北陸地区におけるスクリーニング上部消化管内視鏡検査での咽頭観察の現状

[背景・目的] 現在, スクリーニング上部消化管内視鏡検査における咽頭領域の観察が十分に浸透しているとはいい難い状況である. 北陸地区における上部消化管内視鏡での咽頭観察の現状について調査した. [方法] 日本消化器内視鏡学会専門医114名にアンケートを送付し, 回答のあった73名を対象とし調査した. [結果] 咽頭観察を全例に行っている医師は79.5%, スクリーニングに画像強調観察(image-enhanced endoscopy:IEE)を用いた(I群)のは61.6%であった. 観察時間はI群が白色光(W群)と比べ有意に長く(p<0.001), 1年以内の癌の発見率はI群がW群と比べ有意に高かった(p=0.007). 問題点として, 観察の困難さ, 苦痛増強の可能性などの意見が多かった. [結論] スクリーニングにおける咽頭観察において, 癌の発見にはIEEにて時間をかけて観察することが重要である可能性が示唆された. 今後, さらなる咽頭観察の啓蒙活動が重要と考えられる.出版者照会後に全文公

Risk Factors for Bleeding After Endoscopic Submucosal Dissection for Gastric Cancer in Elderly Patients Older Than 80 Years in Japan.

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

Serum cytokine profiles predict survival benefits in patients with advanced hepatocellular carcinoma treated with sorafenib: A retrospective cohort study

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\u27s 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)

Sporadic PCDH18 somatic mutations in EpCAM-positive hepatocellular carcinoma

Abstract 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

Serum cytokine profiles predict survival benefits in patients with advanced hepatocellular carcinoma treated with sorafenib: a retrospective cohort study

Abstract 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

Interlaboratory evaluation of LC–MS-basedbiomarker assays: supplementary materials

Validation of biomarker assays is crucial for effective drug development and clinical applications.Interlaboratory reproducibility is vital for reliable comparison and combination of data from differentcenters. This review summarizes interlaboratory studies of quantitative LC–MS-based biomarker assaysusing reference standards for calibration curves. The following points are discussed: trends in reports,reference and internal standards, evaluation of analytical validation parameters, study sample analysisand normalization of biomarker assay data. Full evaluation of these parameters in interlaboratory studiesis limited, necessitating further research. Some reports suggest methods to address variations in biomarkerassay data among laboratories, facilitating organized studies and data combination. Method validationacross laboratories is crucial for reducing interlaboratory differences and reflecting target biomarkerresponses.</p