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PeerJ 2022This study aimed to assess the diagnostic performance of circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC). (Meta-Analysis)
Meta-Analysis
PURPOSE
This study aimed to assess the diagnostic performance of circulating tumor DNA (ctDNA) in hepatocellular carcinoma (HCC).
MATERIALS AND METHODS
We enrolled all relevant studies published up to 5 January 2022. Three primary subgroups were investigated: qualitative or quantitative ctDNA analyses, combined alpha-fetoprotein (AFP), and ctDNA assay. In addition to the three primary subgroups, we also evaluated the diagnostic value of methylated SEPTIN9 (mSEPT9), which has been studied extensively in the diagnosis of hepatocellular carcinoma. After a search based on four primary databases, we used a bivariate linear mixed model to analyze the pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR). We also plotted hierarchical summary receiver operating characteristics (HSROC) and utilized lambda as well as the area under the curve (AUC) to create summary receiver operating characteristic (SROC) curves to estimate the diagnostic value of ctDNA.
RESULTS
A total of 59 qualified articles with 9,766 subjects were incorporated into our meta-analysis. The integrated SEN, SPE, and DOR in the qualitative studies were 0.50 (95% CI [0.43-0.56]), 0.90 (95% CI [0.86-0.93]), and 8.72 (95% CI [6.18-12.32]), respectively, yielding an AUC of 0.78 and lambda of 1.93 (95% CI [1.56-2.33]). For quantitative studies, the corresponding values were 0.69 (95% CI [0.63-0.74]), 0.84 (95% CI [0.77-0.89]), 11.88 (95% CI [7.78-18.12]), 0.81, and 2.32 (95% CI [1.96-2.69]), respectively. Six studies were included to evaluate the SETP9 methylation, which yielded an AUC of 0.86, a SEN of 0.80 (95% CI [0.71-0.87]), and a SPE of 0.77 (95% CI [0.68-0.85]). Likewise, ctDNA concentration yielded an AUC of 0.73, with a SEN of 0.63 (95% CI [0.56-0.70]) and a SPE of 0.86 (95% CI [0.74-0.93]). AFP combined with ctDNA assay resulted in an AUC of 0.89, with a SEN of 0.82 (95% CI [0.77-0.86]) and a SPE of 0.84 (95% CI [0.76-0.90]).
CONCLUSION
This study shows that circulating tumor DNA, particularly mSEPT9, shows promising diagnostic potential in HCC; however, it is not enough to diagnose HCC independently, and ctDNA combined with conventional assays such as AFP can effectively improve diagnostic performance.
Topics: Humans; Carcinoma, Hepatocellular; alpha-Fetoproteins; Liver Neoplasms; Circulating Tumor DNA; ROC Curve
PubMed: 36348665
DOI: 10.7717/peerj.14303 -
Expert Review of Molecular Diagnostics Nov 2022Identify original articles that analyzed the diagnostic value of miR-21 in hepatocellular carcinoma without language restriction or publication date. (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Identify original articles that analyzed the diagnostic value of miR-21 in hepatocellular carcinoma without language restriction or publication date.
METHODOLOGY
We performed structured searches on PubMed, Web of Science, VHL, and EMBASE. The Standard Quality Assessment Criteria for Evaluating Primary Research Papers from a Variety of Fields was used to assess the quality of each study. Random effect models were used to study heterogeneity, evaluated based on the Higgins I2 statistic.
RESULTS
12 articles were evaluated and contained raw data from 1,329 individuals, of which 617 had HCC, 473 were healthy, and 239 had Chronic liver disease. The combined sensitivity and combined specificity of miR-21 for diagnosing HCC were, respectively, 0.83(95% CI:0.78-0.89) and 0.85(95% CI:0.80-0.90). The sensitivity and specificity, in that order, by type of control were 0.81 (95% CI: 0.71-0.91) and 0.88 (95% CI: 0.82-0.93) for CLDs and 0.86(95% CI: 0.81-0.91) and 0.83(95% CI:0.74-0.91) for Healthy controls.
CONCLUSION
miR-21 has a moderate overall performance in diagnosing HCC and may serve as a potential non-invasive marker for this early-stage disease. Thus, it may contribute to complementing the results of alpha-fetoprotein in the diagnosis and help to detect HCC at an earlier stage, increasing the survival chances of these patients.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; MicroRNAs; Biomarkers, Tumor; Sensitivity and Specificity
PubMed: 36348568
DOI: 10.1080/14737159.2022.2145189 -
Journal of Cancer Research and... Sep 2022This study aimed to systemically explore the risk factors of secondary infection/recurrence after ablation in patients with liver cancer. (Meta-Analysis)
Meta-Analysis
BACKGROUND
This study aimed to systemically explore the risk factors of secondary infection/recurrence after ablation in patients with liver cancer.
