Hyperglycaemia induces metabolic reprogramming into a glycolytic phenotype and promotes epithelial-mesenchymal transitions via YAP/TAZ-Hedgehog signalling axis in pancreatic cancer.

BACKGROUND: Hyperglycaemia is a well-known initial symptom in patients with pancreatic ductal adenocarcinoma (PDAC). Metabolic reprogramming in cancer, described as the Warburg effect, can induce epithelial-mesenchymal transition (EMT). METHODS: The biological impact of hyperglycaemia on malignant behaviour in PDAC was examined by in vitro and in vivo experiments. RESULTS: Hyperglycaemia promoted EMT by inducing metabolic reprogramming into a glycolytic phenotype via yes-associated protein (YAP)/PDZ-binding motif (TAZ) overexpression, accompanied by GLUT1 overexpression and enhanced phosphorylation Akt in PDAC. In addition, hyperglycaemia enhanced chemoresistance by upregulating ABCB1 expression and triggered PDAC switch into pure basal-like subtype with activated Hedgehog pathway (GLI1 high, GATA6 low expression) through YAP/TAZ overexpression. PDAC is characterised by abundant stroma that harbours tumour-promoting properties and chemoresistance. Hyperglycaemia promotes the production of collagen fibre-related proteins (fibronectin, fibroblast activation protein, COL1A1 and COL11A1) by stimulating YAP/TAZ expression in cancer-associated fibroblasts (CAFs). Knockdown of YAP and/or TAZ or treatment with YAP/TAZ inhibitor (K975) abolished EMT, chemoresistance and a favourable tumour microenvironment even under hyperglycemic conditions in vitro and in vivo. CONCLUSION: Hyperglycaemia induces metabolic reprogramming into glycolytic phenotype and promotes EMT via YAP/TAZ-Hedgehog signalling axis, and YAP/TAZ could be a novel therapeutic target in PDAC.

Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development.

BACKGROUND & AIMS: There is a major unmet need to assess the prognostic impact of antifibrotics in clinical trials because of the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression. METHODS: A fibrosis progression signature (FPS) was defined to predict fibrosis progression within 5 years in patients with hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) with no to minimal fibrosis at baseline (n = 421) and was validated in an independent NAFLD cohort (n = 78). The FPS was used to assess response to 13 candidate antifibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n = 78) and cenicriviroc in patients with nonalcoholic steatohepatitis enrolled in a clinical trial (n = 19, NCT02217475). A serum protein-based surrogate FPS was developed and tested in a cohort of compensated cirrhosis patients (n = 122). RESULTS: A 20-gene FPS was defined and validated in an independent NAFLD cohort (adjusted odds ratio, 10.93; area under the receiver operating characteristic curve, 0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacologic target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate antifibrotics identified rational combination therapies based on epigallocatechin gallate, which were validated for enhanced antifibrotic effect in ex vivo culture of clinical liver tissues. In patients with nonalcoholic steatohepatitis treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of the PPARα pathway was absent in patients without fibrosis improvement, suggesting a benefit of combining PPARα agonism to improve the antifibrotic efficacy of cenicriviroc. A 7-protein serum protein-based surrogate FPS was associated with the development of decompensation in cirrhosis patients. CONCLUSION: The FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform antifibrotic drug development.

Estimation of Degradation Degree in Road Infrastructure Based on Multi-Modal ABN Using Contrastive Learning.

This study presents a method for distress image classification in road infrastructures introducing self-supervised learning. Self-supervised learning is an unsupervised learning method that does not require class labels. This learning method can reduce annotation efforts and allow the application of machine learning to a large number of unlabeled images. We propose a novel distress image classification method using contrastive learning, which is a type of self-supervised learning. Contrastive learning provides image domain-specific representation, constraining such that similar images are embedded nearby in the latent space. We augment the single input distress image into multiple images by image transformations and construct the latent space, in which the augmented images are embedded close to each other. This provides a domain-specific representation of the damage in road infrastructure using a large number of unlabeled distress images. Finally, the representation obtained by contrastive learning is used to improve the distress image classification performance. The obtained contrastive learning model parameters are used for the distress image classification model. We realize the successful distress image representation by utilizing unlabeled distress images, which have been difficult to use in the past. In the experiments, we use the distress images obtained from the real world to verify the effectiveness of the proposed method for various distress types and confirm the performance improvement.

