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Introduction: Few studies have focused on bleeding following endoscopic submucosal dissection (ESD) in surgically altered stomach. We aimed to reveal the bleeding risk in surgically altered stomach following ESD for early gastric cancer (EGC). Methods: We enrolled patients with ESD for EGC at 33 institutions between 2013 and 2016. In study 1, we evaluated bleeding risk following ESD in surgically altered stomach, compared with whole stomach. In study 2, we evaluated factors associated with bleeding following ESD in patients with surgically altered stomach. Results: Of 11,452 patients, 445 patients had surgically altered stomach with the bleeding rate following ESD of 4.9%. In study 1, the bleeding risk in surgically altered stomach was not significant (odds ratio [OR], 1.37; 95% confidence interval [CI], 0.87–2.17) in the multivariate logistic regression analysis. No significant results were obtained when the surgically altered stomach was subdivided into various types. In study 2, the multivariate logistic regression analysis revealed that independent risk factors for bleeding following ESD were ischemic heart disease (OR, 7.52; 95% CI, 2.00–28.25) and P2Y12 receptor antagonist (OR, 4.81; 95% CI, 1.21–19.14). Discussion/Conclusion: In this nationwide study, we found that the bleeding risk of surgically altered stomach following ESD for EGC did not significantly differ from that of whole stomach. The risk factors for ESD in patients with surgically altered stomach were ischemic heart disease and P2Y12 receptor antagonist.

Information on whether there is a relationship between hospital volume and bleeding after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) is limited. This study aimed to compare the bleeding rates after ESD for EGC according to the hospital volume. Patients who underwent ESD for EGC at 33 institutions in Japan between November 2013 and October 2016 were included in this multicenter retrospective study. Hospital volume was categorized into three groups, based on the average annual number of ESD procedures: low- and medium-volume group (LMVG), high-volume group (HVG), and very high-volume group (VHVG). The bleeding rate after ESD for EGC was compared between the three hospital volume groups after propensity score matching. A total of 10,320 patients, including 2797 patients in the LMVG, 4646 patients in the HVG, and 2877 patients in the VHVG, were identified. Propensity score matching yielded 2002 patients in each hospital volume group, with an improved balance of confounding variables between the three groups. The bleeding rates in the LMVG, HVG, and VHVG were 4.3%, 3.7%, and 4.9%, respectively, and no significant difference was noted between the three groups. The bleeding rate after ESD for EGC did not differ between hospitals in Japan. The finding indicated that ESD for EGC is equally feasible across Japanese hospitals of different volumes regarding bleeding after ESD.

BACKGROUND AND AIM This study aimed to reveal the timing of bleeding and thromboembolism associated with endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). METHODS We retrospectively reviewed 10,320 patients who underwent ESD for EGC during November 2013-October 2016. We evaluated overall bleeding rates and their inter-group differences. Factors associated with early/late (cut-off 5 days) bleeding and thromboembolism frequency and its association with the intake of antithrombotic agents were investigated. RESULTS Overall, the post-ESD bleeding rate was 4.7% (489/10 320); the median time to post-ESD bleeding was 4 days. The post-ESD bleeding rates were 3.2%, 8.7%, 15.5%, and 29.9% in those not taking antithrombotic agents, those taking antiplatelet agents, those taking anticoagulants (ACs), and those taking antiplatelet agents and ACs. Warfarin (odds ratio [OR], 9.16), direct oral ACs (OR, 4.16), chronic kidney disease with hemodialysis (OR, 2.93), thienopyridine (OR, 2.25), aspirin (OR, 1.66), tumor size >30 mm (OR, 1.86), multiple tumors' resection (OR, 1.54), and tumor in the lower third of the stomach (OR, 1.40) were independent risk factors for early bleeding. The independent risk factors for late bleeding were direct oral ACs (OR, 7.42), chronic kidney disease with hemodialysis (OR, 4.99), warfarin (OR, 3.90), thienopyridine (OR, 3.09), liver cirrhosis (OR, 2.43), cilostazol (OR, 1.93), aspirin (OR, 1.92), ischemic heart disease (OR, 1.77), and male sex (OR, 1.65). There were three (0.03%) thromboembolic events (cerebral infarction = 2, transient ischemic attack = 1). CONCLUSION We revealed the timing of bleeding and risk factors for early/late bleeding and showed the thromboembolism frequency associated with ESD for EGC.