METHODS
Relevant literature in PubMed, EMbase, and Cochrane Library databases were searched with keywords including "liver cancer or carcinoma," "ablation," "infectious or infection or recurrence," and "risk factor or relevant factor or correlative factor or influencing factor." Meta-analyses were performed and forest plots were drawn for risk factors, including the tumor size and location, number of tumor nodules, hepatitis B virus (HBV) DNA levels, serum alpha fetal protein (AFP) levels and serum albumin levels, Child-Pugh Class, and lack of antiviral therapy. A funnel plot was drawn to assess the publication bias.
RESULTS
A total of 23 studies were included from the initial 701 potentially relevant articles. Our meta-analyses showed that a large tumor size (odds ratio [OR] = 1.58; 95% confidence interval [CI]: 1.31-1.92); proximity to the colon, large vessels, and large hepatic vein (OR = 4.10; 95% CI: 2.26-7.43); multinodular tumor (OR = 2.10; 95% CI: 1.46-3.03), the higher HBV DNA levels (OR = 1.34; 95% CI: 1.09-0.64); higher serum AFP levels (OR = 1.56; 95% CI: 1.18-2.05), lower serum albumin levels (OR = 1.67; 95% CI: 1.06-2.65); Child-Pugh Class B and Class C (OR = 1.27; 95% CI: 1.05-1.54); and lack of antiviral therapy (OR = 1.75; 95% CI: 0.93-3.28) were associated with an increased risk of post-ablation infection/recurrence in patients with liver cancers.
CONCLUSION
Our results indicated that the tumor size and location, number of tumor nodules, HBV DNA levels, serum AFP levels and serum albumin levels, Child-Pugh Class, and lack of antiviral therapy were the risk factors for post-ablation infection/recurrence in patients with liver cancer. Here, we have provided directions for the clinical prevention of secondary infection/recurrence in patients with liver cancer who underwent ablation therapy.
Topics: Antiviral Agents; Carcinoma, Hepatocellular; Catheter Ablation; Coinfection; DNA, Viral; Hepatitis B virus; Humans; Liver Neoplasms; Risk Factors; Serum Albumin; alpha-Fetoproteins
PubMed: 36204883
DOI: 10.4103/jcrt.jcrt_291_21 -
Liver Transplantation : Official... Dec 2022Patients with indeterminate liver nodules, classified as LR-3 and LR-4 observations per the Liver Imaging Reporting and Data System, are at risk of developing...
Clinical outcomes of patients with Liver Imaging Reporting and Data System 3 or Liver Imaging Reporting and Data System 4 observations in patients with cirrhosis: A systematic review.
Patients with indeterminate liver nodules, classified as LR-3 and LR-4 observations per the Liver Imaging Reporting and Data System, are at risk of developing hepatocellular carcinoma (HCC), but risk estimates remain imprecise. We conducted a systematic review of Ovid MEDLINE, EMBASE, and Cochrane databases from inception to December 2021 to identify cohort studies examining HCC incidence among patients with LR-3 or LR-4 observations on computed tomography (CT) or magnetic resonance imaging (MRI). Predictors of HCC were abstracted from each study, when available. Of 13 total studies, nine conducted LR-3 observation-level analyses, with the proportions of incident HCC ranging from 1.2% to 12.5% at 12 months and 4.2% to 44.4% during longer study follow-up. Among three studies with patient-level analyses, 8%-22.2% of patients with LR-3 lesions developed LR-4 observations and 11.1%-24.5% developed HCC. Among nine studies conducting LR-4 observation-level analyses, incident HCC ranged from 30.8% to 44.0% at 12 months and 30.9% to 71.0% during study follow-up; conversely, 6%-42% of observations were downgraded to LR-3 or lower. Patient-level factors associated with HCC included older age, male sex, higher alpha-fetoprotein levels, viral etiology, and prior history of HCC; observation-level factors included maximum diameter, threshold growth, T2 hyperintensity, and visibility on ultrasound. Studies were limited by small sample sizes, inclusion of patients with prior HCC, short follow-up duration, and failure to account for clustering of observations in patients or competing risks of transplantation and death. LR-3 and LR-4 observations have elevated but variable risks of HCC. Higher quality studies are necessary to identify high-risk patients who warrant close CT or MRI-based follow-up.
