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Cancers Sep 2020Cholangiocarcinoma (CCA) is a rare disease with poor outcomes and limited research efforts into novel treatment options. A systematic review of CCA biomarkers was... (Review)
Review
Cholangiocarcinoma (CCA) is a rare disease with poor outcomes and limited research efforts into novel treatment options. A systematic review of CCA biomarkers was undertaken to identify promising biomarkers that may be used for theranosis (therapy and diagnosis). MEDLINE/EMBASE databases (1996-2019) were systematically searched using two strategies to identify biomarker studies of CCA. The PANTHER Go-Slim classification system and STRING network version 11.0 were used to interrogate the identified biomarkers. The TArget Selection Criteria for Theranosis (TASC-T) score was used to rank identified proteins as potential targetable biomarkers for theranosis. The following proteins scored the highest, CA9, CLDN18, TNC, MMP9, and EGFR, and they were evaluated in detail. None of these biomarkers had high sensitivity or specificity for CCA but have potential for theranosis. This review is unique in that it describes the process of selecting suitable markers for theranosis, which is also applicable to other diseases. This has highlighted existing validated markers of CCA that can be used for active tumor targeting for the future development of targeted theranostic delivery systems. It also emphasizes the relevance of bioinformatics in aiding the search for validated biomarkers that could be repurposed for theranosis.
PubMed: 33007872
DOI: 10.3390/cancers12102817 -
Artificial Intelligence in Medicine Sep 2023DNA methylation biomarkers have great potential in improving prognostic classification systems for patients with cancer. Machine learning (ML)-based analytic techniques... (Review)
Review
BACKGROUND
DNA methylation biomarkers have great potential in improving prognostic classification systems for patients with cancer. Machine learning (ML)-based analytic techniques might help overcome the challenges of analyzing high-dimensional data in relatively small sample sizes. This systematic review summarizes the current use of ML-based methods in epigenome-wide studies for the identification of DNA methylation signatures associated with cancer prognosis.
METHODS
We searched three electronic databases including PubMed, EMBASE, and Web of Science for articles published until 2 January 2023. ML-based methods and workflows used to identify DNA methylation signatures associated with cancer prognosis were extracted and summarized. Two authors independently assessed the methodological quality of included studies by a seven-item checklist adapted from 'A Tool to Assess Risk of Bias and Applicability of Prediction Model Studies (PROBAST)' and from the 'Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK). Different ML methods and workflows used in included studies were summarized and visualized by a sunburst chart, a bubble chart, and Sankey diagrams, respectively.
RESULTS
Eighty-three studies were included in this review. Three major types of ML-based workflows were identified. 1) unsupervised clustering, 2) supervised feature selection, and 3) deep learning-based feature transformation. For the three workflows, the most frequently used ML techniques were consensus clustering, least absolute shrinkage and selection operator (LASSO), and autoencoder, respectively. The systematic review revealed that the performance of these approaches has not been adequately evaluated yet and that methodological and reporting flaws were common in the identified studies using ML techniques.
CONCLUSIONS
There is great heterogeneity in ML-based methodological strategies used by epigenome-wide studies to identify DNA methylation markers associated with cancer prognosis. In theory, most existing workflows could not handle the high multi-collinearity and potentially non-linearity interactions in epigenome-wide DNA methylation data. Benchmarking studies are needed to compare the relative performance of various approaches for specific cancer types. Adherence to relevant methodological and reporting guidelines are urgently needed.
Topics: Humans; DNA Methylation; Epigenome; Prognosis; Neoplasms; Machine Learning
PubMed: 37673571
DOI: 10.1016/j.artmed.2023.102589 -
The Lancet. Gastroenterology &... May 2024Microsatellite instability (MSI) status and tumour-infiltrating lymphocytes (TIL) are established prognostic factors in colorectal cancer. Previous studies evaluating...
Clinical significance of combined tumour-infiltrating lymphocytes and microsatellite instability status in colorectal cancer: a systematic review and network meta-analysis.
