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Background: Dysphagia caused by tumor strictures is a major symptom in patients with advanced esophageal cancer. However, the prognostic effect of dysphagia in resectable cases is insufficiently investigated. This study aimed to investigate the prognostic value of dysphagia scores in resectable advanced esophageal cancer who underwent radical esophagectomy after preoperative treatment., Methods: This retrospective study enrolled 302 consecutive patients with advanced resectable esophageal cancer who received preoperative treatment. The preoperative dysphagia score was used to assess the relationship between tumor stricture and clinical outcomes., Results: Almost half of the patients had dysphagia scores of 2 to 4 (n = 152 [50.3%]). Lower body mass index, circumferential tumors, and noncurative resection were significantly more common as dysphagia scores worsened. Patients with dysphagia had significantly more advanced ypT stage and worse histopathologic response than those without dysphagia. The 5-year disease-free survival and overall survival (OS) rates for dysphagia scores of 0 to 1, 2 to 3, and 4 were 52.9%, 35.3%, and 26.7% and 60.7%, 40.4%, and 26.7%, respectively. Multivariate analysis identified dysphagia score as an independent factor of OS, similar to surgical curability and ypN stage. The postoperative recurrence rate was significantly higher among patients with dysphagia scores of 2 to 3 (56%) and 4 (67%) than among those with dysphagia scores of 0 to 1 (36%) (P < .001 and P = .037, respectively). Furthermore, distant recurrence in dysphagia scores of 2 to 3 and 4 was higher than in dysphagia scores of 0 to 1 (26%, 46%, and 42%, respectively)., Conclusion: The dysphagia score before initial treatment is associated with postoperative survival in patients with resectable advanced esophageal cancer., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Society for Surgery of the Alimentary Tract. Published by Elsevier Inc. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients 1 , yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3 . Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8 + T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence., (© 2023. The Author(s).)

Nerves are a component of the tumor microenvironment contributing to cancer progression, but the role of cells from nerves in facilitating cancer invasion remains poorly understood. Here we show that Schwann cells (SC) activated by cancer cells collectively function as tumor-activated Schwann cell tracks (TAST) that promote cancer cell migration and invasion. Nonmyelinating SCs form TASTs and have cell gene expression signatures that correlate with diminished survival in patients with pancreatic ductal adenocarcinoma. In TASTs, dynamic SCs form tracks that serve as cancer pathways and apply forces on cancer cells to enhance cancer motility. These SCs are activated by c-Jun, analogous to their reprogramming during nerve repair. This study reveals a mechanism of cancer cell invasion that co-opts a wound repair process and exploits the ability of SCs to collectively organize into tracks. These findings establish a novel paradigm of how cancer cells spread and reveal therapeutic opportunities., Significance: How the tumor microenvironment participates in pancreatic cancer progression is not fully understood. Here, we show that SCs are activated by cancer cells and collectively organize into tracks that dynamically enable cancer invasion in a c-Jun-dependent manner. See related commentary by Amit and Maitra, p. 2240. This article is highlighted in the In This Issue feature, p. 2221., (©2022 The Authors; Published by the American Association for Cancer Research.)

Transcription factors ThPOK and Runx3 regulate the differentiation of "helper" CD4+ and "cytotoxic" CD8+ T cell lineages respectively, inducing single positive (SP) T cells that enter the periphery with the expression of either the CD4 or CD8 co-receptor. Despite the expectation that these cell fates are mutually exclusive and that mature CD4+CD8+ double positive (DP) T cells are present in healthy individuals and augmented in the context of disease, yet their molecular features and pathophysiologic role are disputed. Here, we show DP T cells in murine and human tumors as a heterogenous population originating from SP T cells which re-express the opposite co-receptor and acquire features of the opposite cell type's phenotype and function following TCR stimulation. We identified distinct clonally expanded DP T cells in human melanoma and lung cancer by scRNA sequencing and demonstrated their tumor reactivity in cytotoxicity assays. Our findings indicate that antigen stimulation induces SP T cells to differentiate into DP T cell subsets gaining in polyfunctional characteristics., (© 2022 Schad et al.)

Group 2 innate lymphoid cells (ILC2s) are lymphocytes that both promote and suppress antitumor immunity. Jou and colleagues now report in colorectal tumorigenesis that the cytokine interleukin-25 activates ILC2s to induce myeloid cells that suppress antitumor immunity.

Cancer immunoediting 1 is a hallmark of cancer 2 that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice 1,3 , whether immunoediting occurs naturally in human cancers remains unclear. Here, to address this, we investigate how 70 human pancreatic cancers evolved over 10 years. We find that, despite having more time to accumulate mutations, rare long-term survivors of pancreatic cancer who have stronger T cell activity in primary tumours develop genetically less heterogeneous recurrent tumours with fewer immunogenic mutations (neoantigens). To quantify whether immunoediting underlies these observations, we infer that a neoantigen is immunogenic (high-quality) by two features-'non-selfness'  based on neoantigen similarity to known antigens 4,5 , and 'selfness'  based on the antigenic distance required for a neoantigen to differentially bind to the MHC or activate a T cell compared with its wild-type peptide. Using these features, we estimate cancer clone fitness as the aggregate cost of T cells recognizing high-quality neoantigens offset by gains from oncogenic mutations. With this model, we predict the clonal evolution of tumours to reveal that long-term survivors of pancreatic cancer develop recurrent tumours with fewer high-quality neoantigens. Thus, we submit evidence that that the human immune system naturally edits neoantigens. Furthermore, we present a model to predict how immune pressure induces cancer cell populations to evolve over time. More broadly, our results argue that the immune system fundamentally surveils host genetic changes to suppress cancer., (© 2022. The Author(s).)

