scholarly journals Gut microbiome analysis as a tool towards targeted non-invasive biomarkers for early hepatocellular carcinoma

Gut ◽  
2018 ◽  
Vol 68 (6) ◽  
pp. 1014-1023 ◽  
Author(s):  
Zhigang Ren ◽  
Ang Li ◽  
Jianwen Jiang ◽  
Lin Zhou ◽  
Zujiang Yu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Gut Microbiome ◽  
Cross Validation ◽  
Area Under The Curve ◽  
Northwest China ◽  
Central China ◽  
Advanced Hcc ◽  
Non Invasive ◽  
Faecal Samples ◽  
Early Hcc

ObjectiveTo characterise gut microbiome in patients with hepatocellular carcinoma (HCC) and evaluate the potential of microbiome as non-invasive biomarkers for HCC.DesignWe collected 486 faecal samples from East China, Central China and Northwest China prospectively and finally 419 samples completed Miseq sequencing. We characterised gut microbiome, identified microbial markers and constructed HCC classifier in 75 early HCC, 40 cirrhosis and 75 healthy controls. We validated the results in 56 controls, 30 early HCC and 45 advanced HCC. We further verified diagnosis potential in 18 HCC from Xinjiang and 80 HCC from Zhengzhou.ResultsFaecal microbial diversity was increased from cirrhosis to early HCC with cirrhosis. Phylum Actinobacteria was increased in early HCC versus cirrhosis. Correspondingly, 13 genera including Gemmiger and Parabacteroides were enriched in early HCC versus cirrhosis. Butyrate-producing genera were decreased, while genera producing-lipopolysaccharide were increased in early HCC versus controls. The optimal 30 microbial markers were identified through a fivefold cross-validation on a random forest model and achieved an area under the curve of 80.64% between 75 early HCC and 105 non-HCC samples. Notably, gut microbial markers validated strong diagnosis potential for early HCC and even advanced HCC. Importantly, microbial markers successfully achieved a cross-region validation of HCC from Northwest China and Central China.ConclusionsThis study is the first to characterise gut microbiome in patients with HCC and to report the successful diagnosis model establishment and cross-region validation of microbial markers for HCC. Gut microbiota-targeted biomarkers represent potential non-invasive tools for early diagnosis of HCC.

scholarly journals Diagnostic Value of Imaging Methods in the Histological Four Grading of Hepatocellular Carcinoma

Diagnostics ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 321 ◽  
Author(s):  
Feiqian Wang ◽  
Kazushi Numata ◽  
Masayuki Nakano ◽  
Mikiko Tanabe ◽  
Makoto Chuma ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Area Under The Curve ◽  
Diagnostic System ◽  
Diagnostic Value ◽  
Imaging Method ◽  
Multicenter Studies ◽  
Diagnostic Efficacy ◽  
Portal Phase ◽  
Contrast Enhanced ◽  
Early Hcc

We attempted to establish an ultrasound (US) imaging-diagnostic system for histopathological grades of differentiation of hepatocellular carcinoma (HCC). We conducted a retrospective study of histopathologically confirmed 200 HCCs, classified as early (45 lesions), well- (31 lesions), moderately (68 lesions) or poorly differentiated (diff.) (56 lesions) HCCs. We performed grayscale US to estimate the presence/absence of halo and mosaic signs, Sonazoid contrast-enhanced US (CEUS) to determine vascularity (hypo/iso/hyper) of lesion in arterial and portal phase (PP), and echogenicity of lesion in post-vascular phase (PVP). All findings were of significance for the diagnosis of some (but not all) histological grades (p < 0.001–0.05). Combined findings with a relatively high diagnostic efficacy for early, poorly and moderately diff. HCC were a combination of absence of halo sign and isoechogenicity in PVP of CEUS (accuracy: 93.0%, AUC: 0.908), hypovascularity in PP (accuracy: 78.0%, area under the curve (AUC): 0.750), and a combination of isovascularity in PP and hypoechogenicity in PVP (accuracy: 75.0%, AUC: 0.739), respectively. On the other hand, neither any individual finding nor any combination of findings yielded an AUC of over 0.657 for the diagnosis of well-diff. HCC. Our study provides encouraging data on Sonazoid CEUS in the histological differential diagnosis of HCC, especially in early HCC, and the effectiveness of this imaging method should be further proved by prospective, large sample, multicenter studies.

