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Gastric cancer is a heterogeneous cancer, making treatment responses difficult to predict. Here we show that we identify two distinct molecular subtypes, mesenchymal phenotype (MP) and epithelial phenotype (EP), by analyzing genomic and proteomic data. Molecularly, MP subtype tumors show high genomic integrity characterized by low mutation rates and microsatellite stability, whereas EP subtype tumors show low genomic integrity. Clinically, the MP subtype is associated with markedly poor survival and resistance to standard chemotherapy, whereas the EP subtype is associated with better survival rates and sensitivity to chemotherapy. Integrative analysis shows that signaling pathways driving epithelial-to-mesenchymal transition and insulin-like growth factor 1 (IGF1)/IGF1 receptor (IGF1R) pathway are highly activated in MP subtype tumors. Importantly, MP subtype cancer cells are more sensitive to inhibition of IGF1/IGF1R pathway than EP subtype. Detailed characterization of these two subtypes could identify novel therapeutic targets and useful biomarkers for prognosis and therapy response. The prognosis and treatment of gastric cancer is complicated by heterogeneity. Here, the authors reveal two molecular subtypes, the mesenchymal subtype associated with poor survival and chemoresistance, and the epithelial phenotype associated with better survival and sensitivity to chemotherapy.

Nonalcoholic steatohepatitis (NASH) is considered as a progressive form of nonalcoholic fatty liver disease (NAFLD). To distinguish NASH from nonalcoholic fatty liver (NAFL), we evaluated the diagnostic value of circulating miRNAs. Small RNA sequencing was performed on 12 NAFL patients and 12 NASH patients, and the miRNA expression was compared. After selecting miRNAs for the diagnosis of NASH, we analyzed the diagnostic accuracy of each miRNA and the combination of miRNAs. External validation was performed using quantitative reverse transcription PCR. Among the 2,588 miRNAs, 26 miRNAs significantly increased in the NASH group than in the NAFL group. Among the 26 elevated miRNAs in the NASH group, 8 miRNAs were selected, and in silico analysis was performed. Only four miRNAs (miR-21-5p, miR-151a-3p, miR-192-5p, and miR-4449) showed significant area under the receiver operating characteristic curve (AUC) values for NASH diagnosis. The combination of the four miRNAs showed satisfactory diagnostic accuracy for NASH (AUC 0.875; 95% CI 0.676–0.973). External validation revealed similar diagnostic accuracy for NASH (AUC 0.874; 95% CI 0.724–0.960). NASH represents significantly distinct miRNA expression profile compared with NAFL. The combination of serum circulating miRNAs can be used as a novel biomarker for the NASH diagnosis in NAFLD.

Although triglyceride accumulation in the liver causes non-alcoholic fatty liver disease (NAFLD), hypercholesterolemia is also a main cause of NAFLD as well as atherosclerosis. However, NAFLD and atherosclerosis have not been investigated simultaneously in animal models fed a high-cholesterol diet. Moreover, it is unclear whether systemic inflammation can exacerbate both pathologies in the same model. Accordingly, this study investigated the effect of additional systemic inflammation on NAFLD and atherosclerosis induced by cholesterol overload in wild animals. New Zealand white rabbits were divided into 4 groups: groups I (control) and II received normal chow, and groups III and IV received a 1% cholesterol diet. To induce inflammation via toll-like receptor (TLR)-4 signaling, groups II and IV received subcutaneous injections of 0.5 mL of 1% carrageenan every 3 weeks. After 3 months, total cholesterol markedly increased in groups III and IV, and the serum expressions of systemic inflammatory markers were elevated in the groups II-IV. Early NAFLD lesions (e.g., mild fatty changes in the liver with sporadic fibrosis) and atherosclerosis (e.g., intimal hyperplasia composed of foam cells) were observed in both the liver and aorta specimens from group III, and advanced lesions were observed in group IV. The expressions of inflammatory cellular receptors, TLR-2 and TLR-4, in the aorta gradually increased from group I to IV but were similar in the liver in groups II-IV. Cholesteryl ester (CE) levels were higher in group IV than in group III, although the difference was not significant. CE levels in the aorta were similar between groups III and IV. Systemic inflammation can simultaneously exacerbate existing early lesions due to cholesterol overload in both the liver and aorta of rabbits. However, the cellular response of inflammatory receptors and expression of cholesterol metabolites differ between these organs.

Tumor budding (TB), a histopathological manifestation of epithelial–mesenchymal transition, is an important step in cancer invasion and metastasis development. TB has been considered a strong prognostic indicator in colorectal cancer. The International Tumor Budding Consensus Conference (ITBCC) scoring system is the standardized method used for patient outcome prediction in several human tumors. We investigated the clinicopathological implications and applicability of TB measured using the ITBCC scoring system in gallbladder cancer (GBC). The TB grades assigned to the 78 GBC patients were as follows: Bd1 (low TB), 41 (52.6%) patients; Bd2 (intermediate TB), 22 (28.2%) patients; and Bd3 (high TB), 15 (19.2%) patients. A higher TB grade correlated with a poorer histological differentiation (P < 0.000), higher pT category (P < 0.000), the involvement of surgical resection margin (P = 0.005), presence of nodal metastasis (P < 0.000), lymphatic and venous invasion (P < 0.000), and perineural invasion (P = 0.004). Univariate Cox regression analysis revealed that a poor histological grade, high pT category, lymphatic invasion, perineural invasion, and intermediate to high TB grades were associated with worse 5-year overall survival and disease-free survival. TB was not significantly associated with death or recurrence risk in multivariate Cox analysis. The interobserver agreement of TB grading was substantial. This study is the first to apply the ITBCC scoring system and suggest the prognostic value of TB in GBC.