The Impact of Histologic Liver Inflammation on Oncology and the Prognosis of Patients Undergoing Hepatectomy for Hepatocellular Carcinoma.

BACKGROUND: Liver inflammation is a reaction to disease-causing stress in the liver that induces fibrosis and cirrhosis. However, its prognostic impact after hepatectomy remains unclear. This study aimed to evaluate the prognostic and oncologic impacts of liver inflammation on patients after curative hepatectomy for hepatocellular carcinoma (HCC). METHODS: The study enrolled 500 consecutive patients with primary HCC who underwent curative and primary hepatectomy. Patient characteristics and prognoses were evaluated according to histologic liver inflammation assessed by the New Inuyama Classification. RESULTS: Severe liver inflammation (A3) was observed in 97 patients (19.4%) and nonsevere liver inflammation (A0-2) in 403 patients (80.6%). The patients with A3 had a significantly poorer prognosis than those with A0-2 in terms of relapse-free survival (p < 0.0001, log-rank) and overall survival (p = 0.0013, log-rank). The study showed that A3 is an independent poor prognostic factor (hazard ratio, 1.36; 95% confidence interval [Cl], 1.02-1.81; p = 0.039), and that Child-Pugh grade B and multiple tumors are associated with relapse-free survival. Furthermore, The significant predictors of early recurrence (within 2 years after hepatectomy) were A3 (odds ratio, 2.10; 95% CI, 1.25-3.55; p = 0.005), a des-γ-carboxyprothrombin level higher than 40 mAU/mL, and multiple tumors. CONCLUSIONS: Severe liver inflammation was associated with poor short- and long-term prognoses independently of cirrhosis. Controlling liver inflammation in the perioperative period may be essential to improving the prognosis of patients with HCC after hepatectomy.

Major postoperative complications are associated with early recurrence of hepatocellular carcinoma following hepatectomy.

BACKGROUND AND AIM: Early recurrence (ER) is a strong predictor of poor prognosis in patients with hepatocellular carcinoma (HCC) after hepatectomy. The aim of this study was to examine manageable factors associated with ER. METHODS: Overall, 475 consecutive patients with primary HCC who underwent curative hepatectomy were included (R0/R1). We defined ER as recurrence within 2 years after hepatectomy and analyzed predictors for ER. We also defined postoperative complication as Clavien-Dindo classification grade III or IV. RESULTS: ER after hepatectomy was observed in 209 cases (44.0%). Patients with ER had a significantly poor prognosis compared with those with late recurrence (log-rank p < 0.0001) and were more likely to be diagnosed with extrahepatic metastasis (p = 0.009). Significant predictors for ER were des-γ-carboxyprothrombin > 40 mAU/mL (odds ratio (OR) 2.06, 95% confidence interval (CI) 1.36-3.14, p = 0.001), multiple tumors (OR 2.80 95%CI 1.83-4.32, p < 0.0001), cirrhosis (OR 1.53, 95%CI 1.01-2.32, p = 0.043), and postoperative complications (OR 1.72, 95% CI 1.05-2.85, p = 0.032). Blood loss (OR 1.09, 95%CI 1.05-1.13, p < 0.0001) and cirrhosis (OR 1.74, 95%CI 1.05-2.86, p = 0.031) were significant predictors for postoperative complications. CONCLUSIONS: We should pay close attention to surgical associated- and disease-specific factors in hepatectomy for HCC to prevent ER.

Brain Decoding of Multiple Subjects for Estimating Visual Information Based on a Probabilistic Generative Model.

Brain decoding is a process of decoding human cognitive contents from brain activities. However, improving the accuracy of brain decoding remains difficult due to the unique characteristics of the brain, such as the small sample size and high dimensionality of brain activities. Therefore, this paper proposes a method that effectively uses multi-subject brain activities to improve brain decoding accuracy. Specifically, we distinguish between the shared information common to multi-subject brain activities and the individual information based on each subject's brain activities, and both types of information are used to decode human visual cognition. Both types of information are extracted as features belonging to a latent space using a probabilistic generative model. In the experiment, an publicly available dataset and five subjects were used, and the estimation accuracy was validated on the basis of a confidence score ranging from 0 to 1, and a large value indicates superiority. The proposed method achieved a confidence score of 0.867 for the best subject and an average of 0.813 for the five subjects, which was the best compared to other methods. The experimental results show that the proposed method can accurately decode visual cognition compared with other existing methods in which the shared information is not distinguished from the individual information.