Background: Due to its tumor-specific metabolic pathway characteristics, 5-aminolevulinic acid (5-ALA) is a natural amino acid widely used in cancer treatment. The current study, demonstrated that 5-ALA induced ferroptosis via glutathione peroxidase 4 (GPX4) and heme oxygenase 1 (HMOX1) and had an antitumor effect in esophageal squamous cell carcinoma (ESCC)., Methods: Expression of GPX4 and HMOX1 in pathologic specimens of 97 ESCC patients was examined, and prognostic analyses were performed. Real-time polymerase chain reaction (RT-PCR), RNA microarray, and Western blotting analyses were used to evaluate the role of 5-ALA in ferroptosis in vitro. In addition, this study used ferrostatin-1, a ferroptosis inhibitor, and a lipid peroxidation reagent against cell lines treated with 5-ALA. Finally, the role of 5-ALA was confirmed by its effect on an ESCC subcutaneous xenograft mouse model., Results: The study showed that upregulation of GPX4 and downregulation of HMOX1 were poor prognostic factors in ESCC. In an RNA microarray analysis of KYSE30, ferroptosis was one of the most frequently induced pathways, with GPX4 suppressed and HMOX1 overexpressed by 5-ALA treatment. These findings were verified by RT-PCR and Western blotting. Furthermore, 5-ALA led to an increase in lipid peroxidation and exerted an antitumor effect in various cancer cell lines, which was inhibited by ferrostatin-1. In vivo, 5-ALA suppressed GPX4 and overexpressed HMOX1 in tumor tissues and led to a reduction in tumor size., Conclusions: Modulation of GPX4 and HMOX1 by 5-ALA induced ferroptosis in ESCC. Thus, 5-ALA could be a promising new therapeutic agent for ESCC.

Background: As antithrombin III (AT-III) is produced in the hepatocytes, its serum activity decreases at the time of liver failure, in addition to ischemia reperfusion injury, vascular endothelial dysfunction, and disseminated intravascular coagulation (DIC). Here, we examined whether the serum AT-III value after hepatectomy could be a prognostic factor for hepatocellular carcinoma (HCC)., Methods: Of 141 patients who underwent hepatectomy for HCC, data for 101 patients in whom serum AT-III activity was measured on the first postoperative day were extracted. Patients with serum AT-III activity > 50% and ≤ 50% were assigned to high value (72 cases) and low value (29 cases) groups, respectively. We examined the clinical and prognostic differences between these two groups., Results: The average age of enrolled patients (83 men and 18 women) was 68.0 years. The 5-year overall survival rate was 88% and 60% in the high and low value groups, respectively ( P < 0.01). Furthermore, the 2-year relapse-free survival rate was 71% and 54% in the high and low value groups, respectively ( P = 0.03)., Conclusion: This is the first study to demonstrate that serum AT-III levels on the first postoperative day may serve as a prognostic factor in HCC patients., Competing Interests: The authors declare no conflict of interest., (©2021 Tottori University Medical Press.)

Our previous study showed that adhesion molecule with immunoglobulin like domain 2 (AMIGO2) is a pivotal driver gene of liver metastasis via regulating tumor cell adhesion to liver endothelial cells in mouse models. The aim of the present study was to clarify the role of AMIGO2 in liver metastasis in patients the colorectal cancer (CRC). Two human CRC cell lines, Caco-2 (AMIGO2-low) and HCT116 (AMIGO2-high), were used in this study. AMIGO2-overexpressing Caco-2 and AMIGO2-knockdown HCT116 cells were generated by transfection with an AMIGO2 expression vector or AMIGO2 small interfering RNA, respectively. Cell proliferation, invasion and adhesion to human liver endothelial cells were examined in in vitro studies. Immunohistochemical analysis was also performed to evaluate the association between AMIGO2 expression and liver metastasis in patients with CRC. In vitro studies revealed that cell proliferation, invasion and adhesion to liver endothelial cells were accelerated by upregulation of AMIGO2 expression, but suppressed by downregulation of AMIGO2 expression in human CRC cells. Immunohistochemical analysis using clinical CRC specimens revealed that AMIGO2 expression was associated with the frequency of liver metastasis (P<0.01), but not that of pulmonary metastasis (P=0.611) and peritoneal dissemination (P=0.909). In addition, AMIGO2 expression levels in tumor cells were significantly higher in liver metastatic foci than primary lesions (P=0.012). In conclusion, the present results indicated that AMIGO2 expression may contribute to the formation of liver metastasis in CRC., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Tanio et al.)

CD44, a cancer stem cell (CSC) marker, is required for maintaining CSC properties in hepatocellular carcinoma (HCC). Nuclear enriched abundant transcript 1 (NEAT1), a long noncoding RNA (lncRNA), is an oncogenic driver in HCC. In the present study, we investigated the significance of the NEAT1 gene in association with CD44 expression in liver CSCs of human HCC cell lines. The CSC properties were evaluated by spheroid culture, CSC marker expression, and sensitivity to anti-cancer drugs. The expression of both NEAT1 variant 1 (NEAT1v1) and variant 2 (NEAT1v2) as well as CD44 was significantly increased in the spheroid culture, compared with that in monolayer culture. Overexpression of Neat1v1, but not Neat1v2, enhanced the CSC properties, while knockout of the NEAT1 gene suppressed them. CD44 expression was increased by the overexpression of Neat1v1 and abrogated by NEAT1 knockout. The overexpression of NEAT1v1 restored the CSC properties and CD44 expression in NEAT1-knockout cells. NEAT1v1 expression in HCC tissues was correlated with poor prognosis and CD44 expression. These results suggest that NEAT1v1 is required for CD44 expression. To our surprise, NEAT1v1 also restored the CSC properties even in CD44-deficient cells, suggesting that NEAT1v1 maintains the properties of CSCs in a CD44-independent manner.

