valve (ICV) Design Retrospective study. Patients We retrospectively evaluated 1507 consecutive patients undergoing ESD at two tertiary referral centres for ESD (Italy and Japan) from January 2008 to March 2020. Main Outcome Measures Demographic, clinical, procedural, and follow-up data was collected, analysed, and compared between patients with ileocecal valve lesions (ICVL) and patients with non-ICVL. Results Overall, 1507 patients were enrolled (872 M, 57.8%), of these 53 patients had lesions involving the ICV. Mean age was 70.2 years (range, 53–83 years). En-bloc resection was achieved in 52 (98%) patients. The median specimen size of ICVL was 36.4 mm (range, 8–80 mm), significantly smaller than non-ICVL (p = 0.005). Procedure time was significantly longer in the ICVL group, (71.3 vs. 58.9 min; p = 0.03). Non Granular Type Laterally Spreading Tumors (LST-NG) were significantly more frequent in the ICVL group compared to rectum (52.8% vs. 25.7; p = 0.0001). En-bloc resection rate in the ileocecal region did not differ significantly between groups (p = 0.20). Complications such as perforation and postoperative occurred respectively in 3/53 (5.7%) and 1/53 (2%) patient, and were treated conservatively. At first surveillance colonoscopy performed at 6 months, recurrent adenoma was detected in 2/53 patients (3.9%). Conclusions ESD is safe and effective for the treatment of colorectal neoplasia involving the ileocecal valve if performed by expert endoscopist in referral centres.

The mechanism of H. pylori-induced atrophy and metaplasia has not been fully understood. Here, we demonstrate the novel role of Apoptosis signal-regulating kinase 1 (ASK1) and downstream MAPKs as a regulator of host immune responses and epithelial maintenance against H. pylori infection. ASK1 gene deficiency resulted in enhanced inflammation with numerous inflammatory cells including Gr-1+CD11b+ myeloid-derived suppressor cells (MDSCs) recruited into the infected stomach. Increase of IL-1β release from apoptotic macrophages and enhancement of TH1-polarized immune responses caused STAT1 and NF-κB activation in epithelial cells in ASK1 knockout mice. Dysregulated immune and epithelial activation in ASK1 knockout mice led to dramatic expansion of gastric progenitor cells and massive metaplasia development. Bone marrow transplantation experiments revealed that ASK1 in inflammatory cells is critical for inducing immune disorder and metaplastic changes in epithelium, while ASK1 in epithelial cells regulates cell proliferation in stem/progenitor zone without changes in inflammation and differentiation. These results suggest that H. pylori-induced immune cells may regulate epithelial homeostasis and cell fate as an inflammatory niche via ASK1 signaling.

Backgrounds: Accurate differential diagnosis regarding histological grades of hepatocellular carcinoma (HCC) is critical for targeted treatment and prognostic evaluation. However, the currently used descriptive diagnosis of histological grading have to observe tedious item of neovascularization, stromal invasion, cellular and structural atypia, which have drawbacks of subjectivity and error-prone. Immunohistochemical (IHC) markers-based diagnosis only needs to determine whether there is staining in the cell membrane, cytoplasm and / or nucleus. Using IHC markers targeted heat shock protein (HSP)70, glypican (GPC)3, glutamine synthetase (GS), and organic anion transport peptide (OATP), we sought to establish an easy method for the diagnosis of the histopathological grades and further explore the best efficacy by their combined or independent application.Methods: We retrospectively conducted a study of 157 patients with 200 histologically confirmed HCCs, which were classified into early (n= 45), well (n=31), moderately (n=68), and poorly (n=56) differentiated (diff.) HCC. The sensitivity, specificity, accuracy of HSP70, GPC3, GS and OATP on each histological grade were examined. Results: HSP70 and GPC3 showed difference in most histological grades of HCC ( P < 0.05). GS distinguished early HCC from three other histological grades (p < 0.01). OATP8 only differentiated early HCC from poorly diff. HCC (P=0.019). When any two of the three indicators (HSP, GPC3, and GS) were negatively expressed, the diagnostic efficacy of early HCC was the highest, with an area under the curve (AUC) of 0.802 and accuracy of 80.5%. The optimal efficacy for poorly diff. HCC detection was obtained when both GPC3 and HSP70 were positively expressed (74.4% accuracy; AUC = 0.703). However, for well and moderately diff. HCC, a relative satisfactory AUC value (>0.60) failed to yield either by the independent or combined diagnosis of any IHC indicators.Conclusion: Using GS, HSP70, and GPC3, early and poorly diff. HCC can be properly diagnosed. IHC markers might be a potential alternative tool for histological differential diagnosis of HCC.

Aim To evaluate the safety and efficacy of the administration of radiofrequency ablation (RFA) and stereotactic body radiotherapy (SBRT) in the short term to the same patients in Barcelona Clinical Liver Cancer (BCLC) stages 0–B1. Methods From April 2014 to June 2019, we retrospectively reviewed BCLC stage 0–B1 patients with fresh hepatocellular carcinoma (HCC) lesions that were repeatedly treated by RFA (control group, n = 72), and by RFA and subsequent SBRT (case group, n = 26). Propensity score matching (PSM) was performed to reduce the selection bias between two groups. Recurrence, survival, Child–Pugh scores and short-term side effects (fever, bleeding, skin change, abdominal pain and fatigue) were recorded and analyzed. Results After PSM, 21 patients remained in each group. Seventeen and 20 patients in the case and control groups experienced recurrence. For these patients, the median times to progression and follow-up were 10.7 and 35.8 months, respectively. After PSM, the 1-year progression-free survival rate in case and control groups were 66.7% and 52.4%, respectively (P = 0.313). The inter-group overall survival (OS) was comparable (3 and 5-year OS rates in case groups were 87.3% and 74.8%, while rates in control groups were 73.7% and 46.3%, respectively; P = 0.090). The short-term side effects were mild, and the incidence showed no inter-group difference. The 1-year rates of the Child–Pugh score deterioration of ≥2 in case and control groups were 23.8% and 33.3% (P > 0.05), respectively. Conclusion The short-term administration of RFA and SBRT to the same BCLC stage 0–B1 patients may be feasible and effective because of their good prognosis and safety.