BACKGROUND Pharyngeal anesthesia’s role in improving observational ability during upper gastrointestinal endoscopy is controversial. No randomized controlled trials have evaluated observational ability with and without pharyngeal anesthesia (PA + vs. PA- group) under sedation with midazolam. We report the non-inferiority of the PA- group in the pharyngeal observation success rate. METHODS This prospective, single-blinded, randomized study included 500 patients, randomly allocated to PA + or PA- groups (250 cases/group), undergoing transoral upper gastrointestinal endoscopy under intravenous sedation with midazolam. RESULTS The pharyngeal observation success rate was 72.0% and 84.0% in the PA- and PA + groups, respectively; non-inferiority in PA- group was not observed (p = 0.707). In the PA- group, observable sites were fewer (8.33 vs 8.86, p = 0.006), time was longer (67.2 vs. 58.2 s, p = 0.001), and pain scores were higher. Image quality at the posterior wall of oropharynx, vocal fold and pyriform sinus was significantly inferior in PA- group. Subgroup analysis showed a higher sedation level (Ramsay score ≥ 5); no differences in the pharyngeal observation success rate were observed between the groups. CONCLUSION Pharyngeal anesthesia may improve pharyngeal observation ability in the hypopharynx and reduce pain. However, this difference may be reduced with deeper sedation.

Salvage photodynamic therapy with talaporfin sodium has a high local control rate for esophageal cancer after definitive chemoradiotherapy. The eligibility criteria for photodynamic therapy include the absence of invasion to the cervical esophagus and a 3 cm maximum longitudinal lesion length. There is little evidence regarding the efficacy and safety of lesions outside the eligibility criteria. This retrospective cohort study evaluated the efficacy and safety of photodynamic therapy of such lesions. Patients with consecutive lesions between February 2016 and May 2020 (n = 36) were enrolled. The local complete response rates and adverse events were compared between patients with cervical and non-cervical lesions and those with lesions larger and smaller than 3 cm. The local complete response rate was 77.8% and was significantly lower in cervical than in non-cervical lesions (20.0% vs 80.6%, p = 0.005). Esophageal stricture, laryngeal pain, and fever were significantly higher in the cervical than in the non-cervical lesion group; however, the detected adverse events were up to grade 2. Laser exposure dose was high in lesions larger than 3 cm (median, 650 vs 400 J; p

Pancreatic lymphoepithelial cysts (LECs) are rare cystic lesions filled with a keratinous substance and lined by squamous epithelium with underlying lymphoid tissue. Because pancreatic LECs are entirely benign, correct preoperative diagnosis is important to avoid unnecessary surgery. However, the imaging features of pancreatic LECs are not specific and preoperative diagnosis has proven difficult. A pancreatic mass was incidentally detected through abdominal ultrasonography in a 63-year-old male presenting without any symptoms. Computed tomography showed an exophytic cystic lesion in the pancreatic head. The lesion had heterogeneous high signal intensity with partial low intensity on T2-weighted magnetic resonance imaging (MRI) and high signal intensity on diffusion MRI. Endoscopic ultrasound (EUS) examination showed an encapsulated cystic lesion with relatively homogenous and highly echoic contents. EUS-guided fine-needle aspiration (EUS-FNA) revealed caseous appearance and rare fragments of apparently benign squamous epithelium on a background of keratinous debris, cyst contents, and scattered lymphocytes. We diagnosed a pancreatic LEC and opted for conservative management without surgery. Pathological evaluation based on images obtained through EUS-FNA showed macro- and microscopic features that were critical to determining the management strategy. In conclusion, the imaging and pathological features of pancreatic LECs can inform preoperative diagnosis, which may enable conservative management.