scholarly journals Urine biomarker: novel approach to hepatocellular carcinoma screening

2020 ◽  
Author(s):  
Amy K Kim ◽  
James P. Hamilton ◽  
Selena Y. Lin ◽  
Ting-Tsung Chang ◽  
Hie-Won Hann ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cross Validation ◽  
Learning Algorithm ◽  
Early Stage ◽  
High Risk Patient ◽  
Circulating Tumor Dna ◽  
Urine Samples ◽  
Detection Rates ◽  
Non Invasive ◽  
Fold Cross Validation

ABSTRACTBackground & AimsContinued limitations in hepatocellular carcinoma (HCC) screening have led to late diagnosis with poor survival, despite well-defined high-risk patient populations. Our aim is to develop a non-invasive urine circulating tumor DNA (ctDNA) biomarker panel for HCC screening to aid in early detection.MethodsCandidate ctDNA biomarkers was prescreened in urine samples obtained from HCC, cirrhosis, and hepatitis patients. Then, 609 patient urine samples with HCC, cirrhosis, or chronic hepatitis B were collected from five academic medical centers and evaluated by serum alpha feto-protein (AFP) and urine ctDNA panel using logistic regression, a Two-Step machine learning algorithm, and iterated 10-fold cross-validation.ResultsMutated TP53, and methylated RASSF1a and GSTP1, were selected for the urine ctDNA panel. The sensitivity of AFP-alone (9.8 ng/mL cut-off) to detect HCC was 71% by Two-Step. The combination of ctDNA and AFP increased the sensitivity to 81% at a specificity of 90%. The AUROC for the combination of ctDNA and AFP vs. AFP-alone were 0.925 (95% CI, 0.924-0.925) and 0.877 (95% CI, 0.876-0.877), respectively. Notably, among the patients with AFP <20 ng/mL, the combination panel correctly identified 64% of HCC cases. The panel performed superiorly to AFP-alone in early-stage HCC (BCLC A) with 80% sensitivity and 90% specificity. In an iterated 10-fold cross-validation analysis, the AUROC for the combination panel was 0.898 (95% CI, 0.895-0.901).ConclusionsThe combination of urine ctDNA and serum AFP can increase HCC detection rates including in those patients with low-AFP. Given the ease of collection, a urine ctDNA panel could be a potential non-invasive HCC screening test.

scholarly journals Genome-wide mapping of 5-hydroxymethylcytosines in circulating cell-free DNA as a non-invasive approach for early detection of hepatocellular carcinoma

Gut ◽  
2019 ◽  
Vol 68 (12) ◽  
pp. 2195-2205 ◽  
Author(s):  
Jiabin Cai ◽  
Lei Chen ◽  
Zhou Zhang ◽  
Xinyu Zhang ◽  
Xingyu Lu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
High Risk ◽  
Early Detection ◽  
Diagnostic Model ◽  
Invasive Approach ◽  
Non Invasive ◽  
Free Dna ◽  
Genome Wide ◽  
Early Hcc ◽  
Validation Set