The aim of the present study was to evaluate the long-term outcomes and the impact of repeated conventional transarterial chemoembolization (C-TACE) and transarterial chemoembolization with epirubicin-loaded superabsorbent polymer embolics (SAP-TACE) on liver function in TACE-naive patients with unresectable hepatocellular carcinoma (HCC). Overall, 155 consecutive patients with HCC received either C-TACE or SAP-TACE. The first cohort (n=71), treated between 2011 and 2014, received C-TACE; the second cohort (n=84), treated between 2014 and 2016, received SAP-TACE. Overall survival and deterioration of liver function were compared between the two cohorts. The 1-, 2- and 3-year overall survival rates and median survival times were 74, 50, 35% and 26 months in the C-TACE cohort and 75, 60, 39% and 28 months in the SAP-TACE cohort, respectively. There were no significant differences between the two groups (P=0.289). Age

Background: Coronavirus disease 2019 (COVID-19) continues to spread worldwide. Because of the absence of reliable rapid diagnostic systems, patients with COVID-19 symptoms are suspected of disease. Computed tomography (CT) in patients with suspected COVID-19 may be reasonable for triaging, and CT-first triage strategies have been proposed. However, clinical evaluation of a CT-first triage protocol is lacking. The aim of this study is to investigate the real-world efficacy and limitations of a CT-first triage strategy in patients with suspected COVID-19.Methods: This was a single-center cohort study evaluating outpatients with suspected COVID-19 who underwent a medical examination at Yokohama City University Hospital and who were prospectively registered between 9 February and 5 May 2020. We treated patients according to the CT-first triage protocol. CT findings were classified into five categories according to the COVID-19 Reporting and Data System (CO-RADS). With the CT-first triage protocol, patients with a suspicious clinical history, symptoms, or suspicious findings on chest CT were allocated to the COVID-19 suspected group. The primary outcome was efficacy of the CT-first triage protocol for outpatients with suspected COVID-19. We conducted additional analyses of the isolation time of outpatients with suspected COVID-19 and reached final diagnoses.Results: In total, 108 outpatients with suspected COVID-19 were examined at our hospital. Forty-eight patients (44.9%) were categorized as CO-RADS 1, 26 patients (24.3%) as CO-RADS 2, 14 patients (13.1%) as CO-RADS 3, 6 patients (5.6%) as CO-RADS 4, and 13 patients (12.1%) as CO-RADS 5. One patient was excluded because of pregnancy. Using the CT-first triage protocol, 48 (44.9%) patients were suspected of having COVID-19. Nine patients (18.8%) in this group were positive for severe acute respiratory syndrome coronavirus 2 using polymerase chain reaction; no patients in the group not suspected of having COVID-19 were diagnosed with COVID-19 during follow up. The protocol significantly shortened the duration of isolation for the not-suspected versus the suspected group (70.5 vs. 1037.0 minutes, P < .001). Conclusions: Our CT-first triage protocol was acceptable for triaging outpatients with suspected COVID-19. This protocol will be helpful for appropriate triage, especially in areas where polymerase chain reaction is limited.

Cecal volvulus is an uncommon cause of colonic obstruction. First-line treatment for cecal volvulus is surgery, as nonoperative management is rarely achievable. We herein report an extremely rare case of a patient with spontaneously resolved cecal volvulus; no recurrence occurred without elective surgery. A 47-year-old woman presented with acute lower abdominal pain. She was misdiagnosed with small bowel obstruction and treated conservatively. A few hours later, she was correctly diagnosed with cecal volvulus. Subsequently, her symptoms and computed tomography findings of cecal volvulus completely disappeared. She refused elective surgery, but no recurrence occurred during five months of follow-up.

To estimate the role of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced MRI (EOB-MRI) in predicting hypervascularization outcome of non-hypervascular hypointense hepatic lesions in high-risk patients for hepatocellular carcinoma (HCC). Under the premise of non-hyperenhance in arterial phase (AP) and hypointensity in hepatobiliary phase (HBP) of EOB-MRI, 29 fresh lesions from 22 patients with chronic viral hepatitis (median (range) age: 69(57–82) years) were prospectively enrolled. During continuously followed-up by EOB-MRI, lesional vascularity in AP, the signal intensity (SI) ratios of lesions-to-parenchyma in HBP images (post-contrast ratio) and adjusted enhancement with reference of unenhanced images (EOB enhancement ratio) were examined. After 644 (220–2912) days of follow-up, 20 lesions changed into hyperenhancement in AP of EOB-MRI (hypervascularized group), while nine remained non-hyperenhanced (maintained non-hypervascular group). There is no statistical difference of post-contrast ratio at the initial detection. The post-contrast ratios in hypervascularized group were different between each follow-up time point when followed-up ≥ three (P

Background & aims To explore the ability of gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid magnetic resonance imaging (EOB-MRI)/ultrasound (US) fusion imaging (FI) to improve the prognosis of radiofrequency ablation (RFA) by ablating the characteristic findings of hepatocellular carcinoma (HCC) in hepatobiliary phase (HBP) imaging. Methods We retrospectively recruited 115 solitary HCC lesions with size of (15.9 ± 4.6) mm. They were all treated by RFA and preoperative EOB-MRI. According to the modalities guiding RFA performance, the lesions were grouped into contrast enhanced US (CEUS)/US guidance group and EOB-MRI/US FI guidance group. For the latter group, the ablation scope was set to cover the HBP findings (peritumoral hypointensity and irregular protruding margin). The presence of HBP findings, the modalities guided RFA, the recurrence rate were observed. Results After an average follow-up of 377 days, local tumor progression (LTP) and intrahepatic distant recurrence (IDR) were 14.8% and 38.4%, respectively. The lesions having HBP findings exhibited a higher recurrence rate (73.7%) than the lesions without HBP findings (42.9%) (p = 0.002) and a low overall recurrence-free curve using the Kaplan-Meier method (p = 0.038). Using EOB-MRI/US FI as guidance, there was no difference in the recurrence rate between the groups with and without HBP findings (p = 0.799). In lesions with HBP findings, RFA guided by EOB-MRI/US FI (53.8%) produced a lower recurrence rate than CEUS/US (84.0%) (p = 0.045). Conclusions The intraprocedurally application of EOB-MRI/US FI to determine ablation scope according to HBP findings is feasible and beneficial for prognosis of RFA.

Aims To assess the safety, efficacy, and prognostic impact of clinical factors associated with lenvatinib treatment in highly advanced hepatocellular carcinoma (HCC) with tumor thrombus in the main portal vein trunk (VP4) or tumor with more than 50% liver occupation (tm50%LO). Methods A total of 61 highly advanced HCC patients (41 patients with tm50%LO and 20 patients with VP4) who were treated with lenvatinib at multicenter were enrolled and retrospectively analyzed for treatment outcomes according to their clinical status, including tumor morphology. Results The most frequent grade ≥3 adverse event in tm50%LO HCC was elevated aspartate aminotransferase (17.1%). Objective response rates were 37.5% and 0% in tm50%LO HCC patients with Child-Pugh grade (CP)-A and CP-B, respectively, and 26.7% and 0% in VP4 HCC patients with CP-A and CP-B, respectively. Estimated median progression-free survival and overall survival were 132 days and 229 days, and 101 days and 201 days in patients with tm50%LO and VP4, respectively. In multivariate analysis, modified albumin-bilirubin grade (hazard ratio 0.372, 95% CI 0.157-0.887; p = 0.0241) and tumor morphology (hazard ratio 0.322, 95% CI 0.116-0.889; p = 0.0287) were independently associated with progression-free survival in patients with tm50%LO HCC. In VP4 HCC, median progression-free survival was worse in CP-B (57 days) than in CP-A patients (137 days, p = 0.0462). Conclusions Lenvatinib treatment offers a benefit in highly advanced HCC (tm50%LO or VP4) patients with good liver function or nodular-type tumor. The various characteristics identified in this study might be useful as indicators of lenvatinib treatment in highly advanced HCC with tm50%LO or VP4, which are considered very refractory cancers.