MicroRNA-25 Exerts an Oncogenic Function by Regulating the Ubiquitin Ligase Fbxw7 in Hepatocellular Carcinoma.

BACKGROUND: MicroRNA (miRNA) expression abnormalities are implicated in tumor progression. Previous reports have indicated that microRNA-25 (miR-25) acts as a tumor suppressor or oncogene in diverse cancers. However, its molecular mechanisms in hepatocellular carcinoma (HCC) are still unclear. F-box and WD repeat domain 7 (Fbxw7) is a critical tumor suppressor and is one of the most important deregulated proteins of the ubiquitin-proteasome system in cancer. Our objective was to elucidate the role of miR-25 and Fbxw7 in HCC and to clarify the mechanism by which Fbxw7 is regulated. METHODS: Fbxw7 expression was estimated in 210 fixed paraffin-embedded HCC samples by immunohistochemistry, and miR-25 expression was evaluated in 142 frozen HCC tissue samples by quantitative real-time PCR. Oncogenic functions of miR-25 and its role in the regulation of Fbxw7 expression were assayed in vitro. RESULTS: miR-25 was overexpressed in HCC tissue compared with adjacent normal tissue and significantly correlated with a poorer prognosis. Moreover, it was inversely correlated with Fbxw7 expression in HCC tissues. Furthermore, miR-25 inhibition significantly reduced the proliferation, migration, and invasion of HCC cells in vitro. CONCLUSION: miR-25 may promote tumor progression in HCC patients by repression of Fbxw7 and could serve as a promising molecular target for HCC treatment.

Novel Approach via the Round Ligament in Portal Vein Embolization.

BACKGROUND: The objective of this study was to describe the detailed technique and clinical outcomes of portal vein embolization via the round ligament (RL-PVE) prior to major hepatectomy. METHODS: Between January 2010 and March 2020, a total of 50 portal vein embolization (PVE) procedures were performed in 50 patients. Of them, seven patients who underwent RL-PVE were enrolled in this study. Percutaneous transhepatic portal vein embolization (PTPE) was not indicated due to the following reasons: bile duct dilation (n = 4), difficulty in visualizing the portal vein on ultrasonography because of severe fatty liver (n = 1), large tumor size (n = 1), and combined surgery with staging laparoscopy (n = 1). The following were reasons for avoiding trans-ileocecal PVE: past laparotomy (n = 5), difficulty in accessing the portal vein due to a large tumor (n = 1), and purpose of preventing small intestinal adhesions before hepatopancreatoduodenectomy (n = 1). The percentage of functional hepatic remnant rates was calculated before and after RL-PVE. RESULTS: Technical success was achieved in all cases. Five patients underwent embolization of the right portal vein, while two underwent embolization of the left portal vein. The median operative time and blood loss during RL-PVE were 181 min and 33 g, respectively. Morbidity and mortality related to RL-PVE were not observed. The median functional hepatic remnant rate before and after PVE was 55.6% and 63.2%, respectively. Liver functions including Child-Pugh classification were equivalent before and after RL-PVE. CONCLUSIONS: The RL-PVE technique may be useful in elective cases for which it is difficult to safely perform PTPE or trans-ileocecal approaches.

12-Chemokine signature, a predictor of tumor recurrence in colorectal cancer.

Tertiary lymphoid structures (TLSs) provide an immunological antineoplastic effect. Recent evidences link a unique 12-chemokine (CCL2, -3, -4, -5, -8, -18, -19, -21, CXCL9, -10, -11, -13) signature status from tumor tissue and the TLS expression. However, the potential significance of 12-chemokine signature status for clinical use is unknown. We aimed to evaluate the association of 12-chemokine signature status with patient outcomes in colorectal cancer (CRC). We used integrated data of resected 975 CRC cases within three independent cohorts from France, Japan and the United States (GSE39582, KUMAMOTO from Kumamoto university hospital and TCGA). The association of 12-chemokine signature status with clinicopathological features, patient outcome, TLS expression status and key tumor molecular features was analyzed. Patients with low 12-chemokine signature status had a significant shorter relapse-free survival in discovery cohort (HR: 1.61, 95% CI: 1.11-2.39, p = 0.0123), which was confirmed in validation cohort (HR: 3.31, 95% CI: 1.33-10.08, p = 0.0087). High 12-chemokine signature status had significant associations with right-sided tumor, high tumor-localized TLS expression, BRAF mutant, CIMP-high status and MSI-high status. Furthermore, RNA-seq based analysis showed that high 12-chemokine signature status was strongly associated with inflammation-related, immune cells-related and apoptosis pathways (using gene set enrichment analysis), and more tumor-infiltrating immune cells, such as cytotoxic T lymphocytes and myeloid dendritic cells (using MCP-counter analysis). We investigated a promising effect of 12-chemokine signature status in CRC patients who underwent resection. Our data may be helpful in developing novel immunological treatment strategies for CRC.