BACKGROUND
Microsatellite instability (MSI) status and tumour-infiltrating lymphocytes (TIL) are established prognostic factors in colorectal cancer. Previous studies evaluating the combination of TIL and MSI status identified distinct colorectal cancer subtypes with unique prognostic associations. However, these studies were often limited by sample size, particularly for MSI-high (MSI-H) tumours, and there is no comprehensive summary of the available evidence. We aimed to review the literature to compare the survival outcomes associated with the subtypes derived from the integrated MSI-TIL classification in patients with colorectal cancer.
METHODS
In this systematic review and network meta-analysis, we searched PubMed, Embase, Scopus, and the Cochrane Library without language restrictions, for articles published between Jan 1, 1990, and March 13, 2024. Patient cohorts comparing different combinations of TIL (high or low) and MSI status (MSI or microsatellite stable [MSS]) in patients with surgically resected colorectal cancer were included. Studies were excluded if they focused on neoadjuvant therapy or on other immune markers such as B cells or macrophages. Methodological quality assessment was done with the Newcastle-Ottawa scale; data appraisal and extraction was done independently by two reviewers. Summary estimates were extracted from published reports. The primary outcomes were overall survival, disease-free survival, and cancer-specific survival. A frequentist network meta-analysis was done to compare hazard ratios (HRs) and 95% CI for each outcome. The MSI-TIL subgroups were prognostically ranked based on P-score, bias, magnitude, and precision of associations with each outcome. The protocol is registered with PROSPERO (CRD42023461108).
FINDINGS
Of 302 studies initially identified, 21 studies (comprising 14 028 patients) were included in the systematic review and 19 (13 029 patients) in the meta-analysis. Nine studies were identified with a low risk of bias and the remaining ten had a moderate risk of bias. The MSI-TIL-high (MSI-TIL-H) subtype exhibited longer overall survival (HR 0·45, 95% CI 0·34-0·61; I=77·7%), disease-free survival (0·43, 0·32-0·58; I=61·6%), and cancer-specific survival (0·53, 0·43-0·66; I=0%), followed by the MSS-TIL-H subtype for overall survival (HR 0·53, 0·41-0·69; I=77·7%), disease-free survival (0·52, 0·41-0·64; I=61·6%), and cancer-specific survival (0·55, 0·47-0·64; I=0%) than did patients with MSS-TIL-low tumours (MSS-TIL-L). Patients with the MSI-TIL-L subtype had similar overall survival (0·88, 0·66-1·18; I=77·7%) and disease-free survival (0·93, 0·69-1·26; I=61·6%), but a modestly longer cancer-specific survival (0·72, 0·57-0·90; I=0%) than did the MSS-TIL-L subtype. Results from the direct and indirect evidence were strongly congruous.
INTERPRETATION
The findings from this network meta-analysis suggest that better survival was only observed among patients with TIL-H colorectal cancer, regardless of MSI or MSS status. The integrated MSI-TIL classification should be further explored as a predictive tool for clinical decision-making in early-stage colorectal cancer.
FUNDING
German Research Council (HO 5117/2-2).