Unconventional prefoldin RNA polymerase II subunit 5 interactor (URI1) has emerged as an oncogenic driver in hepatocellular carcinoma (HCC). Although the hepatitis B virus (HBV) represents the most common etiology of HCC worldwide, it is unknown whether URI1 plays a role in HBV-related HCC (HCC-B). In the present study, we investigated URI1 expression and its underlying mechanism in HCC-B tissues and cell lines. URI1 gene-promoter activity was determined by a luciferase assay. Human HCC-B samples were used for a chromatin immunoprecipitation assay. We found that c-MYC induced URI1 expression and activated the URI1 promoter through the E-box in the promoter region while the HBx protein significantly enhanced it. The positivity of URI1 expression was significantly higher in HCC-B tumor tissues than in non-HBV-related HCC tumor tissues, suggesting that a specific mechanism underlies URI1 expression in HCC-B. In tumor tissues from HCC-B patients, a significantly higher level of c-MYC was recruited to the E-box than in non-tumor tissues. These results suggest that HBx and c-MYC are involved in URI1 expression in HCC-B. URI1 expression may play important roles in the development and progression of HCC-B because HBx and c-MYC are well-known oncogenic factors in the virus and host, respectively., Competing Interests: We declare the following conflict of interest: GS has more than 5% of the total shares of KanonCure Inc. The other authors have no conflict of interest.

Background/aim: Recent studies have investigated a novel inflammation-based prognostic system using the combination of platelet count and neutrophil-lymphocyte ratio (COP-NLR). As platelet count decreases with liver damage, we hypothesized that COP-NLR could indicate both inflammation and hepatic reserve in patients with hepatocellular carcinoma (HCC). This study was conducted to clarify the prognostic significance of preoperative COP-NLR in patients with HCC., Patients and Methods: We enrolled 176 patients with histologically-proven HCC who underwent initial curative hepatectomy. Patients were assigned one point each for low platelet count (<15×10 4 /μl) or for high NLR (≥2.0), for hepatic-COP-NLR scores (h-COP-NLR) of 0, 1 or 2., Results: Five-year overall survival (OS) and recurrence-free survival (RFS) rates were 74.5±9%, and 62.2%±9.3% for score 0, 63.6±5.4% and 50.3%±5.6% for score 1, and 45.2±8.8% and 40.6±8.7% for score 2, respectively, and significantly differed (OS: p=0.01; RFS: p=0.03). In multivariate analysis, h-COP-NLR was an independent risk factor for tumor recurrence (HR=1.39, p=0.03) and death (HR=1.71, p=0.02)., Conclusion: h-COP-NLR was an independent predictor for prognosis of HCC patients after hepatic resection., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: To evaluate the impact of DEPDC1 expression on patient prognosis after hepatic resection for hepatocellular carcinoma (HCC)., Patients and Methods: We reviewed data from 75 patients who underwent hepatic resection for HCC between 2004 and 2013. Recurrence at 2 years following resection, which mainly included metastatic recurrence, was defined as late recurrence., Results: DEPDC1 was up-regulated in HCC tissue and in non-tumor tissue of patients with HCC compared to normal liver (p<0.01 and p<0.01, respectively). High expression of DEPDC1 was associated with poor overall, disease-specific, and disease-free survival (p=0.02, p<0.01, and p<0.01, respectively). High DEPDC1 expression was an independent predictor of death and recurrence (p=0.03 and p<0.01, respectively). High expression of DEPDC1 in non-tumor liver was an independent risk factor for late recurrence (p=0.04)., Conclusion: High expression of DEPDC1 in tumor tissue appears to be associated with tumor progression and poor prognosis., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Carbohydrate antigen 19-9 (CA19-9) is the most frequently used tumor marker and serves as a prognostic indicator in patients with pancreatic cancer (PC). The platelet-to-lymphocyte ratio (PLR) is thought to be an inflammation-related serum marker. An elevated PLR represents increased inflammatory status and is associated with poor prognosis in patients with various cancers including PC., Methods: This study involved 103 patients with a histopathological diagnosis of pancreatic ductal adenocarcinoma who underwent pancreatectomy. The patients were assessed to determine the prognostic significance of the combination of the PLR and CA19-9 level., Results: Based on the receiver operating characteristic analysis results, the patients were divided into PLR High (PLR ≥ 129.1) and PLR Low (PLR < 129.1) groups and into CA19-9 High (CA19-9 ≥ 74.0 U/mL) and CA19-9 Low (CA19-9 < 74.0 U/mL) groups. The cumulative 5-year overall survival (OS) and disease-specific survival (DSS) rates significantly differed by both the PLR (PLR High group: 19.5% and 22.9%; PLR Low group: 39.1% and 45.9%) and CA19-9 (CA19-9 High group: 19.1% and 25.6%; CA19-9 Low group: 41.0% and 41.0%). We then divided the patients into Groups A (PLR Low /CA19-9 Low ), B (PLR Low /CA19-9 High or PLR High /CA19-9 Low ), and C (PLR High /CA19-9 High ). The cumulative 5-year OS rates in Groups A, B, and C were 44.0%, 31.9%, and 11.9%, respectively (P = 0.002). The cumulative 5-year DSS rates in Groups A, B, and C were 47.7%, 36.4%, and 16.8%, respectively (P = 0.002). Multivariate analysis revealed that the combination of the PLR and CA19-9 was an independent prognostic factor in patients with resected PC., Conclusions: The combination of the PLR and CA19-9 is useful for predicting the prognosis of patients with resected PC., (Copyright © 2019. Published by Elsevier B.V.)