MRI radiomics features predict immuno-oncological characteristics of hepatocellular carcinoma.

OBJECTIVE: To assess the value of qualitative and quantitative MRI radiomics features for noninvasive prediction of immuno-oncologic characteristics and outcomes of hepatocellular carcinoma (HCC). METHODS: This retrospective, IRB-approved study included 48 patients with HCC (M/F 35/13, mean age 60y) who underwent hepatic resection or transplant within 4 months of abdominal MRI. Qualitative imaging traits, quantitative nontexture related and texture features were assessed in index lesions on contrast-enhanced T1-weighted and diffusion-weighted images. The association of imaging features with immunoprofiling and genomics features was assessed using binary logistic regression and correlation analyses. Binary logistic regression analysis was also employed to analyse the association of radiomics, histopathologic and genomics features with radiological early recurrence of HCC at 12 months. RESULTS: Qualitative (r = - 0.41-0.40, p < 0.042) and quantitative (r = - 0.52-0.45, p < 0.049) radiomics features correlated with immunohistochemical cell type markers for T-cells (CD3), macrophages (CD68) and endothelial cells (CD31). Radiomics features also correlated with expression of immunotherapy targets PD-L1 at protein level (r = 0.41-0.47, p < 0.029) as well as PD1 and CTLA4 at mRNA expression level (r = - 0.48-0.47, p < 0.037). Finally, radiomics features, including tumour size, showed significant diagnostic performance for assessment of early HCC recurrence (AUC 0.76-0.80, p < 0.043), while immunoprofiling and genomic features did not (p = 0.098-0929). CONCLUSIONS: MRI radiomics features may serve as noninvasive predictors of HCC immuno-oncological characteristics and tumour recurrence and may aid in treatment stratification of HCC patients. These results need prospective validation. KEY POINTS: • MRI radiomics features showed significant associations with immunophenotyping and genomics characteristics of hepatocellular carcinoma. • Radiomics features, including tumour size, showed significant associations with early hepatocellular carcinoma recurrence after resection.

Clinical significance of half-lives of tumor markers α-fetoprotein and des-γ-carboxy prothrombin after hepatectomy for hepatocellular carcinoma.

AIM: The prognostic significance of the half-lives (HLs) of α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) in patients undergoing hepatectomy for hepatocellular carcinoma (HCC) is unclear. We evaluated the HLs of AFP and DCP in a cohort of such patients. METHODS: This study included data on 202 patients with HCC who underwent curative hepatectomy and had preoperative AFP concentrations ≥100 ng/mL or DCP ≥200 mAU/mL. We calculated the HLs of AFP and DCP from their values just before and 1 month after hepatectomy. We identified three groups: a normalization group, tumor marker concentrations within normal range 1 month post-hepatectomy; a long group, HL of AFP ≥7 days or DCP ≥4 days; and a short group, remaining patients. We evaluated associations between HL and prognosis. RESULTS: Three-year recurrence-free survival (RFS) in the normalization (n = 70), short (n = 71), and long groups (n = 61) was 41.3%, 46.0%, and 16.8%, respectively (P = 0.002). Five-year overall survival (OS) of normalization, short, and long groups was 72.6, 70.6 and 43.8%, respectively (P = 0.002). Multivariate analysis revealed that long HL is an independent risk factor for poor RFS (hazard ratio [HR] 2.21, P = 0.0006) and poor OS (HR 2.70, P = 0.004). The extrahepatic recurrence rate was 21.3% (13/61) in the long group, which is higher than in the normalization group (8.6%, 6/70) (P = 0.04) and short group (9.9%, 7/71) (P = 0.07). CONCLUSION: Post-hepatectomy HLs of AFP and DCP are predictors of long-term outcome in patients with HCC.