By analyzing possible factors contributing to imaging misevaluation of arterial phase (AP) vascularity, we aimed to provide a more proper way to detect AP hypervascularity of hepatocellular carcinomas (HCCs) using the noninvasive imaging modalities magnetic resonance imaging (MRI) and contrast-enhanced ultrasound (CEUS).We retrospectively recruited 164 pathologically confirmed HCC lesions from 128 patients. Using CEUS with Sonazoid (SCEUS) and gadolinium-ethoxybenzyl-diethylenetriamine penta-acetic acid MRI (EOB-MRI), AP vascularity of the lesions was evaluated and inconsistencies in interpretation were examined. Indicators of margin, echogenicity, and halo and mosaic signs of lesions on grayscale US; depth of lesions on SCEUS; and tumoral homogeneity, signal contrast ratio of lesions to the surrounding area on precontrast and AP images on EOB-MRI, and histological grade were investigated.When precontrast images were used to adjust the AP enhancement ratio, the proportion of inconsistent interpretations of AP vascularity declined from 26.2% (43/164; 29 non-hypervascularity instances using EOB-MRI and 14 using SCEUS) to 16.5% (27/164; 7 using EOB-MRI and 20 using SCEUS). Greater lesion depth (P = 0.017), ill-defined tumoral margin (P = 0.028), absence of halo sign (P = 0.034), and histologically early HCC (P = 0.007) on SCEUS, and small size (P = 0.012) and heterogeneity (P = 0.013) of lesions and slight enhancement (low AP enhancement ratio) (P = 0.018 and 0.009 before and after adjustment) on EOB-MRI, may relate to undetectable hypervascularity.SCEUS and EOB-MRI may show discrepancies in evaluating AP vascularity in the case of deep, ill-defined, heterogeneous, slightly enhanced lesions, and histologically early HCCs. We recommend adjusting AP with precontrast images in EOB-MRI, and combining both modalities to detect hypervascularity.

We investigated whether or not nitric oxide synthase 3 (NOS3) rs2070744 genotypes can affect the response for lenvatinib treatment in patients with hepatocellular carcinoma (HCC). We evaluated the relation of the NOS3 rs2070744 genotypes to the tumor response, progression-free survival (PFS), and overall survival (OS) as the response for lenvatinib. We also examined the association between fibroblast growth factor receptor (FGFR) gene polymorphisms, a potential feature of lenvatinib, and the response. There were no significant differences between the studies for either PFS or OS, even though patients with the TT genotype had a longer mean PFS (hazard ratio [HR] 0.60; p = 0.069) and mean OS (HR 0.46; p = 0.075) than those with the TC/CC genotypes. However, patients with a single-nucleotide polymorphism (SNP) combination pattern of the NOS3 rs2070744 TC/CC and FGFR4 rs351855 CT/TT genotypes had a significantly shorter mean PFS (HR 2.56; p = 0.006) and mean OS (HR 3.36; p = 0.013) than those with the other genotypes. The NOS3 rs2070744 genotypes did not influence the clinical response. However, the SNP combination pattern of the NOS3 rs2070744 and FGFR4 rs351855 genotypes may be helpful as treatment effect predictors and prognostic factors for HCC patients treated with lenvatinib.

BACKGROUND AND AIM The usefulness of second-generation colon capsule endoscopy (CCE2) in ulcerative colitis (UC), especially in clinically inactive patients, has been reported. Capsule Scoring of Ulcerative Colitis (CSUC) was developed as a severity index for UC. We aimed to determine whether CSUC is useful for predicting relapse during clinical remission. METHODS Forty-one UC patients in clinical remission who underwent CCE2 were prospectively registered from April 2016 to August 2019. Patients' CSUC score was obtained; those with subsequent relapse were followed up retrospectively. The correlation of CSUC with white blood cell count, platelet count, albumin, C-reactive protein, fecal calprotectin and fecal lactoferrin levels, and fecal immunochemical test results was evaluated; their predictive values for future relapse were compared. RESULTS The correlations of CSUC with white blood cell, platelet, albumin, C-reactive protein, fecal calprotectin, fecal immunochemical test, and fecal lactoferrin values were rs = 0.13, 0.27, -0.25, 0.15, 0.50, 0.43, and 0.50, respectively. CSUC was higher in 12 patients who relapsed within 1 year than in 29 patients who remained in clinical remission (2.83 ± 1.95 vs 0.72 ± 1.00, P

BACKGROUND In hepatocellular carcinoma (HCC), detection and treatment prior to growth beyond 2 cm are relevant as a larger tumor size is more frequently associated with microvascular invasion and/or satellites. AIM To examine the impact of the tumor marker alpha-fetoprotein (AFP) or PIVKA-II in detecting very small HCC nodules (≤ 2 cm in maximum diameter, Barcelona stage 0) in the large number of very small HCC. The difference in the behavior of these tumor markers in HCC development was also examined. METHODS A total of 933 patients with single-nodule HCC were examined. They were subdivided into 394 patients with HCC nodules ≤ 2 cm in maximum diameter and 539 patients whose nodules were > 2 cm. The rates of patients whose AFP and PIVKA-II showed normal values were examined. RESULTS The positive ratio of the marker PIVKA-II was significantly different (P < 0.0001) between patients with nodules ≤ 2 cm in diameter and those with nodules > 2 cm, but there was no significant difference in AFP (P = 0.4254). In the patients whose tumor was ≤ 2 cm, 50.5% showed normal levels in AFP and 68.8% showed normal levels in PIVKA-II. In 36.4% of those patients, both AFP and PIVKA-II showed normal levels. The PIVKA-II-positive ratio was markedly increased with an increase in the tumor size. In contrast, the positivity in AFP was increased gradually and slowly. CONCLUSION In the surveillance of very small HCC nodules (≤ 2 cm in diameter, Barcelona clinical stage 0) the tumor markers AFP and PIVKA-II are not so useful.

Background: The Coronavirus disease 2019 pandemic continues to spread worldwide. Because of the absence of reliable rapid diagnostic systems, patients with symptoms of Coronavirus disease 2019 are treated as suspected of the disease. Use of computed tomography findings in Coronavirus disease 2019 are expected to be a reasonable method for triaging patients, and computed tomography-first triage strategies have been proposed. However, clinical evaluation of a computed tomography-first triage protocol is lacking.The aim of this study is to investigate the real-world efficacy and limitations of a computed tomography-first triage strategy in patients with suspected Coronavirus disease 2019.Methods: This was a single-center cohort study evaluating outpatients with fever who received medical examination at Yokohama City University Hospital, prospectively registered between 9 February and 5 May 2020. We treated according to the computed tomography-first triage protocol. The primary outcome was efficacy of the computed tomography-first triage protocol for patients with fever in an outpatient clinic. Efficacy of the computed tomography-first triage protocol for outpatients with fever was evaluated using sensitivity, specificity, positive predictive value, and negative predictive value. We conducted additional analyses of the isolation time of feverish outpatients and final diagnoses.Results: In total, 108 consecutive outpatients with fever were examined at our hospital. Using the computed tomography-first triage protocol, 48 (44.9%) patients were classified as suspected Coronavirus disease 2019. Nine patients (18.8%) in this group were positive for severe acute respiratory syndrome coronavirus 2 using polymerase chain reaction; no patients in the group considered less likely to have Coronavirus disease 2019 tested positive for the virus. The sensitivity, specificity, positive predictive value, and negative predictive value of our computed tomography-first triage protocol for Coronavirus disease 2019 were 100%, 60.2%, 18.8%, and 100%, respectively. The protocol significantly shortened the duration of isolation for the not-suspected versus the suspected group (70.5 vs. 1037.0 minutes, P < .001). Conclusions: Our computed tomography-first triage protocol was acceptable for screening patients with suspected Coronavirus disease 2019. This protocol will be helpful for appropriate triage, especially in areas where polymerase chain reaction is inadequate.