ObjectiveThe lack of highly sensitive and specific diagnostic biomarkers is a major contributor to the poor outcomes of patients with hepatocellular carcinoma (HCC). We sought to develop a non-invasive diagnostic approach using circulating cell-free DNA (cfDNA) for the early detection of HCC.DesignApplying the 5hmC-Seal technique, we obtained genome-wide 5-hydroxymethylcytosines (5hmC) in cfDNA samples from 2554 Chinese subjects: 1204 patients with HCC, 392 patients with chronic hepatitis B virus infection (CHB) or liver cirrhosis (LC) and 958 healthy individuals and patients with benign liver lesions. A diagnostic model for early HCC was developed through case-control analyses using the elastic net regularisation for feature selection.ResultsThe 5hmC-Seal data from patients with HCC showed a genome-wide distribution enriched with liver-derived enhancer marks. We developed a 32-gene diagnostic model that accurately distinguished early HCC (stage 0/A) based on the Barcelona Clinic Liver Cancer staging system from non-HCC (validation set: area under curve (AUC)=88.4%; (95% CI 85.8% to 91.1%)), showing superior performance over α-fetoprotein (AFP). Besides detecting patients with early stage or small tumours (eg, ≤2.0 cm) from non-HCC, the 5hmC model showed high capacity for distinguishing early HCC from high risk subjects with CHB or LC history (validation set: AUC=84.6%; (95% CI 80.6% to 88.7%)), also significantly outperforming AFP. Furthermore, the 5hmC diagnostic model appeared to be independent from potential confounders (eg, smoking/alcohol intake history).ConclusionWe have developed and validated a non-invasive approach with clinical application potential for the early detection of HCC that are still surgically resectable in high risk individuals.

scholarly journals Abnormally Expressed Circular RNAs as Novel Non-Invasive Biomarkers for Hepatocellular Carcinoma: A Pair-wise Meta-Analysis

2019 ◽  
Author(s):  
Yanlin Jiang ◽  
Mengmeng Shang ◽  
Shizhen Dong ◽  
Menglu Chen ◽  
Xiaoli Wang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Meta Analysis ◽  
Area Under The Curve ◽  
Circular Rnas ◽  
Sample Type ◽  
Analysis Model ◽  
Diagnostic Efficacy ◽  
Non Invasive ◽  
Trim And Fill ◽  
Sensitivity Specificity

Abstract Background: In the recent literature, dysregulated circular RNAs (circRNAs) have been extensively investigated in hepatocellular carcinoma (HCC). This study strives to evaluate the diagnostic as well as the predictive value of abnormally expressed circRNAs in HCC. Methods: Eligible studies were sourced from PubMed, EMBASE, and CNKI online databases. Data on patients’ clinical characteristics, including diagnostic efficacy and overall survival (OS) were extracted. The diagnostic and prognostic parameters were respectively synthesized using the bivariate meta-analysis model and multivariate Cox hazard regression analysis based on STATA 12.0. The trim and fill approach was employed to evaluate the impacts of publication bias. Results: A sum of 21 eligible types of research was incorporated. The pooled sensitivity, specificity and area under the curve (AUC) of abnormally expressed circRNAs in distinguishing HCC from non-cancer controls were estimated to be 0.78 (95% confidence interval (CI): 0.69–0.85), 0.80 (95% CI: 0.74–0.86) and 0.86, respectively. Survival analyses expressed that the down-regulated circRNA expression signature correlated perfectly with HCC survival (hazard ratio (HR) = 0.42, 95% CI: 0.19–0.91, p = 0.028; I2 = 92.7%; p = 0.000), whereas the HCC cases with high circRNA levels had significantly poorer prognoses than those of patients with low circRNA levels (HR = 2.22, 95% CI: 1.50–3.30, p = 0.000; I2 = 91%; p = 0.000). Moreover, abnormally expressed circRNAs were intimately linked with tumor size, differentiation grade, microvascular invasion, metastasis, TNM stage, and serum AFP level in patients with HCC. Stratified analysis based on sample type, control source, and expression status also yielded robust results. Conclusions: Abnormally expressed circRNA signatures show immense potential as novel non-invasive biomarker(s) in complementing HCC diagnosis and prognosis.

scholarly journals PRM-MS Quantitative Analysis of Isomeric N-Glycopeptides Derived From Human Serum Haptoglobin of Patients With Cirrhosis and Hepatocellular Carcinoma