PubMed: 38734024
DOI: 10.1016/S2468-1253(24)00091-8 -
Clinical Epidemiology 2023Post-operative inflammation in cancer patients can be modulated by drugs and diets, but evidence on its prognostic role, which would be crucial for personalized... (Review)
Review
Post-operative inflammation in cancer patients can be modulated by drugs and diets, but evidence on its prognostic role, which would be crucial for personalized treatment and surveillance schemes, remains rather limited. We aimed to systematically review and meta-analyse studies on the prognostic value of post-operative C-reactive protein (CRP)-based inflammatory biomarkers among patients with colorectal cancer (CRC) (PROSPERO#: CRD42022293832). PubMed, Web of Science and Cochrane databases were searched until February 2023. Studies reporting associations between post-operative CRP, Glasgow Prognostic Score (GPS) or modified Glasgow Prognostic Score (mGPS) with overall survival (OS), CRC-specific survival (CSS) and recurrence-free survival (RFS) were included. Hazard ratios (HRs) with 95% confidence intervals (CIs) for the predictor-outcome associations were pooled using R-software, version 4.2. Sixteen studies (n = 6079) were included in the meta-analyses. Elevated post-operative CRP was a predictor of poor OS, CSS and RFS compared with low CRP levels [HR (95% CI): 1.72 (1.32-2.25); 1.63 (1.30-2.05); 2.23 (1.44-3.47), respectively]. A unit increase in post-operative GPS predicted poor OS [HR (95% Cl): 1.31 (1.14-1.51)]. Moreover, a unit increase in post-operative mGPS was associated with poor OS and CSS [HR (95% Cl): 1.93 (1.37-2.72); 3.16 (1.48-6.76), respectively]. Post-operative CRP-based inflammatory biomarkers have a significant prognostic role for patients with CRC. Prognostic value of these easy-to-obtain routine measurements thereby seems to outperform most of the much more complex blood- or tissue-based predictors in the current focus of multi-omics-based research. Future studies should validate our findings, establish optimal time for biomarker assessment and determine clinically useful cut-off values of these biomarkers for post-operative risk-stratification and treatment-response monitoring.
PubMed: 37396024
DOI: 10.2147/CLEP.S415171 -
International Journal of Cancer May 2015Antibodies against tumor-associated antigens have been found in serum of patients with various types of cancers and may serve as biomarkers for early detection of... (Review)
Review
Antibodies against tumor-associated antigens have been found in serum of patients with various types of cancers and may serve as biomarkers for early detection of gastric cancer as well. This systematic review aims to give an overview about known autoantibodies and their diagnostic value in gastric cancer. We conducted a systematic literature search in two databases to identify studies which performed serological testing for autoantibodies in gastric cancer patients and controls. Data on study characteristics and results were extracted independently by two reviewers. Overall, 39 articles reporting the detection of 34 different autoantibodies met the inclusion criteria for this review. The most common antibody detection method was enzyme-linked immunosorbent assay and the most frequently assessed autoantibody was anti-p53, which was tested in 13 studies. Most antibodies were assessed in only one study and only few authors have evaluated the diagnostic value of combinations of multiple autoantibodies. For single autoantibodies, specificity was generally very high (median: 99.15%), but sensitivity was mostly rather low (median: 12.35%). For some autoantibody combinations, substantially higher sensitivity at reasonably high levels of specificity could be achieved. Development of extended and optimized multimarker panels of autoantibodies might be a promising approach for gastric cancer early detection.
Topics: Antibodies, Neoplasm; Autoantibodies; Databases, Bibliographic; Early Detection of Cancer; Enzyme-Linked Immunosorbent Assay; Humans; Sensitivity and Specificity; Stomach Neoplasms
PubMed: 24615018
DOI: 10.1002/ijc.28807 -
Cancers Jul 2018Several approaches have been suggested to be useful in the early detection of colorectal neoplasms. Since metabolites are closely related to the phenotype and are... (Review)
Review
BACKGROUND
Several approaches have been suggested to be useful in the early detection of colorectal neoplasms. Since metabolites are closely related to the phenotype and are available from different human bio-fluids, metabolomics are candidates for non-invasive early detection of colorectal neoplasms.
OBJECTIVES
We aimed to summarize current knowledge on performance characteristics of metabolomics biomarkers that are potentially applicable in a screening setting for the early detection of colorectal neoplasms.
DESIGN
We conducted a systematic literature search in PubMed and Web of Science and searched for biomarkers for the early detection of colorectal neoplasms in easy-to-collect human bio-fluids. Information on study design and performance characteristics for diagnostic accuracy was extracted.
RESULTS
Finally, we included 41 studies in our analysis investigating biomarkers in different bio-fluids (blood, urine, and feces). Although single metabolites mostly had limited ability to distinguish people with and without colorectal neoplasms, promising results were reported for metabolite panels, especially amino acid panels in blood samples, as well as nucleosides in urine samples in several studies. However, validation of the results is limited.