Topics: Humans; Male; Carcinoma, Hepatocellular; Liver Neoplasms; Retrospective Studies; Liver Transplantation; Liver Cirrhosis; Magnetic Resonance Imaging; Contrast Media; Sensitivity and Specificity
PubMed: 35980600
DOI: 10.1002/lt.26562 -
Journal of Gastrointestinal Cancer Jun 2023Hepatocellular carcinoma has a dismal prognosis, except in patients diagnosed early who are candidates for potentially curative therapies. Most HCC cases develop in... (Review)
Review
PURPOSE
Hepatocellular carcinoma has a dismal prognosis, except in patients diagnosed early who are candidates for potentially curative therapies. Most HCC cases develop in patients with chronic liver disease. Therefore, expert society guidelines recommend surveillance every 6 months with ultrasound with or without serum alpha-fetoprotein for high-risk patients. However, fewer than 20% of patients in the USA undergo appropriate surveillance.
METHODS
A systematic scoping review was performed with the objective of identifying barriers to screening among high-risk patients in the USA including mapping key concepts in the relevant literature, identifying the main sources and types of evidence available, and identifying gaps in the literature. A total of 43 studies published from 2007 to 2021 were included. Data were extracted and a conceptual framework was created.
RESULTS
Assessment of quantitative studies revealed poor surveillance rates, often below 50%. Three categories of barriers to surveillance were identified: patient-level, provider-level, and system-level barriers. Prevalent patient-level barriers included financial constraints, lack of awareness of surveillance recommendations, and scheduling difficulties. Common provider-level barriers were lack of provider awareness of guidelines for surveillance, difficulty accessing specialty resources, and time constraints in the clinic. System-level barriers included fewer clinic visits and rural/safety-net settings. Proposed interventions include improved patient/provider education, patient navigators, increased community/academic collaboration, and EMR-based reminders.
CONCLUSION
Based on these findings, there is a crucial need to implement and evaluate proposed interventions to improve HCC surveillance.
Topics: Humans; Carcinoma, Hepatocellular; Liver Neoplasms; Prognosis; Ultrasonography; Early Detection of Cancer; Liver Cirrhosis
PubMed: 35879510
DOI: 10.1007/s12029-022-00851-x -
BMC Cancer Jul 2022To describe and analyze the predictive models of the prognosis of patients with hepatocellular carcinoma (HCC) undergoing systemic treatment.
OBJECTIVE
To describe and analyze the predictive models of the prognosis of patients with hepatocellular carcinoma (HCC) undergoing systemic treatment.
DESIGN
Systematic review.
DATA SOURCES
PubMed and Embase until December 2020 and manually searched references from eligible articles.
ELIGIBILITY CRITERIA FOR STUDY SELECTION
The development, validation, or updating of prognostic models of patients with HCC after systemic treatment.
RESULTS
The systematic search yielded 42 eligible articles: 28 articles described the development of 28 prognostic models of patients with HCC treated with systemic therapy, and 14 articles described the external validation of 32 existing prognostic models of patients with HCC undergoing systemic treatment. Among the 28 prognostic models, six were developed based on genes, of which five were expressed in full equations; the other 22 prognostic models were developed based on common clinical factors. Of the 28 prognostic models, 11 were validated both internally and externally, nine were validated only internally, two were validated only externally, and the remaining six models did not undergo any type of validation. Among the 28 prognostic models, the most common systemic treatment was sorafenib (n = 19); the most prevalent endpoint was overall survival (n = 28); and the most commonly used predictors were alpha-fetoprotein (n = 15), bilirubin (n = 8), albumin (n = 8), Child-Pugh score (n = 8), extrahepatic metastasis (n = 7), and tumor size (n = 7). Further, among 32 externally validated prognostic models, 12 were externally validated > 3 times.
CONCLUSIONS
This study describes and analyzes the prognostic models developed and validated for patients with HCC who have undergone systemic treatment. The results show that there are some methodological flaws in the model development process, and that external validation is rarely performed. Future research should focus on validating and updating existing models, and evaluating the effects of these models in clinical practice.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO CRD42020200187 .