Purpose: We conducted this study to evaluate the impact of the postoperative mean arterial pressure (MAP) on surgical complications after hepatic resection., Methods: The subjects of this study were 199 patients who underwent hepatic resection for primary liver malignancy between 2004 and 2013. A clinically relevant postoperative complication was defined as a Clavien-Dindo grade ≥ III complication., Results: Based on an MAP cut-off value of 81.1 mmHg, the patients were grouped as follows: low MAP on both postoperative days (PODs) 1 and 2 (continuously low MAP), normal MAP on both PODs 1 and 2 (normal MAP), and others (transiently low MAP). The continuously low MAP group had the highest incidence of complications and the normal MAP group had the lowest incidence of complications compared with the expected incidence for this cohort (p < 0.01 and p = 0.01, respectively). Multivariate analysis revealed that both a continuously and transiently low MAP were independent predictors of postoperative complications (p = 0.03 and p < 0.01, respectively). Among the subtypes of complications, a low MAP had a significant relationship with ascites/pleural effusion and respiratory complications (p < 0.01 and p = 0.03, respectively)., Conclusions: A low MAP on POD 1 and/or 2 is an independent predictor of postoperative complications.

Objectives: It is widely accepted that postoperative pancreatic fistula (POPF) accompanied by bacterial infection results in a worse outcome than POPF alone. However, few studies evaluating predictive indicators of POPF have focused on bacterial infection., Methods: A consecutive 100 patients who underwent pancreaticoduodenectomy at our institute for periampullary disease were enrolled. POPF was assessed according to the International Study Group of Pancreatic Fistula consensus guidelines; grades B and C were defined as clinically relevant POPF (CR-POPF). The patients' characteristics, perioperative surgical factors, and laboratory data including the results of culture and smear testing performed using drainage fluid on postoperative days (PODs) 1 and 3 were analyzed., Results: The overall incidence of CR-POPF was 25%. Univariate analyses revealed that the factors associated with CR-POPF were male sex, soft pancreas, MPD diameter, higher serum C-reactive protein concentration and white blood cell count on POD 3, higher amylase concentration in drainage fluid, and culture and/or smear positivity of drainage fluid. Multivariate analysis newly revealed that the smear positivity of drainage fluid on POD 3 was the independent risk factors for CR-POPF (p = 0.027)., Conclusions: Smear positivity of drainage fluid on POD 3 after pancreaticoduodenectomy may be a new predictor of CR-POPF., (Copyright © 2019 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Background: The albumin-bilirubin (ALBI) grade assesses the severity of liver dysfunction in patients with hepatocellular carcinoma. Herein we investigated the prognostic significance of the combination of the ALBI grade with serum carbohydrate antigen 19-9 (CA 19-9) concentration, the most frequently used tumor marker in pancreatic cancer (PC) in resected patients with PC., Materials and Methods: Included patients (n=100) had a histopathological diagnosis of pancreatic cancer and underwent pancreatectomy. Serum concentrations of albumin, bilirubin, and CA19-9 were measured within 5 days before surgery. Patients were divided into groups with high and low CA19-9 (cut-off ≥35 U/ml) and ALBI grade (2 and 3 vs. 1)., Results: The 5-year overall survival (OS) rates of the ALBI High and ALBI Low groups were 21.6% and 35.3%, respectively (p=0.015). The 5-year OS rates of the CA19-9 High and CA19-9 Low groups were 22.2% and 41.5%, respectively (p=0.017). Patients were divided into groups A (ALBI High and CA19-9 High ), B (ALBI High and CA19-9 Low or ALBI Low and CA19-9 High ), and C (ALBI Low and CA19-9 Low ). The 5-year OS rates of groups A, B, and C were 13.8%, 31.0%, and 43.3%, respectively (p=0.0006). Multivariate analysis revealed that the ALBI grade combined with the CA19-9 concentration, served as an independent prognostic indicator., Conclusion: The combination of ALBI grade and CA19-9 concentration predicted the prognosis of patients with PC., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Hepatocellular carcinoma (HCC) is one of the leading causes of cancer death worldwide. Cancer stem cells (CSCs) have attracted attention as a novel therapeutic target for cancer because they play important roles in the development and aggravation of cancer. CD44 is expressed as a standard isoform (CD44s) and several variant isoforms. CD44v is a major isoform expressed on CSCs of a variety of tumors and has been extensively studied. However, HCC tissues dominantly express CD44s, whose function in CSCs remains unclear. In the present study, we investigated the roles of CD44s in CSCs of HCC. Knock-out of the CD44 gene in HuH7 HCC cells on which only CD44s is expressed resulted in decreased spheroid formation and increased drug sensitivity. The expression of CSC marker genes, including CD133 and EpCAM, was significantly downregulated in the spheroids of CD44-deficient cells compared with those in the spheroids of HuH7 cells. In addition, CD44 deficiency impaired antioxidant capacity, concomitant with downregulation of glutathione peroxidase 1 (GPX1) and thioredoxin. Because GPX1 uses the reduced form of glutathione (GSH) to regenerate oxidized cellular components, GSH levels were significantly increased in the CD44-deficient cells. We also found that NOTCH3 and its target genes were downregulated in the spheroids of CD44-deficient cells. NOTCH3 expression in HCC tissues was significantly increased compared with that in adjacent nontumor liver tissues and was correlated with CD44 expression. These results suggest that CD44s is involved in maintenance of CSCs in a HCC cell line, possibly through the NOTCH3 signaling pathway., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Telomerase reverse transcriptase (TERT) promotes immortalization by protecting telomeres in cancer cells. Mutation of the TERT promoter is one of the most common genetic alterations in hepatocellular carcinoma (HCC), indicating that TERT upregulation is a critical event in hepatocarcinogenesis. Regulators of TERT transcription are, therefore, predicted to be plausible targets for HCC treatment. We undertook a genome-wide shRNA library screen and identified C15orf55 and C7orf43 as regulators of TERT expression in HepG2 cells. Promoter assays showed that C15orf55- and C7orf43-responsive sites exist between base pairs -58 and +36 and -169 and -59 in the TERT promoter, respectively. C15orf55 upregulates TERT expression by binding to two GC motifs in the SP1 binding site of the TERT promoter. C7orf43 upregulates TERT expression through Yes-associated protein 1. The expression levels of C15orf55 and C7orf43 also correlated with that of TERT, and were significantly increased in both HCC tissues and their adjacent non-tumor tissues, compared to normal liver tissues from non-HCC patients. Analysis of 377 HCC patients in The Cancer Genome Atlas dataset showed that overall survival of patients with low levels of C15orf55 and C7orf43 expression in tumor tissues was better compared with patients with high levels of C15orf55 and/or high C7orf43 expression. These results indicate that C15orf55 and C7orf43 are involved in the incidence and progression of HCC by upregulating TERT. In conclusion, we identified C15orf55 and C7orf43 as positive regulators of TERT expression in HCC tissues. These genes are promising targets for HCC treatment., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: The neutrophil lymphocyte ratio (NLR) has been proposed to be a surrogate marker of inflammation and immunological status and to have prognostic value in various malignancies. This study was conducted to clarify the prognostic significance of preoperative NLR in hepatocellular carcinoma (HCC)., Methods: We enrolled 135 patients with histologically-proven HCC who underwent initial curative hepatectomy. Based on the median NLR values, patients were divided into: NLR ≥ 2.0 (NLR-high, n = 69) and NLR < 2.0 (NLR-low, n = 66)., Results: In univariate analysis, the 5-year overall survival (OS) rates were 59.8 % ± 6.7% and 75.6% ± 6.5% ( P = 0.028) in the NLR-high and NLR-low groups, respectively. Furthermore, the 5-year disease specific survival rates were 68.6% ± 6.7%, and 81.2 ± 6.4% ( P = 0.048) in the NLR-high and NLR-low groups, respectively., Conclusion: Our results showed that high NLR was an independent predictor for OS in hepatectomy-treated HCC, suggesting that NLR may be a novel prognostic biomarker for HCC. On the other hand, NLR also has a limitation to predict postoperative prognosis of HCC patients by itself.