Non-alcoholic steatohepatitis (NASH) is a complex disease consisting of various components including steatosis, lobular inflammation, and ballooning degeneration, with or without fibrosis. Therefore, it is difficult to diagnose NASH with only one imaging modality. This study was aimed to evaluate the feasibility of magnetic resonance imaging (MRI) for predicting NASH and to develop a non-invasive multiparametric MR index for the detection of NASH in non-alcoholic fatty liver disease (NAFLD) patients. This prospective study included 47 NAFLD patients who were scheduled to undergo or underwent ultrasound-guided liver biopsy within 2 months. Biopsy specimens were graded as NASH or non-NASH. All patients underwent non-enhanced MRI including MR spectroscopy (MRS), MR elastography (MRE), and T1 mapping. Diagnostic performances of MRS, MRE, and T1 mapping for grading steatosis, activity, and fibrosis were evaluated. A multiparametric MR index combining fat fraction (FF), liver stiffness (LS) value, and T1 relaxation time was developed using linear regression analysis. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of the newly devised MR index. Twenty NASH patients and 27 non-NASH patients were included. Using MRS, MRE, and T1 mapping, the mean areas under the curve (AUCs) for grading steatosis, fibrosis, and activity were 0.870, 0.951, and 0.664, respectively. The multiparametric MR index was determined as 0.037 × FF (%) + 1.4 × LS value (kPa) + 0.004 × T1 relaxation time (msec) −3.819. ROC curve analysis of the MR index revealed an AUC of 0.883. The cut-off value of 6 had a sensitivity of 80.0% and specificity of 85.2%. The multiparametric MR index combining FF, LS value, and T1 relaxation time showed high diagnostic performance for detecting NASH in NAFLD patients.

Background: Despite the increasing use of liquid-based cytology (LBC) for pancreatic cancer diagnosis, relatively few studies have directly examined such research. This study analyzed the cytopathological features of pancreatic cancer in LBC and demonstrated the utility of cell blocks in diagnosing pancreatic lesions. Methods: A retrospective review identified LBC from 254 pancreatic fine-needle aspirations (FNAs) (221 patients). FNAs were categorized into five subgroups based on cytopathological, clinical, and histopathological findings. Two pathologists evaluated cytological features in LBC samples, cell blocks, and tissue slides. Comparative analysis assessed differences between groups. Results: Compared to benign lesions, LBC of pancreatic cancer more frequently showed a necrotic background, intermediate to high cellularity, mixed architecture, nuclear/cytoplasmic ratio >0.8, anisonucleosis >4:1, irregular and thick nuclear membranes, multinucleated tumor cells, hyperchromatic nuclei, coarse to clumped chromatin, and a prominent single nucleolus. In cases of conventional pancreatic ductal adenocarcinoma, the palliative treatment subgroup showed a higher incidence of necrotic background than the resection subgroup. In the cell block analysis, tumor cells not identified in LBC slides were detected in 16 FNAs. Additionally, 13 FNAs contributed to differential diagnosis: ancillary tests aided diagnosis in 12 FNAs, while histopathological evaluation of the cell block slide alone was helpful in one case. Conclusions: The cytological features of pancreatic cancer in LBC are similar to those observed in conventional smears, with a necrotic background suggesting advanced (unresectable) disease. The cell block methodology minimizes tumor cell loss and facilitates differential diagnosis by enabling ancillary testing.

To date, there have been no studies comparing the molecular subtypes of Index gastric cancers (IGCs) and metachronous gastric cancers (MGCs). We evaluated a cohort of 42 patients with 43 IGCs and 45 MGCs. Molecular subtyping was performed by immunohistochemistry of mismatch repair (MMR) proteins, E-cadherin, p53, and Epstein–Barr virus– (EBV–) in situ hybridization (ISH). Gastric adenocarcinomas were classified into 5 subtypes: EBV-associated, MMR deficient (MMRD), E-cadherin aberrant, p53-aberrant [p53(+)], and p53 non-aberrant [p53(neg)]. All IGCs had been successfully treated by either surgery (19%) or endoscopic resection (81%). The mean interval between IGCs and MGCs was 85 months. Among the IGCs, EBV-associated, MMRD, E-cadherin–aberrant, p53(+), and p53(neg) molecular subtypes represented 2 (5%), 4 (9%), 2 (5%), 21 (49%), and 14 (32%) of the cases, respectively. Two cases had concomitant p53(+) and aberrant E-cadherin molecular subtypes. Among metachronous cancers, EBV-associated, MMRD, E-cadherin–aberrant, p53(+), and p53(neg) molecular subtypes represented 3 (7%), 11 (24%), 0 (0%), 22 (49%), and 9 (20%) cases. Concomitant p53(+) was observed in 1 EBV-associated and 2 MMRD MGCs. Although, there was no significant difference in the frequency of most molecular subtypes in IGCs and MGCs, the number of MMRD gastric cancers more than doubled in the MGC group. Half of the MGCs had a divergent molecular subtype compared to that of the IGCs. Notably, the interval between the development of IGCs and MGCs was significantly longer in patients with divergent molecular subtypes (P = 0.010). All 4 patients with MMRD IGC developed MMRD MGCs. Although the concept of mucosal field cancerization may explain the matching molecular subtypes in early-developing MGCs, the presence of divergent subtypes in late-occurring MGCs suggests a shift in the carcinogenic mechanism affecting the residual mucosa possibly related to Helicobacter pylori eradication.