The Prognostic Impact of Controlling Nutritional Status (CONUT) in Intrahepatic Cholangiocarcinoma Following Curative Hepatectomy: A Retrospective Single Institution Study.

BACKGROUND: Several studies have examined controlling nutritional status (CONUT), which is one of the useful biomarkers for predicting patients' prognosis following cancer treatment. The aim of this study was to evaluate the value of CONUT as a postoperative prognostic marker in patients with intrahepatic cholangiocarcinoma (ICC) following curative hepatectomy. METHODS: We retrospectively analyzed 71 patients who underwent curative hepatectomy for ICC between May 2002 and November 2016. Patients were divided into two groups according to their preoperative CONUT score (i.e., CONUT â‰§ 2 or CONUT < 2). RESULTS: The number of patients assigned to the normal, mild, moderate, or severe malnutrition groups was 40, 28, two, and one, respectively. The high CONUT group (CONUT â‰§ 2) consisted of 31 patients (43.7%) and had a poor prognosis with regard to overall survival (OS) (p = 0.0149). A high CONUT score is also identified as one of the independent predictors of poor prognosis in OS (hazard ratio 3.02; 95% confidence interval 1.4-6.8; p = 0.007). However, in the current study, a high CONUT score was not associated with postoperative complications (Clavien-Dindo classification â‰§ III or more). CONCLUSIONS: CONUT may be useful for the preoperative assessment of prognosis in patients with ICC who have undergone curative hepatectomy.

Cell type-specific pharmacological kinase inhibition for cancer chemoprevention.

Safety is prerequisite for preventive medicine, but non-toxic agents are generally ineffective as clinical chemoprevention. Here we propose a strategy overcoming this challenge by delivering molecular-targeted agent specifically to the effector cell type to achieve sufficient potency, while circumventing toxicity in the context of cancer chemoprevention. Hepatic myofibroblasts drive progressive fibrosis that results in cirrhosis and liver cancer. In a rat model of cirrhosis-driven liver cancer, a small molecule epidermal growth factor receptor inhibitor, erlotinib, was delivered specifically to myofibroblasts by a versatile nanoparticle-based system, targeting platelet-derived growth factor receptor-beta uniquely expressed on their surface in the liver. With systemic administration of erlotinib, tumor burden was reduced to 31%, which was further improved to 21% by myofibroblast-targeted delivery even with reduced erlotinib dose (7.3-fold reduction with equivalent erlotinib dose) and less hepatocyte damage. These findings demonstrate a strategy, cell type-specific kinase inhibition, for more effective and safer precision cancer chemoprevention.

Impact of surgical treatment after sorafenib therapy for advanced hepatocellular carcinoma.

BACKGROUND: For advanced hepatocellular carcinoma (HCC), surgical treatment after sorafenib induction has rarely been reported. We examined the survival benefit of additional surgical treatment in sorafenib-treated patients. METHODS: Thirty-two advanced HCC patients were given sorafenib from July 2009 to July 2012, and we statistically analyzed the relevant predictive factors of the long-term survival. The institutional review board of Kumamoto University Hospital approved this study (Approval number 1038). RESULTS: The median duration of sorafenib administration was 56.5 days (range 5-945). The cumulative overall survival rate was 44.6, 33.4, 26.0 and 17.8% at 1, 2, 3 and 5 years, respectively. The median survival time was 11.2 months. A survival of more than 3 years after the initiation of sorafenib induction was observed in seven patients, five of whom were subjected to additional surgical intervention. Additional surgery was the most significant factor predicting a survival exceeding 3 years (P < 0.0001) and represents an independent prognostic factor [hazard ratio (HR) 0.07; P = 0.01], followed by the total dose of sorafenib. The surgical interventions comprised two hepatic resections ± radiofrequency ablation, two radiofrequency ablations and one lung resection. CONCLUSIONS: A long-term survival might be obtained for select HCC patients given adequate additional surgical treatment, even after sorafenib induction.

Enhancer of zeste homolog 2 (EZH2) regulates tumor angiogenesis and predicts recurrence and prognosis of intrahepatic cholangiocarcinoma.