BACKGROUND AND AIM Endoscopic resection is feasible for superficial tumors in patients with ulcerative colitis; however, endoscopic resection options have not been evaluated comprehensively. We evaluated the efficacy and safety of endoscopic submucosal dissection and endoscopic mucosal resection, and decision making regarding endoscopic resection options for patients with ulcerative colitis. METHODS Endoscopically treated tumors from patients with ulcerative colitis were analyzed retrospectively. We evaluated en bloc and R0 resection, adverse events, local tumor recurrence, and metachronous lesion occurrence rates. RESULTS We examined 102 tumors (mean size, 12 mm; non-polypoid, 55 tumors) from 74 patients with ulcerative colitis, of whom, 39 and 63 underwent endoscopic submucosal dissection and endoscopic mucosal resection, respectively. The R0 resection rate was significantly higher for endoscopic submucosal dissection (97%) than for endoscopic mucosal resection (80%) (P = 0.0015). For 11-20-mm tumors, the R0 resection rate was significantly higher for endoscopic submucosal dissection (94%) than for endoscopic mucosal resection (55%) (P = 0.0027); the endoscopic submucosal dissection and endoscopic mucosal resection R0 rates did not differ for ≤ 10-mm tumors. The non-polypoid tumor R0 resection rates were significantly higher for endoscopic submucosal dissection (100%) than for endoscopic mucosal resection (65%) (P

BACKGROUND The undifferentiated-type (UDT) component profoundly affects the clinical course of early gastric cancers (EGCs). However, an accurate preoperative diagnosis of the histological types is unsatisfactory. To date, few studies have investigated whether the UDT component within mixed-histological-type (MT) EGCs can be recognized preoperatively. AIM To clarify the histopathological characteristics of the endoscopically-resected MT EGCs for investigating whether the UDT component could be recognized preoperatively. METHODS This was a single-center retrospective study. First, we attempted to clarify the histopathological characteristics of the endoscopically-resected MT EGCs with emphasis on the UDT component. Histopathological examination investigated each lesion’s UDT component: (1) Whole mucosal layer occupation of the UDT component; (2) UDT component exposure to the surface of the mucosa; and (3) existence of a clear border between the differentiated-type and UDT components. Then, preoperative endoscopic images with magnifying endoscopy with narrow-band imaging (ME-NBI) were examined to identify whether the endoscopic UDT component finding was recognizable within the area where it was present in the histopathological examination. The preoperative biopsy results and comparative relationships between endoscopic and histopathological findings were also examined. RESULTS In the histopathological examination, the whole mucosal layer occupation of the UDT component and exposure of the UDT component to the mucosal surface were observed in 67.3% (33/49) and 79.6% (39/49) of samples, respectively. A clear distinction of the border between the differentiated-type and UDT components could not be drawn in 65.3% (32/49) of MT lesions. In the endoscopic examination, the preoperative endoscopic images showed that only 24.5% (12/49) of MT EGCs revealed the UDT component within the area where it was present histopathologically. Histopathological UDT predominance was the single significant factor associated with the presence of the endoscopic UDT component finding (61.5% vs 11.1%, P = 0.0009). Only 26.5% (13/49) of the lesions were diagnosed from the pretreatment biopsy as having a UDT component. Combined results of the pretreatment biopsy and ME-NBI showed the preoperative presence of the UDT component in 40.8% (20/49) of MT EGCs. CONCLUSION Recognition of a UDT component within MT EGCs is difficult even when pretreatment biopsy and ME-NBI are combined. Endoscopic resection plays a significant role in both treatment and diagnosis.

We attempted to establish an ultrasound (US) imaging-diagnostic system for histopathological grades of differentiation of hepatocellular carcinoma (HCC). We conducted a retrospective study of histopathologically confirmed 200 HCCs, classified as early (45 lesions), well- (31 lesions), moderately (68 lesions) or poorly differentiated (diff.) (56 lesions) HCCs. We performed grayscale US to estimate the presence/absence of halo and mosaic signs, Sonazoid contrast-enhanced US (CEUS) to determine vascularity (hypo/iso/hyper) of lesion in arterial and portal phase (PP), and echogenicity of lesion in post-vascular phase (PVP). All findings were of significance for the diagnosis of some (but not all) histological grades (p < 0.001–0.05). Combined findings with a relatively high diagnostic efficacy for early, poorly and moderately diff. HCC were a combination of absence of halo sign and isoechogenicity in PVP of CEUS (accuracy: 93.0%, AUC: 0.908), hypovascularity in PP (accuracy: 78.0%, area under the curve (AUC): 0.750), and a combination of isovascularity in PP and hypoechogenicity in PVP (accuracy: 75.0%, AUC: 0.739), respectively. On the other hand, neither any individual finding nor any combination of findings yielded an AUC of over 0.657 for the diagnosis of well-diff. HCC. Our study provides encouraging data on Sonazoid CEUS in the histological differential diagnosis of HCC, especially in early HCC, and the effectiveness of this imaging method should be further proved by prospective, large sample, multicenter studies.

A 40-year-old man presented to the emergency department with periumbilical pain and fever. A computed tomographic scan confirmed multiple jejunal diverticulum with localized extraluminal air and panniculitis around it, and jejunal diverticulitis with localized perforation was suspected. His symptoms were mild, and extraluminal air was localized;therefore, he was advised bowel rest and administered only antibiotics. The patient's symptoms resolved without surgical treatment, and at the time of writing this report, there had been no recurrence. Small bowel diverticulitis is rare, and careful analysis of imaging studies is necessary for establishing a diagnosis. This was a rare case where small bowel diverticulitis was resolved without surgical treatment.