Objective Bleeding after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) is a frequent adverse event after ESD. We aimed to develop and externally validate a clinically useful prediction model (BEST-J score: Bleeding after ESD Trend from Japan) for bleeding after ESD for EGC. Design This retrospective study enrolled patients who underwent ESD for EGC. Patients in the derivation cohort (n=8291) were recruited from 25 institutions, and patients in the external validation cohort (n=2029) were recruited from eight institutions in other areas. In the derivation cohort, weighted points were assigned to predictors of bleeding determined in the multivariate logistic regression analysis and a prediction model was established. External validation of the model was conducted to analyse discrimination and calibration. Results A prediction model comprised 10 variables (warfarin, direct oral anticoagulant, chronic kidney disease with haemodialysis, P2Y12 receptor antagonist, aspirin, cilostazol, tumour size >30 mm, lower-third in tumour location, presence of multiple tumours and interruption of each kind of antithrombotic agents). The rates of bleeding after ESD at low-risk (0 to 1 points), intermediate-risk (2 points), high-risk (3 to 4 points) and very high-risk (≥5 points) were 2.8%, 6.1%, 11.4% and 29.7%, respectively. In the external validation cohort, the model showed moderately good discrimination, with a c-statistic of 0.70 (95% CI, 0.64 to 0.76), and good calibration (calibration-in-the-large, 0.05; calibration slope, 1.01). Conclusions In this nationwide multicentre study, we derived and externally validated a prediction model for bleeding after ESD. This model may be a good clinical decision-making support tool for ESD in patients with EGC.

Despite the widespread use of endoscopic submucosal dissection (ESD) for early gastric cancer, post-ESD bleeding remains a significant problem. Intragastric pH plays an important role in intragastric bleeding. Because gastric acid secretion contributes to intragastric pH, both the presence or absence of Helicobacter pylori infection and the degree of gastric mucosal atrophy may affect bleeding. The present study aimed to clarify the relationship between post-ESD bleeding and the degree of gastric mucosal atrophy based on H. pylori infection status.We included 8170 patients who underwent ESD for early gastric cancer at 33 hospitals in Japan from November 2013 to October 2016. We analyzed the risk factors contributing to post-ESD bleeding.There were 3935 H. pylori-positive patients and 4235 H. pylori-negative patients. A nonsevere degree of gastric mucosal atrophy was an independent risk factor for post-ESD bleeding in H. pylori-negative patients (odds ratio: 1.51, P = 0.007), but not in H. pylori-positive patients (odds ratio: 0.91, P = 0.600). Further, in H. pylori-negative, but not H. pylori-positive, patients, the rate of post-ESD bleeding increased in a stepwise manner for patients continuing antithrombotic drug use, patients who withdrew antithrombotic drug use, and antithrombotic drug nonusers.Nonsevere gastric mucosal atrophy was a risk factor for post-ESD bleeding in early gastric cancer in H. pylori-negative patients but not in H. pylori-positive patients.

Information on whether there is a relationship between hospital volume and bleeding after endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) is limited. This study aimed to compare the bleeding rates after ESD for EGC according to the hospital volume.Patients who underwent ESD for EGC at 33 institutions in Japan between November 2013 and October 2016 were included in this multicenter retrospective study. Hospital volume was categorized into three groups, based on the average annual number of ESD procedures: low- and medium-volume group (LMVG), high-volume group (HVG), and very high-volume group (VHVG). The bleeding rate after ESD for EGC was compared between the three hospital volume groups after propensity score matching.A total of 10,320 patients, including 2797 patients in the LMVG, 4646 patients in the HVG, and 2877 patients in the VHVG, were identified. Propensity score matching yielded 2002 patients in each hospital volume group, with an improved balance of confounding variables between the three groups. The bleeding rates in the LMVG, HVG, and VHVG were 4.3%, 3.7%, and 4.9%, respectively, and no significant difference was noted between the three groups.The bleeding rate after ESD for EGC did not differ between hospitals in Japan. The finding indicated that ESD for EGC is equally feasible across Japanese hospitals of different volumes regarding bleeding after ESD.