BACKGROUND: Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the polycomb repressive complex 2 (PRC2) and regulates tumor malignancy by gene silencing via histone methylation. In this study we investigate the role of EZH2 in angiogenesis of intrahepatic cholangiocarcinoma (ICC). METHODS: The influence of EZH2 on tumor angiogenesis was examined by bioinformatics analysis of a public database. We also assessed the correlation between EZH2 and vasohibin 1 (VASH1) expression in 47 patients with ICC by immunohistochemical (IHC) staining and in vitro gene silencing assays. The prognostic significance of EZH2 and VASH1 expression by IHC was also examined in the ICC cohort. RESULTS: Bioinformatics analysis showed that EZH2 was associated with several angiogenesis gene sets in the public database. EZH2 suppressed VASH1 expression in in vitro assays and IHC studies. EZH2-high/VASH1-low status was independently associated with poor disease-free survival (P = 0.019) and poor overall survival (P = 0.0055). CONCLUSION: The current study demonstrated that high EZH2 expression was associated with activation of tumor angiogenesis, and activation of the EZH2-mediated angiogenesis pathway predicted the prognosis of patients with ICC.

CONUT: a novel independent predictive score for colorectal cancer patients undergoing potentially curative resection.

BACKGROUND: Controlling nutritional status (CONUT) score, calculated from serum albumin and total cholesterol concentrations and total lymphocyte count, is reportedly valuable for nutritional assessment. This study investigated whether CONUT score was predictive of outcomes in colorectal cancer (CRC) patients undergoing surgical resection. METHODS: Preoperative CONUT scores were retrospectively evaluated in 417 CRC patients who underwent potentially curative resection at Kumamoto University Hospital from March 2005 to August 2014. Patients were divided into four groups based on preoperative CONUT scores: normal, light, moderate, and severe. The associations of CONUT score with clinicopathological factors, patient survival, and postoperative complications were examined. RESULTS: CONUT score correlated significantly with age (P < 0.001), body mass index (P = 0.005), carcinoembryonic antigen (P = 0.002), and carbohydrate antigen 19-9 (P = 0.005) concentrations. Overall survival (OS) rate was significantly lower in patients with moderate/severe than light or normal CONUT scores. CONUT score was independently prognostic of OS [moderate/severe vs. normal, hazard ratio = 5.92, 95 % confidence interval (CI) 2.30-14.92; P < 0.001)]. Patients with moderate/severe CONUT scores were at greater risk for complications, especially for severe complications. Multivariate analysis showed that CONUT score was independently predictive of severe complications (moderate/severe vs. normal, odds ratio = 4.51, 95 % CI 1.89-10.74; P < 0.001). CONCLUSIONS: CONUT score may predict survival and postoperative severe complications in CRC patients undergoing potentially curative resection. Management of CRC patients may need consideration of host nutritional status.

Thrombospondin-1 expression may be implicated in liver atrophic mechanism due to obstructed portal venous flow.

AIM: Liver is an amazing organ that can undergo regenerative and atrophic changes inversely, depending on blood flow conditions. Although the regenerative mechanism has been extensively studied, the atrophic mechanism remains to be elucidated. METHODS AND RESULTS: To assess the molecular mechanism of liver atrophy due to reduced portal blood flow, we analyzed the gene expressions between atrophic and hypertrophic livers induced by portal vein embolization in three human liver tissues using microarray analyses. Thrombospondin (TSP)-1 is an extracellular protein and a negative regulator of liver regeneration through its activation of the transforming growth factor-ß/Smad signaling pathway. TSP-1 was extracted as the most upregulated gene in atrophic liver compared to hypertrophic liver due to portal flow obstruction in human. Liver atrophic and hypertrophic changes were confirmed by HE and proliferating cell nuclear antigen staining and terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling. In an in vivo model with portal ligation, TSP-1 and phosphorylated Smad2 expression were continuously induced at 6 h and thereafter in the portal ligated liver, whereas the induction was transient at 6 h in the portal non-ligated liver. Indeed, while cell proliferation represented by proliferating cell nuclear antigen expression at 48 h was induced in the portal ligated liver, the sinusoidal dilatation and hepatocyte cell death with terminal deoxynucleotidyl transferase-mediated digoxigenin-dUTP nick-end labeling was detectable at 48 h in the portal ligated liver. CONCLUSIONS: Obstructed portal flow induces persistent TSP-1 expression and transforming growth factor-ß/Smad signal activation in atrophic liver. Thrombospondin-1 may be implicated in the liver atrophic change due to obstructed portal flow as a pro-atrophic factor.

Preoperative platelet-to-lymphocyte ratio can predict recurrence beyond the Milan criteria after hepatectomy for patients with hepatocellular carcinoma.