BACKGROUND Persistent Helicobacter pylori (H. pylori) infection causes chronic inflammation, atrophy of the gastric mucosa, and a high risk of developing gastric cancer. In recent years, awareness of eradication therapy has increased in Japan. As H. pylori infections decrease, the proportion of gastric cancers arising from H. pylori uninfected gastric mucosa will increase. The emergence of gastric cancer arising in H. pylori uninfected patients though rarely reported, is a concern to be addressed and needs elucidation of its clinicopathological features. AIM To evaluate the clinicopathological features of early gastric cancer in H. pylori-uninfected patients. METHODS A total of 2462 patients with 3375 instances of early gastric cancers that were treated by endoscopic submucosal dissection were enrolled in our study between May 2000 and September 2019. Of these, 30 lesions in 30 patients were diagnosed as H. pylori-uninfected gastric cancer (HpUIGC). We defined a patient as H. pylori-uninfected using the following three criteria: (1) The patient did not receive treatment for H. pylori, which was determined by investigating medical records and conducting patient interviews; (2) Lack of endoscopic atrophy; and (3) The patient was negative for H. pylori after being tested at least twice using various diagnostic methods, including serum anti-H. pylori-IgG antibody, urease breath test, rapid urease test, and microscopic examination. RESULTS The frequency of HpUIGC was 1.2% (30/2462) for the patients in our study. The study included 19 males and 11 females with a mean age of 59 years. The location of the stomach lesions was divided into three sections; upper third (U), middle third (M), lower third (L). Of the 30 lesions, 15 were U, 1 was M, and 14 were L. Morphologically, 17 lesions were protruded and flat elevated type (0-I, 0-IIa, 0-IIa + IIc), and 13 lesions were flat and depressed type (0-IIb, 0-IIc). The median tumor diameter was 8 mm (range 2-98 mm). Histological analysis revealed that 22 lesions (73.3%) were differentiated type.The HpUIGC lesions were classified into fundic gland type adenocarcinoma (7 cases), foveolar type well-differentiated adenocarcinoma (8 cases), intestinal phenotype adenocarcinoma (7 cases), and pure signet-ring cell carcinoma (8 cases). Among 30 HpUIGCs, 24 lesions (80%) were limited to the mucosa; wherein, the remaining 6 lesions showed submucosal invasion. One of the submucosal invasive lesions showed more than 500 μm invasion. The mucin phenotype analysis identified 7 HpUIGC with intestinal phenotype and 23 with gastric phenotype. CONCLUSION We elucidated the clinicopathological characteristics of HpUIGC, revealing recognition not only undifferentiated-type but also differentiated-type. In addition, intestinal phenotype tumors were also observed and could be an important tip.

Predictive biomarkers of the response of hepatocellular carcinoma (HCC) to Lenvatinib therapy have not yet been clarified. The aim of this study was to identify clinically significant biomarkers of response to Lenvatinib therapy, to target strategies against HCC. Levels of circulating angiogenic factors (CAFs) were analyzed in blood samples collected at baseline and after introducing lenvatinib, from 74 Child-Pugh class A HCC patients who received lenvatinib. As CAF biomarkers, serum vascular endothelial growth factor (VEGF), fibroblast growth factor 19 (FGF19), FGF23, and angiopoietin-2 (Ang-2) were measured using enzyme-linked immunosorbent assays. Results: Significantly increased FGF19 (FGF19-i) levels and decreased Ang-2 (Ang-2-d) levels were seen in Lenvatinib responders as compared to non-responders (ratio of FGF19 level at 4 weeks/baseline in responders vs. non-responders: 2.09 vs. 1.32, respectively, p = 0.0004, ratio of Ang-2 level at four weeks/baseline: 0.584 vs. 0.810, respectively, p = 0.0002). Changes in FGF23 and VEGF levels at four weeks versus baseline, however, were not significantly different in responders versus non-responders. In multivariate analysis, the combination of serum FGF19-i and Ang-2-d was the most independent predictive factor for Lenvatinib response (Odds ratio, 9.143, p = 0.0012). Furthermore, this combination biomarker showed the greatest independent association with progression-free survival (Hazard ratio, 0.171, p = 0.0240). Early changes in circulating FGF19 and Ang-2 levels might be useful for predicting clinical response and progression-free survival in HCC patients on Lenvatinib therapy.

Background: Gastrointestinal endoscopy (GIE) is useful for the early detection and treatment of many diseases; however, GIE is considered a high-risk procedure in the coronavirus disease 2019 (COVID-19) pandemic era. This study aimed to explore the rate of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positivity in saliva and gastric and intestinal fluids to which endoscopy medical staff are exposed. Methods: The study was a single-center cross-sectional study. From June 1 to July 31, 2020, all patients who underwent GIE at Yokohama City University Hospital endoscopy center were registered. All patients provided 3 ml of saliva. For upper GIE, 10 ml of gastric fluid was collected through the endoscope. For lower GIE, 10 ml of intestinal fluid was collected through the endoscope. The primary outcome was the positive rate of SARS-CoV-2 in saliva and gastric and intestinal fluids. We also analyzed serum-specific antibodies for SARS-CoV-2 and patients’ background information. Findings: A total of 783 samples (560 upper GIE and 223 lower GIE samples) were analyzed. Polymerase chain reaction (PCR) on saliva samples did not show any positive results in either upper or lower GIE samples. However, 2.0% (16/783) of gastrointestinal fluid samples tested positive for SARS-CoV-2. No significant differences in age, sex, purpose of endoscopy, medication, or rate of antibody test positivity were found between PCR positive and PCR negative cases. Interpretation: Asymptomatic patients, even those with no detectable virus in their saliva, had SARS-CoV-2 in their gastrointestinal tract. Endoscopy medical staff should be aware of infection when performing procedures. Trial Registration: The study was registered in the University Hospital Medical Information Network Clinical Trials Registry as UMIN000040587. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of Interests: The authors declare that they have no conflicts of interests. Ethics Approval Statement: The institutional review board at YCU Hospital approved this prospective study on May 17, 2020 (approval number: B200500054). Written consent for participation in the study was obtained from all patients.

Therapeutic endoscopic ultrasound has become widespread as an effective procedure for biliary drainage; however, it is rarely used to remove foreign bodies such as a biliary stent. A 57-year-old man was referred to our hospital for a benign biliary stricture in the left hepatic duct after hepatectomy. Initially, a 7-Fr plastic stent was placed in the left hepatic duct with the distal end set above the papilla, and it was replaced with an 8.5-Fr stent as the stricture remained after 3 months. Endoscopic retrograde cholangiopancreatography was performed to retrieve the plastic stent 3 months later; however, the stent could not be moved because the proximal flap was caught in the stricture. Attempts using various devices failed to retrieve the stent; thus, endoscopic ultrasound-guided hepaticogastrostomy was performed to create a route for stent retrieval. Eventually, the plastic stent was successfully retrieved with biopsy forceps through a fully covered self-expandable metallic stent located in a transgastric fistula. We propose our new method involving endoscopic ultrasound-guided hepaticogastrostomy for endoscopic stent retrieval that fails via the transpapillary route.

Ultrasound (US) is a cost-effective and noninvasive procedure without radiation exposure, with real-time evaluation and high spatial resolution. Although it is useful for the detection of gallbladder (GB) polyps, including gallbladder cancer, adenoma, and benign polyps, conventional US is insufficient for differential diagnosis because it is not capable of evaluating hemodynamic information, unlike computed tomography or magnetic resonance imaging. With recent technological advances in US equipment and contrast agents, Doppler imaging and contrast-enhanced ultrasonography (CEUS) are being used to characterize GB polyps, and several reports on evaluation of the vascularity of GB polyp have been published. In this review, we aimed to report the latest developments in the hemodynamic diagnosis of GB polyps based on previous reports, with an emphasis on CEUS, and to evaluate the efficacy for differential diagnosis. The information in this article is expected to enable early diagnosis and prompt surgical treatment for gallbladder cancer.