Aim. Hepatitis B virus (HBV) infection is a major public health concern worldwide. Entecavir (ETV), a first-line nucleos(t)ide analogue (NA) for HBV, has a low risk of resistance. We evaluated the efficacy of ETV monotherapy, ratio of ETV-resistant, and the clinical features of patients with ETV resistance. Methods. A total of 130 patients (72 males, 58 females; mean age, 61 ± 15 years) were divided into a NA-naïve group (n = 108) and NA-experienced group (n = 22). We examined the clinical outcomes of ETV monotherapy and associated factors. We also assessed the clinical features of 15 patients with resistance to ETV (mean, 51.0 ± 27.4 weeks). Results. Among the 130 patients, 94.1% achieved ALT normalization and 63.6% achieved serum HBV DNA negativity after ETV monotherapy for 96 weeks. Of the patients in the NA-naïve group, 93.1% and 60.4% achieved ALT normalization and HBV DNA negativity, respectively. Of the patients in the NA-experienced group, 100% and 74.9% achieved ALT normalization and HBV DNA negativity, respectively. Compared to patients on ETV continuously, 15 ETV-resistant patients had a higher baseline HBV viral load. There was a significant difference in the time to HBV DNA negativity, but not ALT normalization after ETV monotherapy in these groups. Rescue treatment with other NAs led to ALT normalization in all of these patients, but not HBV DNA negativity. Conclusions. ETV monotherapy has a long-term clinical efficacy. While some patients especially with HBV DNA high viral load developed ETV resistance, rescue treatment led to ALT normalization in these patients.

Aim. Cytomegalovirus (CMV) can cause hepatitis, encephalomyelitis, and pneumonitis in immunocompromised patients. In contrast, CMV infection of immunocompetent patients can lead to the development of infectious mononucleosis and is typically self-limiting; severe complications are rare. We evaluated the pathophysiology and immunological aspects of CMV hepatitis in recently immunocompetent adult patients. Methods. We examined the clinical features and outcomes of 47 adult immunocompetent patients with CMV hepatitis (29 men, 18 women; mean age, 34 ± 11 years) from January 2005 to August 2019 treated in our hospital. We also assayed T-cell activation to evaluate the immune responses in these patients. Results. Fever (74.5%), hepatosplenomegaly (74.5%), sore throat (36.2%), headache (31.9%), abdominal pain (27.7%), lymphadenopathy (23.4%), and skin rash (6.4%) were present at admission. Complications included gastrointestinal injury (25.5%), neuropathy (4.3%), thrombocytopenia (2.1%), and splenic infarction (2.1%). All patients had a good clinical course without liver failure or transition to chronic liver injury. The time to recover from liver injury ranged from 12 to 142 days (mean, 43.4 ± 28.7 days). The serum sIL-2R level, which reflects T-cell activation, was transiently elevated and correlated with the extent of hepatic inflammation. Conclusions. CMV hepatitis in immunocompetent individuals has a satisfactory outcome, but occasionally results in complications in other organs. The sIL-2R level has potential as a surrogate marker of hepatic inflammation in immunocompetent patients with CMV hepatitis.

Introduction:As the aging of people in a society advances, the number of elderly patients older than 80 years in Japan with gastric cancer continues to increase. Although delayed ulcer bleeding is a major adverse event after endoscopic submucosal dissection (ESD), little is known about characteristic risk factors for bleeding in elderly patients undergoing ESD. This study aimed to evaluate risk factors for delayed bleeding after ESD for gastric cancer in elderly patients older than 80 years., Methods:We retrospectively evaluated the incidence of delayed bleeding after ESD in 10,320 patients with early-stage gastric cancer resected by ESD between November 2013 and January 2016 at 33 Japanese institutions and investigated risk factors for delayed bleeding in elderly patients older than 80 years., Results:The incidence of delayed bleeding in elderly patients older than 80 years was 5.7% (95% confidence interval [CI]: 4.6%-6.9%, 95/1,675), which was significantly higher than that in nonelderly (older than 20 years and younger than 80 years) patients (4.5%, 4.1%-5.0%, 393/8,645). Predictive factors for ESD-associated bleeding differed between nonelderly and elderly patients. On multivariate analysis of predictive factors at the time of treatment, risk factors in elderly patients were hemodialysis (odds ratio: 4.591, 95% CI: 2.056-10.248, P < 0.001) and warfarin use (odds ratio: 4.783, 95% CI: 1.689-13.540, P = 0.003)., Discussion:This multicenter study found that the incidence of delayed bleeding after ESD in Japanese patients older than 80 years was high, especially in patients receiving hemodialysis and taking warfarin. Management of ESD to prevent delayed bleeding requires particular care in patients older than 80 years.