CONCLUSIONS
Panels of metabolites consisting of amino acids in blood and nucleosides in urinary samples might be useful biomarkers for early detection of advanced colorectal neoplasms. However, to make metabolomic biomarkers clinically applicable, future research in larger studies and external validation of the results is required.
PubMed: 30060469
DOI: 10.3390/cancers10080246 -
Oncotarget Mar 2016Pancreatic cancer is a leading cause of cancer-related deaths in the western world. Patients with pancreatic cancer have poor prognosis, partly due to difficulties in... (Review)
Review
Pancreatic cancer is a leading cause of cancer-related deaths in the western world. Patients with pancreatic cancer have poor prognosis, partly due to difficulties in detecting it at early stages. While different markers have been associated with pancreatic cancer, many of them show suboptimal sensitivity and specificity. Serum autoantibodies against tumor-associated antigens have recently emerged as early stage biomarkers for different types of cancers. Given the urgent need for early and reliable biomarkers for pancreatic cancer, we undertook a systematic review of the published literature to identify primary articles that evaluated serum autoantibodies in pancreatic cancer detection by searching PubMed and ISI Web of Knowledge. Two reviewers extracted data on study characteristics and results independently. Overall, 31 studies evaluating 124 individual serum autoantibodies in pancreatic cancer detection met the inclusion criteria. In general, single autoantibody markers showed relatively low sensitivities at high specificity. A combination of markers, either multiple serum autoantibodies or serum autoantibodies combined with tumor-associated markers, led to a better diagnostic performance. However, most of the analyzed autoantibodies have only been reported in single studies and therefore need to be independently validated. We conclude that serum autoantibodies might present an option as biomarkers for early detection of pancreatic cancer, but more work is needed to identify and validate autoantibody signatures that are associated with early stage pancreatic cancer.
Topics: Antibodies, Neoplasm; Antigens, Neoplasm; Autoantibodies; Biomarkers, Tumor; Early Detection of Cancer; Humans; Pancreatic Neoplasms
PubMed: 26840568
DOI: 10.18632/oncotarget.7098 -
Oncotarget Nov 2015Timely diagnosis of cancer represents a challenging task; in particular, there is a need for reliable non-invasive screening tools that could achieve high levels of... (Review)
Review
BACKGROUND
Timely diagnosis of cancer represents a challenging task; in particular, there is a need for reliable non-invasive screening tools that could achieve high levels of adherence at virtually no risk in population-based screening. In this review, we summarize the current evidence of exhaled breath analysis for cancer detection using standard analysis techniques and electronic nose.
METHODS
Relevant studies were identified searching Pubmed and Web of Science databases until April 30, 2015. Information on breath test performance, such as sensitivity and specificity, was extracted together with volatile compounds that were used to discriminate cancer patients from controls. Performance of different breath analysis techniques is provided for various cancers together with information on methodological issues, such as breath sampling protocol and validation of the results.
RESULTS
Overall, 73 studies were included, where two-thirds of the studies were conducted on lung cancer. Good discrimination usually required a combination of multiple biomarkers, and area under the receiver operating characteristic curve or accuracy reached levels of 0.9 or higher in multiple studies. In 25% of the reported studies, classification models were built and validated on the same datasets. Huge variability was seen in different aspects among the studies.
CONCLUSIONS
Analyses of exhaled breath yielded promising results, although standardization of breath collection, sample storage and data handling remain critical issues. In order to foster breath analysis implementation into practice, larger studies should be implemented in true screening settings, paying particular attention to standardization in breath collection, consideration of covariates, and validation in independent population samples.