Background Endoscopic resection is recommended for non-ampullary duodenal neuroendocrine tumors (NAD-NETs) ≤10 mm in diameter and confined to the submucosal layer, without lymph node or distant metastasis. However, the efficacy and safety of endoscopic submucosal dissection (ESD) for NAD-NET remains unclear. The aim of this study was to assess the short-term efficacy and safety and the long-term outcomes of ESD for NAD-NET. Methods Eight patients with 8 NAD-NETs who underwent ESD between 2015 and 2018 were included. The indications for ESD were: i) tumor ≤10 mm in diameter; ii) NET G1; iii) confined to the submucosal layer; and iv) without lymph node or distant metastasis. We retrospectively assessed the short- and long-term outcomes and safety. Results The median patient age was 69 (48-76) years. All tumors were located in the duodenal bulb and showed 0-Is morphology. The median size was 6.4 (3-9.3) mm. The rates of en bloc resection, histologically free horizontal and vertical margins, and curative resection were 100%, 88%, and 88%, respectively. Intraoperative and postoperative perforation each occurred in 13% of patients, all of whom were treated conservatively and avoided emergent surgery. Delayed bleeding was not observed. No local, lymph node or distant recurrence was observed during a median follow-up period of 34 (18.5-62.5) months. Conclusions The rates of en bloc and curative resection, and histologically free margins were sufficiently high. Although intraoperative and postoperative perforations occurred, emergency surgery was not needed. The results show that ESD is an efficacious and safe treatment for NAD-NET.

Acute and chronic pancreatitises are gastrointestinal inflammatory diseases, the incidence of which is increasing worldwide. Most (~ 80%) acute pancreatitis (AP) patients have mild disease, and about 20% have severe disease, which causes multiple organ failure and has a high mortality rate. Chronic pancreatitis (CP) is characterized by chronic inflammation and destruction of normal pancreatic parenchyma, which leads to loss of exocrine and endocrine tissues. Patients with CP also have a higher incidence of pancreatic ductal adenocarcinoma. Although a number of factors are associated with the development and progression of AP and CP, the underlying mechanism is unclear. Adhesion molecules play important roles in cell migration, proliferation, and signal transduction, as well as in development and tissue repair. Loosening of cell–cell adhesion between pancreatic acinar cells and/or endothelial cells increases solute permeability, resulting in interstitial edema, which promotes inflammatory cell migration and disrupts tissue structure. Oxidative stress, which is one of the important pathogenesis of pancreatitis, leads to upregulation of adhesion molecules. Soluble adhesion molecules are reportedly involved in AP. In this review, we focus on the roles of tight junctions (occludin, tricellulin, claudin, junctional adhesion molecule, and zonula occludin), adherens junctions (E-cadherin and p120-, α-, and β-catenin), and other adhesion molecules (selectin and intercellular adhesion molecules) in the progression of AP and CP. Maintaining the normal function of adhesion molecules and preventing their abnormal activation maintain the structure of the pancreas and prevent the development of pancreatitis.

Background The efficacy of hepatic arterial infusion chemotherapy (HAIC) for advanced hepatocellular carcinoma (HCC) remains unclear. We conducted a multi-center randomized phase II study comparing a sequential HAIC-sorafenib regimen versus sorafenib alone as an initial therapy for HCC. Methods Patients were randomly assigned (ratio, 1:1) to receive sequential HAIC with cisplatin followed by sorafenib (HAIC group, n = 35) or sorafenib alone (sorafenib group, n = 33) as an initial therapy. The primary endpoint was the one-year survival rate. Secondary endpoint included overall survival (OS), the 2-year survival rate, the time-to-progression (TTP), the objective response rate (ORR), the disease control rate (DCR), and safety. Results For the primary endpoint, the one-year survival rates were 46% in the HAIC group and 58% in the sorafenib group. The median OS period was 10.0 months (95% CI, 7.0–18.8) in the HAIC group and 15.2 months (95% CI, 8.2–19.7) in the sorafenib group (hazard ratio [HR], 1.08; 95% CI, 0.63 to 1.86, P = 0.78). The median TTP, ORR and DCR in the HAIC group were 2.8 months (95% CI, 1.7–5.5), 14.3, and 45.7%, respectively, while those in the sorafenib group were 3.9 months (95% CI, 2.3–6.8), 9.1, and 45.5%, respectively. No unexpected adverse events related to HAIC or sorafenib were observed in either group. Conclusions Sequential HAIC with cisplatin and sorafenib does not improve the survival benefit, compared with sorafenib alone, when used as an initial therapy for advanced HCC. However, this study was underpowered in regard to its primary and secondary endpoints, so the results should be interpreted with caution. Trial registration UMIN ID 000006147, registration data: August 11, 2011.

Background Although Helicobacter-induced gastric inflammation is the major predisposing factor for gastric carcinogenesis, the precise mechanism by which chronic gastritis causes gastric cancer remains unclear. Intestinal and spasmolytic polypeptide-expressing metaplasia (SPEM) is considered as precancerous lesions, changes in epithelial tissue stem/progenitor cells after chronic inflammation has not been clarified yet. In this study, we utilized three-dimensional gastric epithelial cell culture systems that could form organoids, mimicking gastric epithelial layer, and characterized the changes in epithelial cells after chronic Helicobacter felis infection. Methods We used three mice model; 1) long-term H. felis infection, 2) H. felis eradication, and 3) MNU chemical carcinogenesis model. We performed cRNA microarray analysis after organoid culture, and analyzed the effects of chronic gastric inflammation on tissue stem cells, by the size of organoid, mRNA expression profile and immunohistochemical analysis. Results The number of organoids cultured from gastric epithelial cells was significantly higher in organoids isolated from H. felis-infected mice compared with those from uninfected gastric mucosa. Based on the mRNA expression profile, we found that possible stem cell markers such as Cd44, Dclk1, and genes associated with the intestinal phenotype, such as Villin, were increased in organoids isolated from H. felis-infected mucosa compared with the control. The upregulation of these genes were cancelled after H. felis eradication. In a xenograft model, tumors were generated only from organoids cultured from carcinogen-treated gastric mucosa, not from H. felis infected mucosa or control organoids. Conclusions Our results suggested that, as a possible mechanism of gastric carcinogenesis, chronic inflammation induced by H. felis infection increased the number of tissue stem/progenitor cells and the expression of stem cell markers. These findings suggest that chronic inflammation may alter the direction of differentiation toward undifferentiated state and that drawbacks may enable cells to redifferentiate to intestinal metaplasia or neoplasia.