Background: Although Child-Pugh grade A patients with hepatocellular carcinoma (HCC) are candidates for curative resection, some may have a poor prognosis. The albumin-bilirubin (ALBI) grade, a measure of liver function based on albumin and bilirubin, has the potential to detect Child-Pugh grade A HCC patients with poor prognosis. Because components of the ALBI grade can be measured easily even after surgery, we explored the predictive values of ALBI in patient prognosis after HCC resection., Methods: In this retrospective case-control study, we included 136 HCC patients who underwent curative resection between January 2004 and December 2013 at our hospital. ALBI grade was calculated from laboratory data recorded the day before surgery and at post-operative day 5., Results: Pre- and post-operative ALBI grade predicted patients' long-term outcomes (P = 0.020 and P < 0.001, respectively, for overall survival, and P = 0.012 and P = 0.015, respectively, for recurrence-free survival). Post-operative ALBI grade was associated with patients' surgical factors of repeated hepatic resection (P = 0.012), intra-operative bleeding (P = 0.006), and surgery duration (P = 0.033). Furthermore, post-operative ALBI grade, rather than pre-operative ALBI grade, was an independent predictive factor of long-term outcome of Child-Pugh grade A patients with HCC., Conclusions: Post-operative ALBI grade is useful to predict the prognosis in patients after HCC resection., (Copyright © 2018. Published by Elsevier B.V.)

Portal vein stenosis, which results in serious clinical conditions such as gastrointestinal variceal bleeding and liver failure, is caused by hepatobiliary pancreatic cancer or major postoperative complications after hepatobiliary pancreatic surgery. In recent years, portal vein stenting under interventional radiology has been applied as a more useful treatment method for portal vein stenosis than invasive surgery. We herein report the successful use of a vascular stent for portal vein stenosis after pancreatoduodenectomy. A 66-year-old man with distal cholangiocarcinoma underwent subtotal stomach-preserving pancreatoduodenectomy with resection of the portal vein because of direct invasion to the main portal vein at our hospital. The portal vein was reconstructed without a venous graft. He developed jejunal bleeding near the pancreatojejunostomy on postoperative day (POD) 2. Although embolization of the responsible vessel achieved hemostasis, an intraoperatively inserted drainage tube was needed for a long period of time postoperatively because the embolized afferent jejunum was perforated. He was discharged on POD 39 after removal of the drainage tube. On POD 282, he was readmitted with melena and severe fatigue. Computed tomography revealed an obstruction of the reconstructed portal vein and varices at the hepaticojejunostomy site. We diagnosed variceal bleeding and performed percutaneous transhepatic stenting in the obstructed portal vein. The patient was discharged in good clinical condition on day 15 after stenting. In conclusion, portal vein stenting is a useful and less invasive therapy for portal vein stenosis.