Background The relationship between specific genome alterations and hepatocellular carcinoma (HCC) cancer stem cells (CSCs) remains unclear. In this study, we evaluated the relationship between somatic mutations and epithelial cell adhesion molecule positive (EpCAM+) CSCs. Methods Two patient-derived HCC samples (HCC1 and HCC2) were sorted by EpCAM expression and analyzed by whole exome sequence. We measured PCDH18 expression level in eight HCC cell lines as well as HCC1 and HCC2 by real-time quantitative RT-PCR. We validated the identified gene mutations in 57 paired of HCC and matched non-cancerous liver tissues by Sanger sequence. Results Whole exome sequencing on the sorted EpCAM+ and EpCAM− HCC1 and HCC2 cells revealed 19,263 nonsynonymous mutations in the cording region. We selected mutations that potentially impair the function of the encoded protein. Ultimately, 60 mutations including 13 novel nonsense and frameshift mutations were identified. Among them, PCDH18 mutation was more frequently detected in sorted EpCAM+ cells than in EpCAM− cells in HCC1 by whole exome sequences. However, we could not confirm the difference of PCDH18 mutation frequency between sorted EpCAM+ and EpCAM− cells by Sanger sequencing, indicating that PCDH18 mutation could not explain intracellular heterogeneity. In contrast, we found novel PCDH18 mutations, including c.2556_2557delTG, c.1474C>G, c.2337A>G, and c.2976G>T, were detected in HCC1 and 3/57 (5.3%) additional HCC surgical specimens. All four HCCs with PCDH18 mutations were EpCAM-positive, suggesting that PCDH18 somatic mutations might explain the intertumor heterogeneity of HCCs in terms of the expression status of EpCAM. Furthermore, EpCAM-positive cell lines (Huh1, Huh7, HepG2, and Hep3B) had lower PCDH18 expression than EpCAM-negative cell lines (PLC/PRL/5, HLE, HLF, and SK-Hep-1), and PCDH18 knockdown in HCC2 cells slightly enhanced cell proliferation. Conclusions Our data suggest that PCDH18 is functionally suppressed in a subset of EpCAM-positive HCCs through somatic mutations, and may play a role in the development of EpCAM-positive HCCs. Electronic supplementary material The online version of this article (doi:10.1186/s12935-017-0467-x) contains supplementary material, which is available to authorized users.

Background and study aims It is important to examine the pharynx during upper gastrointestinal endoscopy. Pharyngeal anesthesia using topical lidocaine is generally used as pretreatment. In Japan, lidocaine viscous solution is the anesthetic of choice, but lidocaine spray is applied when the former is considered insufficient. However, the relationship between the extent of pharyngeal anesthesia and accuracy of observation is unclear. We compared the performance of lidocaine spray alone versus lidocaine spray combined with lidocaine viscous solution for pharyngeal observation during transoral endoscopy. Patients and methods In this prospective, double-blinded, randomized clinical trial conducted between January and March 2015, 327 patients were randomly assigned to lidocaine spray alone (spray group, n = 157) or a combination of spray and viscous solution (combination group, n = 170). We compared the number of pharyngeal observable sites (non-inferiority test), pain by visual analogue scale, observation time, and the number of gag reflexes between the two groups. Results The mean number of images of suitable quality taken at the observable pharyngeal sites in the spray group was 8.33 (95 % confidence interval [CI]: 7.94 – 8.72) per patient, and 8.77 (95 % CI: 8.49 – 9.05) per patient in the combination group. The difference in the number of observable pharyngeal sites was – 0.44 (95 % CI: – 0.84 to – 0.03, P = 0.01). There were no differences in pain, observation time, or number of gag reflexes between the 2 groups. Subgroup analysis of the presence of sedation revealed no differences between the two groups for the number of pharyngeal observation sites and the number of gag reflexes. However, the number of gag reflexes was higher in the spray group compared to the combination group in a subgroup analysis that looked at the absence of sedation. Conclusions Lidocaine spray for pharyngeal anesthesia was not inferior to lidocaine spray and viscous solution in terms of pharyngeal observation. It was considered that lidocaine viscous solution was unnecessary for pharyngeal observation. UMIN000016073