Topics: Bilirubin; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Prognosis; Sorafenib
PubMed: 35810271
DOI: 10.1186/s12885-022-09841-5 -
Cancers Jun 2022Acute porphyrias are a group of metabolic disorders resulting in defective porphyrin synthesis and reduced heme production, which carries a risk of malignancy.... (Review)
Review
Acute porphyrias are a group of metabolic disorders resulting in defective porphyrin synthesis and reduced heme production, which carries a risk of malignancy. Porphyrias are inborn defects in the heme biosynthesis pathway resulting in neurovisceral manifestations and cutaneous photosensitivity attacks with multi-systemic involvement. Its estimated prevalence nears 5 per 100,000 patients worldwide. Subclinical liver disease is common, which can progress into transaminitis, fibrosis, cirrhosis, and malignancy. However, data on the incidence of primary liver cancer are lacking. We aim to determine the risk of hepatocellular carcinoma (HCC) in patients with porphyria. A systematic review and pooled analysis were conducted through 2021 on studies assessing blood tests, imaging, cancer development, liver transplant, surgical resection, and outcomes in porphyria. In total, 19 studies, which included 7381 patients with porphyria (3476 females), were considered for the final review. In eight studies, alpha-fetoprotein levels were elevated between 200 and 1000 IU/mL. Of the total cohort of patients with porphyria, primary liver cancer was diagnosed in 351 patients (4.8%), of whom 243 (3.3% of the total) were found to have HCC. A subset of patients was found to have cholangiocarcinoma ( = 18; 0.3% of the total). Interestingly, advanced liver disease or cirrhosis was not a prerequisite for the formation of HCC in a small group of patients. Of the total cohort, 30 patients underwent liver resection, 48 patients underwent liver transplantation, and 327 patients died. Patients with porphyria are at risk of developing primary liver malignancy. Further studies should aim to develop diagnostic and prognostic models aimed at the early detection of HCC in porphyria.
PubMed: 35740611
DOI: 10.3390/cancers14122947 -
The Cochrane Database of Systematic... May 2022Hepatocellular carcinoma occurs mostly in people with chronic liver disease and ranks sixth in terms of global incidence of cancer, and third in terms of cancer deaths.... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Hepatocellular carcinoma occurs mostly in people with chronic liver disease and ranks sixth in terms of global incidence of cancer, and third in terms of cancer deaths. In clinical practice, magnetic resonance imaging (MRI) is used as a second-line diagnostic imaging modality to confirm the presence of focal liver lesions suspected as hepatocellular carcinoma on prior diagnostic test such as abdominal ultrasound or alpha-fetoprotein, or both, either in surveillance programmes or in clinical settings. According to current guidelines, a single contrast-enhanced imaging study (computed tomography (CT) or MRI) showing typical hallmarks of hepatocellular carcinoma in people with cirrhosis is considered valid to diagnose hepatocellular carcinoma. The detection of hepatocellular carcinoma amenable to surgical resection could improve the prognosis. However, a significant number of hepatocellular carcinomas do not show typical hallmarks on imaging modalities, and hepatocellular carcinoma may, therefore, be missed. There is no clear evidence of the benefit of surveillance programmes in terms of overall survival: the conflicting results can be a consequence of inaccurate detection, ineffective treatment, or both. Assessing the diagnostic accuracy of MRI may clarify whether the absence of benefit could be related to underdiagnosis. Furthermore, an assessment of the accuracy of MRI in people with chronic liver disease who are not included in surveillance programmes is needed for either ruling out or diagnosing hepatocellular carcinoma.
OBJECTIVES
Primary: to assess the diagnostic accuracy of MRI for the diagnosis of hepatocellular carcinoma of any size and at any stage in adults with chronic liver disease. Secondary: to assess the diagnostic accuracy of MRI for the diagnosis of resectable hepatocellular carcinoma in adults with chronic liver disease, and to identify potential sources of heterogeneity in the results.
SEARCH METHODS
We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Hepato-Biliary Group Diagnostic Test of Accuracy Studies Register, the Cochrane Library, MEDLINE, Embase, and three other databases to 9 November 2021. We manually searched articles retrieved, contacted experts, handsearched abstract books from meetings held during the last 10 years, and searched for literature in OpenGrey (9 November 2021). Further information was requested by e-mails, but no additional information was provided. No data was obtained through correspondence with investigators. We applied no language or document-type restrictions.
SELECTION CRITERIA
Studies assessing the diagnostic accuracy of MRI for the diagnosis of hepatocellular carcinoma in adults with chronic liver disease, with cross-sectional designs, using one of the acceptable reference standards, such as pathology of the explanted liver and histology of resected or biopsied focal liver lesion with at least a six-month follow-up.
DATA COLLECTION AND ANALYSIS
At least two review authors independently screened studies, extracted data, and assessed the risk of bias and applicability concerns, using the QUADAS-2 checklist. We presented the results of sensitivity and specificity, using paired forest plots, and we tabulated the results. We used a hierarchical meta-analysis model where appropriate. We presented uncertainty of the accuracy estimates using 95% confidence intervals (CIs). We double-checked all data extractions and analyses.