Background and Aims Colorectal neoplasms with submucosal fibrosis are the most challenging targets of endoscopic resection. Water pressure endoscopic submucosal dissection (WP-ESD) is a recently introduced procedure that has several advantages over conventional endoscopic submucosal dissection (C-ESD). This study aimed to assess the efficacy and safety of WP-ESD for fibrotic colorectal neoplasms. Methods This retrospective observational study investigated 133 colorectal neoplasms expected to have submucosal fibrosis that were resected by WP-ESD or C-ESD between April 2012 and April 2020. Eighty-seven lesions after endoscopic or surgical treatment, 18 with biopsy scar with fold convergence and 28 in patients with ulcerative colitis, were included. The differences in treatment outcomes, including procedure time and adverse event proportions, between the WP-ESD and C-ESD groups were analyzed. The clinical course after perforation using WP-ESD was also evaluated, including postprocedural multidetector CT findings obtained immediately after WP-ESD. Results Severe submucosal fibrosis was observed in 96 lesions (72.2%). The median procedure time was significantly shorter in the WP-ESD group than in the C-ESD group (43.5 minutes [interquartile range {IQR}, 32.8-73] vs 72 minutes [IQR, 45-105]; P = .0041). The multivariate analysis revealed WP-ESD as an independent factor for a short procedure time (odds ratio, 2.90; 95% confidence interval, 1.28-6.55). The proportions of post-ESD electrocoagulation syndrome (11.6% vs 13.1%) and perforation (20.4% vs 22.8%) were similar between the groups. Four of 11 patients with perforation who underwent WP-ESD showed fluid collection on postprocedural multidetector CT images. Conclusions WP-ESD can shorten procedure time for treating fibrotic colorectal neoplasms.

A 67-year-old male with type 2 diabetes (T2DM) was diagnosed with postoperative intrahepatic recurrence for hepatocellular carcinoma (HCC). Nine sessions of transarterial chemoembolization (TACE) proved ineffective, and the patient was diagnosed as having TACE-refractory disease and received seven cycles of atezolizumab–bevacizumab combination therapy. After that, the patient developed hyperglycemia with the HbA1c elevation and the marked fasting serum C-peptide reduction and was diagnosed with developed immune-mediated diabetes (IMD) (T2DM exacerbation with insulin-dependent diabetes development). Subsequently, the hepatobiliary enzyme levels, which were high before the systemic therapy, worsened. Thus, we clinically diagnosed an exacerbation of liver injury due to TACE-induced liver injury complicated by drug-induced liver injury such as immune-mediated hepatotoxicity (IMH). Meanwhile, after contrast-enhanced computed tomography revealed complete response, contrast-enhanced ultrasound was performed to assess intrahepatic recurrence. We found that the latter modality allowed earlier and more definitive diagnosis of intrahepatic recurrence of HCC. Subsequently, despite systemic therapy discontinuation and steroids administration, the liver injury worsened, and the patient died. The autopsy revealed intrahepatic recurrence of HCC and extensive arterial obstruction by the beads used for TACE within the liver, which indicated that disturbed circulation was the primary cause of the liver injury and histopathologically confirmed IMD, but not IMH.

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

Pancreatic ductal adenocarcinoma (PDAC) is a life‐threatening disease and there is an urgent need to develop improved therapeutic approaches. The role of c‐Jun N‐terminal kinase (JNK) in PDAC stroma is not well defined even though dense desmoplastic reactions are characteristic of PDAC histology. We aimed to explore the role of JNK in PDAC stroma in mice. We crossed Ptf1a Cre/+;Kras G12D/+ mice with JNK1 −/− mice to generate Ptf1a Cre/+ ;Kras G12D/+ ;JNK1 −/− (Kras;JNK1−/−) mice. Tumor weight was significantly lower in Kras;JNK1−/− mice than in Kras;JNK1+/− mice, whereas histopathological features were similar. We also transplanted a murine PDAC cell line (mPC) with intact JNK1 s.c. into WT and JNK1 −/− mice. Tumor diameters were significantly smaller in JNK1 −/− mice. Phosphorylated JNK (p‐JNK) was activated in α‐smooth muscle actin (SMA)‐positive cells in tumor stroma, and mPC‐conditioned medium activated p‐JNK in tumor‐associated fibroblasts (TAF) in vitro. Relative expression of Ccl20 was downregulated in stimulated TAF. Ccl20 is an important chemokine that promotes CD8+ T‐cell infiltration by recruitment of dendritic cells, and the number of CD8+ T cells was decreased in Kras;JNK1+/− mice compared with Kras;JNK1−/− mice. These results suggest that the cancer secretome decreases Ccl20 secretion from TAF by activation of JNK, and downregulation of Ccl20 secretion might be correlated with reduction of infiltrating CD8+ T cells. Therefore, we concluded that inhibition of activated JNK in pancreatic tumor stroma could be a potential therapeutic target to increase Ccl20 secretion from TAF and induce accumulation of CD8+ T cells, which would be expected to enhance antitumor immunity.

Radiofrequency ablation for liver tumors (liver RFA) is widely performed under ultrasound guidance. However, discriminating between the tumor and the needle is often difficult because of cavitation caused by RFA-induced coagulation. An unclear ultrasound image can lead to complications and tumor residue. Therefore, image-guided navigation systems based on fiducial registration have been developed. Fiducial points are usually set on a patient’s skin. But the use of internal fiducial points can improve the accuracy of navigation. In this study, a new device is introduced to use internal fiducial points using 2D US. 3D Slicer as the navigation software, Polaris Vicra as the position sensor, and two target tumors in a 3D abdominal phantom as puncture targets were used. Also, a new device that makes it possible to obtain tracking coordinates in the body was invented. First, two-dimensional reslice images from the CT images using 3D Slicer were built. A virtual needle was displayed on the two-dimensional reslice image, reflecting the movement of the actual needle after fiducial registration. A phantom experiment using three sets of fiducial point configurations: one conventional case using only surface points, and two cases in which the center of the target tumor was selected as a fiducial point was performed. For each configuration, one surgeon punctured each target tumor ten times under guidance from the 3D Slicer display. Finally, a statistical analysis examining the puncture error was performed. The puncture error for each target tumor decreased significantly when the center of the target tumor was included as one of the fiducial points, compared with when only surface points were used. This study introduces a new device to use internal fiducial points and suggests that the accuracy of image-guided navigation systems for liver RFA can be improved by using the new device.

Although magnifying endoscopy with narrow-band imaging (ME-NBI) can help identify the horizontal margin (HM) of early gastric cancer (EGC), little is known about the factors that can clarify the HM by using ME-NBI. We aimed to characterize the pathological features of lesions in which the HM was identified using ME-NBI. The HMs of 639 differentiated-type EGCs treated with endoscopic submucosal dissection or surgery were analyzed using conventional endoscopy and ME-NBI. The number and width of the intervening parts (IP) and the number, width, and depth of the subepithelial capillaries (SEC) in cancerous and noncancerous areas were measured. In 13 lesions (2.0%), more than 90% of the HM was not recognized with conventional endoscopy, but 11 of these lesions were detectable with ME-NBI (NBI group). The HMs of the other 626 lesions were mostly recognized using conventional endoscopy (WLI/CE group). In the NBI group, the IP width, standard deviation (SD), and number of IPs did not significantly differ between the cancerous and noncancerous areas. However, the SEC number was significantly larger and the depth was shallower in cancerous areas. In the WLI/CE group, the IP width and SD were significantly larger, but the IP number was significantly smaller in cancerous areas. The SEC depth was significantly shallower in cancerous areas. Differences of IP width, SD, and IP number may be factors for identifying HMs with conventional endoscopy. Because NBI can better visualize vessel structures, the increased SEC number and shallow SECs may clarify the HM.