Background & Aims Sorafenib is a multireceptor tyrosine kinase inhibitor that can prolong overall survival in patients with advanced hepatocellular carcinoma (HCC). Although most HCC patients who receive sorafenib ultimately show disease progression, it still is unclear whether and how HCC cells acquire chemoresistance during sorafenib treatment in human beings. Methods We analyzed surgically resected HCC tissues from a patient who received sorafenib for prevention of HCC recurrence after surgery (Adjuvant Sorafenib for Hepatocellular Carcinoma after Resection or Ablation trial) and established patient-derived HCC cells. Whole-exome sequence analysis was performed to detect mutations in sorafenib-resistant clones. We examined 30 advanced HCC cases immunohistochemically and 140 HCC cases enrolled in the Adjuvant Sorafenib for Hepatocellular Carcinoma after Resection or Ablation trial using microarray analysis to evaluate the association of Capicua Transcriptional Repressor (CIC) status with sorafenib treatment response. Results We found a CIC mutation in recurrent HCC specimens after sorafenib. CIC encodes Capicua, a general sensor of receptor tyrosine kinase signaling. HCC cells established from the recurrent tumor specimen showed chemoresistance to sorafenib in vitro and in vivo. Established sorafenib-resistant Huh1 and Huh7 cell lines showed reduced expression of Capicua without mutations. Immunohistochemical analysis showed that HCC patients with low Capicua expression showed poor overall survival. Microarray analysis showed that the CIC gene signature could predict the preventive effect of adjuvant sorafenib treatment on HCC recurrence. Intriguingly, although CIC knockdown induced sorafenib resistance in HCC cell lines, regorafenib suppressed growth of sorafenib-resistant, Capicua-inactivated HCC cells and inhibited extracellular signal-regulated kinase phosphorylation. Conclusions Evaluation of Capicua status may be pivotal to predict response to sorafenib, and regorafenib treatment could be effective to treat HCC with functional Capicua impairment.

金沢大学先進予防医学研究科, Background: Sorafenib is a multiple receptor tyrosine kinase inhibitor known to prolong overall survival in patients with advanced hepatocellular carcinoma (HCC). Predicting this drug's survival benefits is challenging because clinical responses are rarely measurable during treatment. In this study, we hypothesized that serum cytokines levels could predict the survival of advanced HCC patients, as sorafenib targets signaling pathways activated in the tumor stromal microenvironment and potentially affects serum cytokine profiles. Methods: Of 143 patients with advanced-stage HCC, 104 who were recruited between 2003 and 2007 received hepatic arterial infusion chemotherapy (HAIC) that mainly targets tumor epithelial cells at S-phase (cohort 1); additionally, 39 recruited between 2010 and 2012 received sorafenib, which primarily targets the stromal vascular endothelial cells. Serum samples were collected and aliquoted prior to the treatment. Serum EGF, bFGF, HGF, IFN-γ, IL-10, IL-12, IL-2, IL-4, IL-5, IL-6, IL-8, IP-10, MIG, PDGF-BB, SCF, SDF1, TGF-β, TGF-α, TNF-α, and VEGF-A were measured via enzyme-linked immunosorbent assays. The Modified Response Evaluation Criteria in Solid Tumors were used to assess tumor responses. Results: The median survival time of HCC patients in cohorts 1 (HAIC-treated) and 2 (sorafenib-treated) were 12.0 and 12.4 months, respectively. Kaplan-Meier analysis revealed no significant survival differences between the 2 groups. Patients who survived more than 2 years after sorafenib treatment exhibited higher serum levels of IL-10, IL-12, TNF-a, IL-8, SDF-1, EGF, PDGF-BB, SCF, and TGF-α. Furthermore, cohort 2 patients with higher serum IL-5 (>12 pg/mL), IL-8 (>10 pg/mL), PDGF-BB (>300 pg/mL), and VEGF-A (>50 pg/mL) levels achieved longer survival; cohort 1 patients did not. Hierarchical cluster analysis of 6 cytokines robustly enriched for comparison analysis between cohorts 1 and 2 (IL-5, IL-8, TGF-α, PDGF-BB, CXCL9, and VEGF-A) revealed that elevation of these cytokines correlated with better survival when treated with sorafenib but not with HAIC. Conclusions: Patients who exhibited survival benefits owing to sorafenib treatment tended to present higher serum cytokines levels, potentially reflecting the activation of stromal signaling in the tumor microenvironment. Our study thus introduces novel biomarkers that may identify advanced HCC patients who may experience survival benefits with sorafenib treatment. © 2017 The Author(s).