MAIN RESULTS
We included 34 studies, with 4841 participants. We judged all studies to be at high risk of bias in at least one domain because most studies used different reference standards, often inappropriate to exclude the presence of the target condition, and the time interval between the index test and the reference standard was rarely defined. Regarding applicability, we judged 15% (5/34) of studies to be at low concern and 85% (29/34) of studies to be at high concern mostly owing to characteristics of the participants, most of whom were on waiting lists for orthotopic liver transplantation, and due to pathology of the explanted liver being the only reference standard. MRI for hepatocellular carcinoma of any size and stage: sensitivity 84.4% (95% CI 80.1% to 87.9%) and specificity 93.8% (95% CI 90.1% to 96.1%) (34 studies, 4841 participants; low-certainty evidence). MRI for resectable hepatocellular carcinoma: sensitivity 84.3% (95% CI 77.6% to 89.3%) and specificity 92.9% (95% CI 88.3% to 95.9%) (16 studies, 2150 participants; low-certainty evidence). The observed heterogeneity in the results remains mostly unexplained. The sensitivity analyses, which included only studies with clearly prespecified positivity criteria and only studies in which the reference standard results were interpreted without knowledge of the results of the index test, showed no variation in the results.
AUTHORS' CONCLUSIONS
We found that using MRI as a second-line imaging modality to diagnose hepatocellular carcinoma of any size and stage, 16% of people with hepatocellular carcinoma would be missed, and 6% of people without hepatocellular carcinoma would be unnecessarily treated. For resectable hepatocellular carcinoma, we found that 16% of people with resectable hepatocellular carcinoma would improperly not be resected, while 7% of people without hepatocellular carcinoma would undergo inappropriate surgery. The uncertainty resulting from the high risk of bias in the included studies and concerns regarding their applicability limit our ability to confidently draw conclusions based on our results.
Topics: Adult; Carcinoma, Hepatocellular; Cross-Sectional Studies; Humans; Liver Neoplasms; Magnetic Resonance Imaging; Sensitivity and Specificity; Ultrasonography
PubMed: 35521901
DOI: 10.1002/14651858.CD014798.pub2 -
Cancer Cell International Apr 2022Delayed cancer diagnosis and inefficient cancer prognosis determination are problems faced in cancer diagnosis and treatment. MicroRNAs (miRs), especially miR-212, have... (Review)
Review
BACKGROUND
Delayed cancer diagnosis and inefficient cancer prognosis determination are problems faced in cancer diagnosis and treatment. MicroRNAs (miRs), especially miR-212, have shown a promise in cancer diagnosis and prognosis. Herein, we performed a systematic review and meta-analysis to assess the prognostic and diagnostic value of miR-212 level in cancer and evaluated its association with patient characteristics.
METHODS
A fully electronic literature search using related keywords was performed in PubMed, Scopus, Web of Science, Embase, and ScienceDirect databases by June 6, 2021, with no time or language restriction. Meta-analysis was performed to pool survival prognosis data using hazard ratio (HR), association using odds ratio (OR), and diagnostic data using sensitivity, specificity, and diagnostic odds ratio (DOR). Sub-group analysis and meta-regression were performed as appropriate.
RESULTS
Results of 28 studies on 1880 patients showed a poor cancer prognosis with high levels of miR-212 in pancreatic ductal adenocarcinoma (PDAC, HR = 2.451 [1.447-4.149]), and a poor cancer prognosis with low levels of miR-212 in other cancers (HR = 2.514 [2.162-2.923]). Higher alpha-fetoprotein (AFP) level and Edmondson-Steiner grade were factors associated with miR-212 low level incidence. Diagnostic odds ratio 10.688 (3.644-31.348) and SROC AUC of 0.84 confirmed high diagnostic performance of miR-212.
CONCLUSION
Our systematic review and meta-analysis results confirm miR-212 high value in cancer prognosis and diagnosis. High level of miR-212 showed poor prognosis in PDAC and low level of miR-212 showed poor prognosis in other cancers. in conclusion, miR-212 could be a novel potential biomarker in cancer diagnosis and prognosis.
PubMed: 35473623
DOI: 10.1186/s12935-022-02584-0 -
Clinics and Research in Hepatology and... May 2022
Meta-Analysis
Topics: Angiopoietin-2; Biomarkers, Tumor; Carcinoma, Hepatocellular; Diagnostic Tests, Routine; Humans; Liver Neoplasms; alpha-Fetoproteins
PubMed: 35318139
DOI: 10.1016/j.clinre.2022.101909