AIM: Postoperative recurrence beyond the Milan criteria is a poor prognostic factor for patients with hepatocellular carcinoma (HCC) treated with various therapies. We investigated the most useful inflammation-based prognostic score for predicting recurrence beyond the Milan criteria after initial liver resection. METHODS: From January 2007 to December 2012, 271 consecutive patients with HCC who underwent curative liver resection were enrolled. Patients were divided according to the initial recurrence pattern: recurrence beyond the Milan criteria; and recurrence within the Milan criteria, or no recurrence. The patients were classified into two groups, low platelet-to-lymphocyte ratio (PLR) (<150) and high PLR (≥150), additionally using other inflammation-based prognostic scores. Then we analyzed the association between the recurrence patterns and the clinicopathological factors including PLR. RESULTS: Fifty-five (20.2%) patients had recurrence beyond the Milan criteria. The 5-year survival rate in patients with recurrence beyond the Milan criteria (41.6%) was significantly lower than in those with other recurrence patterns (79.7%). High PLR level was observed in 15.5% of the patients. Multivariate analysis revealed that PLR was the only independent predictive factor of recurrence patterns (odds ratio, 2.55; 95% confidence interval, 1.17-5.49; P = 0.018). The high PLR level was significantly associated with higher serum des-γ-carboxy prothrombin level, larger tumor size, and poor histological differentiation. CONCLUSION: Among several inflammatory indices, PLR is a good indicator to predict recurrence beyond the Milan criteria after liver resection for patients with HCC.

Comparison of systemic inflammatory and nutritional scores in colorectal cancer patients who underwent potentially curative resection.

BACKGROUND: Various systemic inflammatory and nutritional scores have been reported to predict postoperative outcomes. This study aimed to investigate the best systemic inflammatory and nutritional scores in colorectal cancer (CRC) patients who underwent potentially curative resection. METHOD: We evaluated 468 consecutive CRC patients in this study. Comparisons of systemic inflammatory and nutritional scores, including the neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), prognostic index (PI), prognostic nutritional index (PNI), and modified Glasgow prognostic score (mGPS), were performed using univariate/multivariate analyses for patient survival. RESULTS: The PNI and mGPS, but not the NLR, PLR, and PI, were significantly associated with overall and relapse-free survival. The mGPS, but not the PNI, was strongly correlated with TNM stage (P < 0.001). Cox multivariate analysis showed that both the PNI and mGPS were exclusive independent prognostic factors for both overall and relapse-free survival (P < 0.001). Furthermore, the PNI status predicted patient survival more clearly than the mGPS in combination with TNM stage. CONCLUSIONS: This study suggests that the PNI and mGPS are useful predictive scores in CRC patients who undergo potentially curative resection, especially the PNI in combination with TNM stage. Routine evaluation of the host status using the scores may be useful in CRC treatment.

Neutrophil-to-lymphocyte ratio predicts metachronous liver metastasis of pancreatic neuroendocrine tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (PNETs) are clinically malignant, having metastatic potential. Histological tumor grade is an accepted indicator of malignant potential, but noninvasive prognostic markers have not yet been identified. This study assessed whether the preoperative neutrophil-to-lymphocyte ratio (NLR) could predict clinical outcomes of PNET patients. METHODS: Fifty-eight patients who underwent curative resection for PNETs between 2001 and 2015 were retrospectively evaluated. The correlations between the preoperative NLR and clinicopathological parameters, including patient baseline clinical characteristics, tumor progression, and postoperative oncological outcome were evaluated. RESULTS: A high preoperative NLR was significantly associated with large tumor size (P = 0.0015) and high tumor grade (P < 0.0001). Overall survival and relapse-free survival of patients with a high NLR (≥2.4) were significantly shorter than those of patients with a low NLR (<2.4, P = 0.0481 and P < 0.0001, respectively). Multivariate analysis revealed that NLR ≥2.4 and tumor size ≥2 cm were independent predictors of postoperative recurrence (hazard ratio 6.012, P = 0.0035 and 6.760, P = 0.0049, respectively). Interestingly, a high NLR independently predicted postoperative liver, but not lymph node, metastasis. CONCLUSIONS: In this patient series, a high NLR (≥2.4) was a noninvasive marker that independently predicted postoperative liver metastasis in patients with PNETs, and thereby could be clinically useful.