Cancer stem cells (CSCs) are a pivotal target for eradicating hepatocellular carcinoma (HCC). We previously reported that distinctive CSCs regulating tumorigenicity (EpCAM+ CSCs) and metastasis (CD90+ CSCs) have different epithelial/mesenchymal gene expression signatures. Here, we examined the influence of sorafenib, a multiple-receptor tyrosine kinase inhibitor used as a first-line treatment for advanced HCC, on EpCAM+ and CD90+ CSCs. CD90+ cells showed higher c-Kit gene/protein expression than EpCAM+ cells. Sorafenib treatment reduced the number of CD90+ cells with attenuated c-Kit phosphorylation, whereas it enriched the EpCAM+ cell population. We evaluated the role of CD90+ and EpCAM+ CSCs in vivo by subcutaneously injecting these CSCs together in immune-deficient mice. We observed that sorafenib subtly affected the suppression of primary tumor growth maintained by EpCAM+ CSCs, but completely inhibited the lung metastasis mediated by CD90+ CSCs. We further evaluated the effect of sorafenib on extracellular vesicle (EV) production and found that sorafenib suppressed the production of EVs containing TGF-β mRNA in CD90+ cells and inhibited the cell-cell communication and motility of EpCAM+ cells. Our data suggest the following novel effects of sorafenib: suppressing CD90+ CSCs and inhibiting the production of EVs regulating distant metastasis.

Background/aim Anthracimycin, a secondary metabolite of Streptomyces, has been shown to inhibit the invasion of certain cancer cell lines. Materials and methods In this study we evaluated the effect of anthracimycin on cell growth and signaling pathways in hepatocellular carcinoma (HCC). Results Anthracimycin suppressed cell proliferation and motility and induced apoptosis in human HCC cell lines. Furthermore, anthracimycin had no effect on the enrichment of EpCAM-high liver cancer stem cells (CSCs), while fluorouracil dramatically enriched the CSCs with activation of the stemness-related genes EPCAM and SOX9 in HuH7 cells. Mechanistically, anthracimycin suppressed mammalian target of rapamycin (mTOR) signaling, and was most effective at inhibiting HCC cell proliferation with mTOR activation. Conclusion Anthracimycin is a novel mTOR inhibitor capable of suppressing the proliferation of CSCs and non-CSCs equally well in HCC, and it is suggested that anthracimycin could be effective in the eradication of HCC associated with mTOR-signaling activation.