Background/aims This study's purpose was to compare the efficacy of CO2-enhanced ultrasonography (US) with that of Sonazoid-enhanced US and conventional US in detecting local tumor residue after percutaneous radiofrequency (RF) ablation therapy for hepatocellular carcinoma. Materials and methods Between February 2009 and March 2010, 141 lesions of 121 hepatocellular carcinoma patients were treated by percutaneous RF ablation, and 22 tumor residues were detected in 22 patients by contrast-enhanced computed tomography. These 22 patients were examined by conventional US, Sonazoid-enhanced US (0.5 mL/body of Sonazoid, intravenous administration), and CO2-enhanced US (10 mL of CO2, hepatic arterial administration). Results Tumor residue was confirmed by CO2-enhanced US in all the 22 patients (sensitivity: 100%) in 19 of the 22 patients by Sonazoid-enhanced US (sensitivity: 86%; 3 lesions that were not detected by this modality were located deeper than the sonographic depth (p=0.0109)), and in 17 of the 22 patients by conventional US (sensitivity: 77%; 5 lesions that were not detected by this modality were smaller in terms of the sonographic tumor size (p=0.0278)). Conclusion Although CO2-enhanced US requires angiography, it was superior to both Sonazoid-enhanced US and conventional US for detecting tumor residues, particularly deep-seated ones, after percutaneous RF ablation.

The purpose of this study was to evaluate whether the hypervascularity of hepatocellular carcinomas (HCCs) on contrast-enhanced ultrasonography (CEUS) prior to radiofrequency ablation (RFA) is a significant risk factor for local recurrence after RFA.Institutional review board approval and informed consent were obtained. Overall, 208 patients (mean age, 71.7 years; range, 50-87 years; 137 men, 71 women) with 282 HCCs treated with RFA were analyzed retrospectively. The mean maximum tumor diameter was 15.7mm. We compared the abilities of CEUS and contrast-enhanced computed tomography (CECT) to detect hypervascularity in HCCs. We then classified the HCCs into two groups according to the arterial-phase CEUS findings: a "hypervascular group" with whole or partial hypervascular areas within the lesions compared with the surrounding liver parenchyma, and a "non-hypervascular group" with isovascular or hypovascular areas within the lesions. We assessed the cumulative rate of local recurrence after RFA, and we also evaluated the risk factors for local recurrence using a univariate analysis.The detection rate for hypervascular HCCs was significantly higher using CEUS (78%, 221/282) than that using CECT (66%, 186/282) (P0.001). Using the CEUS findings, the cumulative rate of local recurrence was significantly higher in the hypervascular group (41.2%, 56/221) than in the non-hypervascular group (18.4%, 6/61) (P=0.007). A univariate analysis revealed that hypervascularity on CEUS was an independent risk factor for local recurrence (P=0.010).Hypervascularity in HCCs as observed using CEUS is a significant risk factor for local recurrence after RFA.

Background. Sorafenib is a first-line treatment option for advanced hepatocellular carcinoma (HCC) patients; however, survival predictors upon progression have not been well characterized. In the present study, we aimed to show the efficacy of multidisciplinary therapy for patients who had failed to respond to sorafenib treatment. Methods. Among 146 BCLC stage B or C HCC patients treated with sorafenib monotherapy between July 2009 and August 2014, the first radiological progression according to the modified RECIST was identified in 71 patients; factors predicting overall survival (OS) and survival postprogression (SPP) were analyzed in these patients. Results. The median OS and SPP for patients who failed to respond to sorafenib treatment were 10.5 and 6.2 months, respectively, and the SPP was strongly correlated with the OS (r=0.982, P<0.01, and R2=0.965). The independent predictors of OS and SPP were identical. The predictors of SPP were des-gamma-carboxy prothrombin, progression of portal vein thrombosis, and subsequent second-line or additional treatment. Conclusions. SPP is closely associated with OS and might be notable in patients who have failed to respond to initial sorafenib treatment. Furthermore, interventions consisting of other treatment options upon the appearance of progression might prolong OS.

Stomach cancer rarely develops in patients with familial adenomatous polyposis (FAP), and Helicobacter pylori infection may increase the risk of FAP-related gastric cancer. We describe the case of a 64-year-old woman who developed multiple synchronous early gastric cancers without H. pylori infection. Nine cancer lesions were successfully treated by endoscopic submucosal dissection. An immunohistochemical analysis revealed that the tumors were positive for mucin (MUC)2, MUC6, and CDX2, but negative for MUC5AC, suggesting that the tumors were gastrointestinal mixed type. Periodical endoscopic surveillance is important for the detection of cancers at an early stage.

Aki Kawakami,1,2 Makoto Tanaka,3 Makoto Naganuma,4 Shin Maeda,5 Reiko Kunisaki,1 Noriko Yamamoto-Mitani2 1Inflammatory Bowel Disease Center, Yokohama City University Medical Center, Minami-ku, Yokohama, Japan; 2Department of Gerontological Home Care and Long-term Care Nursing, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan; 3Ramathibodi School of Nursing, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Ratchathewi, Bangkok, Thailand; 4Division of Gastroenterology and Hepatology, Keio University, Shinjuku-ku, Tokyo, Japan; 5Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Kanazawa-ku, Yokohama, Japan Background: Overall, 30%–45% of patients with ulcerative colitis (UC) are non-adherent and have difficulties taking their medications; this non-adherence increases the risk of clinical relapse 1.4- to 5.5-fold. This study aimed to clarify the strategies patients employ to facilitate adherence and determine whether the strategies had an impact on good adherence.Methods: This was a cross-sectional survey using a self-administered questionnaire and review of medical records. Patients diagnosed as having UC and attending one of the outpatient clinics of four urban hospitals from June 2009 to December 2012 were enrolled. A questionnaire was developed to identify the strategies patients employ to facilitate adherence and then administered to patients with UC. Adherence to 5-aminosalicylic acid was calculated, and univariate and multiple logistic regression analyses were performed to determine the strategies that were associated with good adherence.Results: The final analyses included 671 participants (mean age 40.2years; 54.3% males). The valid response rate was 96.9%; 186 (27.7%) participants were classified as non-adherent, the mean adherence rate being 86.1% (standard deviation [SD] 17.9). Seven strategies that patients employ to facilitate adherence were identified, the following two being significantly associated with good adherence: “I keep my medicines where I eat meals” and “I keep each day’s medicine in a pill case or something similar to make sure I have taken them”.Conclusion: The identified strategies might be used to develop a program to improve medication adherence in patients with UC. Keywords: medication adherence, self-management, ulcerative colitis, 5-aminosalicylic acid