2021 ◽  
Author(s):  
Cristian D. Gutierrez Reyes ◽  
Yifan Huang ◽  
Mojgan Atashi ◽  
Jie Zhang ◽  
Jianhui Zhu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Early Detection ◽  
Large Scale ◽  
Scale Validation ◽  
Area Under The Curve ◽  
Glycosylation Site ◽  
Protein Glycosylation ◽  
Serum Haptoglobin ◽  
Parallel Reaction Monitoring ◽  
Early Hcc

Abstract Currently surveillance strategies have inadequate performance for the early detection of hepatocellular carcinoma (HCC). Protein glycosylation is a potential source of biomarkers to differentiate between cirrhosis and HCC. We performed a comprehensive LC-PRM-MS approach where a targeted parallel reaction monitoring (PRM) strategy was coupled to a powerful LC system to study the microheterogeneity of haptoglobin (Hp) extracted from 15 patients with cirrhosis and 15 with HCC. We found that our strategy was able to identify a large number of isomeric N-glycopeptides mainly located in the glycosylation site Asn207. Nine out of twelve N-glycopeptides, located in the Asn207 site, had significant differences in abundance between patients with cirrhosis and HCC (p < 0.05). The area under the curve (AUC) of alpha-fetoprotein (AFP) was alone 0.85, which improved to 0.95 (95% CI: 0.88, 1) when NLF_5613 Isomer 1 was combined with AFP. When comparing the early HCC vs. cirrhosis, four sialylated-fucosylated glycopeptides better estimated AUCs with respect to AFP (AUCAFP = 0.66, and AUCN−glycopeptides = 0.86, 0.84, 0.88, and 0.80, respectively). Further large scale validation of glycopeptides for the early detection of HCC is warranted.

Phase I study of safety, pharmacokinetics, and efficacy of TSU-68 plus S-1 combination in patients with advanced hepatocellular carcinoma.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 262-262 ◽  
Author(s):  
Masafumi Ikeda ◽  
Shuichiro Shiina ◽  
Kohei Nakachi ◽  
Shuichi Mitsunaga ◽  
Satoshi Shimizu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Area Under The Curve ◽  
Maximum Tolerated Dose ◽  
Advanced Hepatocellular Carcinoma ◽  
Advanced Hcc ◽  
Treatment Dose ◽  
Pugh Class ◽  
Prior Systemic Therapy ◽  
Grade 3 ◽  
Treatment Safety

262 Background: Sorafenib is the standard chemotherapy for advanced hepatocellular carcinoma (HCC), but its efficacy is limited. TSU-68 is an oral anti-angiogenesis agent that blocks VEGFR-2 and PDGFR. TSU-68 and S-1 have shown favorable efficacy and safety profile for advanced HCC (Kanai et al. 2011; Furuse et al. 2010). This study investigated the safety, tolerability, pharmacokinetics (PK), and efficacy of the TSU-68 plus S-1 combination in patients (pts) with advanced HCC. We also determined the maximum tolerated dose of TSU-68 plus S-1 on the basis of the frequency of associated dose-limiting toxicity (DLT) in this population. Methods: Pts who had not received any prior systemic therapy received 400 mg/day TSU-68 orally and one of the following doses of S-1: 50 mg/m2 (level 0), 80 mg/m2 (level 1), or 100 mg/m2 (level 2). Treatment duration was 4 weeks followed by 2-week rest (A group) or 2 weeks followed by 1-week rest (B group). The starting treatment dose and duration level was 1B, followed by progression to levels 2A and 2B. Treatment safety and tolerability at each level were assessed by enrolling 6 pts according to CTCAE v3.0. Results: Eighteen pts (6 each at levels 1B, 2A, and 2B) were enrolled (age, 58-85 years; male/female, 15/3; HCV/HBV/nBnC, 12/3/4; Child-Pugh class A/B, 18/0). Two pts each at levels 1B (grade 3 gastrointestinal bleeding, grade 2 ascites) and 2A (grade 3 fatigue, grade 3 hand-foot skin reaction) showed DLTs, but no pts at level 2B showed DLTs. The common adverse events were hemoglobin decrease, hypoalbuminemia, and anorexia; these were mild in severity (grade 1-2). PK data from 12 pts at levels 1B and 2A indicated that the area under the curve (AUC) of TSU-68 and 5-FU was unlikely to be affected by TSU-68 plus S-1. Response rate, disease control rate, median time to progression, and median overall survival time were 27.8%, 61.1%, 160 days, and 391 days, respectively. Conclusions: Our findings revealed thatthe TSU-68 plus S-1 combination was well tolerated and had favorable efficacy in patients with advanced HCC, and we recommend treatment with 400 mg/day TSU-68 and 100 mg/m2 S-1 for 4 weeks followed by 2-week rest in these patients. Clinical trial information: Japic CTI-121970.