Background Nonmagnifying observation by using narrow-band imaging (NBI) is useful for detecting pharyngeal lesions. Magnifying observation by using NBI can distinguish between cancerous and noncancerous lesions and is therefore useful for the early detection of pharyngeal cancer. Objective To evaluate the usefulness of observation of the pharynx by using NBI in the overall population undergoing upper GI endoscopy. Design Retrospective study. Setting Single tertiary referral center. Patients A total of 11,050 upper GI endoscopies between January 2009 and December 2012. Interventions Observation of the pharynx by using NBI. Main Outcome Measures The rate of detection of pharyngeal cancer, the rates of detection according to the reason for endoscopy, and the types of cancers detected. Results Thirty-eight cancerous lesions were detected in 29 patients (0.26%, 29/11,050). The rate of detection of pharyngeal cancer was significantly higher in patients with a history of head and neck cancer (9.7%, 3/31) or a history of esophageal cancer (3.5%, 10/282). In patients undergoing endoscopy for screening, pharyngeal discomfort, and a history of gastric cancer, the rates of detection of pharyngeal cancer were 0.11% (10/8872), 1.1% (3/265), and 0.19% (3/1600), respectively. Two patients (6.9%) were female. One had a history of esophageal cancer, and the other had pharyngeal discomfort. Limitations Single-center, retrospective study. Conclusions Observation of the pharynx by using NBI in patients with previous head and neck cancer or esophageal cancer or who have pharyngeal discomfort is very important. Moreover, pharyngeal cancer was certainly found in the male patients undergoing screening endoscopy, although the rate was lower.

A 55-year-old man who was a heavy drinker with a history of diabetes mellitus was admitted to our hospital with the complaint of dysphagia. Upper gastrointestinal endoscopy revealed multiple intramural pseudodiverticula of the esophagus with candida infection in the cervical and thoracic esophagus. It was difficult to pass the endoscope through the lower thoracic esophagus, indicating stenosis. Thoracic computed tomography and esophagogram revealed widespread, multiple confluent pseudodiverticula in the submucosa. A diagnosis of esophageal intramural pseudodiverticulosis with candida esophagitis was made. The stenosis of the esophagus was improved by endoscopic balloon dilatation and antifungal therapy.

TSU-68 is a multikinase inhibitor that targets platelet-derived growth factor receptors (PDGFRs). In the present study, we evaluated the effect of TSU-68 on the tumor-microenvironment interaction in hepatocellular carcinoma (HCC).HCC and fibroblast cell lines (HuH7, Hep3B, HuH1 and WI-38) were used to evaluate their interactions. Cancer characteristics were evaluated by spheroid formation and tumorigenicity in immunodeficient mice. Time-lapse image analysis was performed to monitor cell motility.Although PDGFA was abundantly expressed, PDGFR-α was predominantly located in the cytoplasm and was not functional in HuH7 cells. Co-culture experiments demonstrated that HCC cells induced phosphorylation of PDGFR-α in WI-38 fibroblasts and that stimulated fibroblasts, in turn, boosted the spheroid formation capacity of HCC cells. TSU-68 inhibited phosphorylation of PDGFR-α in WI-38 cells and suppressed the growth of subcutaneously co-injected HuH7/WI-38 tumor xenografts.TSU-68 inhibits stromal PDGF signaling activated by cancer cells and suppresses HCC growth.

Background and Aim Transoral endoscopy with narrow band imaging (NBI) is useful for identifying early-stage head and neck cancer. However, the screening capability of transoral upper gastrointestinal endoscopy has not yet been systematically evaluated. We evaluated the usefulness of transoral upper gastrointestinal endoscopy for pharyngeal examination. Methods This cross-sectional study evaluated 480 patients. All endoscopic pharyngeal examinations with NBI were carried out in accordance with prescribed procedures, consisting of 10 images each and all images were assessed by a blinded reviewer. We examined the association between the diagnostic usefulness of pharyngeal examination and other factors. Results Median subject age was 64 years (range 22–90 years), and 64% were male. Almost all patients (98%) had an Eastern Cooperative Oncology Group Performance Status of 0 or 1.Butylscopolamine bromide was given to 382 patients (80%), and a sedative was given to 460 (96%) patients. Median observation time was 74 s (range, 16–362 s), resulting in a mean of 9.0 usable images per patient. However, photographs of the right and left pyriform sinuses were consistently poor. Ordered logistic regression analysis showed that quality images were positively correlated with increased patient age. Conclusions Transoral endoscopic examination was possible in most patients for screening of the head and neck. However, results were poor in the pyriform sinuses, indicating that additional improvements of examination methods and instruments are needed to enhance screening accuracy.