AimsInterobserver variability in the assessment of gastric neoplasia biopsies between most Western and Eastern (predominantly represented by Japanese in the literature) pathologists has been documented. It is unknown if such variability exists between the US and Korean pathologists in the current era.MethodsTen gastrointestinal (GI) pathologists from the USA (n=5) and South Korea (n=5) evaluated 100 scanned images of gastric (n=50) and colorectal (n=50) neoplasia biopsies and answered multiple questionnaires. Consensus was defined as the answer chosen by the majority. Cohen’s (κc) and Fleiss’ kappa (κf) values were calculated between the consensus of the two groups and among the raters, respectively.ResultsBoth groups reached a consensus in the majority of cases (74%–100%) with slight to perfect intergroup (κc=0.049–1.000) and no to substantial intragroup (κf=−0.083 to 0.660) agreements. For gastric neoplasia, Korean pathologists relied heavily on cytoarchitectural atypia, whereas the US pathologists focused on stromal invasion when diagnosing adenocarcinoma. For colorectal neoplasia, the Korean pathologists identified concurrent intramucosal carcinoma when diagnosing invasive adenocarcinoma, while the presence of desmoplasia was a prerequisite for the diagnosis of invasive adenocarcinoma for the US pathologists.ConclusionsFor GI neoplasia biopsy interpretation, the diagnostic approach of Korean pathologists is similar to that of Eastern/Japanese pathologists. Consensus outperformed kappa statistics in capturing the magnitude of inter-rater and intergroup reliability, highlighting the potential benefit of consensus meetings to decrease the gap between Western and Eastern diagnostic approaches.

Noninvasive techniques for evaluating the severity of nonalcoholic fatty liver disease (NAFLD) have shown limited diagnostic performance. MicroRNAs (miRNAs) are useful biomarkers for diagnosing and monitoring the progression and treatment response to several diseases. Here, we evaluated whether serum exosomal miRNAs could be used for the diagnosis and prognosis of NAFLD severity. Exosomal miRNAs were isolated from the sera of 41 patients with NAFLD (diagnosed using liver biopsy) for microarray profiling. The degree of NAFLD severity was determined using inflammation, steatosis, and ballooning scores and the NAFLD activity score (NAS). Correlations between miRNA expression, clinical and biochemical parameters, and mRNA expression were analyzed. Overall, 25, 11, 13, and 14 miRNAs correlated with the inflammation score, steatosis score, ballooning score, and NAS, respectively, with 33 significant correlations observed between 27 miRNAs and six clinical variables. Eight miRNAs (let-7b-5p, miR-378h, -1184, -3613-3p, -877-5p, -602, -133b, and 509-3p) showed anticorrelated patterns with the corresponding mRNA expression. In fibrosis, 52 and 30 interactions corresponding to high miRNA-low mRNA and low miRNA-high mRNA expression, respectively, were observed. The present results therefore suggest that serum exosomal miRNAs can be used to evaluate NAFLD severity and identify potential targets for NAFLD treatment.

Translation plays an important role in the carcinogenesis of various human tumors. Paip1 and eIF4A1 are translation-associated proteins that mediate the function of eukaryotic initiation factor 4F complex. This study aimed to analyse the relationship between the expression status of Paip1 and eIF4A1 and clinicopathologic features in hepatocellular carcinoma (HCC). Immunohistochemical analysis was used to evaluate the expression status of Paip1 and eIF4A1. Two pathologists independently interpreted the immunostained slides. The prognostic value of Paip1 and eIF4A1 was evaluated by the Kaplan-Meier plotter. Among 173 HCC patients, 28 (16.1%) and 46 (26.6%) belonged in the Paip1 and eIF4A1 high-expression groups. High expression of Paip1 and eIF4A1 was associated with advanced TNM stage and more frequent vascular tumor invasion. Univariate analysis indicated that high Paip1 expression was associated with worse five-year overall survival (OS). Public dataset analysis by Kaplan-Meier plotter revealed that high mRNA expression of Paip1, and not of eIF4A1, was significantly associated with worse five-year OS and disease-free survival. Paip1 expression has a potential prognostic value in human HCC.