Background/aim: We retrospectively investigated the relationship between prognosis and combined neutrophil-to-lymphocyte ratio (NLR) and serum carbohydrate antigen 19-9 (CA19-9) levels in patients with recurrent pancreatic cancer., Patients and Methods: We enrolled 66 patients whose pancreatic cancer recurred., Results: Based on ROC analysis results, the patients were divided into NLR High (NLR ≥1.69) or NLR Low (NLR <1.69), and into CA19-9 High (CA19-9 ≥107.95 U/ml) or CA19-9 Low (CA19-9 <107.95 U/ml). When the patients were grouped by combined NLR and CA19-9, their 2-year survival rates were NLR Low /CA19-9 Low : 58.7%; NLR Low /CA19-9 High or NLR High /CA19-9 Low (grouped together): 11.2%; and NLR High /CA19-9 High : 0% (p<0.0001). Finally, in multivariate analysis, the combination of NLR and serum CA19-9 level was an independent prognostic factor in patients with recurrent pancreatic cancer., Conclusion: The combination of NLR and serum CA19-9 level is a useful prognostic indicator for recurrent pancreatic cancer., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Postoperative complications may adversely affect oncological outcomes. The aim of this study was to evaluate the impact of postoperative complications on early-phase recurrence after curative resection for hepatocellular carcinoma (HCC)., Methods: We included 145 HCC patients who underwent initial and curative resection between January 2004 and December 2013. Postoperative complications of grade III or higher based on Clavien-Dindo classification were defined as clinically relevant postoperative complications. Recurrence within two years after hepatectomy was defined as early-phase recurrence., Results: Thirty-eight patients (26%) developed postoperative complications. The only predictive factor for postoperative complication was longer operative duration (P = 0.037). The disease-specific survival rate of patients with complication was lower than that of patients without complications (P = 0.015). Early-phase recurrence was observed in 20/38 (53%) patients who suffered postoperative complications and 36/107 (34%) patients with no complications, which was statistically significant (P = 0.039). Multivariate analysis identified four factors contributing to early-phase recurrence: high serum AFP level (P = 0.042), multiple tumors (P < 0.001), poor differentiation (P = 0.036) and presence of postoperative complication (P = 0.039)., Conclusions: Postoperative complication is an independent prognostic factor for early-phase recurrence after curative resection of HCC. Close observation of patients with postoperative complications may be a necessary treatment strategy for HCC., (Copyright © 2018 First Affiliated Hospital, Zhejiang University School of Medicine in China. Published by Elsevier B.V. All rights reserved.)

Background/aim: Probe-based confocal laser endomicroscopy (pCLE) is a novel diagnostic technique that can provide real-time imaging of tissues at the cellular level. In this study, pCLE was applied to liver tumors and its diagnostic value was evaluated., Patients and Methods: Ten patients who underwent hepatectomy for liver tumors were evaluated with pCLE from February to May 2017. Immediately after liver resection, pCLE evaluation was performed in the operating room as an ex vivo study. The newly-adopted "fluorescein-dripping method" was used for the observation., Results: First, the optimal fluorescein exposure time for the surface of liver was defined in the fluorescein-dripping method. Next, the distinctive findings in the cancerous region were investigated. The characteristic appearance of irregular arrangements of concentrated cells under fluorescein dripping was observed in six of seven hepatocellular carcinoma (HCC) tumors., Conclusion: In all HCC specimens, discrimination of the cancerous region from normal liver was possible with pCLE., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Indirubin, a constituent of the Chinese herbal medicine "Qing-Dai," has anti-cancer and anti-inflammatory activities. We aimed to evaluate the efficacy of indirubin for ameliorating colonic inflammation in a mouse model of inflammatory bowel disease., Methods: Mice with dextran sulfate sodium (DSS)-induced acute and chronic colitis were treated with indirubin in their diet. Clinical and histologic changes were evaluated. In addition, colon levels of interleukin-6, a critical pro-inflammatory mediator, was detected by enzyme-linked immunosorbent assay., Results: In the model of acute colitis, indirubin treatment improved the loss of body weight. Histology of colonic tissue revealed that indirubin treatment improved the histology grading of colitis ( P = 0.02), the extent of submucosal fibrosis ( P = 0.018), the number of mucosal toluidine blue-positive cells ( P = 0.004) and colon length ( P = 0.01). In the model of chronic colitis, indirubin treatment had no significant effect on pathologic findings except for colon length ( P = 0.003). However, indirubin administration significantly reduced colon levels of interleukin-6 in the chronic-colitis model ( P = 0.001)., Conclusion: Our study clearly showed that oral intake of indirubin can improve murine DSS-induced colitis (which mimics human inflammatory bowel disease).

Purpose: Pancreatic fistula (PF) is the most serious complication following pancreaticoduodenectomy (PD). This study was performed to identify new clinical factors that may predict the development of PF after PD to improve perioperative management., Methods: Seventy-five consecutive patients who underwent PD from 2012 to 2015 were evaluated. The patients' perioperative data including the computed tomography (CT) parameters were collected. The minimum, maximum, and mean CT attenuation values (HU min , HU max , and HU mean , respectively) were extracted from the pancreatic parenchyma (≥ 100 pixels), and the standard deviation of these values (HU SD ) was determined from the slice in which the superior mesenteric and splenic veins were merged. PF was defined as grade B or C according to the International Study Group for Pancreatic Fistula criteria., Results: The PF occurrence rate (grade B or C) was 25.3% in 75 patients. A multivariate analysis identified a larger HU SD (odds ratio 3.092; 95% CI 1.018-9.394) and higher amylase concentration in drainage fluid on postoperative day 1 (odds ratio 1.0001; 95% CI 1.00001-1.00022) as significant risk factors for PF., Conclusions: The HU SD of preoperative CT attenuation values in the pancreatic parenchyma was found to be an independent predictor for PF after PD and it might therefore positively contribute to the perioperative management of PD.