scholarly journals Diagnostic Value of Immunohistochemical Markers in Four-grade Histological Classification of Hepatocellular Carcinoma

2020 ◽  
Author(s):  
Feiqian Wang ◽  
Kazushi Numata ◽  
Masayuki Nakano ◽  
Mikiko Tanabe ◽  
Makoto Chuma ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Differential Diagnosis ◽  
Histological Grade ◽  
Organic Anion ◽  
Area Under The Curve ◽  
Diagnostic Value ◽  
Easy Method ◽  
Diagnostic Efficacy ◽  
Early Hcc ◽  
Ihc Markers

Abstract Backgrounds: Accurate differential diagnosis regarding histological grades of hepatocellular carcinoma (HCC) is critical for targeted treatment and prognostic evaluation. However, the currently used descriptive diagnosis of histological grading have to observe tedious item of neovascularization, stromal invasion, cellular and structural atypia, which have drawbacks of subjectivity and error-prone. Immunohistochemical (IHC) markers-based diagnosis only needs to determine whether there is staining in the cell membrane, cytoplasm and / or nucleus. Using IHC markers targeted heat shock protein (HSP)70, glypican (GPC)3, glutamine synthetase (GS), and organic anion transport peptide (OATP), we sought to establish an easy method for the diagnosis of the histopathological grades and further explore the best efficacy by their combined or independent application.Methods: We retrospectively conducted a study of 157 patients with 200 histologically confirmed HCCs, which were classified into early (n= 45), well (n=31), moderately (n=68), and poorly (n=56) differentiated (diff.) HCC. The sensitivity, specificity, accuracy of HSP70, GPC3, GS and OATP on each histological grade were examined. Results: HSP70 and GPC3 showed difference in most histological grades of HCC ( P < 0.05). GS distinguished early HCC from three other histological grades (p < 0.01). OATP8 only differentiated early HCC from poorly diff. HCC (P=0.019). When any two of the three indicators (HSP, GPC3, and GS) were negatively expressed, the diagnostic efficacy of early HCC was the highest, with an area under the curve (AUC) of 0.802 and accuracy of 80.5%. The optimal efficacy for poorly diff. HCC detection was obtained when both GPC3 and HSP70 were positively expressed (74.4% accuracy; AUC = 0.703). However, for well and moderately diff. HCC, a relative satisfactory AUC value (>0.60) failed to yield either by the independent or combined diagnosis of any IHC indicators.Conclusion: Using GS, HSP70, and GPC3, early and poorly diff. HCC can be properly diagnosed. IHC markers might be a potential alternative tool for histological differential diagnosis of HCC.

scholarly journals Role of circulating microRNA-21 and microRNA-215 in the diagnosis of hepatitis C related hepatocellular carcinoma

2021 ◽  
Vol 15 (07) ◽  
pp. 997-1003
Author(s):  
Zeinab Sayed Abdelkhalek ◽  
Mohamed Shehata Abdalla ◽  
Mona Mohamed Fathy ◽  
Tamer Mahmoud Elbaz ◽  
Ashraf Omar Abdelaziz ◽  
...  
Keyword(s):  
Gene Expression ◽  
Hepatocellular Carcinoma ◽  
Hepatitis C ◽  
Area Under The Curve ◽  
Expression Level ◽  
Receiver Operating Curve ◽  
Circulating Microrna ◽  
Stem Loop ◽  
Non Invasive ◽  
Reverse Transcription Pcr