Topics: Biomarkers, Tumor; Breath Tests; Exhalation; Humans; Lung Neoplasms
PubMed: 26440312
DOI: 10.18632/oncotarget.5938 -
Cancers Jun 2021Antibodies against HPV16 early proteins have been shown to be promising biomarkers for the identification of HPV-driven oropharyngeal cancer (HPV-OPC) among OPC cases in... (Review)
Review
Antibodies against HPV16 early proteins have been shown to be promising biomarkers for the identification of HPV-driven oropharyngeal cancer (HPV-OPC) among OPC cases in multiple studies. A systematic literature search was performed to identify original research articles comparing HPV early antigen serology with established reference methods to determine molecular HPV tumor status. Random-effects models were used to calculate summary estimates for sensitivity and specificity of HPV16 E2, E6 and E7 serology for HPV-OPC. Subgroup analyses were performed to explore heterogeneity across studies and describe variables associated with test performance. We identified = 23 studies meeting all eligibility criteria and included these in the meta-analysis. E6 serology showed the best performance with pooled sensitivity and specificity estimates of 83.1% (95% confidence interval (CI) 72.5-90.2%) and 94.6% (95% CI 89.0-97.4%), respectively, while E2 and E7 serological assays were highly specific (E2: 92.5% (95% CI 79.1-97.6%); E7: 88.5% (95% CI 77.9-94.4%)) but moderately sensitive (E2: 67.8% (95% CI 58.9-75.6%); E7: 67.0% (95% CI 63.2-70.6%)). Subgroup analyses revealed increased pooled sensitivity for bacterially (89.9% (95% CI 84.5-93.6%)) vs. in vitro expressed E6 antigen (55.3% (95% CI 41.0-68.7%)), while both showed high specificity (95.2% (95% CI 93.0-96.7%) and 91.1% (95% CI 46.6-99.2%), respectively). Pooled specificity estimates for HPV16 E2, E6 and E7 serology were significantly lower in studies utilizing HPV DNA PCR as the only molecular reference method compared to those using a combination of any two reference methods (HPV DNA, RNA, in situ hybridization (ISH), p16 immunohistochemistry (IHC)), or histopathological reference methods (ISH or p16 IHC) as stand-alone marker. In conclusion, HPV16 E6 seropositivity is a highly sensitive and specific biomarker for HPV-OPC. However, its performance differs between serological assays and depends on molecular reference methods.
PubMed: 34208476
DOI: 10.3390/cancers13123010 -
European Journal of Human Genetics :... Dec 2009Apart from Helicobacter pylori infection and lifestyle factors, host genetic susceptibility has been suggested to contribute to individual variation in gastric cancer... (Meta-Analysis)
Meta-Analysis Review
Apart from Helicobacter pylori infection and lifestyle factors, host genetic susceptibility has been suggested to contribute to individual variation in gastric cancer risk as well. Aiming to evaluate the associations between host cell proliferation-related genetic polymorphisms and gastric cancer susceptibility, we reviewed the related studies published until 15 September 2008 and quantitatively summarized the associations of the most widely studied polymorphisms (TP53 Arg72Pro, L-myc EcoRI) using meta-analysis. Fifty-five eligible studies were included in this review. Twenty-three polymorphisms significantly related to gastric cancer risk in at least one study were identified. Polymorphisms determining higher levels of growth factors, which are important for tissue repair, were recently observed to be associated with reduced risk of gastric cancer. In the meta-analysis, TP53 72Pro was associated with increased risk of diffuse gastric cancer among Asians (OR, 1.44; 95% CI, 1.04-1.99), but decreased risk of intestinal gastric cancer among Caucasians (OR, 0.56; 95% CI, 0.36-0.89). This review suggests that cell proliferation-related genetic polymorphisms could be candidate biomarkers of gastric cancer risk, but current evidence for the use for risk stratification is still very limited. Modestly significant associations in meta-analyses stratified by population or type of gastric cancer may be observed by chance because of the limited number of studies and small sample size. Larger studies are warranted to clarify the effect of cell proliferation-related genetic polymorphisms on gastric carcinogenesis.
Topics: Alleles; Apoptosis Regulatory Proteins; Cell Cycle Proteins; Cell Proliferation; Genetic Predisposition to Disease; Humans; Intercellular Signaling Peptides and Proteins; Polymorphism, Genetic; Risk Factors; Stomach Neoplasms; Tumor Suppressor Protein p53
PubMed: 19536170
DOI: 10.1038/ejhg.2009.102