Background: Treatment for tracheoesophageal fistula (TEF), a life-threatening complication after esophagectomy, is challenging., Case Presentation: A 75-year-old man with thoracic esophageal cancer underwent subtotal esophagectomy and gastric tube reconstruction through the post-mediastinal root after neoadjuvant chemotherapy. Owing to postoperative anastomotic leakage, an abscess formed at the anastomotic region. Sustained inflammation from the abscess caused refractory TEF between the esophagogastric anastomotic site and membrane of the trachea, and several conservative therapies for TEF failed. Hence, the patient underwent surgery including division of the fistula, direct suturing of the leakage sites, and reinforcement with the flap of the thymus pedicle. As a result, the abscess and TEF disappeared after surgery and the patient was immediately administered an oral diet and discharged home 103 days after initial surgery., Conclusions: Although pedicle flaps for the reinforcement of TEF are usually obtained from muscle or pericardium, these flaps need enough lengths to overcome moving distance. We are the first in the existing literature to have successfully treated TEF with surgical repair using a thymus flap located close to TEF. The thymus pedicle might be another candidate for the reinforcement flap in TEF.

Background: A few reports have described the effectiveness of resection for recurrent cholangiocarcinoma. However, none have described resection of synchronous pulmonary metastasis from distal cholangiocarcinoma. We report the first case, to the best of our knowledge, of a slow-growing synchronous pulmonary metastasis from distal cholangiocarcinoma resected 3.5 years after the initial surgery., Case Presentation: A 67-year-old Japanese man with a diagnosis of distal cholangiocarcinoma was referred to our hospital. Thickening of the distal bile duct and an air-space pattern in the upper lobe of the left lung were detected by preoperative computed tomography. He underwent pancreaticoduodenectomy for the distal cholangiocarcinoma. Follow-up chest computed tomography demonstrated that the air-space pattern in the left lung had gradually enlarged. Thoracoscopic left S6 segmentectomy with lymph node dissection was performed 3.5 years after the initial surgery. Histopathology of the resected specimen revealed a solitary metastasis from distal cholangiocarcinoma with lepidic growth. We diagnosed the patient with a solitary synchronous pulmonary metastasis from distal cholangiocarcinoma., Conclusions: Surgical resection might offer better long-term survival to patients with synchronous pulmonary metastasis from distant cholangiocarcinoma than nonsurgical treatments. Pulmonary metastasis from distal cholangiocarcinoma may exhibit a lepidic pattern. Therefore, because of the possibility of synchronous pulmonary metastasis, pulmonary resection should be considered for patients with lepidic lesions who have been diagnosed with distal cholangiocarcinoma.

Background: Imaging modalities (computed tomography (CT), ultrasonography, and magnetic resonance imaging (MRI)) have only limited ability to distinguish liver focal nodular hyperplasia (FNH) from metastatic liver tumors. Here, we report a patient who underwent surgery for benign FNH that mimicked a liver metastasis from soft tissue sarcoma (STS)., Case Presentation: A 23-year-old man with a history of several surgeries for metastatic abdominal STS, developed a hepatic tumor accompanying peritoneal STS recurrence. He was diagnosed with a metastatic liver tumor from the STS, based on imaging studies for the hepatic tumor that showed a growing hypervascular lesion and hypo-intensity in hepatic phase on dynamic CT and MRI. However, when the liver and peritoneal tumors were resected, histological diagnosis showed the hepatic tumor to be benign liver FNH., Conclusions: Although FNH should be considered as a differential diagnosis for hypervascular hepatic tumors, it has few typical findings, and its appropriate management is controversial. A lesion strongly suspected of being a metastatic liver tumor might require surgical resection.

Sternal and rib fractures are well-known complications of cardiopulmonary resuscitation (CPR). We experienced a rare case of traumatic gastric perforation associated with CPR that required emergency laparotomy. In this case, we examined whether surgery is essential for gastric perforation associated with CPR. A 67-year-old man experienced cardiopulmonary arrest in the workplace, and bystander CPR was performed by his colleagues. He was then transported by ambulance to our hospital. A large amount of free air was found in the peritoneal cavity on computed tomography at presentation, and perforation of the gastrointestinal tract was suspected. During emergency laparotomy, a 2-cm serosal-muscular layer tear was found in the gastric lesser curvature. The damaged stomach wall was repaired, the abdominal cavity was lavaged, and surgery was completed by placing a drainage tube. The patient's postoperative course was good and he was discharged on the 26th postoperative day. Emergency laparotomy has been performed frequently for traumatic gastric perforation associated with CPR. However, emergency laparotomy may be avoided by conservative treatment in some cases. Traumatic gastric perforation associated with CPR is a serious complication; however, the life prognosis of cardiopulmonary arrest patients depends on the original disease and the success of CPR. Traumatic gastric perforation associated with CPR is rarely fatal, and bystanders should not hesitate to initiate CPR.