Introduction: Several micro ribonucleic acids (miRNAs) are deregulated in hepatocellular carcinoma (HCC). Others are linked to clinical pathological features of HCC. The goal of this study was to investigate whether miRNA-21 and miRNA-215 gene expression could be used as a non-invasive diagnostic tool to diagnose HCC. Methodology: The gene expression of mature miRNA -21 and miRNA -215 in serum was analysed retrospectively using singleplex TaqMan two-step stem-loop quantitative real-time reverse-transcription PCR in 40 patients with HCC, 40 with chronic hepatitis C virus (HCV) with cirrhosis and 40 apparently healthy controls. Results: Expression of miRNA -21 was significantly more down regulated in patients with HCC than in those with non-cirrhotic HCV (P = 0.007; odds ratio = 5; 95% confidence interval 1.6–15.4). The receiver operating curve analysis of the ability of miRNA-21 expression to discriminate between HCC and non-cirrhotic HCV revealed an area under the curve of 0.712 with 70% sensitivity and 68% specificity at a cut-off of ≤ 1.4468. Thus, the expression level of miRNA -21 could discriminate HCC from non-cirrhotic HCV. Significant positive correlation was observed between expression levels of microRNA-21 and miRNA -215 (r = 0.783, p < 0.001), but no association was observed between expression level of miR-215 and HCC or chronic HCV (p = 0.474). Conclusions: MiRNA-21 may be a useful, non-invasive tool for diagnosing HCC. Non-cirrhotic HCV patients have five times the risk of developing HCC when the miRNA -21 level ≤ 1.4468.

scholarly journals Measuring the gut microbiome in birds: comparison of faecal and cloacal sampling

2017 ◽  
Author(s):  
Elin Videvall ◽  
Maria Strandh ◽  
Anel Engelbrecht ◽  
Schalk Cloete ◽  
Charlie K. Cornwallis
Keyword(s):  
Gastrointestinal Tract ◽  
Bacterial Community ◽  
High Throughput ◽  
Gut Microbiome ◽  
Sampling Methods ◽  
Sequence Data ◽  
Sampling Technique ◽  
Non Invasive ◽  
Faecal Samples ◽  
Highly Correlated

AbstractThe gut microbiomes of birds and other animals are increasingly being studied in ecological and evolutionary contexts. While methods for preserving samples and processing high-throughput sequence data to characterise bacterial communities have received considerable attention, there has been little evaluation of non-invasive sampling methods. Numerous studies on birds and reptiles have made inferences about gut microbiota using cloacal sampling, however, it is not known whether the bacterial community of the cloaca provides an accurate representation of the avian gut microbiome. We examined the accuracy with which cloacal swabs and faecal samples measure the microbiota in three different parts of the gastrointestinal tract (ileum, caecum, and colon) using a case study on juvenile ostriches,Struthio camelus, and high-throughput 16S rRNA sequencing. We found that faeces were significantly better than cloacal swabs in representing the bacterial community of the colon. Cloacal samples had a higher abundance of Gammaproteobacteria and fewer Clostridia relative to the gut and faecal samples. However, both faecal and cloacal samples were poor representatives of the microbial communities in the caecum and ileum. Furthermore, the accuracy of the sampling methods in measuring the abundance of different bacterial taxa was highly variable: Bacteroidetes was the most highly correlated phylum between all three gut sections and both methods, whereas colonic Actinobacteria correlated strongly only with faecal samples. This study demonstrates that sampling methods can have significant effects on the inferred gut microbiome in studies of birds. Based on our results, we recommend sampling faeces, whenever possible, as this provides the most accurate assessment of the colon microbiome. The fact that neither sampling technique portrayed the bacterial community of the ileum or the caecum illustrates the difficulty in non-invasively monitoring gut bacteria located further up in the gastrointestinal tract. These results have important implications for the interpretation of avian gut microbiome studies.

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