Introduction: Internal supravesical hernia is one of the rarest types of inguinal hernia. The hernial orifice is surrounded by the transverse vesical fold, median umbilical fold, and medial umbilical fold., Presentation of Case: A 75-year-old male presented with lower abdominal pain and nausea. Plain abdominal CT showed that the bladder was suppressed by small bowel near the left internal inguinal ring. A part of the small bowel wall seemed to be inlaid, and so the patient was diagnosed with a strangulated left inguinal hernia. The hernia repair operation was performed via the anterior approach. There was no internal hernial sac found, but there was a walnut-sized mass in the properitoneal space. A diagnosis was made intraoperatively of internal supravesical hernia with strangulated small bowel. Small bowel resection and hernial orifice closure were performed., Discussion: Although internal supravesical hernia can present with distinctive CT findings, preoperative diagnosis is extremely difficult. Internal supravesical hernia in previous reports has been repaired via open laparotomy or laparoscopic surgery; however, we successfully repaired this intraoperatively-diagnosed internal supravesical hernia by the anterior approach alone., Conclusion: The patient with internal supravesical hernia diagnosed intraoperatively could be treated via the anterior approach alone successfully. Depending on the situation, the anterior approach can be an option., (Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Preoperative transcatheter arterial chemoembolization (TACE) is administered to improve long-term outcome after surgical resection of hepatocellular carcinoma (HCC). However, the survival benefit of preoperative TACE is controversial. We conducted a retrospective case-control study to evaluate the effect of preoperative TACE on prognosis., Methods: A total of 121 patients who underwent curative resection of HCC were divided into two groups according to whether they received preoperative TACE. We determined the control group ( n = 34) and TACE group ( n = 34) through propensity score matching. The primary endpoint of this study was overall survival, and the secondary endpoints were recurrence-free survival., Results: The overall survival rate and the recurrence free survival rate were significantly lower in the TACE group than in the control group ( P = 0.014 and P = 0.043, respectively). Furthermore, recurrence free survival within less than 2 years after resection was significantly worse in the TACE group than in the control group ( P = 0.035)., Conclusion: Preoperative TACE seemed to worsen the long-term outcomes of the patients who underwent surgical resection for the treatment of resectable HCC. Therefore, preoperative TACE should not be considered as a standard therapy in patients with resectable HCC.

Background: Pancreatic cancer (PC) is the most lethal malignancy among solid tumors, and the most common risk factor for its development is cigarette smoking. Atypical protein kinase C (aPKC) isozymes function in cell polarity, proliferation, and survival, and have also been implicated in carcinogenesis. However, the involvement of aPKC in PC progression and the effect of nicotine, a major component of cigarette smoke, on the biological activities of aPKC remain to be fully elucidated., Methods: We investigated the effects of nicotine on the proliferation, migration and invasion of the human PC cell lines Panc1 and BxPC3. We analyzed aPKC localization and activity by immunohistochemistry and in vitro kinase assays, respectively, to assess their involvement in the regulation of PC progression. Moreover, we examined the effect of nicotine on implanted peritoneal tumors of PC cells in mice., Results: Nicotine enhanced cell proliferation, migration and invasion in Panc1 and BxPC3 cells. In nicotine-treated PC cells, the aPKC was significantly activated. We also found that nicotine induced phosphatidylinositol 3-kinase (PI3K) signal activation, and a specific inhibitor of the nicotine acetylcholine receptor (nAChR) as well as knockdown of nAChR prevented nicotine-mediated Akt phosphorylation and aPKC activation. In a peritoneal dissemination model of PC, nicotine-treated mice had larger tumors and increased numbers of nodules. Immunohistochemistry showed enhanced expression levels of aPKC and phosphorylated Akt in nodules from nicotine-treated mice., Conclusions and General Significance: Nicotine induces aberrant activation of aPKC via nAChR/PI3K signaling in PC cells, resulting in enhancement of cellular proliferation, migration and invasion., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Purpose: We evaluated prognostic indicators based on inflammatory and nutritional factors, namely, the modified Glasgow Prognostic Score (mGPS), the Prognostic Nutritional Index (PNI), the neutrophil/lymphocyte ratio (NLR), and the platelet/lymphocyte ratio (PLR), to determine their efficiency and significance after pancreaticoduodenectomy for pancreatic cancer., Methods: The subjects of this study were 46 patients who underwent pancreaticoduodenectomy for pancreatic cancer between October 2007 and December 2014. Patients were divided into preoperative mGPS (0/1 and 2), PNI (<40 and ≥40), NLR (<2.5 and ≥2.5), and PLR (<200 and ≥200) groups, to evaluate various perioperative outcomes., Results: Hemoglobin concentrations were significantly lower (P = 0.019), whereas intra-abdominal bleeding was significantly higher (P = 0.040) in the PNI (<40) group than in the PNI (≥40) group. The incidence of postoperative pneumonia was significantly higher in the mGPS (2) group (P = 0.009), and surgical complications greater than grade 3 (Clavien-Dindo classification) were significantly increased in the NLR (≥2.5) group (P = 0.041). Overall survival rates in the PNI (<40) (P = 0.019), NLR (≥2.5) (P = 0.001), and PLR (≥200) (P < 0.001) groups were significantly lower than those in the other groups. The PLR was the only independent prognostic indicator (P = 0.002) according to multivariate analysis., Conclusions: The mGPS, PNI, and NLR were effective predictive indicators of postoperative complications. The PLR was the most useful prognostic indicator for pancreatic cancer patients after pancreaticoduodenectomy.

Background: Laparoscopic total gastrectomy is not widely performed because of the difficulty of esophagojejunal reconstruction. This study analyzed complication rates of two different methods for reconstruction by a circular stapler after totally laparoscopic total gastrectomy (TLTG)., Methods: Between 2010 and 2014, clinical data of 19 patients who underwent TLTG for gastric adenocarcinoma were collected retrospectively. There were two methods to fix the anvil of a circular stapler into the distal esophagus: In the single-stapling technique (SST) group, Endo-PSI(II) was used for purse-suturing on the distal esophagus for reconstruction, and in the hemi-double-stapling technique (hemi-DST) group, the esophagus was cut by linear stapler with the entry hole of the anvil shaft opened after inserting the anvil tail. In both groups, surgical procedures were the same, except for the reconstruction., Results: All TLTGs were performed securely without mortality. Intracorporeal laparoscopic esophagojejunal anastomosis was performed successfully for all the patients. In the hemi-DST group, four patients experienced anastomotic stenosis, three of whom required endoscopic balloon dilation. In contrast, no stenosis was seen in the SST group (p = 0.033)., Conclusions: Anastomosis with SST is preferred to that with hemi-DST to minimize postoperative complications.